JP2018520195A - Substituted quinazoline compounds and their use as inhibitors of G12C mutant KRAS, HRAS and / or NRAS proteins - Google Patents

Abstract

Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. These compounds have the following structure (I), wherein R, R ¹ , R ^2a , R ^2b , R ^2c , A, B, L ¹ , and E are as defined herein. Or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof. Also provided are methods related to the preparation and use of such compounds, pharmaceutical compositions comprising such compounds, and methods of modulating the activity of G12C variant KRAS protein for the treatment of disorders such as cancer.

Description

The present invention relates generally to, for example, novel compounds for the treatment of cancer and methods for their preparation and use as therapeutic or prophylactic agents.

Description of Related Art RAS represents a closely related monomeric globular protein family of 189 amino acids (molecular mass 21 kDa) that associates with the plasma membrane and binds to either GDP or GTP. RAS acts as a molecular switch. If the RAS has bound GDP, it is dormant or off and is “inactive”. In response to cellular exposure to certain growth-promoting stimuli, RAS is induced to exchange bound GDP for GTP. GTP binding allows the RAS to “switch on”, interact with and activate other proteins (its “downstream target”). The RAS protein itself hydrolyzes GTP back to GDP, thereby having a very low endogenous ability to turn RAS itself off. Switching off RAS requires an exogenous protein called GTPase activating protein (GAP) that interacts with RAS and greatly facilitates the conversion of GTP to GDP. Any mutation in RAS that affects the ability to interact with GAP or convert GTP back to GDP signals that prolong the activation of the protein and consequently direct the cell to continue to grow and divide Is extended. Because these signals cause cells to grow and divide, overactive RAS signaling can ultimately cause cancer.

  Structurally, RAS proteins contain a G domain that is responsible for the enzymatic activity of RAS (guanine nucleotide binding and hydrolysis (GTPase reaction)). The RAS protein also contains a C-terminal extension region known as the CAAX box, which can be post-translationally modified and responsible for targeting the RAS protein to the membrane. The G domain is approximately 21-25 kDa in size and contains a phosphate binding loop (P-loop). P-loop indicates a pocket to which nucleotides in the RAS protein bind and is a fixed part of the domain with conserved amino acid residues (glycine 12, threonine 26, and lysine 16) essential for nucleotide binding and hydrolysis. The G domain also includes the so-called switch I region (residues 30-40) and switch II region (residues 60-76), both of which are often referred to for their ability to switch between dormant and loaded states. It is the dynamic part of the protein expressed as the “spring loading” mechanism. An important interaction is the hydrogen bond formed by threonine-35 and glycine-60 and GTP's γ-phosphate, which maintains the switch 1 and switch 2 regions in their active conformation, respectively. After GTP hydrolysis and phosphate release, the two are relaxed to an inactive GDP conformation.

  The most prominent members of the RAS subfamily are HRAS, KRAS, and NRAS, which are primarily involved in many cancer types. However, many other members (DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD2; RASL11A; RASL10A; RASL10A; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS and RRAS2 are present).

  Mutation of any one of the three major isoforms of the RAS gene (HRAS, NRAS, or KRAS) is the most common event in human tumor development. Approximately 30% of all human tumors have been found to carry some RAS gene mutation. Surprisingly, KRAS mutations are detected in 25-30% of tumors. By comparison, the proportion of carcinogenic mutations occurring in NRAS and HRAS family members is much lower (8% and 3%, respectively). The most common KRAS mutations are found at residues G12 and G13 and residue Q61 in the P-loop.

  G12C is a frequent mutation of the KRAS gene (mutation from glycine-12 to cysteine). This mutation has been found in about 13% cancer, about 43% lung cancer, and almost 100% MYH-related polyposis (familial colon cancer syndrome). However, targeting this gene using small molecules is difficult.

  Thus, although the field is progressing, there remains a need in the art for improved compounds and methods for cancer treatment, for example, by inhibiting KRAS, HRAS, or NRAS. The present invention fulfills this need and provides further related advantages.

SUMMARY Briefly, the present invention provides compounds that can modulate G12C mutants KRAS, HRAS, and / or NRAS proteins (stereoisomers, pharmaceutically acceptable salts, tautomers, and prosthetics). (Includes drag). In some examples, the compound acts as an electrophile that can form a covalent bond with a cysteine residue at position 12 of a KRAS, HRAS, or NRAS G12C variant protein. Also provided are methods of using such compounds for the treatment of various diseases or conditions such as cancer.

（式中、Ｒ、Ｒ^１、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃ、Ａ、Ｂ、Ｌ^１、およびＥは本明細書中に定義の通りである）を有する化合物またはその薬学的に許容され得る塩、立体異性体、もしくはプロドラッグを提供する。構造（Ｉ）の１つまたはそれよりも多くの化合物および薬学的に許容され得るキャリアを含む薬学的組成物も種々の他の実施形態で提供する。 In one embodiment, the following structure (I):

Wherein R, R ¹ , R ^2a , R ^2b , R ^2c , A, B, L ¹ , and E are as defined herein, or a pharmaceutically acceptable salt thereof A salt, stereoisomer, or prodrug is provided. Also provided in various other embodiments are pharmaceutical compositions comprising one or more compounds of structure (I) and a pharmaceutically acceptable carrier.

  In another embodiment, the invention provides a method of treating cancer, wherein the subject requires a pharmaceutical composition comprising an effective amount of any one or more of the compounds of structure (I). A method comprising the steps of:

  Another provided method is a method of modulating the activity of a KRAS, HRAS, or NRAS G12C variant protein, wherein the KRAS, HRAS, or NRAS G12C variant protein is any one of compounds of structure (I) Including the step of reacting with one. In another embodiment, there is also provided a method of inhibiting the growth of a cell population comprising contacting the cell population with any one of the compounds of structure (I).

In another embodiment, the invention provides a method of performing said treatment in a subject in need of treatment of a disorder mediated by a K12, HRAS, or NRAS G12C mutation, comprising:
Determining whether the subject has a KRAS, HRAS, or NRAS G12C mutation; and if the subject is determined to have a KRAS, HRAS, or NRAS G12C mutation, the subject has a therapeutically effective amount of 1 Administering a pharmaceutical composition comprising one or more compounds of structure (I).

  In yet a further embodiment, the invention provides a method of preparing a labeled KRAS, HRAS, or NRAS G12C variant protein, wherein the KRAS, HRAS, or NRAS G12C variant is reacted with a compound of structure (I). And obtaining a labeled KRAS, HRAS, or NRAS G12C protein.

  These and other aspects of the invention will be apparent upon reference to the following detailed description.

  In the drawings, identical reference numbers indicate similar elements. The sizes and relative positions of elements in the figures are not necessarily drawn to scale, and some of these elements are arbitrarily enlarged and arranged to improve the visibility of the drawing. doing. Further, the particular shape of the depicted element is not intended to convey any information regarding the actual shape of the particular element and is selected solely to facilitate recognition of the drawing.

FIG. 1 shows the enzyme activity of RAS.

FIG. 2 shows the RAS signaling pathway.

FIG. 3 shows several common oncogenes, their respective tumor types, and cumulative mutation frequency (all tumors).

DETAILED DESCRIPTION In the following description, specific specific details are set forth in order to provide a thorough understanding of various embodiments of the invention. However, one skilled in the art will understand that the invention may be practiced without these details.

  Unless the context requires otherwise, the term “comprise” and variations thereof (such as “comprises” and “comprising”) are used throughout the specification and claims. , Should be interpreted as open-ended, ie, meaning of inclusion, such as “including but not limited to”.

  Throughout this specification, a reference to “one embodiment” or “an embodiment” refers to a particular property, structure, or characteristic described in conjunction with the embodiment. It is meant to be included in one embodiment. Thus, the phrases “in one embodiment” or “in an embodiment” found in various places throughout this specification refer to embodiments that are not necessarily all identical. Not. Furthermore, the particular properties, structures, or characteristics may be combined in one or more embodiments in any suitable manner.

  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. Unless otherwise clearly indicated by context, the singular forms “a”, “an”, and “the” include plural references as used herein and in the claims.

“Amino” refers to the —NH ₂ radical.

“Carboxy” or “carboxyl” refers to the —CO ₂ H radical.

  “Cyano” refers to the —CN radical.

  “Hydroxy” or “hydroxyl” refers to the —OH radical.

  “Imino” refers to the ═NH substituent.

“Nitro” refers to the —NO ₂ radical.

  “Oxo” refers to the ═O substituent.

  “Thioxo” refers to the ═S substituent.

“Alkyl” consists solely of carbon and hydrogen atoms, is saturated or unsaturated (ie, contains one or more double and / or triple bonds), and has 1 to 12 carbon atoms _(C 1 _{-C 12} alkyl), preferably having 1 to 8 carbon atoms _(C 1 -C ₈ alkyl), or 1 to 6 carbon atoms _(C 1 -C ₆ alkyl), by a single bond Refers to a straight or branched hydrocarbon chain radical attached to the rest of the molecule (eg, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1 -Dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl, penta-1-enyl, penta-1,4-dienyl, ethini , Propynyl, butynyl, pentynyl, and hexynyl, etc.). In some embodiments, alkyl is saturated. In other embodiments, the alkyl is unsaturated, and thus alkenyl (one or more carbon-carbon double bonds) and / or alkynyl (one or more carbon-carbon triplets). A bond such as ethynyl). Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted.

  An “alkylene” or “alkylene chain” consists solely of carbon and hydrogen and is saturated or unsaturated (ie, contains one or more double and / or triple bonds) and has 1 to 12 A linear or branched divalent hydrocarbon chain having the following carbon atoms and connecting the remainder of the molecule to a radical group (for example, methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, Such as propynylene and n-butynylene). The alkylene chain is bonded to the rest of the molecule through a single bond or a double bond, and is bonded to the radical group through a single bond or a double bond. The point of attachment of the alkylene chain to the rest of the molecule and the radical group can be through one carbon or any two carbons in the chain. Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted.

“Alkoxy” refers to a radical of the formula —OR _a , where R _a is an alkyl radical as defined above containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.

“Alkoxyalkyl” is a group of the formula —R _b OR _{a where} R _a is an alkyl radical as defined above containing 1 to 12 carbon atoms and Rb is as defined above containing 1 to 12 carbon atoms. Radical) which is an alkylene radical. Unless stated otherwise specifically in the specification, an alkoxyalkyl group is optionally substituted.

“Alkoxycarbonyl” refers to a radical of the formula —C (═O) OR _a , where R _a is an alkyl radical as defined above containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkoxycarbonyl group is optionally substituted.

“Alkylaminyl” refers to a radical of the formula —NHR _a or —NR _a R _a , wherein each R _a is independently an alkyl radical as defined above containing 1 to 12 carbon atoms. Say. Unless stated otherwise specifically in the specification, an alkylaminyl group is optionally substituted.

“Aminylalkyl” is an alkyl containing at least one aminyl substituent (—NR _a R _b , wherein R _a and R _b are each independently H or C ₁ -C ₆ alkyl). Refers to the group. The aminyl substituent may be present on a tertiary carbon, secondary carbon, or primary carbon. Unless stated otherwise specifically in the specification, an aminylalkyl group is optionally substituted.

“Aminylalkylaminyl” refers to a radical of the formula —NR _a R _b , where R _a is H or C ₁ -C ₆ alkyl and R _b is aminylalkyl. Unless stated otherwise specifically in the specification, an aminylalkylaminyl group is optionally substituted.

“Aminylalkoxy” refers to a radical of the formula —OR _a NH ₂ , where R _a is alkylene. Unless stated otherwise specifically in the specification, an aminylalkoxy group is optionally substituted.

“Alkylaminylalkoxy” has the formula —OR _a NR _b R _c , where R _a is alkylene, R _b and R _c are each independently H or C ₁ -C ₆ alkyl; Provided that one of R _b or R _c is C ₁ -C ₆ alkyl). Unless stated otherwise specifically in the specification, an alkylaminylalkoxy group is optionally substituted.

“Alkylcarbonylaminyl” refers to a radical of the formula —NH (C═O) R _a , where R _a is an alkyl radical as defined above containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkylcarbonylaminyl group is optionally substituted. Alkenylcarbonylaminyl is alkylcarbonylaminyl containing at least one carbon-carbon double bond. Alkenylcarbonylaminyl groups are optionally substituted.

“Alkylcarbonylaminylalkoxy” has the formula —OR _b NH (C═O) R _a , where R _a is an alkyl radical as defined above containing 1 to 12 carbon atoms, and R _b is alkylene. A) radical. Unless stated otherwise specifically in the specification, an alkylcarbonylaminylalkoxy group is optionally substituted.

“Aminylcarbonylalkyl” has the formula —R _c C (═O) NR _a R _b , wherein R _a and R _b are each independently H or alkyl, and R _c is alkylene. The radical of Unless stated otherwise specifically in the specification, an aminylcarbonylalkyl group is optionally substituted.

  “Aryl” refers to a carbocyclic ring system radical comprising hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For the purposes of the present invention, an aryl radical is a monocyclic ring system, a bicyclic ring system, a tricyclic ring system, or a tetracyclic ring system, which ring system is a fused or bridged ring system. Can be included. Aryl radicals include asanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, preaden, pyrene And aryl radicals derived from triphenylene, but are not limited thereto. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-” (in the case of “aralkyl” and the like) is intended to include optionally substituted aryl radicals. means.

“Aralkyl” is a group of the formula —R _b —R _c , wherein R _b is an alkylene chain as defined above, and R _c is one or more aryl radicals as defined above (eg, benzyl and diphenylmethyl Etc.)))). Unless stated otherwise specifically in the specification, an aralkyl group is optionally substituted.

“Carboxyalkyl” refers to a radical of the formula —R _b —R _{c where} R _b is an alkylene chain as defined above and R _c is a carboxyl group as defined above. Unless stated otherwise specifically in the specification, a carboxyalkyl group is optionally substituted.

“Cyanoalkyl” refers to a radical of the formula —R _b —R _{c where} R _b is an alkylene chain as defined above and R _c is a cyano group as defined above. Unless stated otherwise specifically in the specification, a cyanoalkyl group is optionally substituted.

  “Carbocyclic” or “carbocycle” refers to a ring system in which each ring atom is carbon.

  “Cycloalkyl” consists solely of carbon and hydrogen atoms and may include fused or bridged ring systems, having from 3 to 15 carbon atoms, preferably having from 3 to 10 carbon atoms. A stable non-aromatic monocyclic or polycyclic carbocyclic radical that is saturated or unsaturated and is bonded to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo [2.2.1] heptanyl, and the like. “Cycloalkylene” is a divalent cycloalkyl typically connecting one part of a molecule to another. Unless stated otherwise specifically in the specification, a cycloalkyl (or cycloalkylene) group is optionally substituted.

“Cycloalkylalkyl” refers to a radical of the formula —R _b R _d , where R _b is an alkylene chain as defined above and R _d is a cycloalkyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group is optionally substituted.

“Cycloalkylaminyl” refers to a radical of the formula —NR _a R _b , where R _a is H or alkyl and R _b is cycloalkyl. Unless stated otherwise specifically in the specification, a heterocyclylalkoxy group is optionally substituted.

  “Fused” refers to any ring structure described herein fused to an existing ring structure in a compound of the invention. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or fused heteroaryl ring is replaced with a nitrogen atom.

  “Halo” or “halogen” refers to bromo, chloro, fluoro, or iodo.

  “Haloalkyl” refers to an alkyl radical as defined above substituted with one or more halo radicals as defined above (eg, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl). 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl). Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted.

  “Heterocyclyl” or “heterocyclic ring” refers to 1 to 12 ring carbon atoms (eg, 2 to 12) and 1 to 6 ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. A stable 3-18 membered non-aromatic ring radical having. Unless stated otherwise specifically in the specification, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and the ring system Can include fused ring systems, spiro ring systems ("spiro-heterocyclyl"), and / or bridged ring systems; nitrogen, carbon, or sulfur atoms in heterocyclyl radicals are optionally oxidized; nitrogen Atoms are optionally quaternized; heterocyclyl radicals are partially or fully saturated. Examples of such heterocyclyl radicals include dioxolanyl, thienyl [1,3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoin Drill, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, This includes, but is not limited to, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. “Heterocyclylene” refers to a divalent heterocyclyl group that typically connects one part of a molecule to another. Unless stated otherwise specifically in the specification, a heterocyclyl and / or heterocyclylene group is optionally substituted.

  “N-heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and the point of attachment of the heterocyclyl radical to the rest of the molecule through the nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, an N-heterocyclyl group is optionally substituted.

“Heterocyclylalkyl” has the formula —R _b R _e , where R _b is an alkylene chain as defined above, R _e is a heterocyclyl radical as defined above, and when the heterocyclyl is a nitrogen-containing heterocyclyl, the nitrogen of the heterocyclyl A radical in which an atom is optionally bonded to an alkyl radical. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group is optionally substituted.

“Heterocyclylalkoxy” refers to a radical of the formula —OR _a R _{b where} R _a is alkylene and R _b is heterocyclyl. Unless stated otherwise specifically in the specification, a heterocyclylalkoxy group is optionally substituted.

“Heterocyclylaminyl” refers to a radical of the formula —NR _a R _{b where} R _a is H or alkyl and R _b is heterocyclyl. Unless stated otherwise specifically in the specification, a heterocyclylalkoxy group is optionally substituted.

  “Heteroaryl” includes a hydrogen atom, 1-13 ring carbon atoms, 1-6 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. A 14-membered ring system radical. For the purposes of the present invention, a heteroaryl radical may be a monocyclic ring system, a bicyclic ring system, a tricyclic ring system, or a tetracyclic ring system, which ring system is a fused ring system or A bridged ring system can be included; the nitrogen, carbon, or sulfur atom in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1,4] dioxepinyl, 1,4 -Benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo [4,6] imidazo [1,2-a] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazoly , Isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidepyrimidinyl, 1-oxidepyrazinyl, 1-oxidepyridazinyl 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, Thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl KazuSatoshi, thienyl) include, but are not limited to. Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted.

  “N-heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen and the point of attachment of the heteroaryl radical to the rest of the molecule through the nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group is optionally substituted.

“Heteroarylalkyl” refers to a radical of the formula —R _b R _f , where R _b is an alkylene chain as defined above and R _f is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group is optionally substituted.

  “Hydroxylalkyl” refers to an alkyl group that contains at least one hydroxyl substituent. The —OH substituent can be present on a primary carbon, secondary carbon, or tertiary carbon. Unless stated otherwise specifically in the specification, a hydroxylalkyl group is optionally substituted. Unless stated otherwise specifically in the specification, a hydroxylalkyl group is optionally substituted.

“Phosphate” means an —OP (═O) (R _a ) R _b group, where R _a is OH, O ⁻ , or OR _c , and R _b is OH, O ⁻ , OR _c , or Refers to an additional phosphate group (eg, forming a diphosphate or triphosphate), and R _c is a counter ion (eg, Na +, etc.).

  “Phosphoalkoxy” refers to an alkoxy group, as defined herein, substituted with at least one phosphate group, as defined herein. Unless stated otherwise specifically in the specification, a phosphoalkoxy group is optionally substituted.

“Thioalkyl” refers to a radical of the formula —SR _a , where R _a is an alkyl radical as defined above containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group may be optionally substituted.

As used herein, the term “substituted” means that at least one hydrogen atom (eg, one, two, three, or all hydrogen atoms) is a non-hydrogen atom (halogen atom (F, Cl, Br). , And I); oxygen atoms in groups (such as hydroxyl groups, alkoxy groups, and ester groups); sulfur atoms in groups (such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups); groups ( Nitrogen atoms in amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; groups (trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyls) Groups, and triarylsilyl groups, etc.); and other groups in various other groups Any of the above groups (e.g., alkyl, alkylene, alkoxy, alkoxyalkyl, alkoxycarbonyl, aminylalkyl, aminylalkylaminyl, amin) replaced by a bond to, but not limited to, a rho atom Nyl alkoxy, alkyl aminyl alkoxy, alkyl aminyl, alkyl carbonyl aminyl, alkyl carbonyl aminyl alkoxy, aminyl carbonyl alkyl, thioalkyl, aryl, aralkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl N-heterocyclyl, heterocyclyloxy, heterocyclylaminyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl It means heteroarylalkyl, Hosuhoarukokishi, and / or a hydroxyl alkyl). “Substitution” also means that one or more hydrogen atoms are heteroatoms (oxy, oxo, carbonyl, carboxyl, and ester; oxygen; and groups (imine, oxime, hydrazone, and nitriles). Means any group as described above which is replaced by a higher order bond (eg double bond or triple bond) to nitrogen etc.). For example, “substituted” includes one or more hydrogen atoms, —NR _g R _h , —NR _g C (═O) R _h , —NR _g C (═O) NR _g R _h , _{-NR g C (= O) OR} h, -NR g SO 2 R h, -OC (= O) NR g R h, -OR g, -SR g, -SOR g, -SO 2 R g, -OSO _{2 R g, -SO 2 oR g} , = include _NSO 2 _{R g,} and _-SO 2 _NR g any group is replaced above in _{R h.} “Substitution” also means that one or more hydrogen atoms are —C (═O) R _g , —C (═O) OR _g , —C (═O) NR _g R _h , —CH ₂ SO ₂ R _g , refers to any of the above groups replaced by —CH ₂ SO ₂ NR _g R _h . In the foregoing, R _g and R _h are the same or different and are independently hydrogen, alkyl, alkoxy, alkylaminyl, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclyl. Alkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. “Substitution” also means that one or more hydrogen atoms are aminyl, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamido. Nyl group, thioalkyl group, aryl group, aralkyl group, cycloalkyl group, cycloalkylalkyl group, haloalkyl group, heterocyclyl group, N-heterocyclyl group, heterocyclylalkyl group, heteroaryl group, N-heteroaryl group, and / or hetero It means any group described above which is replaced by a bond to an arylalkyl group. In addition, each of the aforementioned substituents can be optionally substituted with one or more of the above substituents.

  An “electrophile” or “electrophilic moiety” reacts with a nucleophile (eg, a lone pair, negative charge, partial negative charge, and / or a moiety having an excess of electrons, eg, an —SH group). Any part that can be. Electrophiles are typically electron deficient or contain electrons deficient atoms. In certain embodiments, the electrophile has a resonant structure that includes a positive or partial positive charge, a positive charge or a partial positive charge, or one or more by electron delocalization or polarization. The portion from which atoms with more positive or partial positive charges are obtained. In some embodiments, the electrophile comprises a conjugated double bond (eg, an α, β-unsaturated carbonyl compound or an α, β-unsaturated thiocarbonyl compound).

  The term “effective amount” or “therapeutically effective amount” is an amount of a compound described herein sufficient to achieve the intended application, including but not limited to disease treatment as defined below. Say. The therapeutically effective amount will vary depending on the intended treatment application (in vivo) or subject and condition being treated (eg, subject weight and age, severity of condition, mode of administration, etc.). Well, it can be easily determined by one skilled in the art. The term also applies to a dose that induces a specific response in the target cell (eg, reduced platelet adhesion and / or cell migration). The particular dose will vary depending on the particular compound selected, the dosing regime to be followed, whether to be administered in combination with other compounds, the timing of administration, the tissue administered, and the physical delivery system possessed.

  As used herein, “treatment” or “treating” is a beneficial or desirable outcome (including therapeutic and / or prophylactic benefits) with respect to a disease, disorder, or condition. , But not limited to)). By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. A therapeutic benefit is also the eradication of one or more physiological symptoms associated with the underlying disorder so that improvement may be observed in the subject, even though the subject may still suffer from the underlying disorder. Achieved with improvements. In certain embodiments, for prophylactic benefits, the composition may comprise one or more of one or more subjects or diseases at risk of developing a particular disease, even if the disease may not have been diagnosed. Administer to subjects with reported physiological symptoms.

  “Therapeutic effect”, as the term is used herein, includes the therapeutic and / or prophylactic benefits described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of the disease or condition, delaying, stopping, or reversing the progression of the disease or condition, or any combination thereof.

  The terms “co-administration”, “administration in combination with”, and grammatical equivalents thereof, as used herein, to an animal (including humans) of two or more drugs are included. Administration, wherein both agents and / or their metabolites are present in the subject at the same time. Co-administration includes co-administration of individual compositions, administration of individual compositions at different times, or administration in a composition in which both drugs are present.

  “Pharmaceutically acceptable salt” includes both acid and base addition salts.

