2-(2-Acryloyl-2,6-diazaspiro[3.4]octan-6-yl)-6-(1H-indazol-4-yl)-benzonitrile derivatives and related compounds as inhibitors of G12C mutant KRAS protein to inhibit tumor metastasis

Abstract

The present invention provides, for example, 2-(2-acryloyl-2,6-diazaspiro[3.4]octan-6-yl)-6-(1H-indazol-4-yl)-benzonitrile and, for example, 2-(2-acryloyl-2,7-diazaspiro[3.5]nonan-7-yl)-6-(1H-indazol-4-yl)-benzonitrile derivatives and related compounds of formula (I) as inhibitors of G12C mutant KRAS proteins for treating tumor metastasis. The present specification discloses exemplary compounds (e.g., pages 53-90; Table 1; compounds I-1 to I-141), pharmacological data (e.g., pages 125-128; Table 2; Example 1), and their syntheses (e.g., pages 129-143; Examples 2 to 7). TIFF2022505835000136.tif4448

Description

[Technical field]

[0001] background Technical Field Embodiments of the present disclosure relate generally to novel compounds, for example for the treatment of cancer, and methods for their preparation and use as therapeutic or prophylactic agents. [Background technology]

[0002] 2. Description of Related Art RAS represents a group of closely related monomeric globular proteins of 189 amino acids (molecular mass 21 kDa) that associate with the plasma membrane and bind either GDP or GTP. RAS acts as a molecular switch. When RAS has bound GDP, it is in the resting or off state and is "inactive". In response to exposure of cells to certain growth-promoting stimuli, RAS is induced to exchange bound GDP for GTP. Upon GTP binding, RAS "switches on" and is able to interact with and activate other proteins (its "downstream targets"). The RAS protein itself has a very low endogenous ability to hydrolyze GTP back to GDP, thereby turning itself into the off state. Switching off RAS requires exogenous proteins called GTPase-activating proteins (GAPs), which interact with RAS and highly promote the conversion of GTP to GDP. Any mutation in RAS that affects its ability to interact with GAP or convert GTP back to GDP prolongs the activation of the protein, thereby prolonging the signals that tell cells to continue growing and dividing. Because these signals cause cells to grow and divide, overly active RAS signaling can ultimately lead to cancer.

[0003] Structurally, RAS proteins contain a G domain that is responsible for the enzymatic activity of RAS (guanine nucleotide binding and hydrolysis (GTPase reaction)). RAS proteins also contain a C-terminal extension region known as the CAAX box, which can be post-translationally modified and is responsible for targeting RAS proteins to membranes. The G domain is approximately 21-25 kDa in size and contains a phosphate-binding loop (P-loop). The P-loop represents the pocket in the RAS protein where nucleotides are bound and is the 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 contains the so-called switch I region (residues 30-40) and switch II region (residues 60-76), which together are the dynamic parts of the protein often represented as a "spring-loaded" mechanism due to their ability to switch between resting and loaded states. The key interactions are the hydrogen bonds formed by threonine-35 and glycine-60 with the γ-phosphate of GTP, which maintain the switch 1 and switch 2 regions, respectively, in their active conformations. After hydrolysis of GTP and release of the phosphate, the two relax to the inactive GDP conformation.

[0004] The most prominent members of the RAS subfamily are HRAS, KRAS, and NRAS, which are primarily involved in many cancer types, but there are numerous other members, including DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS, and RRAS2.

[0005] Mutations in any one of the three major isoforms of the RAS gene (HRAS, NRAS, or KRAS) are the most common events in human tumor development. Approximately 30% of all human tumors have been found to harbor some RAS gene mutation. Surprisingly, KRAS mutations are detected in 25-30% of tumors. In comparison, the proportion of oncogenic 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 in the P-loop and at residue Q61.

[0006] G12C is a frequent mutation in the KRAS gene (glycine-12 to cysteine). This mutation is found in about 13% of cancers, about 43% of lung cancers, and nearly 100% of MYH-associated polyposis (familial colon cancer syndrome). However, targeting this gene with small molecules has been difficult.

