8-substituted and 6-substituted pyridopyrimidine derivatives as KRAS inhibitors

Abstract

The present invention relates to inhibitors of Kirsteen rat sarcoma virus (KRAS), and more particularly to compounds of formula (I), as well as compositions comprising formula (I) and methods of using compounds of formula (I) to treat or prevent diseases, disorders or medical conditions mediated by KRAS, in particular KRAS mutant G12C. # imgabs0 #

Description

[0001] Citations of Related Applications

[0002] This application claims priority under 35. USC §119(e) to U.S. Provisional Patent Application No. 63 / 339,580, filed on May 9, 2022, and is incorporated herein by reference in its entirety. Technical Field

[0003] The present invention relates to inhibitors of Kirsten rat sarcoma virus (KRAS), and more specifically to pyridopyrimidine compounds, compositions and methods for treating or preventing diseases, disorders or medical conditions mediated by KRAS (especially KRAS mutant G12C), including various cancers. Background Art

[0004] Ras is a superfamily of small guanosine triphosphate (GTP) binding proteins consisting of multiple isoforms. Ras genes can mutate into oncogenes associated with a variety of cancers such as lung cancer, pancreatic cancer, and colon cancer. Ras is one of the most frequently mutated oncogenes. KRAS (Kirsten rat sarcoma virus) is an isoform of Ras and is one of the most frequently mutated Ras genes, accounting for approximately 86% of all mutations. KRAS plays an on / off role in cell signaling. KRAS is a proto-oncogene that operates between inactive (GDP-bound) and active (GTP-bound) states to control a variety of functions, including cell proliferation. However, KRAS mutations can lead to uncontrolled cell proliferation and cancer. KRAS-4B is the major 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.

[0005] Past attempts to design KRAS inhibitors have mostly failed, largely due to KRAS's high affinity for GTP. However, the latest approach targeting the KRAS G12C mutation shows greater promise. This mutation is present in approximately 50% of lung cancers and approximately 10-20% of all KRAS G12 mutations. The mutated cysteine ​​residue is located within the active site, allowing the thiol functionality to form a covalent bond with an appropriately functionalized binding ligand (Liu, P. 2019, ActaPharmaceutica Sinica B). This approach has identified irreversible covalent inhibitors of the KRAS G12C mutation that are undergoing clinical studies. Given the important role that KRAS plays as a driver of many malignancies, new KRAS inhibitors with higher selectivity, safety, and efficacy are needed. Summary of the invention

[0006] In one aspect, the present invention relates to a compound of formula I or a salt, solvate or prodrug thereof:

[0007]

[0008] in

[0009] A is selected from aryl or heteroaryl, the aryl or heteroaryl being optionally substituted by 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 One or more substitutions in alkyl)2;

[0010] X is selected from O, NR 2 , S or CH2;

[0011] Y and G may be the same or different and are selected from bromine, iodine, C 1-4 Alkyl, C 1-4 perdeuterated 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-C2alkyl)cyano, or -O(C 1-4 haloalkyl);

[0012] Z is selected from hydrogen, halogen, trifluoromethyl or C 1-6 alkyl;

[0013] R 1 is selected from 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 ;

[0014] n is 1-3;

[0015] Each R 2 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or -(C1-C6 alkyl)P(O)R 2 R 3 ;

[0016] R 3 Selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0017] R 4 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl or aryl.

[0018] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound or salt of formula I and a pharmaceutically acceptable carrier.

[0019] In another aspect, the invention relates to a method of treating a disease, disorder or medical condition in a patient comprising the step of providing a therapeutic agent to a patient in need thereof, wherein the therapeutic agent comprises a compound of formula I or a salt thereof.

[0020] These and other aspects will become apparent upon reading the following detailed description of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The Figure is a graph showing mean plasma concentrations of Example 1 following IV and PO administration. DETAILED DESCRIPTION

[0022] the term

[0023] Standard nomenclature is used to describe the compounds. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0024] The terms "a" and "an" do not denote a limitation of quantity, but rather refer to the presence of at least one of the referenced item. 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").

[0025] Recitation of ranges of values ​​is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All endpoints of ranges are included within the range and are independently combinable.

[0026] Unless otherwise stated herein or clearly contradictory to the context, all methods described herein can be performed in the appropriate order. The use of any and all examples or exemplary language (e.g., "such as") is intended only to better illustrate the present invention and will not limit the scope of the present invention unless otherwise stated. Any language in the specification should not be interpreted as indicating that any unclaimed element is essential to the practice of the present invention used herein. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art of the present disclosure.

[0027] In addition, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more listed claims are introduced into another claim. For example, any claim that is dependent on another claim can be amended to include one or more limitations found in any other claim that is dependent on the same base claim. When elements are presented in list form (e.g., in Markush group format), each subgroup of the elements is also disclosed, and any (one or more) elements may be deleted from the group.

[0028] All compounds are to be understood to include all possible isotopes of atoms present in the compound. Isotopes include atoms having the same atomic number but different mass numbers, and encompass heavy isotopes and radioactive isotopes. By way of general example, but not 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 or radioactive isotopes in the compound structure or as substituents attached thereto. Examples of useful heavy or radioactive isotopes include 18 F. 15 N. 18 O. 76 Br, 125 I and 131 I.

[0029] All formulae disclosed herein include all pharmaceutically acceptable salts of such formulas.

[0030] The open-ended term "comprising" includes the intermediate closed terms "consisting essentially of" and "consisting of.

[0031] The term "substituted" means that any one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the normal valence of the designated atom is not exceeded. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure refers to a compound that is sufficiently stable (robust) to permit isolation from a reaction mixture and subsequent formulation into an effective therapeutic agent.

[0032] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent.

[0033] "Alkyl" includes branched and straight chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms, typically 1 to about 8 carbon atoms. The term C1-C6 alkyl as used herein means an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Other embodiments include alkyl groups having 1 to 8 carbon atoms, 1 to 4 carbon atoms, or 1 or 2 carbon atoms, such as C1-C8 alkyl, C1-C4 alkyl, and C1-C2 alkyl. When C0-C6 alkyl is used herein, C1-C6 alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Other embodiments include alkyl groups having 1 to 8 carbon atoms, 1 to 4 carbon atoms, or 1 or 2 carbon atoms, such as C1-C8 alkyl, C1-C4 alkyl, and C1-C2 alkyl. n When an alkyl group is used in conjunction with another group, such as -C0-C2alkyl(phenyl), the indicated group (phenyl in this case) is either directly bound by a single covalent bond (C0alkyl) or attached by an alkyl chain having the specified number of carbon atoms, in this case 1, 2, 3 or 4 carbon atoms. The alkyl group may also be attached via other groups (e.g., heteroatoms), such as -O-C0-C4alkyl (C3-C7cycloalkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, tert-butyl, n-pentyl, and sec-pentyl.