  “Pharmaceutically acceptable acid addition salts” retain the biological effectiveness and properties of the free base and are not biologically or otherwise undesirable, such as inorganic acids (eg, hydrochloric acid, bromide, Hydrogen acids, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids (eg, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, Benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, Ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, Acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, Methanesulfonic acid, mucinic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, Propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid. Non-limiting) refers to the salt formed.

  “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Not. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include primary amines, secondary amines, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins (eg, Ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline , Betaine, venetamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperi Emissions, and include salts of resin) of the polyamine, but is not limited thereto. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

  The terms “antagonist” and “inhibitor” are used interchangeably and these terms inhibit the biological function of the target protein by inhibiting the activity or expression of the target protein (such as KRAS, HRAS, or NRAS G12C). A compound having capacity. Thus, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact (eg, bind) to a target, biological activity of the target protein by interaction with other members of the signaling pathway of which the target protein is a member Also specifically included within this definition are compounds that inhibit. A preferred biological activity that is inhibited by an antagonist is associated with tumor development, growth, or expansion.

  The term “agonist” as used herein refers to a compound that has the ability to initiate or enhance the biological function of a target protein by inhibiting the activity or expression of the target protein. Thus, the term “agonist” is defined in the context of the biological role of the target polypeptide. While preferred agonists herein interact specifically (eg, bind) to a target, the biology of the target polypeptide by interaction with other members of the signaling pathway of which the target polypeptide is a member Also specifically included within this definition are compounds that initiate or enhance physical activity.

  As used herein, “agent” or “biologically active agent” refers to a biological, pharmaceutical, or chemical compound or other moiety. Non-limiting examples include simple or complex organic or inorganic molecules, peptides, proteins, oligonucleotides, antibodies, antibody derivatives, antibody fragments, vitamin derivatives, carbohydrates, toxins, or chemotherapeutic compounds. A variety of compounds can be synthesized, such as small molecules and oligomers (eg, oligopeptides and oligonucleotides) and synthetic organic compounds based on various core structures. In addition, compounds for screening can be obtained from a variety of natural sources, such as plant or animal extracts.

  “Signal transduction” is the process by which stimulatory or inhibitory signals are transmitted into or into a cell to elicit an intracellular response. A signaling pathway modulator refers to a compound that modulates the activity of one or more cellular proteins that map to the same specific signaling pathway. A modulator can enhance (agonist) or inhibit (antagonist) the activity of a signaling molecule.

  “Anticancer agent”, “antitumor agent”, or “chemotherapeutic agent” refers to any agent useful in the treatment of neoplastic conditions. One class of anticancer drugs includes chemotherapeutic drugs. “Chemotherapy” is one for cancer patients by various methods, including intravenous, oral, intramuscular, intraperitoneal, intracapsular, subcutaneous, transdermal, buccal, or inhalation, or suppository forms. Or the administration of more chemotherapeutic drugs and / or other drugs.

  The term “cell proliferation” refers to a phenomenon in which the number of cells has changed as a result of division. The term also includes cell growth in which the morphology of the cell has changed (eg, increased in size) consistent with a proliferation signal.

  The term “selective inhibition” or “selectively inhibit” means that a biologically active agent is targeted via direct or indirect interaction with the target as compared to off-target signaling activity. The ability of the drug to preferentially reduce signaling activity.

  “Subject” refers to an animal, such as a mammal (eg, a human). The methods described herein may be useful in both human therapy and animal applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is a human.

  “Mammal” includes humans and domestic animals (such as laboratory animals and pets (eg, cats, dogs, pigs, cows, sheep, goats, horses, rabbits)) and non-domestic animals (eg, wild animals). Both are included.

  “Radiotherapy” uses a routine method and composition known to those skilled in the art to treat a subject with a radiation emitter (alpha particle emitting radionuclides (eg, actinium and thorium radionuclides), low linear energy, Includes imparted (LET) radiation emitters (ie, beta emitters), conversion electron emitters (eg, strontium-89 and samarium-153-EDTMP), or high energy radiation (X-rays, gamma rays, and neutrons) Exposure to, but not limited to).

  “Anticancer agent”, “antitumor agent”, or “chemotherapeutic agent” refers to any agent useful in the treatment of neoplastic conditions. One class of anticancer drugs includes chemotherapeutic agents. “Chemotherapy” refers to the administration of one or more chemotherapeutic drugs and / or other drugs in various ways (intravenous, oral, intramuscular, intraperitoneal, intracapsular, subcutaneous, transdermal, buccal, or Means administration to cancer patients by inhalation or suppository form).

  “Prodrug” refers to a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound described herein (eg, a compound of structure (I)). means. Thus, the term “prodrug” refers to a precursor of a pharmaceutically acceptable biologically active compound. In some embodiments, a prodrug is inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis. Prodrug compounds often confer advantages such as solubility, histocompatibility, or delayed release in mammals (eg, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 ( See Elsevier, Amsterdam). Prodrugs are described in Higuchi, T .; , Et al., “Pro-drugs as Novel Delivery Systems,” A. C. S. Symposium Series, Vol. 14 and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are fully incorporated herein by reference. The term “prodrug” is also meant to include any covalently bonded carrier that releases the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the active compound are typically active in a manner such that the modification is cleaved into the parent active compound, either as described herein, either routinely or in vivo. Prepare by modifying functional groups present in the compound. Prodrugs include hydroxy groups, amino groups, or mercapto groups that are cleaved when a prodrug of the active compound is administered to a mammalian subject, resulting in a free hydroxy group, a free amino group, or a free mercapto group Are bonded to any group that forms each. Examples of prodrugs include, but are not limited to, hydroxy-functional acetic acid derivatives, formic acid derivatives, and benzoic acid derivatives or active compounds including amine functional acetamide derivatives, formamide derivatives, and benzamide derivatives.

（式中、各Ｒ’は、独立して、Ｈまたは任意選択の置換基であり、ｎは、１、２、３、または４である）のうちの１つを有する化合物が含まれる。 In some embodiments, prodrugs include compounds of structure (I) having a phosphate substituent, a phosphoalkoxy substituent, an ester substituent, or a boronate ester substituent. Without being bound by theory, it is believed that such substituents are converted to hydroxyl groups under physiological conditions. Thus, embodiments include any compound disclosed herein in which the hydroxyl group is replaced with a phosphate group, phosphoalkoxy group, ester group, or boronate ester group, such as a phosphate or phosphoalkoxy group. . For example, in some embodiments, the hydroxyl group on the R ¹ moiety is replaced with a phosphate group, phosphoalkoxy group, ester group, or boronic ester group, such as a phosphate group or an alkoxyphosphate group. Accordingly, exemplary prodrugs of certain embodiments include the following R ¹ moiety:

Wherein each R ′ is independently H or an optional substituent, and n is 1, 2, 3, or 4.

  The term “in vivo” refers to an event that occurs in a subject's body.

Embodiments of the invention disclosed herein also include all of the isotopically labeled structures (I) by replacing one or more atoms with atoms having different atomic masses or mass numbers. It is meant to include pharmaceutically acceptable compounds. Examples of isotopes that can be incorporated into the disclosed compounds include hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine isotopes ( ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, and ¹²⁵ I). These radiolabeled compounds help to determine or measure the effectiveness of a compound, for example, by characterizing the site or mode of action, or binding affinity for a pharmacologically important site of action. Can be useful. Certain isotopically-labelled compounds of structure (I) (eg, those incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium (ie, ³ H) and carbon-14 (ie, ¹⁴ C) are particularly useful for this purpose in view of their ease of incorporation and ease of detection.

Substitution with heavier isotopes such as deuterium (ie, ² H) provides certain therapeutic benefits due to greater metabolic stability (eg, increased in vivo half-life or reduced dosage required). Is therefore preferred under some circumstances.

Substitution with positron emitting isotopes (such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N) is useful in Positron Emission Topography (PET) studies for examination of substrate receptor occupancy. possible. Isotopically labeled compounds of structure (I) are generally described in the preparations and examples below using appropriate isotope labeled reagents in place of conventional techniques known to those skilled in the art or previously unlabeled reagents. Can be prepared by a process similar to this process.

  Certain embodiments are also meant to include in vivo metabolites of the disclosed compounds. Such metabolites can result, for example, from the oxidation, reduction, hydrolysis, amidation, and esterification of administered compounds primarily by enzymatic processes. Accordingly, embodiments include a compound produced by a process comprising administering to a mammal a compound of the invention for a period of time sufficient to produce its metabolite. Such a product is typically administered to an animal (such as a rat, mouse, guinea pig, monkey, or human) with a detectable dose of a radiolabeled compound of the present invention and allowed to metabolize for a sufficient amount of time to convert the product. Are identified by isolation from urine, blood, or other biological samples.

  “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to withstand isolation to a useful purity from a reaction mixture and formulation into an effective therapeutic agent.

  Often crystallizations produce solvates of the compounds of the invention. As used herein, the term “solvate” refers to an aggregate comprising one or more molecules of a compound of the present invention along with one or more solvent molecules. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Accordingly, the compounds of the present invention include hydrates (including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc.) and corresponding It can exist as a solvated form. In some embodiments, the compounds of the invention are true solvates, while in other cases, the compounds of the invention retain only extraneous water or some exogenous water and It is a mixture with a solvent.

  “Optional” or “optionally” includes that subsequent environmental events may or may not occur, and that the description includes instances where the event or environment occurs and does not occur Means that. For example, “optionally substituted aryl” includes that the aryl radical may or may not be substituted, and that the description includes both substituted and unsubstituted aryl radicals. Means that.

  “Pharmaceutical composition” refers to a formulation of a compound of the invention and a vehicle generally accepted in the art for delivery of a biologically active compound to a mammal (eg, a human). Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients for the compound.

  "Pharmaceutically acceptable carrier, diluent or excipient" includes any adjuvant, carrier, excipient, approved by the US Food and Drug Administration as acceptable for use in humans or domestic animals, Contains glidants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers However, it is not limited to these.

  A compound of the present invention (ie, a compound of structure (I)) or a pharmaceutically acceptable salt thereof can contain one or more asymmetric centers and thus from an absolute stereochemical point of view. The enantiomers, diastereomers, and other stereoisomers defined as the, (R) or (S) form or, in the case of amino acids, as the (D) or (L) form can be produced. Thus, embodiments are meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (−), (R) and (S) isomers, or (D) and (L) isomers are prepared using chiral synthons or chiral reagents. Or can be resolved using conventional techniques (eg, chromatography and fractional crystallization). Prior art for the preparation / isolation of each enantiomer includes chiral synthesis from an appropriate optically pure precursor or racemic (or racemic) using, for example, chiral high pressure liquid chromatography (HPLC). Separation of salts or derivatives thereof. Where a compound described herein contains an olefinic double bond or other geometrically asymmetric center, it is intended that the compound include both E and Z geometric isomers unless otherwise specified. . Likewise, all tautomeric forms are also intended to be included.

Embodiments of the present invention include all modalities with restricted rotational isomers and higher order structures of the compounds of the present invention. Atropisomers are also included. This isomer is a stereoisomer due to a single bond rotation hindrance where the energy difference due to steric strain or other triggers results in a sufficiently high rotation barrier to isolate each conformer. By way of example, certain compounds of the present invention may exist as a mixture of atropisomers or a form in which one atropisomer is purified or enriched for its presence. Non-limiting examples of compounds that exist as atropisomers include the following compounds:

  In some embodiments, the compound of structure (I) is a mixture of atropisomers. In other embodiments, the compound of structure (I) is a substantially purified atropisomer. In some embodiments, the compound of structure (I) is a substantially purified R-atropisomer. In some other embodiments, the compound of structure (I) is a substantially purified R-atropisomer.

  “Stereoisomer” refers to a compound made up of identical atoms joined by identical bonds, but having different three-dimensional structures that are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”. Enantiomers refer to stereoisomers that are two stereoisomers, the two molecules of which are non-superimposable mirror images of each other.

  A “tautomer” refers to a proton transfer from one atom of a molecule to another atom of the same molecule. Accordingly, embodiments include tautomers of the disclosed compounds.

  The chemical nomenclature protocols and structure diagrams used herein are those described in I.C. using the ACD / Name version 9.07 software program and / or the ChemDraw Ultra version 11.0.1 software naming program (CambridgeSoft). U. P. A. C. This is a modified form of nomenclature. For complex chemical names used herein, substituents are typically named before the group to which the substituent is attached. For example, cyclopropylethyl includes an ethyl skeleton with a cyclopropyl substituent. Except as noted below, all bonds except for all bonds on some carbon atoms that are believed to be bonded to sufficient hydrogen atoms to complete the valence are shown in the chemical structure diagrams herein. Identify.

Compounds In one aspect, the present invention provides compounds that can selectively bind to and / or modulate G12C mutant KRAS, HRAS, or NRAS proteins. The compounds can modulate the G12C mutant KRAS, HRAS, or NRAS protein by reaction with amino acids. Without wishing to be bound by theory, Applicants have found that in some embodiments, compounds of the present invention are formed by covalent bond formation with the cysteine at position 12 of the G12C mutant KRAS, HRAS, or NRAS protein. Are preferentially reactive with the G12C mutant KRAS, HRAS, or NRAS protein. By binding to cystine 12, the compounds of the present invention are able to trap the G12C mutant KRAS, HRAS, or NRAS switch II in an inactive phase. This inactive phase may differ from that seen with KRAS, HRAS, or NRAS bound to GTP and GDP. Some compounds of the invention can also disrupt the higher order structure of switch I. Some of the compounds of the invention prefer binding to KRAS, HRAS, or NRAS bound to GDP rather than GTP, thus making KRAS, HRAS, or NRAS inactive KRAS, HRAS, or NRAS GDP. Can be segregated into a combined state. Irreversible binding of these compounds can disrupt downstream signaling of KRAS, HRAS, or NRAS because effector binding to KRAS, HRAS, or NRAS is highly sensitive to the conformation of switches I and II .

（式中、
Ａは、ＮまたはＣであり；
Ｂは、オキソ、シアノ、アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクリル、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、ヘテロアリールアルキル、アミノ、アルキルアミノ、アリールアミノ、−ＣＯ_２Ｈ、−ＣＯＮＨ_２、アミニルカルボニル、アミニルカルボニルアルキル、ヘテロアリールアミノ、ハロ、ハロアルキル、アルコキシ、ハロアルコキシ、アリール、または−Ｘ−Ｌ^２−Ｒ^ａであり；
Ｘは、−ＮＲ^ｂ−または−Ｏ−であり；
Ｌ^１は、アルキレン、シクロアルキレン、ヘテロシクリレンであるか、または存在せず；
Ｌ^２は、アルキレンであるか、または存在せず；
Ｒは、Ｈ、シアノ、アミノ、ハロ、ハロアルキル、ヒドロキシル、シクロアルキル、ヘテロシクリル、ヘテロシクロアルキル、アリール、ヘテロアリール、−ＣＯ_２Ｈ、−ＣＯＮＨ_２、アミニルカルボニル、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６アルキルアミニル、またはＣ_１〜Ｃ_６アルコキシであり；
Ｒ^ａは、シクロアルキル、ヘテロシクリル、ヘテロアリール、−（Ｃ＝Ｏ）ＯＨ、−（Ｃ＝Ｏ）ＮＨ_２、または−（Ｃ＝Ｏ）ＮＨＯＨであり；
Ｒ^ｂは、各出現において独立して、ＨまたはＣ_１〜Ｃ_６アルキルであり；
Ｒ^１は、アリールまたはヘテロアリールであり；
Ｒ^２ａ、Ｒ^２ｂおよびＲ^２ｃは、それぞれ独立して、Ｈ、アミノ、シアノ、ハロ、ヒドロキシル、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６アルキルアミニル、−ＮＲ^ｂ（Ｃ＝Ｏ）Ｒ^ｂ、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６アルコキシ、Ｃ_３〜Ｃ_８シクロアルキル、ヘテロシクリルアルキル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_２〜Ｃ_６アルケニル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、アミニルカルボニル、ヘテロアリール、またはアリールであり；

は、全ての原子価を充足するような単結合または二重結合であり；
Ｅは、ＫＲＡＳ、ＨＲＡＳ、またはＮＲＡＳ Ｇ１２Ｃ変異体タンパク質の１２位のシステイン残基と共有結合を形成することができる求電子部分である）
またはその薬学的に許容され得る塩、立体異性体、もしくはプロドラッグを有する。 As described above, in one embodiment of the present invention, there is provided a compound having activity as a modulator of the G12C mutant KRAS, HRAS, or NRAS protein, which compound has the following structure (I):

(Where
A is N or C;
B is oxo, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl, amino, alkylamino, _arylamino, -CO 2 H, -CONH _2, aminyl carbonyl, aminyl carbonyl alkyl, heteroarylamino, halo, haloalkyl, alkoxy, haloalkoxy, aryl or ^-X-L 2 -R ^a,;
X is —NR ^b — or —O—;
L ¹ is alkylene, cycloalkylene, heterocyclylene, or absent;
L ² is alkylene or absent;
R is, H, cyano, amino, halo, haloalkyl, hydroxyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aryl, _heteroaryl, -CO 2 H, -CONH _2, aminyl _carbonyl, C 1 -C ₆ alkyl, C It is ₁ -C ₆ alkyl aminyl or _C 1 -C ₆ alkoxy;
R ^a is cycloalkyl, heterocyclyl, heteroaryl, — (C═O) OH, — (C═O) NH ₂ , or — (C═O) NHOH;
R ^b is independently at each occurrence H or C ₁ -C ₆ alkyl;
R ¹ is aryl or heteroaryl;
R ^2a , R ^2b and R ^2c are each independently H, amino, cyano, halo, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylaminyl, —NR ^b (C═O) R ^b, _C 1 -C _{6 haloalkyl,} C 1 -C _{6 alkoxy,} C 3 -C ₈ cycloalkyl, _{heterocyclylalkyl,} C 2 -C _{6 alkynyl,} C 2 -C ₆ alkenyl, aminyl alkyl, aminyl alkyl, Is cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl, or aryl;

Is a single or double bond that satisfies all valences;
E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of the KRAS, HRAS, or NRAS G12C variant protein)
Or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

は、全ての原子価を充足するような単結合または二重結合であり；
Ｅは、ＫＲＡＳ、ＨＲＡＳ、またはＮＲＡＳ Ｇ１２Ｃ変異体タンパク質の１２位のシステイン残基と共有結合を形成することができる求電子部分である。 In other embodiments of the compounds of structure (I):
A is N or C;
B is oxo, alkyl, cycloalkyl, heterocyclyl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl, amino, alkylamino, _arylamino, -CO 2 H, -CONH _2, aminyl carbonyl, aminyl carbonyl alkyl, heteroarylamino, halo, haloalkyl, alkoxy, haloalkoxy, aryl or ^-X-L 2 -R ^a,;
X is —NR ^b — or —O—;
L ¹ is alkylene, cycloalkylene, heterocyclylene, or absent;
L ² is alkylene or absent;
R is, H, cyano, amino, halo, haloalkyl, hydroxyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aryl, _heteroaryl, -CO 2 H, -CONH _2, aminyl _carbonyl, C 1 -C ₆ alkyl, C It is ₁ -C ₆ alkyl aminyl or _C 1 -C ₆ alkoxy;
R ^a is cycloalkyl, heterocyclyl, heteroaryl, — (C═O) OH, — (C═O) NH ₂ , or — (C═O) NHOH;
R ^b is independently at each occurrence H or C ₁ -C ₆ alkyl;
R ¹ is aryl or heteroaryl;
R ^2a , R ^2b , and R ^2c are each independently H, amino, halo, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylaminyl, —NR ^b (C═O) R ^b , _C 1 -C _{6 haloalkyl,} C 1 -C _{6 alkoxy,} C 3 -C ₈ cycloalkyl, _{heterocyclylalkyl,} C 2 -C _{6 alkynyl,} C 2 -C ₆ alkenyl, aminyl alkyl, aminyl alkyl, cyano Alkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl, or aryl;

Is a single or double bond that satisfies all valences;
E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of the KRAS, HRAS, or NRAS G12C mutant protein.

は、全ての原子価を充足するような単結合または二重結合であり；
Ｅは、ＫＲＡＳ、ＨＲＡＳ、またはＮＲＡＳ Ｇ１２Ｃ変異体タンパク質の１２位のシステイン残基と共有結合を形成することができる求電子部分である。 In other different embodiments of the compounds of structure (I)
A is N or C;
B is oxo, alkyl, cycloalkyl, heterocyclyl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, arylalkyl or ^-X-L 2 -R ^a,;
X is —NR ^b — or —O—;
L ¹ is alkylene, cycloalkylene, heterocyclylene, or absent;
L ² is alkylene or absent;
R is, H, cyano, _amino, C 1 -C _{6 alkyl,} C 1 -C ₆ alkyl aminyl or _C 1 -C ₆ alkoxy;
R ^a is cycloalkyl, heterocyclyl, heteroaryl, — (C═O) OH, — (C═O) NH ₂ , or — (C═O) NHOH;
R ^b is H or C ₁ -C ₆ alkyl;
R ¹ is aryl or heteroaryl;
R ^2a , R ^2b , and R ^2c are each independently H, amino, halo, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylaminyl, —NR ^b (C═O) R ^b C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl, heteroaryl, or aryl;

Is a single or double bond that satisfies all valences;
E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of the KRAS, HRAS, or NRAS G12C mutant protein.

In some embodiments, B is cycloalkyl, heterocyclyl, or heteroaryl. In other embodiments, L ¹ is alkylene or absent.

（式中、
Ｇ^１は、ＮまたはＣＨであり；
Ｇ^２は、ＮＲ^ｃまたはＣＨＲ^ｃであり；
Ｒ^ｃは、Ｈ、アルキル、アルキルカルボニル、アミノカルボニル、アルキルカルボニルアミニル、アミノカルボニルアミニル、またはヘテロアリールカルボニルであり；
Ｒ^３ａおよびＲ^３ｂは、各出現において独立して、Ｈ、−ＯＨ、−ＮＨ_２、−ＣＯ_２Ｈ、ハロ、シアノ、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキニル、ヒドロキシルアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、またはアミニルカルボニルであるか；あるいはＲ^３ａとＲ^３ｂとが一緒になって、オキソ、炭素環式環、または複素環式環を形成するか；あるいはＲ^３ａは、Ｈ、−ＯＨ、−ＮＨ_２、−ＣＯ_２Ｈ、ハロ、シアノ、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキニル、ヒドロキシルアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、またはアミニルカルボニルであり、Ｒ^３ｂは、Ｒ^４ｂと一緒になって、炭素環式環または複素環式環を形成し；
Ｒ^４ａおよびＲ^４ｂは、各出現において独立して、Ｈ、−ＯＨ、−ＮＨ_２、−ＣＯ_２Ｈ、ハロ、シアノ、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキニル、ヒドロキシルアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、またはアミニルカルボニルであるか；あるいはＲ^４ａとＲ^４ｂとが一緒になって、オキソ、炭素環式環、または複素環式環を形成するか；あるいはＲ^４ａは、Ｈ、−ＯＨ、−ＮＨ_２、−ＣＯ_２Ｈ、ハロ、シアノ、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキニル、ヒドロキシルアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、またはアミニルカルボニルであり、Ｒ^４ｂは、Ｒ^３ｂと一緒になって、炭素環式環または複素環式環を形成し；
ｍ^１およびｍ^２は、それぞれ独立して、１、２、または３であり；
ｎは、０〜５の整数である）
を有する。 In some other of the foregoing embodiments, B is cycloalkyl or heterocyclyl, for example, in some embodiments, the compound has the following structure (IA):

(Where
G ¹ is N or CH;
G ² is NR ^c or CHR ^c ;
R ^c is H, alkyl, alkylcarbonyl, aminocarbonyl, alkylcarbonylaminyl, aminocarbonylaminyl, or heteroarylcarbonyl;
R ^3a and R ^3b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C. ₆ haloalkoxy, C ₂ -C ₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl; or R ^3a and R ^{3 3b} together form an oxo, carbocyclic or heterocyclic ring; or R ^3a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkynyl, hydroxyalkyl, A Lucoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl, R ^3b together with R ^4b is a carbocyclic or heterocyclic ring Forming a formula ring;
R ^4a and R ^4b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C. ₆ haloalkoxy, C ₂ -C ₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl; or R ^4a and R ^{4 4b} together form an oxo, carbocyclic or heterocyclic ring; or R ^4a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkynyl, hydroxyalkyl, A Lucoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl, R ^4b together with R ^3b is a carbocyclic or heterocyclic ring Forming a formula ring;
m ¹ and m ² are each independently 1, 2, or 3;
n is an integer of 0 to 5)
Have

In other embodiments of structure (IA),
R ^3a and R ^3b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, hydroxylalkyl. ), Alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl; or R ^3a and R ^{3b taken} together to form a carbocyclic ring Or forms a heterocyclic ring; or R ^3a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, hydroxylalkyl, Alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxy Alkyl, aminylcarbonylalkyl, or aminylcarbonyl, and R ^3b together with R ^4b forms a carbocyclic or heterocyclic ring;
R ^4a and R ^4b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, hydroxyl alkyl, alkoxy Alkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl; or R ^4a and R ^{4b taken} together to form a carbocyclic or heterocyclic ring Or R ^4a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, hydroxyl alkyl, alkoxyalkyl, Aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonyla Ryl or aminylcarbonyl, R ^4b together with R ^3b forms a carbocyclic or heterocyclic ring.