[0007] Thus, despite advances in the field, there remains a need in the art for improved compounds and methods for treating cancer, for example, by inhibition of KRAS, HRAS, or NRAS. Embodiments of the present disclosure fulfill this need and further provide related advantages. Summary of the Invention [Means for solving the problem]

[0008] overview Briefly, the present disclosure provides a compound (including its pharma- ceutically acceptable salt, isotopic form, stereoisomer or prodrug) that can modulate G12C mutant KRAS, HRAS, and / or NRAS protein. In some examples, the compound acts as an electrophile that can form a covalent bond with the cysteine ​​residue at position 12 of KRAS, HRAS, or NRAS G12C mutant protein. Also provided are methods of using such compounds for treating various diseases or conditions, such as cancer.

[0009] In one embodiment, the following structure (I): [ka] [In the formula, R 1 , R 2 , R 3a , R 3b , R 3c , L 1 , L 2 , L 3 , A 1 , A 2 , A 3 , A 4 , G 1 , G 2 , E, m1, m2, n1 and n2 are as defined herein, or a pharma- ceutically acceptable salt, stereoisomer, isotopic form or prodrug thereof. In various other embodiments, pharmaceutical compositions are also provided that include one or more compounds of structure (I) and a pharma- ceutically acceptable carrier.

[0010] In other embodiments, the disclosure provides a method of treating cancer comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of any one or more of the compounds of structure (I).

[0011] Other provided methods include a method of modulating the activity of a KRAS, HRAS, or NRAS G12C mutant protein, comprising reacting the KRAS, HRAS, or NRAS G12C mutant protein with any one of the compounds of structure (I).In other embodiments, a method of inhibiting the proliferation of a cell population is also provided, comprising contacting the cell population with any one of the compounds of structure (I).

[0012] In other embodiments, the disclosure provides a method of treating a disorder mediated by a KRAS, HRAS, or NRAS G12C mutation in a subject in need of such treatment, comprising: determining whether the subject has a KRAS, HRAS, or NRAS G12C mutation; and If the subject is determined to have a G12C mutation in KRAS, HRAS, or NRAS, then administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of structure (I).

[0013] In yet a further embodiment, the disclosure relates to a method of preparing a labeled KRAS, HRAS, or NRAS G12C mutant protein, comprising reacting a KRAS, HRAS, or NRAS G12C mutant with a compound of structure (I) to obtain a labeled KRAS, HRAS, or NRAS G12C protein.

[0014] These and other aspects of the present disclosure will become evident upon reference to the following detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Detailed Description In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the present disclosure. However, it will be understood by those skilled in the art that the present disclosure may be practiced without these details.

[0016] Unless the context requires otherwise, throughout this specification and claims, the term "comprise" and variations thereof (such as "comprises" and "comprising") are to be construed as open-ended, i.e., inclusive, such as "including, but not limited to."

[0017] Any concentration range, percentage range, ratio range, or integer range herein should be understood to include any integer and, where appropriate, fractions thereof (e.g., tenths and hundredths of integers, etc.) within the recited range, unless otherwise indicated. Also, any numerical range recited herein for any physical characteristic, such as polymer subunits, size, or thickness, should be understood to include any integer within the recited range, unless otherwise indicated. As used herein, the terms "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of the indicated range, value, or structure, unless otherwise indicated. As used herein, the terms "a" and "an" should be understood to refer to "one or more" of the recited components. The use of alternatives (e.g., "or") should be understood to mean one, both, or any combination of the alternatives.

[0018] Throughout this specification, a reference to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Thus, the phrases "in one embodiment" or "in an embodiment" appearing in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise.

[0020] "Amino" refers to the -NH2 radical.

[0021] “Carboxyl” or “carboxyl” refers to the —CO2H radical.

[0022] "Cyano" refers to the -CN radical.

[0023] "Hydroxy" or "hydroxyl" refers to the --OH radical.

[0024] "Nitro" refers to the -NO2 radical.

[0025] "Oxo" refers to the =O substituent.

[0026] "Thioxo" refers to the ═S substituent.