[0034] "Alkoxy" is an alkyl group as defined above, having a specified number of carbon atoms, covalently bound to the group it replaces through an oxygen bridge (-O-). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentyloxy, neopentyloxy, n-hexyloxy, 2-hexyloxy, 3-hexyloxy and 3-methylpentyloxy. Similarly, "alkylthio" or "thioalkyl" groups are alkyl groups as defined above, having a specified number of carbon atoms, covalently bound to the group it replaces through a sulfur bridge (-S-). Similarly, "alkenyloxy", "alkynyloxy" and "cycloalkoxy" refer to alkenyl, alkynyl and cycloalkyl, in each case covalently bound to the group it replaces through an oxygen bridge (-O-).

[0035] "Halo" or "halogen" refers to fluorine, chlorine, bromine or iodine, and is defined herein to include all isotopes thereof, including heavy isotopes and radioactive isotopes. Examples of useful halogen isotopes include 18 F. 76 Br and 131 I. Other isotopes will be readily apparent to those skilled in the art.

[0036] "Haloalkyl" refers to a branched or straight chain alkyl group having a specified number of carbon atoms, which is substituted with one or more halogen atoms, generally up to the maximum number of halogen atoms permitted. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.

[0037] "Haloalkoxy" is a haloalkyl group as defined above attached through an oxygen bridge (the oxygen of the alcohol group).

[0038] A "peptide" is a molecule that is a chain of amino acids linked together by amide bonds (also called peptide bonds).

[0039] "Pharmaceutical composition" refers to a composition comprising at least one active agent (e.g., a compound or salt of Formula II) and at least one other substance (e.g., a carrier). The pharmaceutical composition complies with the GMP (Good Manufacturing Practice) standards of the U.S. FDA for human or non-human drugs.

[0040] "Carrier" refers to a diluent, excipient or vehicle with which an active compound is administered. "Pharmaceutically acceptable carrier" refers to a substance, such as an excipient, diluent or vehicle, used to prepare a pharmaceutical composition that is generally safe, non-toxic and has no biological or other adverse effects, and includes carriers that are acceptable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable carrier" includes both one such carrier and more than one such carrier.

[0041] "Patient" refers to a human or non-human animal in need of medical treatment. Medical treatment can include treatment of an existing condition, such as a disease or disorder, or diagnostic treatment. In some embodiments, the patient is a human patient.

[0042] "Providing" means giving, administering, selling, distributing, transferring (whether for profit or not), manufacturing, formulating or dispensing.

[0043] "Treatment" or "treating" refers to providing a patient with an amount of active compound sufficient to significantly reduce any disease symptoms, slow disease progression, or cause disease regression. In certain embodiments, treatment of a disease can begin before a patient develops disease symptoms.

[0044] A "therapeutically effective amount" of a pharmaceutical composition refers to an amount effective to provide a therapeutic benefit (eg, improve symptoms, slow disease progression, or cause disease regression) when administered to a patient.

[0045] "Therapeutic compound" refers to a compound that can be used to diagnose or treat a disease. The compound can be a small molecule, peptide, protein or other type of molecule.

[0046] A significant change is any detectable change that is statistically significant in a standard parametric test of statistical significance, such as a Student's T-test with p < 0.05.

[0047] Chemical description

[0048] The compounds of the chemical formula disclosed herein may contain one or more asymmetric elements, such as stereocenters (stereoisomer centers, stereogenic centers), stereoaxes (stereoisomer axes, stereogenic axes), etc., such as asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates, atropisomers or optically active forms. For compounds with two or more asymmetric elements, these compounds can also be mixtures of diastereomers. For compounds with asymmetric centers, all optical isomers and mixtures thereof in pure form are covered. In these cases, single enantiomers, i.e. optically active forms, can be obtained by asymmetric synthesis, synthesis from optically pure precursors or by the resolution of racemates. The resolution of racemates and atropisomers can also be achieved, for example, by conventional methods, such as crystallization in the presence of a resolving agent, or using, for example, chromatography using a chiral HPLC column. All forms are contemplated herein, regardless of the method used to obtain them.

[0049] All forms of the active agents (eg, solvates, optical isomers, enantiomeric forms, atropisomeric forms, polymorphs, free compounds and salts) may be used alone or in combination.

[0050] The term "chiral" refers to molecules that have the property that their mirror-image partners are non-superimposable.

[0051] "Stereoisomers" are compounds that have identical chemical constitution but differ in the arrangement of the atoms or groups in space.

[0052] "Diastereomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated under high-resolution analytical procedures, such as electrophoresis, crystallization in the presence of a resolving agent, or chromatography using, for example, a chiral HPLC column.

[0053] "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and may occur in a chemical reaction or process without stereoselectivity or stereospecificity.

[0054] The stereochemical definitions and conventions used herein generally follow those of SP 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. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its (one or more) chiral centers. The prefixes d and l or (+) and (-) are used to indicate the sign of the rotation of the compound with respect to plane polarized light, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are right-handed.

[0055] A "racemic mixture" or "racemate" is an equimolar (or 50:50) mixture of two enantiomeric species that is optically inactive. A racemic mixture may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0056] A "chelating group" or "chelating agent" is a ligand group that can form two or more independent coordination bonds with a single central atom (usually a metal ion). The chelating groups disclosed herein are organic groups having multiple N, O or S heteroatoms and having a structure that allows two or more of the heteroatoms to form bonds with the same metal ion.

[0057] "Salt" includes derivatives of disclosed compounds, wherein the parent compound is modified by preparing its inorganic and organic, nontoxic, acid or base addition salt. The salt of the compounds of the present invention can be synthesized by a parent compound containing an alkaline or acidic part by conventional chemical methods. In general, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric suitable base (for example, hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K), or by reacting the free base form of these compounds with a stoichiometric suitable acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. In general, non-aqueous media, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, are used where feasible. The salt of the compounds of the present invention further includes a solvate of the compound and a solvate of the compound salt. In one embodiment, the compounds of the present invention are synthesized or separated as trifluoroacetic acid (TFA) salts.

[0058] In one embodiment, the salt form of the above-mentioned compounds of the present invention may include pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral acid (inorganic acid) salts or organic acid salts of basic residues (e.g., amines); alkali metal salts or organic salts of acidic residues (e.g., carboxylic acids), etc. Pharmaceutically acceptable salts include conventional non-toxic salts and quaternary ammonium salts of the parent compound formed by, for example, 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 salts derived from organic acids (such as 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, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-aminobenzoic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) n-COOH (wherein n is 0-4), etc.) can be prepared. Lists of other suitable salts can be found in, for example, 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.