（式中、ｐ^１は、０〜３の整数である）を有する。 In other embodiments, the compound has the following structure (IAa) or (IAb):

(Wherein p ¹ is an integer from 0 to 3).

のうちの１つを有する。 In still different embodiments, the compound has the following structure (IAc), (IAd), or (IAe):

One of them.

In other embodiments of the foregoing embodiments, R ^c is alkylcarbonyl, aminocarbonyl, alkylcarbonylaminyl, aminocarbonylaminyl, or heteroarylcarbonyl, for example, in some embodiments, the alkylcarbonyl Is substituted with aminocarbonyl, hydroxylaminocarbonyl, hydroxyl, or amino.

（式中、ｐ^２は、１〜３の整数である）のうちの１つを有する。 In other embodiments, R ^c has the following structure:

(Wherein p ² is an integer from 1 to 3).

のうちの１つを有する。 In other embodiments, R ^c has the following structure:

One of them.

In several different embodiments, B is alkyl, cycloalkyl alkyl, heterocycloalkyl, heteroarylalkyl, or ^-X-L 2 -R ^a,. For example, in some embodiments, B is ^-X-L 2 -R ^a. In other embodiments, R ^a is heterocyclyl or heteroaryl.

In various other embodiments, L ¹ is alkylene or absent. In some embodiments, L ¹ is alkylene. In other embodiments, L ¹ is absent.

（式中、
Ｈは、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^４ａ、およびＲ^４ｂの１つまたはそれよりも多くで任意選択的に置換される５または６員のヘテロアリール環を示し；
Ｇ^１は、ＮまたはＣＨであり；
Ｇ^２は、ＮＲ^ｃまたはＣＨＲ^ｃであり；
Ｒ^ｃは、Ｈ、アルキル、アルキルカルボニル、アミノカルボニル、アルキルカルボニルアミニル、アミノカルボニルアミニル、またはヘテロアリールカルボニルであり；
Ｒ^３ａおよびＲ^３ｂは、各出現において独立して、Ｈ、−ＯＨ、−ＮＨ_２、−ＣＯ_２Ｈ、ハロ、シアノ、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキニル、ヒドロキシルアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、またはアミニルカルボニルであるか；あるいはＲ^３ａとＲ^３ｂとが一緒になって、オキソ、炭素環式環、または複素環式環を形成するか；あるいはＲ^３ａは、Ｈ、−ＯＨ、−ＮＨ_２、−ＣＯ_２Ｈ、ハロ、シアノ、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキニル、ヒドロキシルアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、またはアミニルカルボニルであり、Ｒ^３ｂは、Ｒ^４ｂと一緒になって、炭素環式環または複素環式環を形成し；
Ｒ^４ａおよびＲ^４ｂは、各出現において独立して、Ｈ、−ＯＨ、−ＮＨ_２、−ＣＯ_２Ｈ、ハロ、シアノ、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキニル、ヒドロキシルアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、またはアミニルカルボニルであるか；あるいはＲ^４ａとＲ^４ｂとが一緒になって、オキソ、炭素環式環、または複素環式環を形成するか；あるいはＲ^４ａは、Ｈ、−ＯＨ、−ＮＨ_２、−ＣＯ_２Ｈ、ハロ、シアノ、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキニル、ヒドロキシルアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、またはアミニルカルボニルであり、Ｒ^４ｂは、Ｒ^３ｂと一緒になって、炭素環式環または複素環式環を形成し；
ｍ^１およびｍ^２は、それぞれ独立して、１、２、または３であり；
ｎは、０〜５の整数である）
のうちの１つを有する。 In some embodiments, B is ^{-X-L 2 -R a, L} 1 is either alkylene or absent, for example, in some embodiments, the compound has the following structure (IB) or (IC):

(Where
H represents a 5- or 6-membered heteroaryl ring optionally substituted with one or more of R ^3a , R ^3b , R ^4a , and R ^4b ;
G ¹ is N or CH;
G ² is NR ^c or CHR ^c ;
R ^c is H, alkyl, alkylcarbonyl, aminocarbonyl, alkylcarbonylaminyl, aminocarbonylaminyl, or heteroarylcarbonyl;
R ^3a and R ^3b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C. ₆ haloalkoxy, C ₂ -C ₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl; or R ^3a and R ^{3 3b} together form an oxo, carbocyclic or heterocyclic ring; or R ^3a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkynyl, hydroxyalkyl, A Lucoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl, R ^3b together with R ^4b is a carbocyclic or heterocyclic ring Forming a formula ring;
R ^4a and R ^4b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C. ₆ haloalkoxy, C ₂ -C ₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl; or R ^4a and R ^{4 4b} together form an oxo, carbocyclic or heterocyclic ring; or R ^4a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkynyl, hydroxyalkyl, A Lucoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl, R ^4b together with R ^3b is a carbocyclic or heterocyclic ring Forming a formula ring;
m ¹ and m ² are each independently 1, 2, or 3;
n is an integer of 0 to 5)
One of them.

In other embodiments of structures (IB) and (IC)
R ^3a and R ^3b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, hydroxyl alkyl, alkoxy Alkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl; or R ^3a and R ^{3b taken} together to form a carbocyclic or heterocyclic ring Or R ^3a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, hydroxyl alkyl, alkoxyalkyl, Aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonyla Alkyl or aminylcarbonyl, and R ^3b together with R ^4b forms a carbocyclic or heterocyclic ring;
R ^4a and R ^4b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, hydroxyl alkyl, alkoxy Alkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl; or R ^4a and R ^{4b taken} together to form a carbocyclic or heterocyclic ring Or R ^4a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, hydroxyl alkyl, alkoxyalkyl, Aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonyla Ryl or aminylcarbonyl, R ^4b together with R ^3b forms a carbocyclic or heterocyclic ring.

  In some embodiments, H is pyrrolidinyl or pyridinyl.

（式中、Ｒ^ｄは、各出現において独立して、Ｈ、ハロ、またはヒドロキシルであり、ｐ^３は、０〜３の整数である）のうちの１つを有する。 In other embodiments, the compound has the following structure (IBa) or (IBb):

Wherein R ^d is independently at each occurrence H, halo, or hydroxyl, and p ³ is an integer from 0 to 3.

のうちの１つを有する。 In still different embodiments, the compound has the following structure (IBc), (IBd), (IBe), or (IBf):

One of them.

  In some of the foregoing embodiments, X is —NH—. In some of the other aforementioned embodiments, X is —O—.

のうちの１つを有する。 In still other embodiments, B has the following structure:

One of them.

（式中、ｐ^３は、０〜３の整数である）を有する。 In other embodiments, B is ^-X-L 2 -R ^a, the compound has the following structure (ID):

(Wherein p ³ is an integer from 0 to 3).

In the foregoing embodiments, R ^a is — (C═O) OH, — (C═O) NH ₂ , or — (C═O) NHOH.

を有する。 In yet another embodiment, the compound has the following structure (IDa):

Have

  In some embodiments of compound (ID) or (IDa), X is —NH—. In some other embodiments of compound (ID) or (IDa), X is —O—.

Above In some of the embodiments, B is an alkyl, for example, in some embodiments, the alkyl is, - (C = O) OH , - (C = O) NH 2 or - (C = O) Substituted with NHOH.

  In other different embodiments, B is heteroarylalkyl. In some of these embodiments, the heteroarylalkyl is pyrrolidinylalkyl or pyridinylalkyl.

（式中、
Ｇ^１は、ＣＨであり；
Ｇ^２は、ＮまたはＣＨであり；
Ｒ^３ａおよびＲ^３ｂは、各出現において独立して、Ｈ、−ＯＨ、−ＮＨ_２、−ＣＯ_２Ｈ、ハロ、シアノ、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキニル、ヒドロキシルアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、またはアミニルカルボニルであるか；あるいはＲ^３ａとＲ^３ｂとが一緒になって、オキソ、炭素環式環、または複素環式環を形成するか；あるいはＲ^３ａは、Ｈ、−ＯＨ、−ＮＨ_２、−ＣＯ_２Ｈ、ハロ、シアノ、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキニル、ヒドロキシルアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、またはアミニルカルボニルであり、Ｒ^３ｂは、Ｒ^４ｂと一緒になって、炭素環式環または複素環式環を形成し；
Ｒ^４ａおよびＲ^４ｂは、各出現において独立して、Ｈ、−ＯＨ、−ＮＨ_２、−ＣＯ_２Ｈ、ハロ、シアノ、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキニル、ヒドロキシルアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、またはアミニルカルボニルであるか；あるいはＲ^４ａとＲ^４ｂとが一緒になって、オキソ、炭素環式環、または複素環式環を形成するか；あるいはＲ^４ａは、Ｈ、−ＯＨ、−ＮＨ_２、−ＣＯ_２Ｈ、ハロ、シアノ、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_１〜Ｃ_６ハロアルコキシ、Ｃ_２〜Ｃ_６アルキニル、ヒドロキシルアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、またはアミニルカルボニルであり、Ｒ^４ｂは、Ｒ^３ｂと一緒になって、炭素環式環または複素環式環を形成し；
ｍ^１およびｍ^２は、それぞれ独立して、１、２、または３である）
を有する。 In still other embodiments, B is oxo. In other embodiments, L ¹ is heterocyclylene. In a further embodiment, B is oxo and L ¹ is heterocyclylene. For example, in some embodiments, the compound has the following structure (IE):

(Where
G ¹ is CH;
G ² is N or CH;
R ^3a and R ^3b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C. ₆ haloalkoxy, C ₂ -C ₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl; or R ^3a and R ^{3 3b} together form an oxo, carbocyclic or heterocyclic ring; or R ^3a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkynyl, hydroxyalkyl, A Lucoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl, R ^3b together with R ^4b is a carbocyclic or heterocyclic ring Forming a formula ring;
R ^4a and R ^4b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C. ₆ haloalkoxy, C ₂ -C ₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl; or R ^4a and R ^{4 4b} together form an oxo, carbocyclic or heterocyclic ring; or R ^4a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkynyl, hydroxyalkyl, A Lucoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl, R ^4b together with R ^3b is a carbocyclic or heterocyclic ring Forming a formula ring;
m ¹ and m ² are each independently 1, 2, or 3)
Have

In other embodiments of the compounds of structure (IE):
R ^3a and R ^3b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, hydroxyl alkyl, alkoxy Alkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl; or R ^3a and R ^{3b taken} together to form a carbocyclic or heterocyclic ring Or R ^3a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, hydroxyl alkyl, alkoxyalkyl, Aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonyla Alkyl or aminylcarbonyl, and R ^3b together with R ^4b forms a carbocyclic or heterocyclic ring;
R ^4a and R ^4b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, hydroxyl alkyl, alkoxy Alkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl; or R ^4a and R ^{4b taken} together to form a carbocyclic or heterocyclic ring Or R ^4a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, hydroxyl alkyl, alkoxyalkyl, Aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonyla Ryl or aminylcarbonyl, R ^4b together with R ^3b forms a carbocyclic or heterocyclic ring.

のうちの１つを有する。 In other embodiments, the compound has the following structure (IEa), (IEb), (IEc), or (IEd):

One of them.

のうちの１つを有する。 In some different embodiments, the compound has the following structure (IEe), (IEf), (IEg), (IEh); (IEi) or (of) (IEj):

One of them.

を有する。 In some different embodiments, the compound has the following structure (IEl):

Have

Without wishing to be bound by theory, Applicants believe that the correct choice of R ¹ substituent may play a role in the inhibitory activity of a compound (eg, against K12, HRAS, or NRAS G12C). In some embodiments, R ¹ is aryl or heterocyclyl (eg, heteroaryl or aliphatic heterocyclyl), each of which is optionally substituted with one or more substituents. In some other embodiments, R ¹ is aryl or heteroaryl. In some embodiments, R ¹ can interact reversibly with a KRAS, HRAS, or NRAS G12C variant protein. In some embodiments, R ¹ has a high affinity for KRAS, HRAS, or NRAS and exhibits a high specificity for K12, HRAS, or NRAS of G12C. In some embodiments, R ¹ can interact hydrophobically with KRAS, HRAS, or NRAS G12C. In some embodiments, R ¹ can form hydrogen bonds with various residues of the G12C KRAS, HRAS, or NRAS protein.

In any of the foregoing embodiments, R ¹ is aryl. For example, in some embodiments, R ¹ is phenyl, and in other embodiments, R ¹ is naphthyl. R ¹ is substituted or unsubstituted. In some specific embodiments, R ¹ is substituted with one or more substituents. In some embodiments, R ¹ is halo, amino, hydroxyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cyano, C ₁ -C ₆ haloalkyl, C _1- C ₆ alkoxy, alkyl aminyl, cycloalkyl, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylthio luer mini Le, cycloalkyl aminyl, aryl, heteroaryl, phosphate, Hosuhoarukokishi, boronic acid, boronic acid ester, -OC (= O) R Or substituted with C ₁ -C ₆ alkylcarbonyloxy, or a combination thereof, wherein R is C ₁ -C ₆ alkyl. For example, in some embodiments, R ¹ is halo, amino, hydroxyl, C ₁ -C ₆ alkyl, cyano, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, alkylaminyl, cycloalkyl, heterocyclyl. Alkyl, aryl, heteroaryl, phosphate, phosphoalkoxy, boronic acid, boronic ester, —OC (═O) R, or C ₁ -C ₆ alkylcarbonyloxy, or a combination thereof, wherein R is C ₁ is substituted with -C ₆ alkyl is (alky)). In other embodiments, R ¹ is halo, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ alkylcarbonyloxy, or combinations thereof Replaced. In different embodiments, R ¹ is substituted with fluoro, chloro, cyclopropyl, cyclobutyl, hydroxyl, amino, methyl, ethyl, isopropyl, trifluoromethyl, or methoxy, or combinations thereof. In some still further embodiments, R ¹ is substituted with fluoro, hydroxyl, methyl, isopropyl, trifluoromethyl, or methoxy, or combinations thereof.

のうちの１つ、例えば、

を有する。 In some more specific embodiments, R ¹ has the following structure:

One of the

Have

In several different embodiments of the foregoing compounds, R ¹ is heteroaryl, eg, heteroaryl containing nitrogen. In other embodiments, R ¹ is indazolyl or quinolinyl. In a further embodiment, R ¹ is heteroaryl substituted with one or more substituents. For example, in certain embodiments, R ¹ is substituted with hydroxyl or C ₁ -C ₆ alkyl, or both.

のうちの１つ、例えば、

を有する。 In some other embodiments, R ¹ has the following structure:

One of the

Have

In some of the foregoing embodiments, R ^2c is H. In any other of the foregoing embodiments, R ^2a and R ^2b are each halo. For example, in some embodiments, R ^2a is fluoro and in other embodiments, R ^2b is chloro.

In other embodiments, R ^2a and R ^2b are each independently halo, haloalkyl, alkyl, amino, hydroxyl, or alkoxy. In other embodiments, R ^2a and R ^2b are each independently halo, haloalkyl, alkyl, or alkoxy. In some embodiments, R ^2a is fluoro, chloro, CF ₃ , or methoxy. In some embodiments, R ^2a is fluoro, chloro, or methoxy. In different embodiments, R ^2b is chloro, fluoro, amino, hydroxyl, or CF ₃ . In yet other different embodiments, R ^2b is chloro, fluoro, or CF ₃ .

を有する。 In some more specific embodiments, the compound has the following structure (IF):

Have

のうちの１つを有する。 For example, in a still further different embodiment, the compound has the following structure (IFa) or (IFb):

One of them.

  In any of the foregoing embodiments, R is H.

は、全ての原子価を充足するような単結合である。他の異なる実施形態では、

は、全ての原子価を充足するような二重結合である。 In some other of the above embodiments,

Is a single bond that satisfies all valences. In other different embodiments,

Is a double bond that satisfies all valences.

  In some embodiments, A is N. In other embodiments, A is C.

  As long as it can form a covalent bond with a nucleophile such as a cysteine residue at position 12 of a KRAS, HRAS, or NRAS G12C variant protein, the structure of E in all embodiments described herein is There is no particular limitation. Thus, an E moiety that can react with a nucleophile (eg, by covalent bond formation) is preferred. In certain embodiments, E can react with a nucleophile that exhibits adequate reactivity in a conjugate addition mode (eg, 1,4-conjugated addition). In some embodiments, E includes a conjugated π bond such that electron delocalization yields at least one atom (eg, a carbon atom) having a positive charge, a partial positive charge, or a polarization bond. . In other embodiments, E has an electronegativity of two atoms forming a bond such that a partial positive charge is present on one atom (eg, on a carbon atom) (eg, due to the polarization of the bond). Includes one or more bonds that are sufficiently different. E moieties that include carbon-halogen bonds, carbon-oxygen bonds, or carbon bonds to various leaving groups known in the art are examples of such E moieties.

（式中、
Ｑは、−Ｃ（＝Ｏ）−、−Ｃ（＝ＮＲ^８’）−、−ＮＲ^８Ｃ（＝Ｏ）−、−Ｓ（＝Ｏ）_２−、または−ＮＲ^８Ｓ（＝Ｏ）_２−であり；
Ｒ^８は、Ｈ、Ｃ_１〜Ｃ_６アルキル、またはヒドロキシルアルキルであり；
Ｒ^８’は、Ｈ、−ＯＨ、−ＣＮ、またはＣ_１〜Ｃ_６アルキルであり；
Ｒ^９およびＲ^１０は、それぞれ独立して、Ｈ、ハロ、シアノ、カルボキシル、Ｃ_１〜Ｃ_６アルキル、アルコキシカルボニル、アミニルアルキル、アルキルアミニルアルキル、アリール、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、またはヒドロキシルアルキルであるか、あるいはＲ^９とＲ^１０とが一緒になって、炭素環式環、複素環式環、またはヘテロアリール環を形成する）
を有する。 Thus, in any of the foregoing embodiments, E is the following structure:

(Where
Q is —C (═O) —, —C (═NR ^{8 ′} ) —, —NR ⁸ C (═O) —, —S (═O) ₂ —, or —NR ⁸ S (═O) _2. -Is;
R ⁸ is H, C ₁ -C ₆ alkyl, or hydroxyl alkyl;
R ^{8 ′} is H, —OH, —CN, or C ₁ -C ₆ alkyl;
R ⁹ and R ¹⁰ are each independently H, halo, cyano, carboxyl, C ₁ -C ₆ alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl, or Is hydroxylalkyl or R ⁹ and R ¹⁰ together form a carbocyclic, heterocyclic or heteroaryl ring)
Have

（式中、
Ｑは、−Ｃ（＝Ｏ）−、−ＮＲ^８Ｃ（＝Ｏ）−、−Ｓ（＝Ｏ）_２−、または−ＮＲ^８Ｓ（＝Ｏ）_２−であり；
Ｒ^８は、Ｈ、Ｃ_１〜Ｃ_６アルキル、またはヒドロキシルアルキルであり；
Ｒ^１０は、Ｈ、Ｃ_１〜Ｃ_６アルキル、アミニルアルキル、アルキルアミニルアルキル、またはヒドロキシルアルキルである）
を有する。 In still other embodiments of any of the foregoing embodiments, E has the following structure:

(Where
Q is —C (═O) —, —NR ⁸ C (═O) —, —S (═O) ₂ —, or —NR ⁸ S (═O) ₂ —;
R ⁸ is H, C ₁ -C ₆ alkyl, or hydroxyl alkyl;
R ¹⁰ is H, C ₁ -C ₆ alkyl, aminylalkyl, alkylaminylalkyl, or hydroxylalkyl)
Have

The Q moiety is typically selected to optimize the reactivity (ie, electrophilicity) of E. In some of the foregoing embodiments, Q is —C (═O) —, —NR ⁸ C (═O) —, —S (═O) ₂ —, or —NR ⁸ S (═O). _2- . In certain such embodiments, Q is -C (= O)-. In other embodiments, Q is —S (═O) ₂ —. In still further embodiments, Q is —NR ⁸ C (═O) —. In yet a different embodiment, Q is —NR ⁸ S (═O) ₂ —.

In some other embodiments of the foregoing embodiments, Q is —C (═NR ^{8 ′} ) —, where R ^{8 ′} is H, —OH, —CN, or C ₁ -C ₆ alkyl). For example, in some embodiments, R ^{8 ′} is H. In other embodiments, R ^{8 ′} is —CN. In other embodiments, R ^{8 ′} is —OH.

In some of the foregoing embodiments, R ⁸ is H. In other embodiments of these embodiments, R ⁸ is hydroxylalkyl, for example, in some embodiments, the hydroxylalkyl is 2-hydroxylalkyl.

In some of any one of the foregoing embodiments, at least one of R ⁹ or R ¹⁰ is H. For example, in some embodiments, R ⁹ and R ¹⁰ are each H.

を有する。 In other embodiments of the aforementioned embodiments, R ¹⁰ is alkylaminylalkyl. In some of these embodiments, R ¹⁰ has the following structure:

Have

In other embodiments, R ¹⁰ is hydroxylalkyl (such as 2-hydroxylalkyl).

を有するフェニル環である。 In some other different embodiments of the foregoing embodiment, R ⁹ and R ¹⁰ are taken together to form a carbocyclic ring. For example, in some of these embodiments, the carbocyclic ring is a cyclopentene ring, a cyclohexene ring, or a phenyl ring. In other embodiments, the carbocyclic ring is a cyclopentene ring or a cyclohexene ring. In other embodiments, the carbocyclic ring is a phenyl ring, eg, the structure:

It is a phenyl ring having

のうちの１つを有する。 In some of any of the previous embodiments, E is an electrophile capable of binding to a KRAS, HRAS, or NRAS protein that includes a G12C mutation. In some embodiments, electrophile E can form an irreversible covalent bond with the G12C mutant KRAS, HRAS, or NRAS protein. In some cases, electrophile E can bind to the cysteine residue at position 12 of the G12C mutant KRAS, HRAS, or NRAS protein. In various embodiments of any of the foregoing, E is the structure:

One of them.

のうちの１つを有する。 In some embodiments, E has the following structure:

One of them.

のうちの１つを有する。 In any other embodiment of the foregoing, E is of the structure:

One of them.

のうちの１つを有する。 In a different embodiment, E has the following structure:

One of them.

（式中、
Ｒ^８は、ＨまたはＣ_１〜Ｃ_６アルキルであり；
Ｒ^９は、Ｈ、シアノ、またはＣ_１〜Ｃ_６アルキルであるか、あるいはＲ^９は、Ｒ^１０と一緒になって、炭素環を形成し；
Ｒ^１０は、ＨまたはＣ_１〜Ｃ_６アルキルであるか、あるいはＲ^１０は、Ｒ^９と一緒になって、炭素環を形成し、
Ｒ^１０ａは、ＨまたはＣ_１〜Ｃ_６アルキルである）
のうちの１つを有する。 In some cases, E has the following structure:

(Where
R ⁸ is H or C ₁ -C ₆ alkyl;
R ⁹ is H, cyano, or C ₁ -C ₆ alkyl, or R ⁹ together with R ¹⁰ forms a carbocycle;
R ¹⁰ is H or C ₁ -C ₆ alkyl, or R ¹⁰ together with R ⁹ forms a carbocycle;
R ^10a is H or C ₁ -C ₆ alkyl)
One of them.

である。いくつかの実施形態では、Ｅは、

である。いくつかの実施形態では、Ｅは、

である。 In some embodiments, E is

It is. In some embodiments, E is

It is. In some embodiments, E is

It is.

In certain embodiments, R ^3a and R ^3b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, hydroxylalkyl, aminylalkyl, cyanoalkyl, carboxyalkyl. Or R ^4a and R ^4b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, hydroxylalkyl, aminylalkyl, cyanoalkyl, Carboxyalkyl or aminylcarbonyl.