[0059] The compounds of the present invention relate to substituted pyridopyrimidine derivatives or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein the 4-amino group contains a functional group such as but-3-en-2-one, as shown in Formula I:

[0060]

[0061] In formula I, A is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 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 One or more substitutions in alkyl)2;

[0062] X is selected from O, NR 2 , S or CH2;

[0063] Y and G may be the same or different and are selected from bromine, iodine, C 1-4 Alkyl, C 1-4 perdeuterated 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-C2alkyl)cyano, or -O(C 1-4 haloalkyl);

[0064] Z is selected from hydrogen, halogen, trifluoromethyl or C 1-6 alkyl;

[0065] R 1 is selected from 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 ;

[0066] n is 1-3;

[0067] Each R 2 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or -(C1-C6 alkyl)P(O)R 2 R 3 ;

[0068] R 3 Selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0069] R 4 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl or aryl.

[0070] In a preferred embodiment, the compound of Formula I is represented by 1a-1z and 2a-2g or a pharmaceutically acceptable salt, solvate or prodrug thereof:

[0071]

[0072]

[0073]

[0074]

[0075] Particularly preferred compounds of the present invention are compounds 1d, 1f, 1n and 1z:

[0076]

[0077] In one embodiment, the present invention relates to a pharmaceutical composition comprising Compound 1d, Compound 1f, Compound 1n or Compound 1z, or a salt, solvate or prodrug thereof and a pharmaceutically acceptable carrier.

[0078] The compounds disclosed herein can be administered in the form of pure chemicals, but are preferably administered in the form of pharmaceutical compositions. Therefore, the present invention encompasses pharmaceutical compositions comprising compounds or pharmaceutically acceptable salts of compounds (such as compounds of formula I) and at least one pharmaceutically acceptable carrier. The pharmaceutical composition may contain a compound or salt of formula I as the sole active agent, but preferably contains at least one additional active agent. It will be appreciated by those skilled in the art that the combination of various compounds described in formula I may also be implemented in the compositions and methods of the present invention. In certain embodiments, the pharmaceutical composition is a dosage form containing 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 a compound of formula I in a unit dosage form and optional additional active agents of 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. The pharmaceutical composition may also include a certain molar ratio of a compound (such as a compound of formula I) and an additional active agent. For example, the pharmaceutical composition can contain the additional active agent and the compound of Formula I in a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1, or about 1.5:1 to about 4:1.

[0079] The compounds disclosed herein can be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, buccally, rectally, as an ophthalmic solution, or by other means in dosage unit formulations containing conventional pharmaceutically acceptable carriers. The pharmaceutical composition can be formulated into any pharmaceutically useful form, such as an aerosol, cream, gel, pill, capsule, tablet, syrup, transdermal patch, or ophthalmic solution. Some dosage forms, such as tablets and capsules, are subdivided into unit doses of appropriate size, containing an appropriate amount of active ingredient, such as an effective amount to achieve the intended purpose.

[0080] The carrier includes an excipient and a diluent and must have a sufficiently high purity and sufficiently low toxicity to make it suitable for administration to a patient being treated. The carrier may be inert, or it may be of pharmaceutical benefit in itself. The amount of the carrier used in conjunction with the compound is sufficient to provide a practical (practical) amount of administration material for the compound per unit dose.

[0081] The types of carriers include, but are not limited to, adhesives, buffers, coloring agents, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tablets, and wetting agents. Some carriers may be listed in multiple categories, for example, vegetable oils may be used as lubricants in certain formulations and as diluents in other formulations. Exemplary pharmaceutically acceptable carriers include sugar, starch, cellulose, tragacanth powder, malt, gelatin, talcum powder, and vegetable oils. An optional activating agent may be included in the pharmaceutical composition that does not substantially interfere with the activity of the compounds of this invention.

[0082] The pharmaceutical compositions / combinations can be formulated for oral administration. These compositions contain 0.1 to 99 weight % (wt%) of the compound of formula III and generally at least about 5 wt% of the compound of formula I. Some embodiments contain about 25 wt% to about 50 wt% or about 5 wt% to about 75 wt% of the compound of formula I.

[0083] Treatment

[0084] The compounds of formula I and pharmaceutical compositions comprising the compounds are useful for diagnosing or treating diseases, disorders or medical conditions mediated by KRAS (especially KRAS mutant G12C), and include various cancers, such as glioma (glioblastoma), acute myelogenous leukemia, acute myeloid leukemia, myelodysplastic / myeloproliferative neoplasms, sarcoma, chronic myelomonocytic leukemia, non-Hodgkin's lymphoma, astrocytoma, melanoma, non-small cell lung cancer, bile duct cancer, chondrosarcoma, colon cancer or pancreatic cancer.

[0085] According to the present invention, a method of treating a KRAS-mediated disease or condition comprises providing a therapeutically effective amount of a compound of formula I to a patient in need of such treatment. In one embodiment, the patient is a mammal, and more specifically a human. It will be appreciated by those skilled in the art that the present invention also encompasses methods of treating non-human patients such as companion animals (e.g., cats, dogs) and livestock.

[0086] A therapeutically effective amount of a pharmaceutical composition is preferably an amount sufficient to alleviate or improve the symptoms of a disease or condition. For example, in the case of a KRAS-mediated disease, a therapeutically effective amount may be an amount sufficient to reduce or improve cancer. A therapeutically effective amount of a compound or pharmaceutical composition described herein will also provide a sufficient concentration of a compound of Formula I when administered to a patient. A sufficient concentration is preferably the concentration of the compound in the patient's body necessary to prevent or combat the condition. Such an amount can be determined experimentally, for example by measuring the blood concentration of the compound, or theoretically by calculating bioavailability.

[0087] According to the present invention, the treatment methods disclosed herein include providing a patient with a dose of one or more compounds of formula I. The dosage level of each compound is about 0.1 mg to about 140 mg / kg body weight / day, which can be used to treat the above conditions (about 0.5 mg to about 7 g / patient / day). The amount of the compound that can be combined with a carrier material to produce a single dosage form will vary depending on the patient being treated and the specific mode of administration. The unit dosage form typically contains about 1 mg to about 500 mg of each active compound. In certain embodiments, 25 mg to 500 mg, or 25 mg to 200 mg of a compound of formula I is provided to the patient daily. The frequency of administration may also vary depending on the compound used and the specific disease being treated. However, for the treatment of most KRAS-mediated diseases and conditions, a dosing regimen of 4 times a day or less can be adopted, and in certain embodiments, a dosing regimen of 1 or 2 times a day is adopted.

[0088] However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the specific disease being treated.

[0089] The compounds of Formula I can be administered alone (i.e., the sole therapeutic agent in a regimen) to treat or prevent KRAS-mediated diseases and conditions, such as various cancers, or can be administered in combination with another active agent. One or more compounds of Formula I can be administered in conjunction with a regimen of one or more other active agents (e.g., anticancer toxic agents). In one embodiment, a method of treating or diagnosing KRAS-mediated cancer in a mammal comprises administering to the mammal a therapeutically effective amount of a compound of Formula I, optionally in combination with one or more additional active ingredients.

[0090] Those skilled in the art will appreciate that the treatment methods provided herein can also be used to treat mammals other than humans, including for veterinary applications, such as treating horses and livestock, e.g., cattle, sheep, cows, goats, pigs, etc., and pets (companion animals), such as dogs and cats.

[0091] For diagnostic or research applications, a variety of mammals are suitable subjects, including rodents (e.g., mice, rats, hamsters), rabbits, primates, and pigs (e.g., inbred pigs, etc.). In addition, for in vitro applications, such as in vitro diagnostics and research applications, body fluids (e.g., blood, plasma, serum, interstitial fluid, saliva, feces, and urine) as well as cell and tissue samples of the above subjects will be suitable for use.

[0092] In one embodiment, the present invention provides a method of treating a disease, disorder or medical condition (including various cancers) mediated by KRAS (particularly KRAS mutant G12C) in a patient who is determined to be in need of such treatment, the method comprising providing the patient with an effective amount of a compound of Formula I. The compounds of Formula I provided herein can be administered alone or in combination with one or more other active agents.

[0093] In another embodiment, the method of treating or diagnosing a KRAS-mediated disease or condition may additionally comprise 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 may include additional therapeutic compounds, including anti-cancer therapeutic compounds, such as doxorubicin, paclitaxel, docetaxel, cisplatin, camptothecin, temozolomide, Avastin, Herceptin, Erbitux, and the like.

[0094] Example

[0095] Chemical synthesis

[0096] The synthesis of the compounds of the invention is illustrated in the order of steps shown in Schemes 1-6. Scheme 1 illustrates the synthesis of the example of Formula I, wherein Y and G are hydrogen, X is O, NR 2 , or S (i.e. 10a-10c). In Scheme 1, commercially available compounds 3 and 4 are reacted in the presence of a base (such as DIPEA) in a solvent (such as acetonitrile) to produce 5. 6a-6c are reacted with a base (such as sodium hydride, Hünig base, K2CO3 or Cs2CO3 / DABCO mixture) and then treated with 5 in a polar aprotic solvent (such as N-methyl-2-pyrrolidone) at RT or elevated temperature to produce compounds 7a-7c, respectively. Standard Suzuki coupling procedures between compounds 7a-7c and 8 in solvent mixtures (such as 1,4-dioxane and water) can be used to prepare compounds 9a-9c. Removal of the Boc protecting group of 9a-9c in 1,4-dioxane under acidic conditions (e.g., anhydrous HCl), followed by acylation of the deprotected product with an α,β-unsaturated acyl chloride (e.g., acryloyl chloride) in a solvent (e.g., dichloromethane) containing a base (e.g., triethylamine) will yield the corresponding compounds of Formula I 10a-10c, wherein Y and G are hydrogen and X is O, NR2 , or S.

[0097] Solution 1

[0098]

[0099] Scheme 2 illustrates the synthesis of the example of formula I, wherein Y or G is fluorine and X is O, NR 2 , or S (i.e., 18a-c and 19a-c). Commercially available 7-bromopyrido[3,2-d]pyrimidine-2,4-diol (11) is oxidized with urea-hydrogen peroxide complex in the presence of trifluoroacetic anhydride at 0°C in an aprotic solvent such as DMF to give the N-oxide 12. Subsequently, 12 is reacted with POCl3 in the presence of Hünig's base to produce a mixture of trichloro compounds 13a and 13b in a ratio of about 1:1. Treatment of the 13a / 13b mixture with 4 in the presence of Hünig's base in a solvent such as acetonitrile provides the corresponding products 14a and 14b, which can be separated by chromatography. Treatment of 6a-6c with a base such as sodium hydride, Hünig base, K2CO3 or Cs2CO3 / DABCO mixtures followed by reaction with 14a and 14b in a polar aprotic solvent such as N-methyl-2-pyrrolidone at RT or elevated temperature affords compounds 15a and 15b, respectively. Reaction of 15a and 15b with a fluorine source such as potassium fluoride or cesium fluoride in a polar aprotic solvent such as DMSO at elevated temperature affords the corresponding fluorinated products 16a and 16b. Standard Suzuki coupling procedures between compounds 16a and 16b and 8 in solvent mixtures such as 1,4-dioxane and water can be employed to prepare compounds 17a and 17b. The Boc protecting group of 17a and 17b is removed in 1,4-dioxane under acidic conditions such as anhydrous HCl. The deprotected product is then acylated with an α,β-unsaturated acyl chloride (such as acryloyl chloride) in a solvent (such as dichloromethane) containing a base (such as triethylamine) to produce the corresponding compounds of Formula I 18a-c and 19a-c, wherein Y or G is fluorine and X is O, NR 2 , or S.

[0100] Solution 2

[0101]

[0102] Scheme 3 illustrates the synthesis of an example of formula I, wherein Y is hydrogen, G is fluorine and X is O, NR 2, or S (i.e., 31a-31c). Commercially available 3,5-dibromo-4-fluoropyridine or 3,5-dichloro-4-fluoropyridine (20) was reacted with (1Z)-N-[(methylsulfonyl)oxy]-ethylimide chloride (21; CAS#1228558-17-5) according to the general procedure described by PSFier (J.Am.Chem.Soc.2017,139(28),9499-9736) to provide 3,5-dihalo-4-fluoropicolinonitrile (22). Alternatively, compound 22 can be prepared by oxidizing 20 with H2O2-urea complex in the presence of trifluoroacetic anhydride and then treating the corresponding N-oxide with trimethylsilyl cyanide in the presence of dimethylcarbamoyl chloride in a solvent such as dichloromethane. Following the general description in WO2021117767A1, 22 was subjected to regioselective Suzuki coupling with boronic acid 8 to afford product 23. Subsequently, 23 was reacted with 2,4-dimethoxybenzylamine (24) in the presence of Hünig's base with heating in a suitable solvent such as 1,4-dioxane, following the procedure described in WO2021041671A1, to afford compound 25. Alternatively, 25 can be prepared by the Buchwald-Hartwig amination procedure between 23 and 24 under standard conditions. Pinner reaction of 25 in methanol in the presence of HCl at −78°C to 0°C followed by hydrolysis of the intermediate iminoester in the presence of saturated aqueous NaHCO3 affords compound 26. Reaction of 26 with trichloroacetyl isocyanate at 0°C followed by treatment with anhydrous ammonia in methanol and warming to room temperature affords compound 27. Reaction of 27 with POCl3 at elevated temperature in the presence of Hünig base affords the corresponding 2,4-dichloro-8-fluoropyrido[3,2-d]pyrimidine derivative 28. Compound 28 reacts with 4 in the presence of Hünig base in a solvent such as acetonitrile to afford 29. Treatment of 6a-6c with a suitable base such as potassium fluoride, Hünig base, K2CO3 or Cs2CO3 / DABCO mixtures in neat form or in a suitable aprotic solvent followed by reaction with 29 at elevated temperature affords compounds 30a-30c, respectively. Alternatively, 6a and 29 can be coupled with Pd(OAc)2 in toluene at elevated temperature in the presence of BINAP and CS2CO3 to produce 30a. The Boc protecting groups of 30a-30c are removed in 1,4-dioxane under acidic conditions (e.g., anhydrous HCl). The corresponding deprotected products are acylated with an α,β-unsaturated acyl chloride (e.g., acryloyl chloride) in an aprotic solvent (e.g., dichloromethane) containing a base (e.g., triethylamine) to produce compounds of formula I, wherein Y is hydrogen, G is fluorine, and X is O, NR 2 or S (i.e. 31a-31c).