In other embodiments of the foregoing embodiments, R ^3a and R ^4a are independently at each occurrence H, —OH, hydroxylalkyl, cyano, or aminylcarbonyl, and R ^3b and R ^4b are H It is.

In certain other embodiments, R ^3a and R ^4a are H, and R ^3b and R ^4b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano. , Hydroxylalkyl, aminylalkyl, cyanoalkyl, carboxyalkyl, or aminylcarbonyl.

In any of the foregoing embodiments, at least one of R ^3a , R ^3b , R ^4a , or R ^4b is H. In some embodiments, each of R ^3a , R ^3b , R ^4a , and R ^4b is H.

In other embodiments of the foregoing embodiments, R ^3a and R ^4a are independently at each occurrence H or C ₁ -C ₆ alkyl, provided that at least one of R ^3a or R ^4a is , C ₁ -C ₆ alkyl. In some embodiments, at least one of R ^3a , R ^4a , R ^3b , and R ^4b is independently C ₁ -C ₆ alkyl (such as methyl). In some embodiments, one occurrence of R ^3a is C ₁ -C ₆ alkyl (such as methyl) and the remaining R ^3a and each R ^4a is H. In some other embodiments, two occurrences of R ^3a are C ₁ -C ₆ alkyl (such as methyl) and the remaining R ^3a and each R ^4a is H. In some other embodiments, one occurrence of R ^3a and one occurrence of R ^4a are independently C ₁ -C ₆ alkyl (such as methyl) and the remaining R ^3a and R ^4a are Each is H.

In some embodiments, R ^3a is —OH, —NH ₂ , —CO ₂ H, halo, cyano, hydroxylalkyl, aminylalkyl, cyanoalkyl, carboxyalkyl, or aminylcarbonyl, and R ^3b , R ^4a and R ^4b are H.

In other embodiments, R ^4a is —OH, —NH ₂ , —CO ₂ H, halo, cyano, hydroxylalkyl, aminylalkyl, cyanoalkyl, carboxyalkyl, or aminylcarbonyl; ^3a , R ^3b , and R ^4b are H.

In other embodiments, R ^3a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, hydroxylalkyl, aminylalkyl, cyanoalkyl, carboxyalkyl, or aminylcarbonyl, and R ^3b Together with R ^4b form a carbocyclic or heterocyclic ring;

In still further embodiments, R ^4a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, hydroxylalkyl, aminylalkyl, cyanoalkyl, carboxyalkyl, or aminylcarbonyl, and R ^4b Together with R ^3b form a carbocyclic or heterocyclic ring.

In other embodiments, R ^3a and R ^3b are taken together to form a carbocyclic or heterocyclic ring. In other embodiments, R ^4a and R ^4b are taken together to form a carbocyclic or heterocyclic ring.

である。他の実施形態では、Ｒ^３ａまたはＲ^４ａは、シアノである。他の実施形態では、Ｒ^３ａまたはＲ^４ａは、−ＯＨである。他の実施形態では、Ｒ^３ａまたはＲ^４ａは、ヒドロキシルアルキル、例えば、ヒドロキシルメチルである。 In still other embodiments, R ^3a or R ^4a is aminylcarbonyl. For example, in certain embodiments, aminylcarbonyl is

It is. In other embodiments, R ^3a or R ^4a is cyano. In other embodiments, R ^3a or R ^4a is —OH. In other embodiments, R ^3a or R ^4a is hydroxylalkyl, such as hydroxylmethyl.

In some embodiments of any of the foregoing compounds, R ¹ is aryl or heteroaryl and R ^2a , R ^2b , and R ^2c are independently selected from H and halo, eg, any number In certain further embodiments, R ¹ is aryl or heteroaryl, R ^2a and R ^2b are independently selected from halo (such as chloro and fluoro), and R ^2c is H. In some embodiments, R ¹ is aryl or heteroaryl, R ^2a is chloro, R ^2b is fluoro, and R ^2c is H. In other embodiments, R ¹ is aryl or heteroaryl, one of R ^2a or R ^2b is halo (such as chloro or fluoro), and the other one of R ^2a or R ^2b. One is H.

In some embodiments, m ¹ is 1. In another embodiment, m ¹ is 2. In still further embodiments, m ¹ is 3. In different embodiments, m ² is 1. In some other embodiments, m ² is 2. In still further embodiments, m ² is 3.

In some other specific embodiments of any of the foregoing compounds, m ¹ is 1 and m ² is 1. In another embodiment, m ¹ is 1 and m ² is 2. In still other embodiments, m ¹ is 2 and m ² is 2. In a further embodiment, m ¹ is 1 and m ² is 3.

  Some embodiments of the compounds include more than one stereoisomer. Other embodiments relate to a single stereoisomer. In some embodiments, the compound is a racemate (eg, a mixture of atropisomers), while in other embodiments, the compound is substantially a single isomer, eg, substantially purified. Atropisomers.

In various different embodiments, the compound has one of the structures described in Table 1 below. Each of the compounds in Table 1 was prepared and analyzed by mass spectrometry and / or ¹ H NMR. Experimental mass spectrometry data is included in Table 1. Exemplary synthetic procedures are described in detail below and in the examples. General methods by which the compounds can be prepared are provided below and are shown in Table 1.

  In the present description, it is understood that combinations of substituents and / or variations of the described formula are acceptable only if such a contribution results in a stable compound.

  In addition, all compounds of the present invention that exist in the form of the free base or free acid can be converted to their pharmaceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid by methods known to those skilled in the art. Can be converted. Salts of the compounds of the invention can be converted to their free base or free acid forms by standard techniques.

（式中、Ｒ、Ｒ^１、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃ、Ａ、Ｂ、Ｌ^１、およびＥは本明細書中に定義の通りである）の化合物の化合物またはその薬学的に許容され得る塩、立体異性体、もしくはプロドラッグを作製する例示的な方法を例示している。当業者は、類似の方法によって、または当業者に公知の他の方法を組み合わせることによって、これらの化合物を作製することができ得ると理解される。当業者は、下記に具体的に例示されない構造（Ｉ）の他の化合物を、適切な出発成分を使用し、必要に応じて合成のパラメータを改変することによって、下記に記載されるものと同様の様式で、作製することができるとも理解される。一般に、出発成分を、Ｓｉｇｍａ Ａｌｄｒｉｃｈ、Ｌａｎｃａｓｔｅｒ Ｓｙｎｔｈｅｓｉｓ，Ｉｎｃ．、Ｍａｙｂｒｉｄｇｅ、Ｍａｔｒｉｘ Ｓｃｉｅｎｔｉｆｉｃ、ＴＣＩ、およびＦｌｕｏｒｏｃｈｅｍ ＵＳＡなどの供給者から入手することができるか、当業者に公知の情報源にしたがって合成することができるか（例えば、Ａｄｖａｎｃｅｄ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ：Ｒｅａｃｔｉｏｎｓ，Ｍｅｃｈａｎｉｓｍｓ，ａｎｄ Ｓｔｒｕｃｔｕｒｅ，５ｔｈ ｅｄｉｔｉｏｎ（Ｗｉｌｅｙ，Ｄｅｃｅｍｂｅｒ ２０００）を参照のこと）、または本発明に記載のように調製することができる。 The following general reaction scheme is the structure (I):

Wherein R, R ¹ , R ^2a , R ^2b , R ^2c , A, B, L ¹ , and E are as defined herein, or a pharmaceutically acceptable salt thereof Illustrates exemplary methods of making the resulting salts, stereoisomers, or prodrugs. Those skilled in the art will appreciate that these compounds can be made by similar methods or by combining other methods known to those skilled in the art. Those skilled in the art will recognize other compounds of structure (I) not specifically exemplified below as described below by using appropriate starting components and modifying the parameters of the synthesis as necessary. It is also understood that it can be made in the manner of: In general, starting components are obtained from Sigma Aldrich, Lancaster Synthesis, Inc. , Maybridge, Matrix Scientific, TCI, and Fluorochem USA, or can be synthesized according to sources known to those skilled in the art (eg, Advanced Organic Chemistry: Reactions, Machinery: Structure, 5th edition (see Wiley, December 2000)), or as described in the present invention.

構造（Ｉ）の化合物の実施形態（例えば、化合物Ａ−６）（式中、Ｒ^１、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃ、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^４ａ、Ｒ^４ｂ、Ｒ^９、Ｒ^１０、Ｑ、ｍ^１、およびｍ^２は本明細書中に定義の通りである）を、一般的反応スキーム１（「方法Ａ」）にしたがって調製することができる。一般的反応スキーム１に関して、構造Ａ−１の化合物を商業的供給源から購入するか、または当該分野で公知の技術にしたがって調製する。所望のＲ^１置換基をＳｕｚｕｋｉカップリングによってＡ−１に付加してＡ−２を生成する。Ａ−２を試薬（ホルムアミジン酢酸塩など）で環化することによりキナゾリノンＡ−３を得る。Ａ−３を、適切に置換された環式基および活性化剤（ＨＡＴＵなど）で処理してＡ−４を得て、次いでそれを酸で処理することによって脱保護することができる。次いで、「Ｅ」部分を当該分野で公知の条件下で導入して、Ａ−６を生成する。

An embodiment of a compound of structure (I) (eg, compound A-6) wherein R ¹ , R ^2a , R ^2b , R ^2c , R ^3a , R ^3b , R ^4a , R ^4b , R ⁹ , R ¹⁰ , Q, m ¹ , and m ² are as defined herein) can be prepared according to General Reaction Scheme 1 (“Method A”). With respect to general reaction scheme 1, compounds of structure A-1 are purchased from commercial sources or prepared according to techniques known in the art. The desired R ¹ substituent is added to A-1 by Suzuki coupling to produce A-2. Quinazolinone A-3 is obtained by cyclizing A-2 with a reagent (formamidine acetate, etc.). A-3 can be deprotected by treatment with an appropriately substituted cyclic group and an activator (such as HATU) to give A-4, which is then treated with an acid. The “E” moiety is then introduced under conditions known in the art to produce A-6.

構造（Ｉ）の化合物の実施形態（例えば、化合物Ｂ−３）（式中、Ｒ^１、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃ、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^４ａ、Ｒ^４ｂ、Ｒ^９、Ｒ^１０、ｍ^１、およびｍ^２は本明細書中に定義の通りである）を、一般的反応スキーム２（「方法Ｂ」）にしたがって調製することができる。一般的反応スキーム２に関して、構造Ａ−３の化合物を一般的スキーム１に記載のように調製する。Ａ−３を、適切に置換された環式基および活性化剤（ＨＡＴＵなど）で処理してＢ−１を得る。Ｂ−１を脱保護し、一般的反応スキーム１に関して上に記載されたものと類似の様式で「Ｅ」部分を導入してＢ−３を生成する。

Embodiments of the compound of structure (I) (eg, compound B-3), wherein R ¹ , R ^2a , R ^2b , R ^2c , R ^3a , R ^3b , R ^4a , R ^4b , R ⁹ , R ¹⁰ , M ¹ , and m ² are as defined herein) can be prepared according to General Reaction Scheme 2 (“Method B”). With respect to general reaction scheme 2, the compound of structure A-3 is prepared as described in general scheme 1. Treatment of A-3 with an appropriately substituted cyclic group and an activator (such as HATU) provides B-1. B-1 is deprotected and the “E” moiety is introduced in a manner similar to that described above for general reaction scheme 1 to produce B-3.

構造（Ｉ）の化合物の実施形態（例えば、化合物Ｃ−９）（式中、Ｒ^１、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃ、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^４ａ、Ｒ^４ｂ、Ｒ^９、Ｒ^１０、ｍ^１、およびｍ^２は本明細書中に定義の通りである）を、一般的反応スキーム３（「方法Ｃ」）にしたがって調製することができる。一般的反応スキーム３に関して、構造Ｃ−１の化合物を商業的供給源から購入するか、または当該分野で公知の方法にしたがって調製する。Ｃ−１をジエチル２−（エトキシメチレン）マロナートと反応させて、Ｃ−２を生成する。次いで、Ｃ−２を適切な高沸点溶媒（例えば、Ｐｈ_２Ｏ）中で加熱することによって環化してキノロンＣ−３を生成することができる。Ｃ−３を塩素化してＣ−４を生成し、それを適切な複素環式部分と反応させてＣ−５を生成する。所望のＲ^１部分を、上に記載のようにＳｕｚｕｋｉ化学を用いて導入する。Ｃ−６の保護基を除去し、遊離アミンを任意選択的に官能化してＣ−７を生成する。Ｃ−７の鹸化後、脱炭酸およびアミノ化によりＣ−８を生成する。次いで、Ｃ−８を、方法Ａに対して記載されたものと類似の様式で処理して、Ｃ−９を生成する。

An embodiment of a compound of structure (I) (eg, compound C-9) wherein R ¹ , R ^2a , R ^2b , R ^2c , R ^3a , R ^3b , R ^4a , R ^4b , R ⁹ , R ¹⁰ , M ¹ , and m ² are as defined herein) can be prepared according to General Reaction Scheme 3 (“Method C”). With respect to general reaction scheme 3, compounds of structure C-1 are purchased from commercial sources or prepared according to methods known in the art. C-1 is reacted with diethyl 2- (ethoxymethylene) malonate to produce C-2. C-2 can then be cyclized to form quinolone C-3 by heating in a suitable high boiling solvent (eg, Ph ₂ O). C-3 is chlorinated to produce C-4, which is reacted with an appropriate heterocyclic moiety to produce C-5. The desired R ¹ moiety is introduced using Suzuki chemistry as described above. The C-6 protecting group is removed and the free amine is optionally functionalized to produce C-7. After saponification of C-7, C-8 is produced by decarboxylation and amination. C-8 is then processed in a manner similar to that described for Method A to produce C-9.

  Additional general synthetic methods are provided in the examples. It will be apparent to those skilled in the art that all compounds of structure (I) can be prepared according to one or more methods described herein or otherwise known in the art. I will. In some instances, it may be necessary to use differently substituted starting materials and / or protecting groups to arrive at the desired compound when following the general procedures described herein. It will be clear. Various substituents can also be added at various points in the synthetic scheme to prepare the desired compounds.

Furthermore, those skilled in the art will recognize that different embodiments of compounds of structure (I) can be prepared with certain modifications of the schemes provided in the above schemes and examples. For example, for ease of illustration, the general reaction scheme above shows the preparation of compounds of structure (I) where R ^2a , R ^2b , and R ^2c are present in the starting material. However, these substituents can be added at any point in the synthetic scheme, or can be desired using differently substituted starting materials and / or using methods known in the art. It will be apparent to those skilled in the art that it can be obtained by adding substituents.

  One skilled in the art will also recognize that in the process of preparing the compounds described herein, the functional group of the intermediate compound may need to be protected by a suitable protecting group. Such functional groups include, but are not limited to, hydroxy, amino, mercapto, and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (eg, t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino, and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C (O) -R "(where R" is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl esters, aryl esters, or arylalkyl esters. Protecting groups are known to those skilled in the art and are optionally added or removed according to standard techniques described herein. The use of protecting groups is described in Green, T .; W. and P.M. G. M.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed. , Wiley. As one skilled in the art will recognize, the protecting group can also be a polymer resin, such as a Wang resin, a Rink resin, or a 2-chlorotrityl chloride resin.

  Those skilled in the art will appreciate that protected derivatives of such compounds of the present invention may not possess pharmacological activity per se, but the compounds are administered to mammals and are pharmacologically active after metabolism in the body. It will also be recognized that can be formed. Accordingly, such derivatives can be described as “prodrugs”. All prodrugs of the compounds of the invention are included within the scope of the invention.

Pharmaceutical Compositions Another embodiment relates to a pharmaceutical composition. The pharmaceutical composition comprises any one (or more) of the aforementioned compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In still further embodiments, the pharmaceutical composition comprises a compound disclosed herein and an additional therapeutic agent (eg, an anticancer agent). Non-limiting examples of such therapeutic agents are described herein below.

  Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Furthermore, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, and intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection. included.

  In certain embodiments, the compounds described herein are administered locally rather than in a systemic manner, for example, via direct injection into the organ of a compound often included in a depot or sustained release formulation. In certain embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, eg, liposomes coated with organ-specific antibodies. In such embodiments, the liposome is targeted to and taken up selectively by the organ. In still other embodiments, the compounds described herein are provided in the form of rapid release formulations, extended release formulations, or intermediate release formulations. In yet other embodiments, the compounds described herein are administered topically.

  The compounds of the present invention are effective over a wide dosage range. For example, for adult treatment, dosages of 0.01-1000 mg / day, 0.5-100 mg / day, 1-50 mg / day, and 5-40 mg / day are used in some embodiments. It is an example. An exemplary dosage is 10-30 mg / day. The exact dosage depends on the route of administration, the form in which the compound is administered, the subject to be treated, the weight of the subject to be treated, and the preference and experience of the attending physician.

  In some embodiments, the compounds of the invention are administered in a single dose. Typically, such administration for rapid drug delivery is by injection (eg, intravenous injection). However, other routes are used as needed. A single dose of the compound of the invention can also be used for the treatment of acute conditions.

  In some embodiments, the compounds of the invention are administered in multiple doses. In some embodiments, administration is approximately once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, administration is approximately once a month, once every two weeks, once a week, once every other day. In another embodiment, the compound of the present invention and another agent are both administered about 1 time / day to about 6 times / day. In another embodiment, administration of the compounds and agents of the invention continues for less than about 7 days. In yet another embodiment, administration continues for about 6 days, 10 days, 14 days, 28 days, 2 months, 6 months, or more than 1 year. In some cases, continuous dosing is given and maintained as long as necessary.

  Administration of the compounds of the invention can be continued as long as necessary. In some embodiments, the compound of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compound of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compounds of the invention are administered continuously over time, for example for treatments that obtain a chronic effect.

  In some embodiments, the compounds of the invention are administered in multiple dosages. As the pharmacokinetics of a compound varies from subject to subject, it is known in the art that individualization of the dosage regimen is necessary for optimal treatment. Routine studies in light of the present disclosure can find dosing regimens for the compounds of the present invention.

  In some embodiments, the compounds described herein are formulated into a pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises one or more physiology comprising excipients and adjuvants that facilitate processing of the active compound into a pharmaceutically usable preparation. Is formulated in a conventional manner using a commercially acceptable carrier. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable technique, carrier, and excipient are used as appropriate for the formulation of the pharmaceutical compositions described herein. Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E. , Remington's Pharmaceutical Sciences, Mack Publishing Co. , Easton, Pennsylvania 1975; A. and Lachman, L .; Eds. , Pharmaceutical Dosage Forms, Marcel Decker, New York, N .; Y. 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

  Provided herein are pharmaceutical compositions comprising a compound of structure (I) and a pharmaceutically acceptable diluent, excipient, or carrier. In certain embodiments, the described compounds are administered as a pharmaceutical composition in which the compound of structure (I) is mixed with other active ingredients for the purpose of combination therapy. All combinations of active agents described throughout the following combination therapy section and this disclosure are included herein. In certain embodiments, the pharmaceutical composition comprises one or more compounds of structure (I).

  Pharmaceutical compositions as used herein are other chemical components of the compound of structure (I) (carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or A mixture with excipients). In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, in performing a method of treatment or use provided herein, a therapeutically effective amount of a compound of structure (I) provided herein is included in a pharmaceutical composition. Administer to a mammal having the disease, disorder, or condition to be treated. In certain embodiments, the mammal is a human. In certain embodiments, the therapeutically effective amount will vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds described herein are used alone or in combination with one or more therapeutic agents as a component of a mixture.

  In one embodiment, one or more compounds of structure (I) are formulated in an aqueous solution. In certain embodiments, the aqueous solution is, by way of example only, selected from physiologically compatible buffers (such as Hanks's solution, Ringer's solution, or physiological saline buffer). In other embodiments, one or more compounds of structure (I) are formulated for transmucosal administration. In certain embodiments, the transmucosal formulation includes a penetrant appropriate for the barrier to be permeated. In yet other embodiments where the compounds described herein are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In certain embodiments, such solutions include physiologically compatible buffers and / or excipients.

  In another embodiment, the compounds described herein are formulated for oral administration. The compounds described herein are formulated by combining the active compound with, for example, a pharmaceutically acceptable carrier or excipient. In various embodiments, the compounds described herein are formulated in oral dosage forms, which include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, Slurries and suspensions are included.

  In certain embodiments, a pharmaceutical preparation for oral use is mixed with one or more solid excipients with one or more compounds described herein, and optionally It is obtained by grinding the selectively obtained mixture and processing the mixture of granules after adding appropriate adjuvants as necessary to obtain tablets or dragee cores. Suitable excipients are in particular sugars (including lactose, sucrose, mannitol or sorbitol); cellulose preparations (eg corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystals Fillers such as water-soluble cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; and others (such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate). In certain embodiments, a disintegrant is optionally added. Disintegrants include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

  In one embodiment, dosage forms (such as dragee cores and tablets) with one or more suitable coatings are provided. In certain embodiments, a concentrated sugar solution is used for coating the dosage form. The sugar solution is optionally further components (such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture). including. Dyes and / or pigments are also optionally added to the coating for identification purposes. In addition, dyes and / or pigments are optionally used to characterize different combinations of active compound doses.

  In certain embodiments, a therapeutically effective amount of at least one compound described herein is formulated in other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin and sealed soft capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). In certain embodiments, push-fit capsules contain the active ingredients in a mixture with one or more fillers. Fillers include, by way of example only, lactose, binders (such as starch), and / or lubricants (such as talc or magnesium stearate), and optionally stabilizers. In other embodiments, soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

  In other embodiments, a therapeutically effective amount of at least one compound described herein is formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges or gels. In still other embodiments, the compounds described herein are formulated for parenteral injection (including formulations suitable for bolus injection or continuous infusion). In certain embodiments, injectable formulations are present in unit dosage forms (eg, in ampoules) or multi-dose containers. Preservatives are optionally added to the injectable formulation. In still other embodiments, the pharmaceutical composition is formulated in a form suitable for parenteral injection as a sterile oily or aqueous vehicle suspension, solution or emulsion. Parenteral injection preparations optionally contain a formulation agent (such as a suspending agent, stabilizer, and / or dispersing agent). In certain embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In a further embodiment, suspensions of the active compounds (eg, compounds of structure (I)) are prepared as suitable oily injection suspensions. Lipophilic solvents or vehicles suitable for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils (such as sesame oil), or synthetic fatty acid esters (such as ethyl oleate or triglycerides), Or a liposome is contained. In certain specific embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension includes a suitable stabilizer or an agent that increases the solubility of the compound to allow for the preparation of a concentrated solution. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle (eg, sterile pyrogen-free water) prior to use.

  In still other embodiments, the compound of structure (I) is administered topically. The compounds described herein are formulated into various topically administrable compositions such as solutions, suspensions, lotions, gels, pastes, medicated sticks, salves, creams, or ointments. Such pharmaceutical compositions optionally include solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

  In yet other embodiments, the compound of structure (I) is formulated for transdermal administration. In certain embodiments, the transdermal formulation can be a lipophilic emulsion or aqueous buffer solution that is dissolved and / or dispersed in a polymer or adhesive using transdermal delivery devices and transdermal delivery patches. In various embodiments, such patches are constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical products. In a further embodiment, the compound of structure (I) is delivered transdermally using an iontophoretic patch or the like. In certain embodiments, the transdermal patch provides controlled delivery of the compound of structure (I). In certain embodiments, the rate of absorption is reduced by the use of a rate limiting membrane or by entrapment of the compound in a polymer matrix or gel. In another embodiment, absorption enhancers are used to increase absorption. Absorption enhancers or carriers include pharmaceutically acceptable absorbent solvents that assist passage through the skin. For example, in one embodiment, the transdermal device comprises a backing member, optionally a reservoir containing the compound with a carrier, and optionally for delivering the compound to the host skin at a controlled rate over an extended period of time. In the form of a bandage comprising a rate limiting barrier and means for securing the device to the skin.

  In other embodiments, the compound of structure (I) is formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists, or powders. Any pharmaceutical composition of the compound of any structure (I) uses a suitable propellant (eg, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas) Conveniently delivered in the form of an aerosol spray provided from a pressurized pack or nebulizer. In certain embodiments, the pressurized aerosol dosage unit is determined by providing a valve to deliver a fixed amount. In certain embodiments, by way of example only, capsules and cartridges, such as gelatin, containing a powder mixture of the compound and a suitable powder base (such as lactose or starch) are formulated for use in an inhaler or insufflator.