[0103] Solution 3

[0104]

[0105] Scheme 4 illustrates the synthesis of an example of formula I, wherein 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-C2alkyl)cyano, or -O(C 1-4 haloalkyl), and X is O, NR 2 or S. Oxidation of 32 with urea-hydrogen peroxide complex in the presence of trifluoroacetic anhydride followed by treatment with dimethylcarbamoyl chloride and trimethylsilyl cyanide afforded nitrile 33. Standard Suzuki coupling procedures between 33 and 8 can be employed to prepare compound 34. Reaction of 34 with 2,4-dimethoxybenzylamine (35) at elevated temperature afforded compound 36. Pinner reaction of 36 in methanol in the presence of HCl at −78°C to 0°C followed by hydrolysis of the intermediate iminoester in the presence of saturated aqueous NaHCO3 afforded ester 37. Reaction of 37 with trichloroacetyl isocyanate at 0°C followed by treatment with anhydrous ammonia in methanol and warming to room temperature afforded diol 38. Reaction of 38 with POCl3 at elevated temperature in the presence of Hünig's base afforded dichloro compound 39. Compound 39 reacts with 4 in the presence of Hünig's base in a solvent such as acetonitrile to afford 40. Compounds 6a-6c are treated neat or in a suitable aprotic solvent with a suitable base (e.g., potassium fluoride, Hünig base, K2CO3, or Cs2CO3 / DABCO mixture) and then reacted with 40 at elevated temperature to give compounds 41a-41c, respectively. Alternatively, 6a and 40 can be coupled with Pd(OAc)2 in toluene at elevated temperature in the presence of BINAP and Cs2CO3. 41a is produced. The Boc protecting group of 41a-41c is removed in 1,4-dioxane under acidic conditions (e.g., anhydrous HCl). The corresponding deprotected products are acylated with an α,β-unsaturated acyl chloride (e.g., acryloyl chloride) in an aprotic solvent (e.g., dichloromethane) containing a base (e.g., triethylamine) to produce compounds of formula I, wherein 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 1-4alkyl), -(C0-C2alkyl)cyano, or -O(C 1-4 haloalkyl), and X is O, NR 2 or S (ie 42a-42c).

[0106] Solution 4

[0107]

[0108] Scheme 5 illustrates the synthesis of an example of formula I, wherein 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-C2alkyl)cyano, or -O(C 1--4 haloalkyl) and X is methylene (i.e. 46). Acetylene 44 reacts with a strong base such as sodium hydride to produce the corresponding acetylide anion, which can then react with 43 to give 45. Alternatively, Sonogashira coupling of 43 and 44 using a Pd catalyst such as Pd(dppf)2Cl2 can provide compound 45. Catalytic hydrogenation of 45 followed by removal of the Boc group in dichloromethane under acidic conditions such as TFA provides the corresponding amine, which can then react with acryloyl chloride in a solvent such as dichloromethane containing a base such as triethylamine to produce compounds of formula I, wherein Y and G are hydrogen, halogen, C 1-4 Alkyl, C0-C2 alkenyl, C0-C2 alkynyl, -(C0-C2 alkyl)cycloalkyl, C 1-4 Haloalkyl, -O(C 1-4 Alkyl), -S(C 1-4 alkyl), C0-C2 cyano, or -O(C 1-4 haloalkyl), and X is methylene (ie, 46).

[0109] Solution 5

[0110]

[0111] Scheme 6 illustrates the synthesis of an example of formula I, wherein 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-C2alkyl)cyano, or -O(C 1-4haloalkyl), G is hydrogen and X is O, NR 2 , or S. Nitration of picolinic acid 47 with nitric acid in concentrated sulfuric acid affords the corresponding nitro compound 48. Esterification of 48 with catalytic sulfuric acid in methanol under reflux affords the methyl ester 49. Reduction of the nitro group of 49 with stannous chloride dihydrate in alcohol (e.g., ethanol) in the presence of hydrochloric acid affords the corresponding amino derivative 50. Hydrolysis of the ester portion of 50 in a wet solvent (e.g., acetonitrile or THF) containing 6% water (v / v) affords the 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 affords the corresponding carboxamide derivative 52. Reaction of 52 with triphosgene (bis(trichloromethyl) carbonate) in an aprotic solvent such as 1,4-dioxane at 5 °C followed by heating at 110 °C affords 7-bromopyrido[3,2-d]pyrimidine-2,4(1H,3H)-dione derivative 53. Reaction of 53 with phosphorus oxychloride at 120 °C in the presence of Hünig's base affords the corresponding dichloro derivative 54. Reaction of 54 with 4 in the presence of Hünig's base in a solvent such as acetonitrile affords 55. Treatment of 6a-6c with a suitable base such as sodium hydride, Hünig's base, K2CO3 or Cs2CO3 / DABCO mixtures followed by reaction with 55 at elevated temperature affords compounds 56a-56c, respectively. Alternatively, 6a and 55 can be coupled with Pd(OAc)2 in toluene at elevated temperature in the presence of BINAP and Cs2CO3 to produce 56a. Standard Suzuki coupling procedures between 56a-56c and 8 can be employed to prepare compounds 57a-57c. Removal of the Boc protecting group of 57a-57c in 1,4-dioxane under acidic conditions (e.g., anhydrous HCl) followed by acylation of the corresponding deprotected products with an α,β-unsaturated acyl chloride (e.g., acryloyl chloride) in an aprotic solvent (e.g., dichloromethane) containing a base (e.g., triethylamine) will produce compounds of formula I, wherein 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-C2alkyl)cyano, or -O(C 1-4 haloalkyl), G is hydrogen and X is O, NR 2 , or S (i.e. 58a-58c).

[0112] Solution 6

[0113]

[0114] Abbreviations and Acronyms The following abbreviations and acronyms may be used in this application: ACN = acetonitrile;

[0115] anhyd.=without water;

[0116] aq.=aqueous solution;

[0117] B2pin2 = bis(pinacol)diboron;

[0118] Boc = tert-butyloxycarbonyl;

[0119] BTC = triphosgene (bis(trichloromethyl) carbonate);

[0120] n-Bu3P = tri-n-butylphosphine;

[0121] Compd = compound;

[0122] d = day;

[0123] DABCO = 1,4-diazabicyclo[2.2.2]octane;

[0124] DCM = dichloromethane;

[0125] DIEA=DIPEA=N,N-diisopropylethylamine=Hünig base;

[0126] DMF = N,N-dimethylformamide;

[0127] DMSO = dimethyl sulfoxide;

[0128] DMA = N,N-dimethylacetamide;

[0129] dppf = 1,1'-bis(diphenylphosphino)ferrocene);

[0130] EtOAc = ethyl acetate;

[0131] equiv=equivalent;

[0132] Ex = embodiment;

[0133] h = hours;

[0134] HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0135] LiHMDS = lithium bis(trimethylsilyl)amide [LiN(SiMe3)2];

[0136] MeOH = methanol;

[0137] NMP = N-methyl-2-pyrrolidone;

[0138] min = minutes;

[0139] Pd(dppf)Cl2=[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride;

[0140] PE = petroleum ether;

[0141] RT = room temperature;

[0142] satd.=saturated solution;

[0143] TEA = triethylamine;

[0144] TFA = trifluoroacetic acid;

[0145] TFAA = trifluoroacetic anhydride;

[0146] THF = tetrahydrofuran;

[0147] TMSCN = trimethylsilyl cyanide.

[0148] Example

[0149] The inventive concept has been described by way of exemplary principles and embodiments, but it will be appreciated by those skilled in the art that various changes may be made and equivalents may be substituted for what is described without departing from the scope and spirit of the present disclosure as defined by the following examples.

[0150] Example 1

[0151] 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).

[0152]

[0153] Example 1 (1a) was prepared as shown in Scheme 7 below.

[0154] Solution 7

[0155]

[0156] (S)-tert-butyl 4-(7-bromo-2-chloropyrido[3,2-d]pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (60). A mixture of 7-bromo-2,4-dichloropyrido[3,2-d]pyrimidine (3, where Hal = Br; CAS #1215074-41-1; 1.00 g, 3.61 mmol) and (2S)-tert-butyl 2-(cyanomethyl)piperazine-1-carboxylate (59; CAS #1589565-36-5; 0.90 g, 3.97 mmol) in anhydrous 1,4-dioxane (9.0 mL) was treated with diisopropylethylamine (1.90 mL, 10.8 mmol) added dropwise slowly at room temperature while stirring. After 1 h, 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% EtOAc in hexanes to afford 1.64 g (98%) of (S)-tert-butyl 4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (60) as a light yellow solid: HPLC-MS (ES) + )m / z MH + =467.

[0157] (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). A mixture of (S)-tert-butyl 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#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 with stirring at 90 °C under N2 atmosphere for 16 h. The reaction mixture was cooled to RT, 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 (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) as an off-white solid: HPLC-MS (ES) + )m / z MH + =546.

[0158] (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). A mixture of (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 KCO (494 mg, 3.30 mmol) in 1,4-dioxane (7.0 mL) and water (0.9 mL) was stirred and degassed for 20 minutes by bubbling with N2. Tetrakis(triphenylphosphine)palladium(0) (143 mg, 0.123 mmol) was added and the reaction mixture was stirred and degassed for an additional 15 minutes by bubbling with N2 again. The reaction mixture was stirred under N2 atmosphere at 80 ° C for 16 h, cooled to RT, diluted with EtOAc, and then filtered through celite. The filtrate was washed with saturated aqueous NaCl solution (3X), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with a 0-15% MeOH gradient in DCM to give 130 mg (25%) of (S)-4-(7-(8-chloronaphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (64) as a beige solid: HPLC-MS (ES + )m / z MH + =628; 1H NMR (300MHz, CDCl3) δ8.54(dd,J=3.2,1.2Hz,1H),7.97(dd,J=8.2,1.1Hz,1H),7.91(d,J =2.2Hz,1H),7.89(dd,J=7.0,1.2Hz,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,3 H),2.35-2.24(m,1H),2.15-2.00(m,1H),1.92-1.76(m,3H),1.52(s,9H).

[0159] 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 (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; 160 mg, 0.255 mmol) and 4M HCl in 1,4-dioxane (2.0 mL) was stirred at RT under N2 atmosphere. After 1 h, the reaction mixture was concentrated in vacuo 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 a beige solid: HPLC-MS (ES + )m / z MH + =528; 1H NMR(300MHz,DMSO-d6)δ11.1(br s,1H),10.3(br s,2H),8.68(d,J=1.6Hz,1H),8.22(dd,J=7.2,1.1Hz,1H),8.14(dd,J=8.1,1.2Hz,1H), 8.08(d,J=2.1Hz,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(brs,4H), 3.18-3.05(m,1H),2.96(d,J=4.7Hz,3H),2.36-2.22(m,1H),2.14-1.77(m,4H).

[0160] 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). 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# 430-99-9; 28 mg, 0.314 mmol) and oven-dried A mixture of molecular sieves (132 mg) in EtOAc (2.0 mL) was added and the reaction mixture was stirred at RT. After 5 minutes, a solution of 1-propanephosphonic anhydride (T3P, 0.33 mL, 0.471 mmol, 50% in EtOAc) was added and the reaction mixture was stirred at RT. After 20 minutes, the reaction mixture was diluted with EtOAc, washed with 5% NaHCO3 aqueous solution (3X), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with a gradient of 10-100% EtOAc in DCM containing 1% Et3N (v / v) to afford 40 mg (35%) of 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: HPLC-MS (ES) + )m / z MH + =600;1 HNMR (300MHz, CDCl3) δ8.57(dd,J=2.1,1.3Hz,1H),7.98(dd,J=8.2,1.2Hz,1H),7.93(d,J=2.1Hz,1H),7.90(dd,J=8.1,1.2Hz,1H),7.60-7.54(m,2H),7 .48-7.40(m,2H),5.44(d,J=47.8Hz,1H),5.26(dd,J=13.3,3.6Hz,1H),4.65 xA),2.56(s,3H),2.44-2.30(m,1H),2.18-2.03(m,1H),1.95-1.52(m,10H).

[0161] Intermediate 71 prepared according to Scheme 8 can be used to prepare compounds having an 8-methyl substituent.

[0162] Solution 8

[0163]

[0164] 5-Bromo-3-nitro-4-methylpyridinecarbonitrile (68). Cuprous cyanide (1.83 g, 20.4 mmol) was added to a stirred solution of 2,5-dibromo-3-nitro-4-methylpyridine (67; 5.04 g, 17.0 mmol) in propionitrile (34 mL) at RT. The resulting suspension was heated under nitrogen and rapidly stirred at reflux for 4 days. The cooled reaction mixture was extracted with a mixture of water and ethyl acetate and then filtered through celite. The phases of the filtrate were then separated and the ethyl acetate extracts were washed with saturated NaCl (aq.), dried (CaSO4) and evaporated to give 3.9 g of crude product as a dark brown oil. This was purified by silica gel chromatography eluting with a gradient of 1 to 5% EtOAc in hexanes to give 3.1 g of a yellow solid. The material was recrystallized from heptane to give 2.7 g of 5-bromo-3-nitro-4-methylpyridinecarbonitrile (68) as a white powder. HPLC-MS(ES - )m / z[MH] - =240,242; 1 HNMR(300MHz,DMSO)δ9.18(s,1H),2.52(s,3H); 13 C NMR (75MHz, DMSO) δ154.9,149.7,143.5,129.8,125.9,114.0,19.4.