  In still other embodiments, the compound of structure (I) is a rectal composition (enema, rectal gel) comprising a conventional suppository base (such as cocoa butter or other glycerides) and a synthetic polymer (such as polyvinylpyrrolidone and PEG). , Rectal foam, rectal aerosol, suppository, jelly suppository, or retention enemas). In the suppository form of the composition, a low melting wax (such as but not limited to a mixture of fatty acid glycerides optionally combined with cocoa butter) is first melted.

  In certain embodiments, the pharmaceutical compositions are any conventional using one or more physiologically acceptable carriers including excipients and adjuvants that facilitate processing of the active compound. It is formulated into a preparation that can be used pharmaceutically in a manner. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable technique, carrier, and excipient are optionally used as appropriate. A pharmaceutical composition comprising a compound of structure (I) is converted in a conventional manner (by way of example only by conventional mixing, dissolving, granulating, dragee making, wet milling, emulsifying, encapsulating, entrapment, or compression processes). ) Manufacture.

  The pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, diluent or excipient and at least one compound of structure (I) described herein as an active ingredient. The active ingredient is in the free acid form or free base form or in the form of a pharmaceutically acceptable salt. Furthermore, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity. All tautomeric forms of the compounds described herein are included within the scope of the compounds presented herein. Furthermore, the compounds described herein include unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water and ethanol. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical composition optionally comprises other pharmaceuticals or pharmaceuticals, carriers, adjuvants (preservatives, stabilizers, wetting agents or emulsifiers, solubility enhancers, salts for adjusting osmotic pressure, buffers, etc. And / or other pharmaceutically beneficial substances).

  A method of preparing a composition comprising a compound described herein comprises one or more inert pharmaceutically acceptable excipients or a solid to form a solid, semi-solid, or liquid. Using the carrier to formulate the compound. Solid compositions include, but are not limited to powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semi-solid compositions include, but are not limited to gels, suspensions, and creams. The form of the pharmaceutical composition described herein includes a solution or suspension, a solid suitable for inclusion in a liquid prior to use to form a solution or suspension, or an emulsion. These compositions also optionally contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents and pH buffering agents.

  In some embodiments, a pharmaceutical composition comprising at least one compound of structure (I) illustratively takes the form of a liquid in which the agent is in solution, suspension, or both. Typically, when the composition is administered as a solution or suspension, a first portion of the drug is present in the solution and a second portion of the drug is in particulate form in the suspension in the liquid matrix. Present in form. In some embodiments, the liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.

  In certain embodiments, useful aqueous suspensions contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers (such as cellulose polymers (eg, hydroxypropylmethylcellulose)) and water-insoluble polymers (such as crosslinked carboxyl-containing polymers). Certain pharmaceutical compositions described herein include, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly (methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, alginic acid. A mucoadhesive polymer selected from sodium and dextran.

  Useful pharmaceutical compositions optionally also include solubilizing agents that assist in the solubility of the compound of structure (I). The term “dissolution aid” generally includes agents that form a micellar or true solution of the drug. Certain acceptable nonionic surfactants (eg, polysorbate 80) are useful as dissolution aids, as are ophthalmically acceptable glycols, polyglycols (eg, polyethylene glycol 400), and glycol ethers. is there.

  In addition, useful pharmaceutical compositions optionally include one or more pH adjusting or buffering agents (acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; water; Includes bases such as sodium oxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride )including. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

  In addition, useful compositions also optionally include one or more salts in an amount necessary to bring the osmolality of the composition to an acceptable range. Such salts include salts having a sodium, potassium, or ammonium cation and an anion of chlorine, citric acid, ascorbic acid, boric acid, phosphoric acid, bicarbonate, sulfuric acid, thiosulfuric acid, or bisulfite. Suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

  Other useful pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing materials (such as melphen and thiomersal); stabilized chlorine dioxide; and quaternary ammonium compounds (such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride).

  Still other useful compositions include one or more surfactants for enhancing physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils (eg, polyoxyethylene (60) hydrogenated castor oil); and polyoxyethylene alkyl ethers and alkyl phenyl ethers (eg, octoxynol 10, Octoxynol 40) is included.

  Still other useful compositions include one or more antioxidants to enhance chemical stability as needed. Suitable antioxidants include ascorbic acid and sodium metabisulfite by way of example only.

  In certain embodiments, the aqueous suspension composition is packaged in a single dose, non-resealable container. Alternatively, if it is typical to include a preservative in the composition, multiple dose resealable containers are used.

  In another embodiment, other delivery systems for hydrophobic pharmaceutical compounds are used. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, an organic solvent such as N-methylpyrrolidone is also used. In further embodiments, the compounds described herein are delivered using a sustained release system (such as a semi-permeable matrix of a solid hydrophobic polymer containing a therapeutic agent). A variety of sustained release materials are useful herein. In some embodiments, sustained release capsules release the compound over a period of weeks to 100 days. Additional protein stabilization strategies are used due to the chemical nature and biological stability of therapeutic reagents.

  In certain embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other common stabilizers. Examples of such stabilizers include, but are not limited to: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v. v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (F) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j ) Dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

  In some embodiments, the concentration of one or more compounds provided in a pharmaceutical composition of the invention is 100%, 90% w / w, w / v, or v / v. %, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.000 %, 0.0006%, 0.0005% 0.0004% 0.0003% 0.0002%, or less than 0.0001%.

  In some embodiments, the concentration of one or more compounds of the invention is 90%, 80%, 70%, 60%, 50, w / w, w / v, or v / v. %, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75 %, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15% 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25 %, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10% 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25 %, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50% 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07% 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006% 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0 0009% 0.0008% 0.0007%, 0.0006%, 0.0005% 0.0004% 0.0003% 0.0002% or more than 0.0001%.

  In some embodiments, the concentration of one or more compounds of the invention is about 0.0001% to about 50%, about 0. 0, w / w, w / v, or v / v. 001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0. 05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0. 1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0. 6% to about 16%, about 0.7% to about 5%, about 0.8% to about 14%, about 0.9% to about 12%, in the range of approximately 1% to approximately 10%.

  In some embodiments, the concentration of the one or more compounds of the invention is about 0.001% to about 10%, about 0. 0, w / w, w / v, or v / v. 01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3% Approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% It is in the range of about 0.9%.

  In some embodiments, the amount of one or more compounds of the invention is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6 .5g, 6.0g, 5.5g, 5.0g, 4.5g, 4.0g, 3.5g, 3.0g, 2.5g, 2.0g, 1.5g, 1.0g, 0.95g 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0 .3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0 Equal to or less than 002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g is there.

  In some embodiments, the amount of one or more compounds of the invention is 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g. 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0 .006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g,. 45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or 10g There are many.

  In some embodiments, the amount of one or more compounds of the invention is 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01 It is in the range of -6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

Kits / Products Kits and products are also provided for use in the therapeutic applications described herein. In some embodiments, such a kit includes a carrier, package, or container that includes one or more containers, such as vials and tubes, each container being a method described herein. To contain one of the individual elements to be used). Suitable containers include, for example, bottles, vials, syringes, and test tubes. The container is formed from various materials such as glass or plastic.

  The products provided herein include packaging materials. Packaging materials used in the packaging of pharmaceutical products include, for example, packaging materials found in US Pat. Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include blister packaging, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any package suitable for the selected formulation and intended mode of administration and treatment. Including but not limited to materials. For example, a container contains one or more compounds described herein, optionally in combination with another agent disclosed herein or in the composition. The container optionally has a sterile access port (eg, the container is an intravenous solution bag or vial with a stopper pierceable by a hypodermic needle). Such kits optionally comprise a compound with an identifying description or label or instructions regarding its use in the methods described herein.

  For example, a kit typically includes one or more additional containers, each container being one that is desirable from a commercial and user standpoint for the use of the compounds described herein. Or many more different materials (optionally in concentrated form of reagents and / or devices). Non-limiting examples of such materials include buffers, diluents, filters, needles, syringes; carrier, package, container, vial, and / or tube labels listing instructions for contents and / or use, and This includes, but is not limited to, package inserts containing instructions for use. Typically, a set of instructions will also be included. The label is optionally present on or with the container. For example, if the letters, numbers, or other symbols forming the label are attached to the container itself, molded, or etched, the label is present on the container and in the storage container or carrier that also holds the container, For example, if a label is present as a package insert, the label is present with the container. In addition, a label is used to indicate that the contents should be used to apply to a particular treatment. In addition, the label indicates how to use the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical composition is present in a pack or dispenser device that includes one or more unit dosage forms that include a compound provided herein. The pack includes, for example, a metal or plastic foil (such as a blister pack). Alternatively, the pack or dispenser device is accompanied by instructions for administration. Alternatively, the pack or dispenser may be accompanied by a notice associated with the container in a form directed by a government agency that regulates the manufacture, use, or sale of the medicinal product. Reflects the form of the drug for administration to animals. Such notices are, for example, prescription drug labels approved by the US Food and Drug Administration or approved product attachments. In some embodiments, a composition comprising a compound provided herein formulated in a compatible pharmaceutical carrier is prepared, placed in a suitable container, and indicated for treatment of the indication.

Methods Embodiments of the present invention are methods of inhibiting RAS-mediated cell signaling comprising contacting a cell with an effective amount of one or more of the compounds disclosed herein. I will provide a. Inhibition of RAS-mediated signaling can be assessed and demonstrated by a wide variety of methods known in the art. Non-limiting examples include: (a) decreased RAS GTPase activity; (b) decreased GTP binding affinity or increased GDP binding affinity; (c) GTP K increased off or decreased GDP K off; (d) decreased signaling molecule levels downstream of the RAS pathway (such as decreased pMEK levels); and / or (e) downstream signaling molecules (including Raf, Reduced binding of the RAS complex to (but not limited to). Kits and commercially available assays can be utilized for one or more of the above determinations.

  Embodiments also treat disease states (including but not limited to conditions involving G12C KRAS, HRAS, or NRAS mutations, G12C HRAS mutations and / or G12C NRAS mutations (eg, cancer)). Methods of using the compounds or pharmaceutical compositions of the present invention for the purpose are provided.

  In some embodiments, a method of treating cancer is provided, the method comprising administering to a subject in need of cancer treatment an effective amount of a compound of structure (I) as described above. Administering any of the products. In some embodiments, the cancer is mediated by a K12, HRAS, or NRAS G12C mutation. In other embodiments, the cancer is pancreatic cancer, colon cancer, MYH-related polyposis, colorectal cancer, or lung cancer.

  In some embodiments, the present invention is a method of treating a disorder in a subject in need of treatment of a disorder, wherein the subject has a KRAS, HRAS, or NRAS G12C mutation, and If the subject is determined to have a K12, HRAS, or NRAS G12C mutation, a therapeutically effective dose of at least one compound of structure (I), or a pharmaceutically acceptable salt, ester, prodrug thereof, A method is provided comprising the step of administering a variant, solvate, hydrate, or derivative to a subject.

  The disclosed compounds strongly inhibit anchorage-independent cell growth and thus may inhibit tumor metastasis. Accordingly, in another embodiment, the present disclosure provides a method of inhibiting tumor metastasis comprising a pharmaceutical composition comprising an effective amount of any compound disclosed herein and a pharmaceutically acceptable carrier. A method is provided comprising administering to a subject in need of inhibiting tumor metastasis.

  KRAS, HRAS, or NRAS G12C mutations have also been identified in hematological malignancies (eg, cancers affecting the blood, bone marrow, and / or lymph nodes). Accordingly, certain embodiments relate to the administration of disclosed compounds (eg, in the form of pharmaceutical compositions) to patients in need of treatment for hematological malignancies. Such malignancies include, but are not limited to, leukemia and lymphoma. For example, compounds of the present disclosure can be used for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML). ), Acute monocytic leukemia (AMol) and / or other diseases such as leukemia. In other embodiments, the compounds are useful for the treatment of lymphomas (such as all subtypes of Hodgkin lymphoma or non-Hodgkin lymphoma).

  Determining whether a tumor or cancer contains a K12, HRAS, or NRAS mutation of G12C, evaluating a nucleotide sequence encoding a KRAS, HRAS, or NRAS protein, evaluating an amino acid sequence of a KRAS, HRAS, or NRAS protein; Alternatively, it can be performed by evaluating the characteristics of a putative KRAS, HRAS, or NRAS variant protein. The sequence of wild type human KRAS, HRAS, or NRAS is known in the art (eg, accession number NP203524).

  Methods for detecting mutations in the nucleotide sequence of KRAS, HRAS, or NRAS are known to those skilled in the art. These methods include polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, polymerase chain reaction-single-stranded DNA conformation polymorphism (PCR-SSCP) assay, real-time PCR assay, PCR sequence Determination, variant allele specific PCR amplification (MASA) assay, direct sequencing, primer extension reaction, electrophoresis, oligonucleotide ligation assay, hybridization assay, TaqMan assay, SNP genotyping assay, high resolution melting assay, and Including but not limited to microarray analysis. In some embodiments, the sample is evaluated for G12C KRAS, HRAS, or NRAS mutations by real-time PCR. Real-time PCR uses a fluorescent probe specific for the KRAS, HRAS, or NRAS G12C mutation. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, a KRAS, HRAS, or NRAS G12C mutation is used to directly sequence a particular region (eg, exon 2 and / or exon 3) in a KRAS, HRAS, or NRAS gene. To identify. This technique identifies all possible mutations in the sequenced region.

  Methods for detecting mutations in KRAS, HRAS, or NRAS proteins are known to those skilled in the art. These methods include detection of KRAS, HRAS, or NRAS variants using binding agents specific for variant proteins (eg, antibodies), protein electrophoresis, and Western blotting, and direct peptide sequencing. However, it is not limited to these.

  A variety of samples can be used to determine whether a tumor or cancer contains a G12C KRAS, HRAS, or NRAS mutation. In some embodiments, a sample is taken from a subject having a tumor or cancer. In some embodiments, a sample is taken from a subject having a cancer or tumor. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin fixed paraffin embedded sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA.

  Embodiments of the invention also include administering to a mammal a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. And a method of treating a hyperproliferative disorder in a mammal. In some embodiments, the methods relate to the treatment of cancer such as: acute myeloid leukemia, adolescent cancer, childhood adrenocortical cancer, AIDS-related cancer (eg, lymphoma and Kaposi's sarcoma), anal Cancer, appendix cancer, astrocytoma, atypical teratocarcinoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, bar Kit lymphoma, carcinoid tumor, atypical teratoid tumor, fetal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, heart tumor, chronic lymphocytic leukemia (CLL), chronic Myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic glandular epithelium Cancer (DCIS), fetal tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, sensory neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, ocular Bone fibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational choriocarcinoma, ciliary cell leukemia, head and neck cancer, Heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cancer, liver cancer, Lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic cervical squamous cell carcinoma of unknown primary origin, midline duct cancer, oral cancer multiple endocrine tumor syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungus Disease, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple bone , Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal and sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid gland Cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland Cancer, skin cancer, stomach cancer (gastric cancer), small cell lung cancer, small intestine cancer, soft tissue sarcoma, T cell lymphoma, testicular cancer, throat cancer, thymoma and thymic cancer, thyroid cancer, renal pelvis and ureter Transitional cell cancer, choriocarcinoma, rare childhood cancer, urethral cancer, uterine sarcoma, vaginal cancer, Vulvar cancer or virus-induced cancer. In some embodiments, the method comprises a non-cancerous hyperproliferative disorder (such as benign hyperplasia of the skin (eg, psoriasis), restenosis, or prostate (eg, benign prostatic hypertrophy (BPH))). Regarding treatment.

  In certain specific embodiments, the invention is a method of treating lung cancer, wherein an effective amount of any of the above compounds (or pharmaceutical compositions comprising the compounds) is administered to a subject in need of treatment for lung cancer. The method includes the step of: In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC) (eg, adenocarcinoma, lung squamous cell carcinoma, or large cell lung cancer). In other embodiments, the lung cancer is small cell lung cancer. Other lung cancers that can be treated with the disclosed compounds include, but are not limited to, adenocarcinoma, carcinoid tumor, and undifferentiated cancer.

  Treating with a compound of the invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate, or derivative of said compound, according to the methods of the invention. Possible subjects include, for example, subjects who have been diagnosed with the following: acute myeloid leukemia, acute myeloid leukemia, adolescent cancer, childhood adrenocortical cancer, AIDS-related cancer (eg, Lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratocarcinoma, basal cell cancer, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor Breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid tumor, fetal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, heart tumor, chronic lymphocyte Sexual leukemia (CL ), Chronic myelogenous leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), fetal tumor, CNS Cancer, endometrial cancer, ependymoma, esophageal cancer, sensory neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, bone fibrohistiocytoma, Gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational choriocarcinoma, ciliary cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma , Hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, Lymphoma, metastatic cervical squamous cell carcinoma of unknown primary origin, midline duct cancer, oral cancer Multiple endocrine tumor syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, Malignant fibrous histiocytoma and osteosarcoma of bone, nasal and sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip cancer And oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleura Pulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach cancer (gastric cancer), Small cell lung cancer, small intestine cancer, soft tissue sarcoma, T cell lymphoma, testicular cancer, throat cancer Thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, choriocarcinoma, rare childhood cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer. In some embodiments, a subject treated with a compound of the invention includes a non-cancerous hyperproliferative disorder (benign hyperplasia of the skin (eg, psoriasis), restenosis, or prostate (eg, benign prostate) Subjects with a diagnosis of having hypertrophy (BPH)) and the like.

  Embodiments of the present invention further provide methods for modulating G12C mutant KRAS, HRAS, or NRAS protein activity by contacting said protein with an effective amount of a compound of the present invention. The modulation can be inhibition or activation of protein activity. In some embodiments, the invention provides a method of inhibiting protein activity by contacting a G12C mutant KRAS, HRAS, or NRAS protein with an effective amount of a compound of the invention in solution. In some embodiments, the present invention provides methods of inhibiting G12C mutant KRAS, HRAS, or NRAS protein activity by contacting cells, tissues, or organs that express the protein of interest. In some embodiments, the invention provides for the protein activity of a subject, including but not limited to rodents and mammals (eg, humans), subjecting an effective amount of a compound of the invention to the subject. The method of inhibiting by administering to is provided. In some embodiments, the adjustment rate is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the control rate is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

  In some embodiments, the present invention provides the activity of KRAS, HRAS, or NRAS G12C in a cell in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the cell. Methods of inhibiting by contacting with a compound of the invention are provided. In some embodiments, the present invention relates to the activity of KRAS, HRAS, or NRAS G12C in a tissue in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in said tissue. Methods of inhibiting by contacting with a compound of the invention are provided. In some embodiments, the present invention relates to the activity of KRAS, HRAS, or NRAS G12C in an organism in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the organism. Methods of inhibiting by contacting with a compound of the invention are provided. In some embodiments, the present invention relates to the activity of KRAS, HRAS, or NRAS G12C in an animal in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in said animal. Methods of inhibiting by contacting with a compound of the invention are provided. In some embodiments, the invention provides the activity of KRAS, HRAS, or NRAS G12C in a mammal sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in said mammal. Methods of inhibiting by contacting with an amount of a compound of the invention are provided. In some embodiments, the invention provides an activity of KRAS, HRAS, or NRAS G12C in a human in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in said human. Methods of inhibiting by contacting with a compound of the invention are provided. In other embodiments, the invention provides methods for treating a disease mediated by the activity of KRAS, HRAS, or NRAS G12C in a subject in need of such treatment.

  Other embodiments provide compounds known to modulate other pathways, or other components of the same pathway, or even overlapping target enzyme sets, compounds of the invention, or pharmaceutically acceptable salts thereof, Combination therapies are provided for use in combination with an ester, prodrug, solvate, tautomer, hydrate, or derivative. In one aspect, such therapy includes a combination of one or more compounds of the present invention with a chemotherapeutic agent, therapeutic antibody, and irradiation treatment to obtain a synergistic or additional therapeutic effect. Including, but not limited to.

  A number of chemotherapeutic agents are now known in the art and can be used in combination with the compounds of the present invention. In some embodiments, the chemotherapeutic agent is a mitotic inhibitor, alkylating agent, antimetabolite, insertional antibiotic, growth factor inhibitor, cell cycle inhibitor, enzyme, topoisomerase inhibitor, biological response modifier, anti Selected from the group consisting of hormones, angiogenesis inhibitors, and antiandrogens.

  Non-limiting examples include chemotherapeutic agents, cytotoxic agents, non-peptide small molecules (Gleevec® (imatinib mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (Gefitinib), and adriamycin), as well as a number of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents (such as thiotepa and cyclophosphamide (Cytoxan ™)); alkyl sulfonates (such as busulfan, improsulfan, and pipersulfan); Aziridine (such as benzodopa, carbocon, metredorpa, and ureodopa); ethyleneimine and methylmelamine (artretamine, triethylenemelamine, triethylenephosphoramide), triethylenethiophosphoramide (triethylenethiomethylenetrimolethyraminethrophylamide) trimethylolamine)); Itrogen mustard (chlorambucil, chlornafazine, colophosphamide, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobubiquin, phenesterine, prednisotin, trophosphamide, uracil mustard (nitrosurea) (nitrosururea) , Chlorozotocin, hotemustine, lomustine, nimustine, ranimustine, etc .; antibiotics (aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactomycin, calicheamicin, carabicin, carminomycin, cardinophilin, Casodex (trademark), chromomycin, dactinomycin, daunorubici , Detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogaramycin, olivomycin, peplomycin, podophylomycin, puromycin, keramycin, rodolubicin, Streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, zorubicin, etc .; antimetabolites (such as methotrexate and 5-fluorouracil (5-FU)); folic acid analogs (such as denopterin, methotrexate, pteropterin, trimethrexate); Analogs (fludarabine, 6-mercaptopurine, thiampurine, thioguanine, etc.); pyrimidine analogs (ancitabine, Zacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxyfluridine, enocitabine, floxuridine, etc., androgen (carsterone, drmostanolone propionate, epithiostanol, mepithiostan, test lactone, etc.); Aminoglutethimide, mitotane, trilostane, etc.); folic acid supplements (such as floric acid); acegraton; aldophosphamide glycoside; aminolevulinic acid; amsacrine; vestlabcil; bisantrene, edatlaxate; defofamine; Elliptium acetate; ethogluside; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitguazone; mitoxantrone; Pentostatin; Phenstatin; Pyramubicin; Podorubicin; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK®; Razoxan; Schizophyllan; Spirogermanium; Tenuazonic acid; Triadicon; 2,2 ', 2 "-Trichlorotriethylamine; Vindesine; dacarbazine; mannomustine; mitoblonitol; mitralitol; pipobroman; gacytosine; arabininoside ("Ara-C"); cyclophosphamide; thiotepa; N. J. et al. ) And docetaxel (Taxotere ™, Rhone-Poulenc Roller, Antony, France)); retinoic acid; esperamicin; capecitabine; and any of the above pharmaceutically acceptable salts, acids, or derivatives. Suitable chemotherapeutic cell modulators include anti-hormonal agents that act to regulate or inhibit hormonal effects on tumors (e.g., antiestrogens such as tamoxifen (Norbadex ™), raloxifene, aromatase inhibition 4 (5) -imidazole , 4-hydroxy tamoxifen, trioxyphene, keoxifene, LY 117018, onapristone, and toremifene (Fairston); and antiandrogens (such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin); chlorambucil; gemcitabine 6-thioguanine; mercaptopurine; methotrexate; platinum analogs (such as cisplatin and carboplatin); vinblastine; platinum; etoposide (VP-16); Smitamide; Mitomycin C; Mitoxantrone; Vincristine; Vinorelbine; Navelbine; Novantrone; Teniposide; Daunomycin; Aminopterin; Xeloda; Optionally, the compound or pharmaceutical composition of the present invention may be combined with a commonly prescribed anticancer drug (Herceptin®, Avastin®, Erbitux®, Rituxan (Registered trademark), taxol (registered trademark), Arimidex (registered trademark), taxotere (registered trademark), ABVD, AVICINE, abagobomab, acridinecarboxamide, adecatumumab, 17-N-allylua Mino-17-demethoxygeldanamycin, alpharazine, albocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antineoplastic agent, antitumor-forming herb, Apadicon, atiprimmod, azathioprine, belotecan, bendamustine, BIBW2992, viricodar, brostaricin, bryostatin, buthionine sulphoximine, CBV (chemotherapy), caliculin, cell cycle non-specific antineoplastic agent, dichloroacetic acid, discodermolide, elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan, Exislind, Ferguinol, Forodesine, Phosfestol, ICE chemotherapy regimen, IT-101, Ime Son, imiquimod, indolocarbazole, ilofulvene, ranicidal, larotaxel, lenalidomide, lucanton, luruthecan, mafosfamide, mitozolomide, naphthoxidine, nedaplatin, olaparib, oltaxane, PAC-1, popo, pixatron rebetotecantebilecantebilete SN-38, Salinosporamide A, Sapacitabine, Stanford V, Swainsonine, Taraporfin, Tariquidar, Tegafur-uracil, Temodar, Tesetaxel, Triplatin tetranitrate, Tris (2-chloroethyl) amine, Troxacitabine, Uramstin, Bazimesan, 126D6 , Or Zoschidar).

  Embodiments further relate to methods of using the compounds or pharmaceutical compositions provided herein in combination with radiation therapy for inhibiting abnormal cell growth or treating hyperproliferative disorders in a mammal. Techniques for performing radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. Administration of the compounds of this invention in this combination therapy can be determined as described herein.

  Radiation therapy is one of several methods or a combination of methods (external radiation therapy, internal radiation therapy, intra-tissue radiation, stereotactic surgical radiation, systemic radiation therapy, radiation therapy and continuous or temporary intra-tissue. Brachytherapy, including but not limited to brachytherapy. The term “brachytherapy” as used herein refers to radiation therapy that is delivered by a spatially confined radioactive material inserted at or near the affected site of a tumor or other proliferative tissue in the body. Say. This term refers to radioisotopes (eg, At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and Lu Isotope) is intended to include, but is not limited to. Suitable radiation sources for use as the cell conditioning agents of the present invention include both solids and liquids. As a non-limiting example, the radiation source emits a radionuclide (such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source), or photons. Can be other radionuclides, beta particles, gamma rays, or other therapeutic radiation. The radioactive material can also be a fluid made from any radionuclide solution (eg, a solution of I-125 or I-131), or a radioactive fluid can be a solid radionuclide (Au-198, Y-90, etc.). It can be produced using a slurry of a suitable fluid containing small particles. Furthermore, radionuclides can be incorporated into gels or radiomicrospheres.

  Without being limited to any theory, the compounds of the present invention can be made more sensitive to treatment with irradiation aimed at killing cells and / or inhibiting growth of abnormal cells. Accordingly, the present invention is further a method for increasing the sensitivity of abnormal cells in a mammal to treatment using radiation, comprising a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug thereof, The method comprises administering a solvate, hydrate, or derivative to the mammal in an amount effective to increase the sensitivity of the abnormal cells to treatment using radiation. The amount of a compound, salt, or solvate in the present method can be determined according to means for identifying an effective amount of such a compound described herein.

  A compound or pharmaceutical composition of the invention with an amount of one or more substances selected from anti-angiogenic agents, signaling inhibitors, anti-proliferative agents, glycolytic inhibitors, or autophagy inhibitors Can be used in combination.

  Anti-angiogenic agents, such as MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors, etc.) are described herein. It can be used in conjunction with the compounds and pharmaceutical compositions of the invention described herein. Anti-angiogenic agents include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include Celebrex ™ (arecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are WO96 / 33172 (published 24 October 1996), WO96 / 27583 (published 7 March 1996), European Patent Application No. 97304971.1 (1997 7). No. 9308617.2 (filed Oct. 29, 1999), WO 98/07697 (published Feb. 26, 1998), WO 98/03516 (published Jan. 29, 1998) ), WO 98/34918 (published on August 13, 1998), WO 98/34915 (published on August 13, 1998), WO 98/33768 (published on August 6, 1998), WO 98/30566 (1998) Published on July 16, 1994), European Patent Publication No. 606,046 (published on July 13, 1994), Europe Patent Publication Nos. 931 and 788 (published July 28, 1999), WO 90/05719 (published May 31, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 ( Published on 21 October 1999), WO 99/29667 (published 17 June 1999), PCT International Application No. PCT / IB98 / 01113 (filed 21 July 1998), European Patent Application 993022232.1. No. (filed on Mar. 25, 1999), British Patent Application No. 9912961.1 (filed on Jun. 3, 1999), US Provisional Patent Application No. 60 / 148,464 (filed on Aug. 12, 1999), US Patent No. 5,863,949 (issued January 26, 1999), US Patent No. 5,861,510 (issued January 19, 1999), and European Patent Publication No. 780,386 (published Jun. 25, 1997) (the entire whole literature described above incorporated by reference herein) are described in. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no MMP-1 inhibitory activity. Other matrix-metalloproteinases (ie, MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and More preferred are inhibitors that selectively inhibit MMP-2 and / or AMP-9 as compared to MMP-13). Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO32-3555, and RS13-0830.

  Autophagy inhibitors include chloroquine, 3-methyladenine, hydroxychloroquine (Plakenil ™), bafilomycin A1, 5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid, protein phosphatase type 2A or Examples include, but are not limited to, autophagy-control algal toxins that inhibit type 1, cAMP analogs, and drugs that increase cAMP levels (such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine). In addition, antisense or siRNA that inhibit the expression of proteins (including but not limited to ATG5, which is involved in autophagy) can also be used.

  Embodiments also include an amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate, or derivative thereof, or an isotopically labeled thereof. And methods and pharmaceutical compositions for the treatment of cardiovascular disease in mammals comprising a derivative and a certain amount of one or more therapeutic agents for the treatment of cardiovascular disease.

  Exemplary agents used in cardiovascular disease applications include antithrombotic agents (eg, prostacyclin and salicylate), thrombolytic agents (eg, streptokinase, urokinase, tissue plasminogen activator (TPA), and anisoylated plasminogen- Streptokinase activator complex (APSAC)), antiplatelet agents (eg acetyl-salicylic acid (ASA) and clopidrogel), vasodilators (eg nitrate), calcium channel blockers, antiproliferative agents (eg colchicine and alkyls) Agents), intercalating agents, growth regulators (such as interleukins, transforming growth factor-beta, and platelet-like growth factor analogues, monoclonal antibodies directed against growth factors), anti-inflammatory agents (steroidal and non-steroidal) Both), and vascular tone, function, arteriosclerosis, and other agents that can modulate the healing response to injury of a blood vessel or organ after the intervention. Antibiotics can also be included in the combinations or coatings included in the present invention. In addition, the coating can be used to deliver a therapeutic agent locally within the vessel wall. By incorporating the active agent into the swellable polymer, the active agent is released upon swelling of the polymer.

  In some embodiments, the compounds described herein are formulated or administered in conjunction with a liquid or solid tissue barrier, also known as a lubricant. Examples of tissue barriers include, but are not limited to, polysaccharides, polyglycans, sepra films, interseed, and hyaluronic acid.

  In some embodiments, the drugs administered in conjunction with the compounds described herein include any suitable drug (eg, analgesic (eg, codeine, dihydromorphine, Ergotamine, fentanyl, or morphine); angina preparations (eg, diltiazem); antiallergic agents (eg, cromoglycate, ketotifen, or nedocromil); antiinfectives (eg, cephalosporin, penicillin, streptomycin, sulfonamides) , Tetracycline, or pentamidine); antihistamines (eg, metapyrylene; anti-inflammatory agents (eg, beclomethasone, flunisolide, budesonide, tipredan, triamcinolone acetonide, or fluticasone); antitussives (eg, noscapine); bronchodilators For example, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pyrbuterol, reproterol, limiterol, salbutamol, salmeterol, terbutaline, isoetarine, tulobuterol, orciprenaline, or (-)-4-amino-3 , 5-dichloro-α-[[[6- [2- (2-pyridinyl) ethoxy] hexyl] -amino] methyl] benzenemethanol); diuretics (eg amiloride); anticholinergics (eg ipratropium, Atropine, or oxitropium); hormones (eg, cortisone, hydrocortisone, or prednisolone); xanthines (eg, aminophylline, corinthophyllium) And therapeutic proteins and peptides (eg, insulin or glucagon)), where appropriate, the drug optimizes the activity and / or stability of the drug. For use in the form of salts (for example as alkali metal salts or amine salts or as acid addition salts), as esters (for example lower alkyl esters) or as solvates (for example hydrates) It will be apparent to those skilled in the art.

  Other exemplary therapeutic agents useful in combination therapy include the above radiotherapy drugs, hormone antagonists, hormones and their release factors, thyroid and antithyroid drugs, estrogens and progestins, androgens, adrenocorticotropic hormones; Steroids and their synthetic analogues; synthesis and action of corticosteroids, insulin, oral hypoglycemic agents, inhibitors of pancreatic endocrine pharmacology, drugs affecting calcification and bone turnover: calcium, phosphate, parathyroid hormone Vitamin D, calcitonin, vitamins (water soluble vitamins, vitamin B complexes, ascorbic acid, fat soluble vitamins, vitamins A, K, and E, etc.), growth factors, cytokines, chemokines, muscarinic receptor agonists and antagonists; Drugs acting at neuromuscular junctions and / or autonomic ganglia; catecholamines, sympathomimetic drugs, and agonists or antagonists of adrenergic receptors; and 5-hydroxytryptamine (5-HT, serotonin) Receptor agonists and antagonists are included, but are not limited to.

  Therapeutic agents include drugs for pain and inflammation (such as histamine and histamine antagonists, brandikinin and brandikinin antagonists, 5-hydroxytryptamine (serotonin)), by biotransformation of selective hydrolysis products of membrane phospholipids. Selective cyclooxygenase, a lipid substance produced, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, non-steroidal anti-inflammatory agents, analgesics-antipyretics, drugs that inhibit the synthesis of prostaglandins and thromboxanes Inhibitors, selective inhibitors of inducible cyclooxygenase-2, autocidal, paracrine hormone, somatostatin, gastrin, cytokines that mediate interactions involved in humoral and cellular immune responses , Lipid-derived autacoids, eicosanoids, beta-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers, may include membrane stabilizing agents, and also leukotriene inhibitors.

  Further therapeutic agents contemplated herein include diuretics, vasopressin, drugs that affect water retention in the kidney, rennin, angiotensin, drugs useful for the treatment of myocardial ischemia, antihypertensive drugs, angiotensin converting enzyme Inhibitors, beta-adrenergic receptor antagonists, drugs for the treatment of hypercholesterolemia, and drugs for the treatment of dyslipidemia.

  Other therapeutic agents contemplated include drugs used to adjust gastric acidity, drugs for the treatment of peptic ulcers, drugs for the treatment of gastroesophageal reflux disease, gastrointestinal motility promoters, antiemetics, Drugs used in irritable bowel syndrome, drugs used for diarrhea, drugs used for constipation, drugs used for inflammatory bowel disease, drugs used for bile duct diseases, Includes drugs used for pancreatic disease. Therapeutic agents used to treat protozoal infections, drugs used to treat malaria, amoebiasis, giardiasis, trichomoniasis, trypasonomasis, and / or leishmaniasis, and / or helminthiasis Used in chemotherapy. Other therapeutic agents include antibacterial agents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, and drugs for urinary tract infections, such as penicillins, cephalosporins, β-lactam antibiotics, drugs containing aminoglycosides, Drug synthesis inhibitors, drugs used in chemotherapy for tuberculosis, Mycobacterium avium complex disease, and gonorrhea, antifungals, antivirals (including nonretrovirals and antiretrovirals).

  Examples of therapeutic antibodies that can be combined with the compounds of the present invention include anti-receptor tyrosine kinase antibodies (cetuximab, panitumumab, trastuzumab), anti-CD20 antibodies (rituximab, tositumomab), and other antibodies (alemtuzumab, bevacizumab, and gemtuzumab) Etc.), but is not limited to these.

  In addition, therapeutic agents used for immunomodulation (such as immunomodulators, immunosuppressants, tolerogens, and immunostimulants) are contemplated by the methods herein. In addition, therapeutic agents, hematopoietic agents, growth factors, minerals and vitamins that act on blood and blood-forming organs, anticoagulants, thrombolytics, and antiplatelet agents.

  For the treatment of renal cancer, the compounds of the invention can be combined with sorafenib and / or avastin. For the treatment of endometrial disorders, the compounds of the invention can be combined with doxorubicin, taxotere (taxol), and / or cisplatin (carboplatin). For the treatment of ovarian cancer, the compounds of the invention can be combined with cisplatin (carboplatin), taxotere, doxorubicin, topotecan, and / or tamoxifen. Combining the compounds of the invention with taxotere (taxol), gemcitabine (capecitabine), tamoxifen, letrozole, tarceva, lapatinib, PD0325901, avastin, herceptin, OSI-906, and / or OSI-930 for the treatment of breast cancer Can do. For the treatment of lung cancer, the compounds of the invention can be combined with taxotere (Taxol), gemcitabine, cisplatin, pemetrexed, Tarceva, PD0325901, and / or Avastin.

  In other embodiments, agents useful in methods for combination therapy with one or more compounds of structure (I) include erlotinib, afatinib, iressa, GDC0941, MLN1117, BYL719 (alpericib), BKM120 (Buparurishibu (Buparlisib)), CYT387, GLPG0634, Barishichinibu, lestaurtinib, Momerochinibu, Pakurichinibu, RUXOLITINIB, TG101348, crizotinib, Chibanchinibu, AMG337, Kabozanchinibu, Forechinibu, Onarutsuzumabu, NVP-AEW541, dasatinib, Ponachinibu, Sarakachinibu, bosutinib, Trametinib, Selumetinib, kobimethinib, PD0325901, RO51226766, axitinib, bevacizumab, bosch Breakfast (Bostutinib), cetuximab, crizotinib, Hosutamachinibu, gefitinib, imatinib, lapatinib, lenvatinib, Iburuchinibu, nilotinib, panitumumab, pazopanib, pegaptanib, ranibizumab, RUXOLITINIB, sorafenib, sunitinib, SU6656, trastuzumab, tofacitinib, vandetanib, vemurafenib, irinotecan, taxol , Docetaxel, rapamycin, or MLN0128.

  Further therapeutic agents that can be combined with the compounds of the present invention are described in Goodman and Gilman's “The Pharmacological Basis of Therapeutics” Tenth Edition edited by Hardman, Limand and the whole book. (Incorporated as a reference in)).

  The compounds described herein can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Thus, in some embodiments, one or more compounds of the invention are co-administered with the other agents described above. When used in combination therapy, the compound described herein is administered concurrently or separately with the second agent. This combination administration can include simultaneous administration of two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein and any of the above agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound of the present invention and any of the above agents present in separate formulations can be co-administered. In another alternative, any of the above drugs can be administered immediately after administration of the compound of the invention, or vice versa. In some embodiments of the individual administration protocol, the compound of the invention and any of the above agents are administered at intervals of minutes, hours, or days.

  The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It should be understood that the scope of the invention is in no way limited to the scope of the following examples and preparations. In the following examples and throughout the specification and claims, molecules having a single chiral center exist as racemic mixtures unless otherwise stated. Molecules with two or more chiral centers exist as racemic mixtures of diastereomers unless otherwise stated. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art.

  The following examples are provided for illustrative purposes. Other compounds of structure (I) were prepared according to the following general procedure as shown in Table 1.

Example 1
Synthesis of 3- (1-acryloylpiperidin-3-yl) -6-chloro-8-fluoro-7- (2-fluoro-6-hydroxyphenyl) quinazolin-4 (3H) -one (1)

  Compound 1 was prepared according to the above synthetic scheme as follows.

3-amino-2,2′-difluoro-6′-methoxy- [1,1′-biphenyl] -4-carboxylic acid 1,2-amino-4-bromo-3-fluorobenzoic acid (10 g, 43 mmol) 1, To a stirred solution in 4-dioxane (400 mL) and H ₂ O (100 mL) was added 2-fluoro-6-methoxyphenylboronic acid (36 g, 213 mmol), tetrakis (triphenylphosphine) palladium (2.5 g, 2.15 mmol). ) And Na ₂ CO ₃ (27 g, 258 mmol) were added. The mixture was degassed several times, backfilled with N ₂ and stirred at 100 ° C. overnight. The mixture was partitioned with water (500 mL) and extracted with ethyl acetate (200 mL × 2). The organic layer was discarded and 1M HCl solution was added to the aqueous phase to adjust the pH to <3. The aqueous phase was extracted with ethyl acetate (200 mL × 2), washed with brine, dried over Na ₂ SO ₄ and concentrated to give the desired product (11 g, 92% yield) as a white solid. ESI-MS m / z: 280.1 [M + H] ^< +>.

3-Amino-6-chloro-2,2′-difluoro-6′-methoxy- [1,1′-biphenyl] -4-carboxylic acid RT 3-amino-2,2′-difluoro-6′-methoxy To a solution of [1,1′-biphenyl] -4-carboxylic acid (11 g, 39.6 mmol) in N, N-dimethylformamide (100 mL), N-chlorosuccinimide (5.27 g, 39. 6 mmol) was added. The resulting mixture was stirred at 100 ° C. for 1 hour. The mixture is cooled to RT, the reaction mixture is slowly added to water (300 mL), the mixture is filtered, the cake is dried and the desired product (11.5 g, 93.1% yield) is browned. Obtained as a solid.

6-Chloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinazolin-4-ol 3-amino-6-chloro-2,2'-difluoro-6'-methoxy- [1,1 ' To a mixture of -biphenyl] -4-carboxylic acid (8.1 g, 25.8 mmol) in EtOH (150 mL) was added formimidoamide acetate (35 g, 336.4 mmol). The mixture was stirred at 100 ° C. overnight. The reaction mixture was concentrated and water was added. The mixture was filtered and the cake was dried to give the desired product (7.5 g, 90.3% yield) as a pale yellow solid.

tert-Butyl 3- (6-chloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) -4-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxylate 6-chloro-8 To a solution of -fluoro-7- (2-fluoro-6-methoxyphenyl) quinazolin-4 (3H) -one (1.0 g, 3.1 mmol) in MeCN (20 mL) was added HATU (4.7 g, 12. 4 mmol), DBU (1.9 g, 12.4 mmol) and tert-butyl 3-aminopiperidine-1-carboxylate (2.3 g, 12.4 mmol) were added and the resulting mixture was stirred at RT for 48 h. . The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether = 1: 5 to 1: 3) to give the product (670 mg, 42.7% yield). ESI-MS m / z: 506.2 [M + H] ^< +>.

6-chloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) -3- (piperidin-3-yl) quinazolin-4 (3H) -one tert-butyl 3- (6-chloro-8- To a solution of fluoro-7- (2-fluoro-6-methoxyphenyl) -4-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxylate (230 mg, 0.57 mmol) in dichloromethane (10 mL), TFA (4 mL) was added and the resulting mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue (230 mg) was dissolved in DCM (10 mL), BBr ₃ (1.4 g, 5.7 mmol) was added at −78 ° C. and the mixture was stirred at RT for 3 h. The mixture was quenched with saturated NaHCO ₃ solution and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (MeOH / DCM = 1: 30) to give the product (150 mg, 67% yield). ESI-MS m / z: 392.1 [M + H] ^< +>.

3- (1-acryloylpiperidin-3-yl) -6-chloro-8-fluoro-7- (2-fluoro-6-hydroxyphenyl) quinazolin-4 (3H) -one 6-chloro-8-one at 0 ° C. Fluoro-7- (2-fluoro-6-methoxyphenyl) -3- (piperidin-3-yl) quinazolin-4 (3H) -one (150 mg, 0.38 mmol) and triethylamine (0.3 mL, 1.9 mmol) To a solution of acryloyl chloride in DCM (10 mL) was added acryloyl chloride (70 mg, 0.77 mmol) and the resulting mixture was stirred for 20 minutes. The mixture was quenched with saturated NaHCO ₃ solution and partitioned between water and dichloromethane. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was dissolved in THF (7 mL) and H ₂ O (7 mL). Lithium hydroxide hydrate (70 mg, 1.67 mmol) was added and the mixture was stirred at RT for 40 minutes. The pH of the mixture was adjusted to 7 and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by Pre-TLC plate (MeOH / DCM = 1: 20) to give the product (42 mg, 22.6% yield). ESI-MS m / z: 446.3 [M + H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d6) δ: 10.36 (s, 1H), 8.59 (s, 1H), 8.10 (s, 1H), 7.41-7.35 (m , 1H), 6.90-6.75 (m, 3H), 6.16 (d, J = 16.7 Hz, 1H), 5.73 (dd, J = 2.1, 10.6 Hz, 1H), 4.61-4.48 (m, 2H), 4.19 (dd, J = 12.2, 71.5 Hz, 1H), 3.55-2.65 (m, 1H), 3 20-30.09 (m, 1H), 2.28-2.16 (m, 1H), 2.04-1.88 (m, 2H), 1.59-1.53 (m, 1H) .

Example 2
Synthesis of N- (3- (6-chloro-8-fluoro-7- (2-fluoro-6-hydroxyphenyl) -4-oxoquinazolin-3 (4H) -yl) cyclobutyl) acrylamide (2)

  Compound 2 was prepared according to the above synthetic scheme as follows.

tert-Butyl 3- (6-chloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) -4-oxoquinazolin-3 (4H) -yl) cyclobutylcarbamate 6-chloro-8-fluoro To a solution of -7- (2-fluoro-6-methoxyphenyl) quinazolin-4 (3H) -one (0.6 g, 1.86 mmol) in MeCN (30 mL) was added HATU (1.4 g, 3.72 mmol). , DBU (1.7 g, 11.16 mmol) and tert-butyl 3-aminocyclobutylcarbamate (0.415 g, 2.23 mmol) were added and the resulting mixture was stirred at RT for 48 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether = 1: 3) to give the product (200 mg, 22% yield). ESI-MS m / z: 491.1 [M + H] ^< +>.

N- (3- (6-Chloro-8-fluoro-7- (2-fluoro-6-hydroxyphenyl) -4-oxoquinazolin-3 (4H) -yl) cyclobutyl) acrylamide tert-butyl 3- (6- Chloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) -4-oxoquinazolin-3 (4H) -yl) cyclobutylcarbamate (200 mg, 0.40 mmol) in DCM (5 mL) To this was added TFA (2 mL) and the resulting mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo. The residue was dissolved in DCM (3 mL), BBr ₃ (1 mL, 10.79 mmol) was added at −78 ° C. and the mixture was stirred at RT for 2 h. The mixture was quenched with MeOH and saturated NaHCO ₃ solution at −78 ° C. and then extracted with a mixed solvent (DCM: MeOH = 10: 1). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was dissolved in DCM (2 mL), Et ₃ N (162 mg, 1.6 mmol) and acryloyl chloride (55 mg, 0.6 mmol) were added at 0 ° C. and the resulting mixture was stirred for 20 minutes. The mixture was quenched with saturated NaHCO ₃ solution and partitioned between water and DCM. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was dissolved in THF (3 mL) and H ₂ O (2 mL). Lithium hydroxide hydrate (42 mg, 1.2 mmol) was added and the mixture was stirred at RT for 40 minutes. The pH of the mixture was adjusted to 6 and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by Pre-TLC plate (MeOH / dichloromethane = 1: 20) to give the product (31 mg over 4 steps, 18% yield). ESI-MS m / z: 431.1 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ: 10.35 (s, 1H), 8.75 (d, J = 6.7 Hz, 1H), 8.61 (s, 1H), 8.07 (D, J = 1.4 Hz, 1H), 7.40-7.34 (m, 1H), 6.87-6.79 (m, 2H), 6.30-6.23 (m, 1H) ), 6.15-6.10 (m, 1H), 5.63 (dd, J = 2.1, 9.9 Hz, 1H), 5.30-5.22 (m, 1H), 4.39. -4.33 (m, 1H), 2.91-2.84 (m, 2H), 2.48-2.44 (m, 2H).

Example 3
Synthesis of N- (4- (4-acetylpiperazin-1-yl) -6-chloro-8-fluoro-7- (2-fluoro-6-hydroxyphenyl) quinolin-3-yl) acrylamide (3)

  Compound 3 was prepared according to the above synthetic scheme as follows.

3-Bromo-2-fluorobenzenamine RT 1-bromo-2-fluoro-3-nitrobenzene (13.75 g, 62.76 mmol) in HOAc (26.36 g, 439 mmol), EtOH (150 mL) and H ₂ O ( To the mixture in 60 mL) was added iron powder (9.14 g, 163 mmol) in small portions. The resulting mixture was stirred at RT for 16 hours and then neutralized with NaOH (5N) solution. This mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 10: 1) to give the desired product (7.77 g, 65% yield) as a brown oil.