[0165] 3-Amino-5-bromo-4-methylpicolinamide (69). Concentrated ammonium hydroxide (5.0 mL) was added to a stirred suspension of 5-bromo-3-nitro-4-methylpyridinecarbonitrile (68; 1.20 g, 5.0 mmol) in water (10 mL). The flask was sealed with a septum cap and the suspension was stirred rapidly at RT. After 3 h, the suspension was treated with powdered 85% sodium bisulfite (4.8 g, 27.3 mmol) added in portions over 15 minutes and stirred at RT for 2.5 hours. The resulting yellow solid was isolated by filtration, washed with water and dried to give 511 mg of crude product, which was contaminated with about 25% of 6-bromo-7-methyl-1,2-dihydro-3H-pyrazolo[4,3-b]pyridine-3-one. The material was purified by silica gel chromatography eluting with a gradient of 0 to 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 (300MHz, DMSO) δ7.99(s,1H),7.89(s,1H),7.45(s,1H),7.15(bs,2H),2.25(s,3H); 13 C NMR (75MHz, DMSO) δ170.5,146.7,136.6,132.1,127.7,126.1,17.0.

[0166] 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 heated to reflux under nitrogen for 2 h. The cooled reaction mixture was partitioned between concentrated ammonium hydroxide and ethyl acetate. The resulting insoluble white precipitate was isolated by filtration, washed with water and air-dried on 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; 1 H NMR (300MHz, DMSO) δ8.39 (s, 1H), 7.74 (bs, 2H), 2.43 (s, 3H). 13 C NMR (75MHz, DMSO) δ162.1,152.2,144.2,142.1,135.2,131.0,127.4,17.3.

[0167] 7-Bromo-2,4-dichloro-8-methylpyrido[3,2-d]pyrimidine (71). Phosphorus oxychloride (22.5 mL, 241.4 mmol) was added to a stirred mixture of 7-bromo-8-methylpyrido[3,2-d]pyrimidine-2,4-diol (70; 1.24 g, 4.8 mmol) and triethylamine hydrochloride (2.7 g, 19.3 mmol) in a 50 mL round bottom flask and heated to reflux for 4 h. The resulting black solution was cooled and carefully quenched by slow addition to 0 °C water. Once 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 further purification: HPLC-MS (ES + )m / z MH + =294.

[0168] Intermediate 77, prepared as shown in Scheme 9, can be used to prepare compounds having an 8-chloro substituent.

[0169] Solution 9

[0170]

[0171] 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#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 d, the mixture was cooled to RT and slowly moved into saturated aqueous NaHCO3 solution and stirred at RT. After 2 h, the precipitated solid was filtered and washed with EtOAc to give 2 g of methyl 3-amino-5-bromo-6-iodopicolinate (73) as a beige solid. The aqueous layer was extracted with EtOAc (3X), washed with saturated aqueous NaHCO3 solution (2X), 2% aqueous Na2S2O5 solution (3X), dried (MgSO4), filtered and concentrated. After standing overnight, solids precipitated out of the filtrate. The solid was recrystallized from EtOAc to give 1.0 g of 3-amino-5-bromo-6-iodopicolinic acid methyl ester (73) as a beige solid. The product from the extract was purified by silica gel column chromatography, eluting with a gradient of 10% to 40% EtOAc in hexanes to give 1.13 g of 3-amino-5-bromo-6-iodopicolinic acid methyl ester (73) as a beige solid: HPLC-MS (ES + )m / z[M+H + ]=357,359; 1H NMR (300MHz, CDCl3) δ7.28 (s, 1H), 5.81 (br s, 2H), 3.94 (s, 3H).

[0172] 3-Amino-5-bromo-4-chloro-6-iodopicolinic acid methyl ester (74). N-Chlorosuccinimide (2.76 g, 20.6 mmol) was added to a stirred solution of 3-amino-5-bromo-6-iodopicolinic acid methyl ester (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 (5X) with saturated aqueous NaCl solution, 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 3-amino-5-bromo-4-chloro-6-iodopicolinic acid methyl ester (74) as a fluffy white solid: HPLC-MS (ES + )m / z[M+H + ]=391,393,395; 1 H NMR (300MHz, CDCl3) δ6.45 (br s, 2H), 3.97 (s, 3H).

[0173] 3-amino-5-bromo-4-chloropicolinic acid methyl ester (75). Zinc powder (51 mg, 0.79 mmol) was added to a stirred suspension of 3-amino-5-bromo-4-chloro-6-iodopicolinic acid methyl ester (74; 102 mg, 0.26 mmol) in acetic acid (2.4 mL), and the resulting dark green mixture was stirred at RT. After 4 d, the mixture formed a tan suspension, and 14.4 mg of zinc powder was added. The mixture was stirred at RT for 16 h, then poured into a saturated NaHCO3 aqueous solution, extracted with EtOAc (3X), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluted with a 0% to 10% EtOAc gradient in DCM, to give 30 mg of 3-amino-5-bromo-4-chloropicolinic acid methyl ester (75) as an off-white solid: HPLC-MS (ES + )m / z[M+H + ]=265,267,269; 1 H NMR (300MHz, CDCl3) δ8.16 (s, 1H), 6.45 (br s, 2H), 3.99 (s, 3H).

[0174] 3-Amino-5-bromo-4-chloropicolinamide (76). A mixture of methyl 3-amino-5-bromo-4-chloropicolinamide (75; 200 mg, 0.753 mmol) and anhydrous ammonia in MeOH (4.0 mL, 7N) was stirred at RT in a sealed flask. After 16 h, a white suspension was formed and the reaction mixture was concentrated in vacuo to give 188 mg of 3-amino-5-bromo-4-chloropicolinamide (76) as a white solid: HPLC-MS (ESI): + )m / z[M+H + ]=250,252,254; 1 H NMR (300MHz, DMSO-d6) δ8.09(br s,1H),8.01(s,1H),7.63(br s,1H),7.41(br s,2H).

[0175] 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 N2. After 5 h, additional triphosgene (227 mg) was added and the mixture was heated to reflux for 16 h, cooled to RT, and then concentrated in vacuo. The crude solid was triturated with EtOAc, filtered, and washed with EtOAc to give 166 mg of 7-bromo-8-chloropyrido[3,2-d]pyrimidine-2,4-diol (77) as a gray solid: HPLC-MS (ES + )m / z[M+H + ]=276,278,280;[MH + ]=274,276,278; 1 H NMR (300MHz, DMSO-d6) δ11.8(br s,1H),11.1(br s,1H),8.66(s,1H).

[0176] Nucleotide exchange assay

[0177] The biological activity of the examples was determined in a KRAS G12C / SOS1 nucleotide exchange assay performed by Reaction Biology Corporation (RBC), 1 Great Valley Parkway, Suite 2 Malvern, PA 19355, USA. This assay evaluates the SOS1-mediated exchange of Bodipy-GDP for GTP observed with KRAS G12C.