To a solution of 3-bromo-4-chloro-2-fluorobenzenamine RT in 3-bromo-2-fluorobenzenamine (1.9 g, 10 mmol) in DMF (10 mL) was added NCS (1.4 g, 10.5 mmol). ) Was added and the resulting mixture was stirred at RT for 16 h. The mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 30: 1) to give the desired product (1.15 g, 51% yield). ESI-MS m / z: 225.9 [M + H] ^< +>.

Diethyl 2-((3-bromo-4-chloro-2-fluorophenylamino) methylene) malonate 3-Bromo-4-chloro-2-fluorobenzenamine (2.3 g, 10.2 mmol) and diethyl 2- (ethoxy A mixture of methylene) malonate (2.42 g, 11.22 mmol) was stirred at 120 ° C. for 3 hours. The mixture was cooled to RT. Petroleum was added and stirred at RT for 1 hour. The precipitate was filtered and dried to give the desired product (2.76 g, 68.7% yield). ESI-MS m / z: 395.9 [M + H] ⁺ .

Ethyl 7-bromo-6-chloro-8-fluoro-4-hydroxyquinoline-3-carboxylate diethyl 2-((3-bromo-4-chloro-2-fluorophenylamino) methylene) malonate (2.76 g, 6 .99 mmol) was suspended in Ph ₂ O (20 mL). The mixture was stirred at 250 ° C. for 2 hours. The mixture was cooled to RT and then 100 mL of petroleum ether was added. The white solid was collected by filtration and rinsed with petroleum ether (100 mL) to give the desired product (1.85 g, 76% yield). ESI-MS m / z: 349.9 [M + H] ^< +>.

Ethyl 7-bromo-4,6-dichloro-8-fluoroquinoline-3-carboxylate Ethyl 7-bromo-6-chloro-8-fluoro-4-hydroxyquinoline-3-carboxylate (1.85 g, 5.31 mmol ) And POCl ₃ (10 mL) were stirred at reflux for 4 hours. The mixture was cooled to RT and concentrated in vacuo to give the crude product (1.41 g), which was used directly in the next step.

Ethyl 4- (4- (tert-butoxycarbonyl) piperazin-1-yl) -7-bromo-6-chloro-8-fluoroquinoline-3-carboxylate ethyl 7-bromo-4,6-dichloro-8-fluoro quinoline-3-carboxylate (1.41g, 3.84mmol), tert- butyl piperazine-1-carboxylate _{(1.43g, 7.68mmol), Et 3} N (1.55g, 15.36mmol) in DMSO ( In 20 mL) was stirred at 80 ° C. under argon for 2 hours. The mixture was cooled to RT, poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 3: 1) to give the desired product (1.96 g, 98% yield). ESI-MS m / z: 518.1 [M + H] ⁺ .

Ethyl 4- (4- (tert-butoxycarbonyl) piperazin-1-yl) -6-chloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinoline-3-carboxylate ethyl 4- (4 -(Tert-butoxycarbonyl) piperazin-1-yl) -7-bromo-6-chloro-8-fluoroquinoline-3-carboxylate (1.13 g, 2.19 mmol) and (2-fluoro-6-methoxyphenyl) ) Pd (PPh) ₄ was added under Ar to a mixture of boronic acid (1.86 g, 10.93 mmol) in aqueous Na ₂ CO ₃ (3.64 mL, 1.5 M) and dioxane (80 mL). The mixture was stirred at 90 ° C. for 16 hours. The solvent was removed and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 6: 1) to give the desired product (851 mg, 69% yield). ESI-MS m / z: 562.2 [M + H] ⁺ .

Ethyl 4- (4-acetylpiperazin-1-yl) -6-chloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinoline-3-carboxylate Ethyl 4- (4- (tert -Butoxycarbonyl) piperazin-1-yl) -6-chloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinoline-3-carboxylate (851 mg, 1.52 mmol) in DCM (20 mL) To the mixture was added TFA (4 mL) and the resulting mixture was stirred for 2 h. This mixture was added to a stirred mixture of 2M NaOH (40 mL) and ethyl acetate (40 mL). Acetyl chloride (4 mL) was then slowly added to the reaction. This mixture was extracted with ethyl acetate. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1: 1) to give the desired product (575 mg, 75% yield). ESI-MS m / z: 504.3 [M + H] ^< +>.

4- (4-Acetylpiperazin-1-yl) -6-chloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinoline-3-carboxylic acid ethyl 4- (4-acetylpiperazine-1- Yl) -6-chloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinoline-3-carboxylate (267 mg, 053 mmol) in THF (20 mL) and water (20 mL) Lithium oxide (111 mg, 2.651 mmol) was added and the resulting mixture was stirred at RT for 16 hours. The mixture was diluted with 2M NaOH (30 mL) and extracted with 50% ethyl acetate / petroleum ether. The aqueous layer was acidified with 1M HCl and extracted with ethyl acetate. The solvent was removed to give the product (277 mg, crude). ESI-MS m / z: 476.2 [M + H] ^< +>.

1- (4- (3-Amino-6-chloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinolin-4-yl) piperazin-1-yl) ethanone 4- (4-acetylpiperazine 1-yl) -6-chloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinoline-3-carboxylic acid (277 mg, 0.58 mmol) and _Et 3 N (235mg, _2.33mmol) To a mixture of DMF (20 mL) and t-BuOH (3 mL) was added DPPA (401 mg, 1.456 mmol) and the resulting mixture was stirred at 120 ° C. for 2.5 h. The mixture was cooled to RT and quenched with water (50 mL). The mixture was extracted with ethyl acetate and concentrated in vacuo. The residue was dissolved in a mixture of DCM (10 mL) and TFA (3 mL) and then stirred for 1 hour. This mixture was added to 2M NaOH (30 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM / MeOH = 30: 1) to give the desired product (120 mg, 46% yield). ESI-MS m / z: 447.2 [M + H] ^< +>.

1- (4- (3-Amino-6-chloro-8-fluoro-7- (2-fluoro-6-hydroxyphenyl) quinolin-4-yl) piperazin-1-yl) ethanone 1-(-78 ° C. 4- (3-Amino-6-chloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinolin-4-yl) piperazin-1-yl) ethanone (120 mg, 0.27 mmol) in DCM ( To the mixture in 10 mL) was added BBr ₃ (674 mg, 2.69 mmol) and the resulting mixture was stirred at RT for 2 h. The mixture was poured into ice water and partitioned between ethyl acetate and NaHCO ₃ solution. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give the desired product (194 mg, crude). ESI-MS m / z: 433.2 [M + H] ^< +>.

N- (4- (4-acetylpiperazin-1-yl) -6-chloro-8-fluoro-7- (2-fluoro-6-hydroxyphenyl) quinolin-3-yl) acrylamide 1- (4- (3 - amino-6-chloro-8-fluoro-7- (2-fluoro-6-hydroxyphenyl) quinolin-4-yl) piperazin-1-yl) ethanone (194 mg, 0.45 mmol) and _Et 3 N (181 mg, To a mixture of 1.80 mmol) in DCM (20 mL) and THF (20 mL) was added acryloyl chloride (162 mg, 1.796 mmol) and the resulting mixture was stirred at 0 ° C. for 30 min. The mixture was partitioned between DCM and NaHCO ₃ solution. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was dissolved in THF (10 mL) and water (10 mL) and lithium hydroxide (75 mg, 1.794 mmol) was added. The mixture was stirred at RT for 1 hour. The mixture was adjusted to pH 8 with 1N HCl and NaHCO ₃ solution and then extracted with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (DCM / MeOH = 30: 1) to give the desired product (32 mg, 24% yield over 2 steps). ESI-MS m / z: 487.3 [M + H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d6) δ: 10.26 (s, 1H), 10.06 (s, 1H), 8.70 (s, 1H), 8.04 (s, 1H), 7.39 (t, J ₁ = 7.6 Hz, J ₂ = 15.2 Hz, 1H), 6.88 (m, 2H), 6.61 (m, 1H), 6.36 (m, 1H ), 5.88 (m, 1H), 3.69 (m, 4H), 3.29 (m, 4H), 2.07 (s, 3H).

Example 4
Synthesis of 3- (1-acryloylazetidin-3-yl) -6-chloro-8-fluoro-7- (2-fluoro-6-hydroxyphenyl) quinazolin-4 (3H) -one (4)

  Compound 4 was prepared according to the above synthetic scheme as follows.

tert-Butyl 3- (6-chloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) -4-oxoquinazolin-3 (4H) -yl) azetidine-1-carboxylate 6-chloro-8 To a solution of -fluoro-7- (2-fluoro-6-methoxyphenyl) quinazolin-4 (3H) -one (1 g, 3.1 mmol) in MeCN (20 mL) was added HATU (3.53 g, 9.32 mmol). , DBU (4.73 g, 31.06 mmol) and tert-butyl 3-aminoazetidine-1-carboxylate (2.14 g, 12.42 mmol) were added and the resulting mixture was stirred at RT for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether = 1: 10 to 1: 2) to give the product (500 mg, 34% yield). ESI-MS m / z: 478.2 [M + H] ^< +>.

3- (azetidin-3-yl) -6-chloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinazolin-4 (3H) -one tert-butyl 3- (6-chloro-8- To a solution of fluoro-7- (2-fluoro-6-methoxyphenyl) -4-oxoquinazolin-3 (4H) -yl) azetidine-1-carboxylate (400 mg, 0.84 mmol) in DCM (10 mL) was added. TFA (4 mL) was added and the resulting mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue (220 mg) was dissolved in DCM (20 mL), BBr ₃ (0.2 mL, 2.16 mmol) was added at −78 ° C. and the resulting mixture was stirred at RT for 1.5 h. The mixture was quenched with saturated NaHCO ₃ solution and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel Pre-TLC plates (MeOH / DCM = 1: 10) to give the product (42 mg over 2 steps, 39% yield). ESI-MS m / z: 364.1 [M + H] ^< +>.

3- (1-Acryloylazetidin-3-yl) -6-chloro-8-fluoro-7- (2-fluoro-6-hydroxyphenyl) quinazolin-4 (3H) -one 3- (azetidine at -78 ° C. -3-yl) -6-chloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinazolin-4 (3H) -one (130 mg, 0.36 mmol) and triethylamine (217 mg, 2.15 mmol) To a solution of acryloyl in DCM (10 mL) was added acryloyl chloride (65 mg, 0.72 mmol) and the mixture was stirred at −60 ° C. for 20 minutes. The mixture was quenched with saturated NaHCO ₃ solution and partitioned between water and DCM. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was dissolved in THF (7 mL) and H ₂ O (7 mL). Lithium hydroxide hydrate (360 mg, 8.6 mmol) was added and the resulting mixture was stirred at RT for 40 minutes. The pH of the mixture was adjusted to 6 and then extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by Pre-TLC plate (MeOH / DCM = 1: 15) to give the product (42 mg, 29% yield). ESI-MS m / z: 418.1 [M + H] ⁺ . ¹ HNMR (400 MHz, DMSO-d6) δ: 10.36 (s, 1H), 8.53 (s, 1H), 8.09 (s, 1H), 7.40-7.34 (m, 1H) , 6.87-6.80 (m, 2H), 6.40-6.33 (m, 1H), 6.18-6.13 (m, 1H), 5.76-5.71 (m, 1H) 1H), 5.34-5.30 (m, 1H), 4.68-4.64 (m, 2H), 4.47-4.44 (m, 1H), 4.43-4.31 ( m, 1H).

Example 5
Synthesis of 3- (1-acryloylazetidin-3-yl) -6-amino-8-chloro-7- (3-hydroxynaphthalen-1-yl) quinazolin-4 (3H) -one (12)

2-bromo-6-nitroaniline 1-bromo-2-fluoro-3-nitrobenzene (20.0g, 91.37mmol) A mixture of and NH ₃ in _CH 3 OH solution (7M, 60 mL) at a sealed tube 100 Stir at 16 ° C. for 16 hours. The solvent was removed and the residue was dissolved in H ₂ O and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography eluting with (ethyl acetate / petroleum ether = 1: 100) to give the desired product as a yellow solid (16.0 g, 81.2% yield).

1-bromo-2-chloro-3-nitrobenzene 2-bromo-6-nitroaniline (16.0 g, 74.10 mmol), tert-butyl nitrite (11.40 g 111.15 mmol) and CuCl ₂ (12.0 g, A mixture of 88.90 mmol) in CH ₃ CN (160 mL) was stirred at 60 ° C. for 1 h under argon. The mixture was cooled to RT, quenched with H ₂ O and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica (ethyl acetate / petroleum ether = 1: 100) to give the product (15.0 g, 86.2% yield).

3-Bromo-2-chlorobenzenamine To a mixture of 1-bromo-2-chloro-3-nitrobenzene (15.0 g, 63.60 mmol), HOAc (20 mL), EtOH (120 mL) and H ₂ O (40 mL) in RT. Iron powder (10.7 g, 190.70 mmol) was added in small portions. The resulting mixture was stirred at RT for 16 hours and then neutralized with NaOH (5N) solution. This mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 10: 1) to give the desired product (14.0 g, 100% yield).

(E) -N- (3-Bromo-2-chlorophenyl) -2- (hydroxyimino) acetamide 2,2,2-trichloroethane-1,1-diol (13.5 g, 82.00 mmol) and Na ₂ SO ₄ A mixture of (87.3 g, 614.70 mmol) in water was warmed to 35 ° C. An aqueous solution of 3-bromo-2-chlorobenzenamine (14.0 g, 68.30 mmol) was added followed by 35% aqueous HCl (30 mL) and hydroxylamine hydrochloride (14.2 g, 204.90 mmol). The resulting mixture was stirred at 90 ° C. for 16 hours and a yellow precipitate formed. The mixture was cooled to RT. The solid was filtered, washed with water and air dried to give the desired product (14.5 g, 76.3% yield).

6-Bromo-7-chloroindoline-2,3-dione To concentrated sulfuric acid (120 mL) at 60 ° C., (E) -N- (3-bromo-2-chlorophenyl) -2- (hydroxyimino) acetamide (14. 5 g, 52.25 mmol) was added. The temperature was raised to 90 ° C. and maintained for 3 hours. The reaction mixture was cooled to RT and poured onto ice to give a yellow precipitate. The precipitate was collected by filtration and dried to give the desired product (7.4 g, 54.4% yield).

2-Amino-4-bromo-3-chlorobenzoic acid To a solution of 6-bromo-7-chloroindoline-2,3-dione (7.4 g, 28.57 mmol) in 2N NaOH (200 mL) at 0 ° C. H ₂ O ₂ (30%, 20 mL) was added and the resulting mixture was stirred at 0 ° C. for 30 minutes and then at RT for 16 hours. The mixture was poured into ice water and the solution was acidified with concentrated HCl. The precipitate was collected by filtration and air dried to give the desired product (2.5 g, 35.2% yield).

7-Bromo-8-chloroquinazolin-4 (3H) -one RT in 2-amino-4-bromo-3-chlorobenzoic acid (2.5 g, 10.00 mmol) in 2-methoxyethanol (50 mL) Was added formamidine acetate (6.2 g, 60.00 mmol) and the resulting mixture was stirred at reflux for 16 hours. The mixture was concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM / methanol = 100: 1 to 50: 1) to give the desired product (1.8 g, 69.2% yield). ESI-MS m / z: 258.8 [M + H] ^< +>.

7-Bromo-8-chloro-6-nitroquinazolin -4 (3H) - on RT of 7-bromo-8-chloroquinazoline -4 (3H) - on _{(1.8g, 6.95mmol) H 2 SO} 4 of To a solution in (20 mL) was added KNO ₃ (1.1 g, 10.42 mmol) and the mixture was stirred at 100 ° C. for 16 h. The mixture was poured into ice water. The precipitate was collected by filtration, washed with water and dried to give the desired product (1.5 g, 71.4% yield). ESI-MS m / z: 303.9 [M + H] ^< +>.

tert-Butyl 3- (7-bromo-8-chloro-6-nitro-4-oxoquinazolin-3 (4H) -yl) azetidine-1-carboxylate 7-bromo-8-chloro-6-nitroquinazoline-4 To a solution of (3H) -one (1.5 g, 4.93 mmol) in MeCN (20 mL) was added HATU (3.75 g, 9.86 mmol), DBU (4.5 g, 29.58 mmol) and tert-butyl 3. -Aminoazetidine-1-carboxylate (1.3 g, 7.40 mmol) was added and the resulting mixture was stirred at RT for 2 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether = 1: 5 to 1: 3) to give the product (1.0 g, 43.5% yield). ESI-MS m / z: 459.0 [M + H] ⁺ .

tert-butyl 3- (6-amino-7-bromo-8-chloro-4-oxoquinazolin-3 (4H) -yl) azetidine-1-carboxylate RT tert-butyl 3- (7-bromo-8- Chloro-6-nitro-4-oxoquinazolin-3 (4H) -yl) azetidine-1-carboxylate (300 mg, 0.66 mmol), HOAc (2 mL), EtOH (12 mL) and H ₂ O (4 mL) To this was added iron powder (183.4 mg, 3.28 mmol) in small portions and the resulting mixture was stirred at RT for 16 h. The mixture was neutralized with NaOH (2N) solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 10: 1) to give the desired product (283 mg, 100% yield).

tert-Butyl 3- (6-amino-8-chloro-7- (2-hydroxynaphthalen-4-yl) -4-oxoquinazolin-3 (4H) -yl) azetidine-1-carboxylate tert-butyl 3- (6-Amino-7-bromo-8-chloro-4-oxoquinazolin-3 (4H) -yl) azetidine-1-carboxylate (283 mg, 0.66 mmol), 3-hydroxynaphthalen-1-yl-1- Boronic acid (142.1 mg, 0.66 mmol), Pd (PPh ₃ ) ₄ (76.2 mg, 0.1 mmol) and Na ₂ CO ₃ (209.9 mg, 1.98 mmol) in 1,4-dioxane / H ₂ The mixture in O (16 mL / 4 mL) was stirred at 100 ° C. under argon for 16 hours. The mixture was cooled to RT and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the desired product as a white solid (150 mg, 46.2% yield).

6-amino-3- (azetidin-3-yl) -8-chloro-7- (2-hydroxynaphthalen-4-yl) quinazolin-4 (3H) -one tert-butyl 3- (6-amino-8- To a solution of chloro-7- (2-hydroxynaphthalen-4-yl) -4-oxoquinazolin-3 (4H) -yl) azetidine-1-carboxylate (150 mg, 0.30 mmol) in DCM (16 mL) was added. TFA (4 mL) was added and the resulting mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the desired product (80 mg).

3- (1-acryloylazetidin-3-yl) -6-amino-8-chloro-7- (2-hydroxynaphthalen-4-yl) quinazolin-4 (3H) -one 6-amino-3 at 0 ° C. -(Azetidin-3-yl) -8-chloro-7- (2-hydroxynaphthalen-4-yl) quinazolin-4 (3H) -one (80 mg, 0.20 mmol) and NaOH (5 mL, 2N) in THF ( To the mixture in 20 mL) was added acryloyl chloride (18 mg, 0.20 mmol) and the resulting mixture was stirred at 0 ° C. for 30 min. The mixture was partitioned between ethyl acetate and NaHCO ₃ solution. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (DCM / MeOH = 30: 1) to give the desired product (18 mg, 20.2% yield). ESI-MS m / z: 447.1 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ: 8.31 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz) , 1H), 7.47-7.43 (m, 1H), 7.35-7.33 (m, 1H), 7.26-7.21 (m, 2H), 7.10 (d, J = 2.8 Hz, 1H), 6.44 (dd, J = 1.6, 17.2 Hz, 1H), 6.24 (dd, J = 10.4, 17.2 Hz, 1H), 5 .79 (dd, J = 1.2, 10.4 Hz, 1H), 5.43-5.30 (m, 1H), 4.78-4.56 (m, 4H).

Example 6
Synthesis of 3- (1-acryloylazetidin-3-yl) -8-chloro-5-hydroxy-7- (3-hydroxynaphthalen-1-yl) quinazolin-4 (3H) -one (14)

2-Bromo-4-methoxy-6-nitrobenzenamine To a solution of 4-methoxy-2-nitrobenzenamine (6.72 g, 40 mmol) in DCM (70 mL) at −20 ° C. with bromine (2.50 mL, 48 mmol). It was dripped. The mixture was stirred at −20 ° C. for 30 minutes. The mixture was poured into ice water. The pH was adjusted to 8 with saturated aqueous sodium bicarbonate and then extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM / petroleum ether = 1: 2) to give the product (6.42 g, 65% yield). ESI-MS m / z: 247.0 [M + H] ^< +>.

1-bromo-2-chloro-5-methoxy-3-nitrite t- butyl nitrobenzene 60 ℃ (3.75g, 36.4mmol) and CuCl ₂ (3.92g, 29.2mmol) in acetonitrile (120 mL) To the solution was added 2-bromo-4-methoxy-6-nitrobenzenamine (6.0 g, 24.3 mmol) and the resulting mixture was stirred at 60 ° C. overnight. The mixture was concentrated in vacuo. The residue was dissolved in DCM (100 mL), washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM / petroleum ether = 1: 3) to give the product (5.01 g, 77% yield).

3-bromo-2-chloro-5-methoxybenzenamine RT 1-bromo-2-chloro-5-methoxy-3-nitrobenzene (5.01 g, 18.8 mmol) and HOAc (6 mL) in EtOH (36 mL) and To a mixture in H ₂ O (12 mL), iron powder (3.14 g, 56.3 mmol) was added in portions. The resulting mixture was stirred at RT for 16 hours and then neutralized with NaOH (5N) solution. This mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM / petroleum ether = 1: 3) to give the desired product (3.90 g, 88% yield) as a brown oil. ESI-MS m / z: 237.9 [M + H] ^< +>.

6-Bromo-7-chloro-4-methoxyindoline-2,3-dione 3-Bromo-2-chloro-5-methoxybenzenamine (3.9 g, 16.5 mmol) at 0 ° C. in 1,2-dichloromethane ( To the solution in 50 mL) was added oxalyl chloride (2.7 g, 21.4 mmol) and the resulting mixture was warmed to RT and stirred at RT for 4 h. The mixture was stirred at 55 ° C. for 30 minutes and cooled back to 0 ° C. AlCl ₃ (2.8 g, 21.4 mmol) was added in small portions. The mixture was stirred at 55 ° C. overnight. The mixture was diluted with DCM (50 mL), washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM / petroleum ether = 1: 3) to give the product (3.1 g, 65% yield). ESI-MS m / z: 291.9 [M + H] ⁺ .

2-Amino-4-bromo-3-chloro-6-methoxybenzoic acid 6-bromo-7-chloro-4-methoxyindoline-2,3-dione (3.1 g, 10.7 mmol) in 2N NaOH (80 mL) To the solution in was added H ₂ O ₂ (30%, 8 mL) at 0 ° C. and the mixture was stirred at 0 ° C. for 30 min. After stirring at room temperature for 16 hours, the mixture was poured into ice water, the solution was acidified with conc. HCl, the precipitate was filtered and air dried to give the desired product as a white solid (1.6 g, yield). Rate 53%). ESI-MS m / z: 278.9 [M + H] ^< +>.

7-Bromo-8-chloro-5-methoxyquinazolin-4 (3H) -one RT 2-amino-4-bromo-3-chloro-6-methoxybenzoic acid (1.6 g, 5.7 mmol) in ethanol (1.6 g To the solution in 25 mL) was added formamidine acetate (3.6 g, 34.3 mmol) and the resulting mixture was stirred at reflux for 16 hours. The mixture was concentrated in vacuo and the residue was diluted with water. This aqueous solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM / methanol = 100: 1-50: 1) to give the desired product (700 mg, 42% yield).

tert-Butyl 3- (7-bromo-8-chloro-5-methoxy-4-oxoquinazolin-3 (4H) -yl) azetidine-1-carboxylate 7-bromo-8-chloro-5-methoxyquinazoline-4 To a solution of (3H) -one (630 mg, 2.18 mmol) in MeCN (15 mL) is added HATU (1.66 g, 4.36 mmol), DBU (1.99 g, 13.08 mmol) and tert-butyl 3-amino. Azetidine-1-carboxylate (562 mg, 3.27 mmol) was added and the resulting mixture was stirred at 80 ° C. overnight. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether = 1: 1) to give the product (360 mg, 37% yield). ESI-MS m / z: 446.0 [M + H] ⁺ .

tert-butyl 3- (8-chloro-7- (2-hydroxynaphthalen-4-yl) -5-methoxy-4-oxoquinazolin-3 (4H) -yl) azetidine-1-carboxylate tert-butyl 3- (7-Bromo-8-chloro-5-methoxy-4-oxoquinazolin-3 (4H) -yl) azetidine-1-carboxylate (300 mg, 0.67 mmol), 3-hydroxynaphthalen-1-yl-1- Boronic acid (127 mg, 0.67 mmol), Pd (PPh ₃ ) ₄ (81 mg, 0.07 mmol) and Na ₂ CO ₃ (142 mg, 1.34 mmol) of 1,4-dioxane / H ₂ O (8 mL / 2 mL) The mixture in was stirred overnight at 100 ° C. under argon. The mixture was cooled to RT and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether = 1: 2) to give the product (221 mg, 65% yield). ESI-MS m / z: 508.2 [M + H] ^< +>.

3- (azetidin-3-yl) -8-chloro-7- (2-hydroxynaphthalen-4-yl) -5-methoxyquinazolin-4 (3H) -one tert-butyl 3- (8-chloro-7- To a solution of (2-hydroxynaphthalen-4-yl) -5-methoxy-4-oxoquinazolin-3 (4H) -yl) azetidine-1-carboxylate (160 mg, 0.44 mmol) in DCM (6 mL) was added. TFA (2 mL) was added and the resulting mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM / MeOH / NH ₃ H ₂ O = 5: 1: 0.2) to give the product (160 mg, 90% yield). ESI-MS m / z: 408.1 [M + H] ^< +>.

3- (azetidin-3-yl) -8-chloro-5-hydroxy-7- (2-hydroxynaphthalen-4-yl) quinazolin-4 (3H) -one 3- (azetidin-3-yl at -78 ° C ) -8-Chloro-7- (2-hydroxynaphthalen-4-yl) -5-methoxyquinazolin-4 (3H) -one (160 mg, 0.39 mmol) in DCM (5 mL) was added to BBr ₃ ( 490 mg, 1.96 mmol) was added slowly. The mixture was stirred at RT for 3 hours and poured into ice water. K ₂ CO ₃ was added. The mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (DCM / MeOH / NH ₃ H ₂ O = 5: 1: 0.2) to give the desired product (92 mg, 60% yield). ESI-MS m / z: 394.1 [M + H] ^< +>.

3- (1-Acryloylazetidin-3-yl) -8-chloro-5-hydroxy-7- (2-hydroxynaphthalen-4-yl) quinazolin-4 (3H) -one 3- (azetidine at -78 ° C -3-yl) -8-chloro-5-hydroxy-7- (2-hydroxynaphthalen-4-yl) quinazolin-4 (3H) -one (92 mg, 0.23 mmol) and DIPEA (59 mg, 0.46 mmol) To a mixture of acryloyl chloride (21 mL, 0.23 mmol) in DCM (5 mL) was added dropwise. The mixture was stirred at -78 ° C for 10 minutes. The mixture was concentrated in vacuo and the residue was purified by prep-TLC plate (DCM / MeOH = 8: 1) to give the desired product (8 mg, 8% yield). ESI-MS m / z: 448.1 [M + H] ⁺ . 1H NMR (400 MHz, CDCl ₃ ) δ: 11.36 (s, 1H), 8.28 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.45-7.41. (M, 1H), 7.35-7.32 (m, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.24-7.21 (m, 1H), 7. 06 (d, J = 2.4 Hz, 1H), 7.03 (s, 1H), 6.44 (dd, J = 1.6, 17.2 Hz, 1H), 6.24 (dd, J = 10.4, 16.8 Hz, 1H), 5.80 (dd, J = 1.6, 10.8 Hz, 1H), 5.41-5.34 (m, 1H), 4.77- 4.57 (m, 4H).

Example 7
Compound Biochemical Assays Test compounds were prepared as 10 mM DMSO stock solutions (Fisher catalog number BP-231-100). KRAS G12C 1-169 (his tagged protein, GDP loading) was diluted to 2 μm with buffer (20 mM Hepes, 150 mM NaCl, 1 mM MgCl ₂ ). Compounds were tested for activity as follows.

Compounds were diluted to 50 × final test concentration in DMSO in 96 well storage plates. The compound stock solution was vortexed prior to use and carefully observed for any signs of precipitation. Dilution was as follows.
1. To achieve a final compound concentration of 100 μM, compounds were diluted to 5000 μM (5 μl 10 mM compound stock + 5 μl DMSO) and mixed well by pipetting.
2. To achieve a final compound concentration of 30 μM, the compound was diluted to 1500 μM (3 μl 10 mM compound stock + 17 μl DMSO) and mixed well by pipetting.
3. To achieve a final compound concentration of 10 μM, compounds were diluted to 500 μM (2 μl 10 mM compound stock + 38 μl DMSO) and mixed well by pipetting.

49 μl of protein stock solution was added to each well of a 96-well PCR plate (Fisher catalog number 1423027). 1 μl of 50 × diluted compound was added to the appropriate wells in the PCR plate using a 12-channel pipettor. The reaction was carefully and thoroughly mixed by pipetting up and down using a 200 μl multichannel pipettor. Plates were fully sealed with aluminum plate seals and stored in drawers at room temperature for 30 minutes, 2 hours, or 24 hours. 5 μl of 2% formic acid (Fisher catalog number A117) in DI H ₂ O was then added to each well and mixed using a pipette. The plate was then resealed with an aluminum seal and stored on dry ice until analyzed as described below.

  The assay was analyzed by mass spectrometry according to one of the following two procedures.

RapidFire / TOF assay:
The MS device is set to positive polarity, 2 GHz resolution, and low mass (1700) mode and equilibrated for 30 minutes. The instrument is then calibrated and switched to acquisition mode and the appropriate method is loaded.

  After an additional 30 minutes equilibration time, run in a blank batch (ie, buffer) to ensure that the device is operating properly. Thaw samples at 37 ° C. for 10 minutes, centrifuge briefly, and transfer to bench top. Wells A1 and H12 are spiked with 1 uL of 500 uM internal standard peptide and the plate is centrifuged at 2000 × g for 5 minutes. The method is then performed and the mass of each well is recorded.

  Paste the mass of each well (preferably integrated data) into the plate map and export from the analysis. The internal standard mass is also exported. Data at 50 ppm is extracted for charge state +19, and internal standard spikes are used to assign and integrate well A1 identity. The peak data is exported as a TOF list and the above process is repeated for charge states +20, 21, 22, 23, 24, and 25, respectively.

Q-Exactive assay:
The mass and peak intensity of the KRAS G12C protein species were measured using a Dionex RSLC nanosystem (Thermo Scientific) connected to a Q Exclusive Plus mass spectrometer (Thermo Scientific).

20 mL of each sample was prepared using 20% solvent A (0.1% formic acid in H ₂ O) and 80% solvent B (0.1% formic acid in acetonitrile) at a flow rate of 600 μl min− ¹ . Loaded onto a maintained Aeros ™ 3.6 μm WIDEPORE C4 200Å, LC Column 50 × 2.1 mm column. Liquid chromatography conditions were: 20% solvent B for 1 minute, 20% to 60% solvent B for 1.5 minutes, 60% to 90% solvent for 0.5 minutes, 90% solvent B for 0.2 minutes, 0 90% -20% solvent B for 2 minutes, then equilibration for 1.6 minutes, after which the sample was injected. The flow rate was maintained at 600 μl min- ¹ throughout the sample analysis.

  The mass spectrometer was operated in a profile mode of 17500 resolution, 5 microscan using a maximum injection time of 50 milliseconds and an AGC target of 1e6, and a total mass range of 800-1850 m / z was recorded. The HCD trapping gas was optimized to maximize sensitivity to intact proteins. The method of ionization was electrospray ionization using a 4 kV spray voltage, a sheath gas flow set at 50 au, an auxiliary gas flow set at 10 au, and a sweep gas flow set at 1 au. The capillary ion transfer temperature was 320 ° C. and the S-lens RF level was set to 50 voltages. Protein Devolution software (Thermo Scientific) was used to deconvolute the charge envelope of the protein species in the sample.

  Data was analyzed using a Thermo protein deconvolution package. Briefly, the charge envelope for each observed species was quantitatively deconvoluted to determine the mass and intensity of each parent species (modified protein or unmodified protein). The% modification was calculated based on the deconvoluted peak intensity.

  Other in vitro analyzes are shown below.

Inhibition of cell growth:
The ability of the compounds of the present invention to inhibit RAS-mediated cell growth is evaluated and demonstrated as follows. Cells expressing wild type RAS or mutant RAS are plated at a density of 5,000 cells / well in white clear bottom 96 well plates. Cells are allowed to attach for approximately 2 hours after plating and the compounds disclosed herein are added. After a certain time (eg, after 24, 48, or 72 hours of cell growth), measure cell proliferation and total ATP content using Cell Titer Glo reagent (Promega) according to manufacturer's instructions. Determined by. Proliferation EC50 is determined by analysis of 8-point compound dose response decreasing from 100 μM at half-log intervals.

Inhibition of RAS-mediated signaling:
The ability of the compounds disclosed herein to inhibit RAS-mediated signaling is evaluated and demonstrated as follows. Cells expressing wild type RAS or mutant RAS (such as G12C, G12V, or G12A) are treated with or without (control cells) the compounds of the invention. Phosphorylated MEK, phosphorylation in cells treated with one or more compounds of the present invention when inhibition of RAS signaling by one or more compounds of the present invention is compared to control cells Evidence is demonstrated by reduced steady state levels of ERK, phosphorylated RSK and / or Raf binding.

^＊別途記載がない限り、結合活性を２時間後に測定した
＋は、５％までの結合活性を示す。
＋＋は、５％から５０％までの結合活性を示す。
＋＋＋は、５０％またはそれよりも多くの結合活性を示す。
†は、４時間後に測定した結合活性を示す。
‡は、６時間後に測定した結合活性を示す。
ＴＢＤ＝未測定 When compound 2 was tested according to the above method, it was found to be covalently bound to KRAS G12C in a range greater than about 30% (ie, at least about 30% of the protein present in the well was shared by the test compound). Found to bind). Other compounds were tested under similar conditions. The results are shown in Table 2.

^* Unless otherwise indicated, binding activity measured after 2 hours + indicates up to 5% binding activity.
++ indicates 5% to 50% binding activity.
+++ indicates 50% or more binding activity.
† indicates the binding activity measured after 4 hours.
‡ indicates the binding activity measured after 6 hours.
TBD = not measured

  All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications or accompanying application data sheets referred to in this specification are to the fullest extent consistent with this description. Is incorporated herein by reference.

  US Provisional Patent Application No. 62 / 195,636, filed July 22, 2015, US Provisional Patent Application No. 62 / 342,078, filed May 26, 2016, July 21, 2016 GCC Patent Application No. 31750, filed on July 21, and Jordan Patent Application No. 150/2016, filed July 21, 2016, are hereby incorporated by reference in their entirety.

  From the foregoing, it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications are possible without departing from the spirit and scope of the invention. Let's go. Accordingly, the invention is not limited except as by the appended claims.

Claims (70)

The following structure (I):

(Where
A is N or C;
B is oxo, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl, amino, alkylamino, _arylamino, -CO 2 H, -CONH _2, aminyl carbonyl, aminyl carbonyl alkyl, heteroarylamino, halo, haloalkyl, alkoxy, haloalkoxy, aryl or ^-X-L 2 -R ^a,;
X is —NR ^b — or —O—;
L ¹ is alkylene, cycloalkylene, heterocyclylene, or absent;
L ² is alkylene or absent;
R is, H, cyano, amino, halo, haloalkyl, hydroxyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aryl, _heteroaryl, -CO 2 H, -CONH _2, aminyl _carbonyl, C 1 -C ₆ alkyl, C It is ₁ -C ₆ alkyl aminyl or _C 1 -C ₆ alkoxy;
R ^a is cycloalkyl, heterocyclyl, heteroaryl, — (C═O) OH, — (C═O) NH ₂ , or — (C═O) NHOH;
R ^b is independently at each occurrence H or C ₁ -C ₆ alkyl;
R ¹ is aryl or heteroaryl;
R ^2a , R ^2b and R ^2c are each independently H, amino, cyano, halo, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylaminyl, —NR ^b (C═O) R ^b, _C 1 -C _{6 haloalkyl,} C 1 -C _{6 alkoxy,} C 3 -C ₈ cycloalkyl, _{heterocyclylalkyl,} C 2 -C _{6 alkynyl,} C 2 -C ₆ alkenyl, aminyl alkyl, aminyl alkyl, Is cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl, or aryl;

Is a single or double bond that satisfies all valences;
E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of the KRAS, HRAS, or NRAS G12C variant protein)
Or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof.   2. The compound of claim 1, wherein B is cycloalkyl, heterocyclyl, or heteroaryl. L ¹ is either an alkylene or absent The compound according to any one of claims 1 or 2. Said compound has the following structure (IA):

(Where
G ¹ is N or CH;
G ² is NR ^c or CHR ^c ;
R ^c is H, alkyl, alkylcarbonyl, aminocarbonyl, alkylcarbonylaminyl, aminocarbonylaminyl, or heteroarylcarbonyl;
R ^3a and R ^3b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C. ₆ haloalkoxy, C ₂ -C ₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl; or R ^3a and R ^{3 3b} together form an oxo, carbocyclic or heterocyclic ring; or R ^3a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkynyl, hydroxyalkyl, A Lucoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl, R ^3b together with R ^4b is a carbocyclic or heterocyclic ring Forming a formula ring;
R ^4a and R ^4b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C. ₆ haloalkoxy, C ₂ -C ₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl; or R ^4a and R ^{4 4b} together form an oxo, carbocyclic or heterocyclic ring; or R ^4a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkynyl, hydroxyalkyl, A Lucoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl, R ^4b together with R ^3b is a carbocyclic or heterocyclic ring Forming a formula ring;
m ¹ and m ² are each independently 1, 2, or 3;
n is an integer of 0 to 5)
The compound of any one of Claims 1-3 which has these. Said compound has the following structure (IAa) or (IAb):

(Wherein, ^{p 1} is an integer of 0 to 3) with a compound of claim 4. The compound has the following structure (IAc), (IAd), or (IAe):

6. A compound according to any one of claims 4 or 5 having one of: The compound according to any one of claims 4 to 6, wherein R ^c is alkylcarbonyl, aminocarbonyl, alkylcarbonylaminyl, aminocarbonylaminyl, or heteroarylcarbonyl.   8. The compound of claim 7, wherein the alkylcarbonyl is substituted with aminocarbonyl, hydroxylaminocarbonyl, hydroxyl, or amino. R ^c has the following structure:

(Wherein p ² is an integer of 1 to 3)
9. A compound according to any one of claims 4 to 8 having one of the following. ^2. The compound of claim 1, wherein B is alkyl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl, or -XL2- ^Ra . B is ^-X-L 2 -R ^a, compound of claim 10. 12. A compound according to claim 11 wherein R ^<a> is heterocyclyl or heteroaryl. L ¹ is either an alkylene or absent The compound according to any one of claims 10 to 12. Said compound has the following structure (IB) or (IC):

(Where
H represents a 5- or 6-membered heteroaryl ring optionally substituted with one or more of R ^3a , R ^3b , R ^4a , and R ^4b ;
G ¹ is N or CH;
G ² is NR ^c or CHR ^c ;
R ^c is H, alkyl, alkylcarbonyl, aminocarbonyl, alkylcarbonylaminyl, aminocarbonylaminyl, or heteroarylcarbonyl;
R ^3a and R ^3b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C. ₆ haloalkoxy, C ₂ -C ₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl; or R ^3a and R ^{3 3b} together form an oxo, carbocyclic or heterocyclic ring; or R ^3a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkynyl, hydroxyalkyl, A Lucoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl, R ^3b together with R ^4b is a carbocyclic or heterocyclic ring Forming a formula ring;
R ^4a and R ^4b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C. ₆ haloalkoxy, C ₂ -C ₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl; or R ^4a and R ^{4 4b} together form an oxo, carbocyclic or heterocyclic ring; or R ^4a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkynyl, hydroxyalkyl, A Lucoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl, R ^4b together with R ^3b is a carbocyclic or heterocyclic ring Forming a formula ring;
m ¹ and m ² are each independently 1, 2, or 3;
n is an integer of 0 to 5)
14. A compound according to any one of claims 10 to 13 having one of the following.   15. A compound according to claim 14, wherein H is pyrrolidinyl or pyridinyl. Said compound has the following structure (IBa) or (IBb):

Wherein R ^d is independently at each occurrence H, halo, or hydroxyl, and p ³ is an integer from 0 to 3.
15. A compound according to claim 14 having one of the following: The compound has the following structure (IBc), (IBd), (IBe), or (IBf):

17. A compound according to any one of claims 14 to 16 having one of the following.   18. A compound according to any one of claims 11 to 17, wherein X is NH. L ² is absent The compound according to any one of claims 11 to 18. The compound according to any one of claims 11 to 18, wherein L ² is alkylene. B has the following structure:

21. A compound according to any one of claims 11 to 20 having one of: Said compound has the following structure (ID):

(Wherein p ³ is an integer of 0 to 3)
12. A compound according to claim 11 having R ^a is, - (C = O) OH , - (C = O) NH 2 or is - (C = O) NHOH, The compound of claim 22. The compound has the following structure (IDa):

24. A compound according to any one of claims 22 or 23 having   25. A compound according to any one of claims 22 to 24, wherein X is NH.   11. A compound according to claim 10, wherein B is alkyl. Alkyl, - (C = O) OH, - (C = O) NH ₂ or, - (C = O) is replaced by NHOH, compound of claim 26.   11. A compound according to claim 10, wherein B is heteroarylalkyl.   29. The compound of claim 28, wherein the heteroarylalkyl is pyrrolidinylalkyl or pyridinylalkyl.   2. A compound according to claim 1 wherein B is oxo. Said compound has the following structure (IE):

(Where
G ¹ is CH;
G ² is N or CH;
R ^3a and R ^3b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C. ₆ haloalkoxy, C ₂ -C ₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl; or R ^3a and R ^{3 3b} together form an oxo, carbocyclic or heterocyclic ring; or R ^3a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkynyl, hydroxyalkyl, A Lucoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl, R ^3b together with R ^4b is a carbocyclic or heterocyclic ring Forming a formula ring;
R ^4a and R ^4b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C. ₆ haloalkoxy, C ₂ -C ₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl; or R ^4a and R ^{4 4b} together form an oxo, carbocyclic or heterocyclic ring; or R ^4a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 1 -C _{6 haloalkoxy,} C 2 -C ₆ alkynyl, hydroxyalkyl, A Lucoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, or aminylcarbonyl, R ^4b together with R ^3b is a carbocyclic or heterocyclic ring Forming a formula ring;
m ¹ and m ² are each independently 1, 2, or 3)
32. The compound of claim 30, having: The compound has the following structure (IEa), (IEb), (IEc), or (IEd):

32. The compound of claim 31, having one of: The compound has the following structure (IEe), (IEf), (IEg), (IEh), (IEi), (IEj), (IEk), or (IEl):

33. A compound according to any one of claims 31 or 32 having one of the following: R ¹ is aryl, a compound according to any one of claims 1 to 33. R ¹ is phenyl A compound according to claim 34. R ¹ is a naphthyl compound according to claim 34. R ¹ is one or than is substituted with a number of substituents, compounds according to any one of claims 34 to 36. R ¹ is halo, amino, hydroxyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cyano, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, alkyl aminyl , cycloalkyl, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylthio luer mini Le, cycloalkyl aminyl, aryl, heteroaryl, phosphate, Hosuhoarukokishi, boronic acid, boronic acid ester, -OC (= O) R, or _C 1 -C ₆ substituted with alkylcarbonyloxy or combinations thereof, wherein, R is C ₁ -C ₆ alkyl, a compound according to claim 37. R ¹ is fluoro, chloro, cyclopropyl, cyclobutyl, hydroxy, amino, methyl, ethyl, isopropyl, trifluoromethyl, or methoxy, or substituted with a combination thereof, A compound according to claim 38. R ¹ has the following structure:

40. A compound according to any one of claims 34 to 39 having one of the following. R ¹ is heteroaryl, A compound according to any one of claims 1 to 33. R ¹ has the following structure:

42. The compound of claim 41, having one of: R ^2c is H, and A compound according to any one of claims 1-42. R ^2a and ^{R 2b} are each independently halo, haloalkyl, alkyl, amino, hydroxyl or alkoxy, A compound according to any one of claims 1 to 43,. R ^2a is fluoro, chloro or methoxy, A compound according to any one of claims 1 to 44,. R ^2b is chloro, fluoro, amino, hydroxyl, or CF is ₃ A compound according to any one of claims 1 to 45.   47. The compound of any one of claims 1-46, wherein R is H. E has the following structure:

(Where

Represents a double bond or a triple bond;
Q is —C (═O) —, —C (═NR ^{8 ′} ) —, —NR ⁸ C (═O) —, —S (═O) ₂ —, or —NR ⁸ S (═O) _2. -Is;
R ⁸ is H, C ₁ -C ₆ alkyl, hydroxyl alkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C ₃ -C ₈ cycloalkyl, Or is heterocycloalkyl;
R ^{8 ′} is H, —OH, —CN, or C ₁ -C ₆ alkyl;

R ⁹ and R ¹⁰ are each independently H, halo, cyano, carboxyl, C ₁ -C ₆ alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, Is heterocyclyl, heterocyclylalkyl, heteroaryl, or hydroxylalkyl, or R ⁹ and R ¹⁰ together form a carbocyclic, heterocyclic, or heteroaryl ring;

Is a triple bond, R ⁹ is absent and R ¹⁰ is H, C ₁ -C ₆ alkyl, aminylalkyl, alkylaminylalkyl, or hydroxylalkyl)
48. The compound of any one of claims 1-47, having   49. The compound of claim 48, wherein Q is -C (= O)-. 49. The compound of claim 48, wherein Q is -S (= O) _2- . Q ^{is, -NR 8 C (= O)} - in which A compound according to claim 48. Q _{^{is, -NR 8 S (= O)}} 2 - A compound according to claim 48. Each of R ⁹ and ^{R 10} is H, A compound according to any one of claims 48-52. E has the following structure:

54. A compound according to any one of claims 1 to 53 having one of the following.   The compound of claim 1, wherein the compound is selected from the compounds in Table 1.   56. A substantially purified atropisomer of the compound of any one of claims 1-55.   57. A pharmaceutical composition comprising a compound according to any one of claims 1 to 56 and a pharmaceutically acceptable carrier.   58. The pharmaceutical composition of claim 57, wherein the pharmaceutical composition is formulated for oral administration.   58. The pharmaceutical composition of claim 57, wherein the pharmaceutical composition is formulated for injection.   58. A method of treating cancer comprising administering an effective amount of the pharmaceutical composition of claim 57 to a subject in need of said treatment.   61. The method of claim 60, wherein the cancer is mediated by a KRAS G12C mutation, an HRAS G12C mutation, or an NRAS G12C mutation.   61. The method of claim 60, wherein the cancer is blood cancer, pancreatic cancer, MYH-related polyposis, colorectal cancer, or lung cancer.   57. A method of modulating the activity of a KRAS, HRAS, or NRAS G12C variant protein, comprising reacting the KRAS G12C variant protein with a compound of any one of claims 1-56.   57. A method of inhibiting the growth of a cell population comprising contacting the cell population with a compound according to any one of claims 1-56.   65. The method of claim 64, wherein inhibition of proliferation is measured as a decrease in cell viability of the cell population. The method of treating a disorder in a subject in need of treatment of a disorder mediated by a KRAS G12C mutation, an HRAS G12C mutation, or an NRAS G12C mutation, comprising:
Determining whether the subject has a KRAS, HRAS, or NRAS G12C mutation; and if the subject is determined to have the KRAS, HRAS, or NRAS G12C mutation, the subject is treated 58. A method comprising administering an effective amount of the pharmaceutical composition of claim 57.   68. The method of claim 66, wherein the disorder is cancer.   68. The method of claim 67, wherein the cancer is blood cancer, pancreatic cancer, MYH-related polyposis, colorectal cancer, or lung cancer.   57. A method of preparing a labeled KRAS, HRAS, or NRAS G12C variant protein, wherein the KRAS, HRAS, or NRAS G12C variant is reacted with a compound of any one of claims 1-56. Obtaining the labeled KRAS, HRAS, or NRAS G12C protein.   58. A method of inhibiting tumor metastasis comprising administering an effective amount of the pharmaceutical composition of claim 57 to a subject in need of said inhibition.

Images