[0178] At a concentration of 10 IC 50 The compounds were tested using a 3-fold serial dilution, with a starting concentration of 10 μM for Examples and MRTX-849 (reference standard) and 5 μM for ARS-1620 (reference standard). The compound preincubation time at RT was 30 min, and curve fitting was performed when the activity at the highest compound concentration was less than 65%.

[0179] Reaction buffer: 40 mM HEPES 7.4, 10 mM MgCl2, 1 mM DTT 0.002% Triton X100, 0.5 DMSO.

[0180] Protein: SOS1 (RBC cat# MSC-11-502). Recombinant human SOS1 (Genbank accession # NM_005633.3; aa 564-1049, expressed in E. coli with C-terminal StrepII. MW = 60.59 kDa).

[0181] KRAS G12C: Recombinant human KRAS (Genbank accession # NM_033360.3; aa2-169, expressed in E. coli with an N-terminal TEV-cleavable his-tag. MW 21.4 kDa), KRAS was pre-loaded with 5x excess Bodipy-GDP. Excess Bodipy-GDP was separated from the loaded protein using a spin desalting column.

[0182] Final concentrations: KRAS-bodipy-GDP at 0.125 μM; SOS1 at 70 nM; and GTP at 25 μM.

[0183] Reaction Procedure: 10 μL of 1.5x KRAS solution in freshly prepared reaction buffer was delivered into the reaction wells.

[0184] 1. Compounds in 100% DMSO were delivered into buffer using acoustic technology (Echo 550; nanoliter range).

[0185] 2. Incubate the compounds at room temperature for 30 minutes.

[0186] 3. Prepare 3x (SOS1+GTP) solution in reaction buffer.

[0187] 4. Deliver 5 μL of SOS1+GTP solution into the reaction wells (deliver GTP only to column 1 to serve as a no SOS1 control).

[0188] 5. The progress of the reaction was monitored for 30 minutes at room temperature by measuring the decrease in fluorescent signal in a PHERAstar plate reader (BMG Labtech; Ex / Em=485 / 520) with real-time reaction monitoring function.

[0189] Data analysis (for covalent compounds): The dRFU value was calculated for each compound concentration by subtracting the fluorescence (RFU) during the last 30 minutes of the reaction from the initial fluorescence measured just before the addition of the SOS1 / GTP mixture. Fluorescence data were normalized using the following formula and fitted to a "single-phase exponential decay" equation using GraphPad prism software. The plateau phase was not restricted and the dRFU value was used to calculate the IC 50 value.

[0190]

[0191] where Yraw is defined as the fluorescence at time t, Ao is the average initial fluorescence in the absence of SOS1, and M is the minimum fluorescence at the end of the reaction at maximum SOS1.

[0192] The signal after background subtraction (wells without SOS1 protein were used as background) was converted to % activity relative to the DMSO control. Data were analyzed using GraphPad Prism 4 and "Sigmoidal dose response (variable slope)"; 4 parameters with Hill Slope. Constraints were bottom (constant equal to 0) and top (must be less than 120).

[0193] result:

[0194]

[0195] *The substrate was Bodipy-GDP / Kras G12C and 0.5% DMSO was added to the reaction. IC was calculated using the dRFU assay for covalent inhibitors 50 ARS-1620 and MRTX-849 are reference standards.

[0196] Example 1 Pharmacokinetics in male CD-1 mice

[0197] The pharmacokinetic profile of Example 1 (Compound 1a) in male CD-1 mice was determined by WuXi AppTec Co., Ltd. (Address: No. 1318, Wuzhong Avenue, Wuzhong District, Suzhou, China, Postal Code 215104). The results shown in the table below clearly show that the oral bioavailability of Example 1 in male CD-1 mice is 28.8%.

[0198]

[0199] Note: If the adjusted Rsq (linear regression coefficient of terminal concentration values) is less than 0.9, T may not be estimated accurately. 1 / 2 If %AUC Extra >20%, the AUC may not be accurately estimated 0-inf 、Cl、MRT 0-inf and Vd ss If %AUMC Extra >20%, the MRT may not be accurately estimated 0-inf and Vd ss The composite mean concentration was used for PK parameter calculations. The adjusted linear regression coefficient of the terminal concentration value was less than 0.9 and may not accurately estimate T 1 / 2 The composite mean concentration was used for PK parameter calculations. 0-inf (If all AUC Extra <20%) or AUC0-last (if one or more AUC Extra >20%) was used to calculate the bioavailability (%F) at the nominal dose.

Claims

1. A compound of formula I or a salt, solvate or prodrug thereof: in: A is selected from aryl or heteroaryl, the aryl or heteroaryl being optionally substituted by 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 One or more substitutions in alkyl)2; X is selected from O, NR 2 , S or CH2; Y and G may be the same or different and are selected from bromine, iodine, C 1-4 Alkyl, C 1-4 perdeuterated 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-C2alkyl)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, 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 ; n is 1-3; Each R 2 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or -(C1-C6 alkyl)P(O)R 2 R 3 ; R 3 Selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl; R 4 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl or aryl.

2. The compound or salt according to claim 1, wherein the compound of formula I is a compound selected from 1b-1z and 2a-2g, or a salt, solvate or prodrug thereof:

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

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

5. The method of claim 4, wherein the disease, disorder or medical condition in the patient comprises various cancers.

6. The method of claim 5, wherein the disease, disorder or medical condition in the patient is mediated by KRAS.

7. The method of claim 6, wherein the disease, disorder or medical condition is mediated by KRAS, particularly KRAS mutant G12C.

8. The method of claim 6, wherein the cancer is selected from glioma (glioblastoma), acute myeloid leukemia, acute myeloid leukemia, myelodysplastic / myeloproliferative neoplasms, sarcoma, chronic myelomonocytic leukemia, non-Hodgkin's lymphoma, astrocytoma, melanoma, non-small cell lung cancer, bile duct cancer, chondrosarcoma, colon cancer, or pancreatic cancer.

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

10. The compound according to claim 2, wherein the compound of formula I is a compound selected from compounds 1d, 1f, 1n and 1z, or a salt, solvate or prodrug thereof:

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

12. The method of claim 4, wherein the disease, disorder or medical condition in the patient comprises various cancers.

13. The method of claim 12, wherein the disease, disorder or medical condition is mediated by KRAS.

14. The method of claim 13, wherein the disease, disorder or medical condition is mediated by KRAS mutant G12C.

15. The method of claim 13, wherein the cancer is selected from glioma (glioblastoma), acute myeloid leukemia, acute myeloid leukemia, myelodysplastic / myeloproliferative neoplasms, sarcoma, chronic myelomonocytic leukemia, non-Hodgkin's lymphoma, astrocytoma, melanoma, non-small cell lung cancer, bile duct cancer, chondrosarcoma, colon cancer, or pancreatic cancer.

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