[0027] "Alkyl" means an alkyl group consisting solely of carbon and hydrogen atoms and having 1 to 12 carbon atoms (C1 to C 12 "alkyl" refers to a saturated straight or branched hydrocarbon chain radical having from 1 to 8 carbon atoms (C1-C8 alkyl), preferably from 1 to 6 carbon atoms (C1-C6 alkyl), attached to the remainder of the molecule by a single bond (e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, etc.). Unless specifically stated otherwise in the specification, alkyl groups are optionally substituted.

[0028] "Alkenyl" refers to an alkyl group consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, and having 2 to 12 carbon atoms (C 12alkenyl), preferably having 2 to 8 carbon atoms (C2-C8 alkenyl), or 2 to 6 carbon atoms (C2-C6 alkenyl), and attached to the remainder of the molecule by a single bond (e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc.). Unless specifically stated otherwise in the specification, alkenyl groups are optionally substituted.

[0029] "Alkynyl" refers to an alkyl group consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon triple bonds, and having 2 to 12 carbon atoms (C 12 alkynyl), preferably having 2 to 8 carbon atoms (C2-C8 alkynyl) or 2 to 6 carbon atoms (C2-C6 alkynyl), and attached to the rest of the molecule by a single bond (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.). Unless specifically stated otherwise in the specification, alkynyl groups are optionally substituted.

[0030] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, saturated or unsaturated (i.e., containing one or more double bonds or "alkenylene" and / or triple bonds or "alkynylene"), having 1 to 12 carbon atoms, that links the rest of the molecule to a radical group (e.g., methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, and n-butynylene, etc.). The alkylene chain is attached to the rest of the molecule through a single or double bond and to the radical group through a single or double bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless specifically stated otherwise in the specification, the alkylene chain is optionally substituted.

[0031] "Alkylcarbonyl" is a group of the formula -C(=O)R a (In the formula, Ra is an alkyl radical, as defined above, containing one to twelve carbon atoms. Unless specifically stated otherwise in the specification, an alkylcarbonyl group is optionally substituted.

[0032] "Alkoxy" or "alkyloxy" refers to a group of the formula -OR a (In the formula, R a "Aminylalkyloxy" or "aminylalkoxy" refers to a radical of the form -NR a R b an alkoxy group containing at least one substituent of the formula a and R b are each independently H on the alkyl group or C1-C6 alkyl. Unless specifically stated otherwise in the specification, alkoxy and / or aminylalkyloxy groups are optionally substituted.

[0033] An "alkoxyalkyl" is a group of the formula -R b OR a (In the formula, R a is an alkyl radical as defined above containing 1 to 12 carbon atoms, R b is an alkylene radical, as defined above, containing 1 to 12 carbon atoms. Unless otherwise specifically indicated in the specification, alkoxyalkyl groups are optionally substituted.

[0034] "Alkoxycarbonyl" is a group of the formula -C(=O)OR a (In the formula, R a is an alkyl radical, as defined above, containing 1 to 12 carbon atoms. Unless specifically stated otherwise in the specification, an alkoxycarbonyl group is optionally substituted.

[0035] "Aryloxy" refers to a group of the formula -OR a (In the formula, R awhere X is an aryl radical, as defined herein. Unless stated otherwise specifically in the specification, an aryloxy group is optionally substituted.

[0036] "Alkyl aminyl" refers to a group of the formula -NHR a or -NR a R a (In the formula, each R a and R are independently an alkyl radical, as defined above, containing 1 to 12 carbon atoms. Unless specifically stated otherwise in the specification, alkylaminyl groups are optionally substituted.

[0037] "Aminoalkyl" refers to an alkyl group that contains at least one amino substituent. The amino substituent may be on a tertiary, secondary, or primary carbon. Unless otherwise specifically indicated in the specification, aminoalkyl groups are optionally substituted.

[0038] An "aminylalkyl" is an alkyl group containing at least one aminyl substituent (-NR a R b (In the formula, R a and R b are each independently H or a C1-C6 alkyl. "Aminylalkynyl" refers to an alkynyl group that contains at least one aminyl substituent. The aminyl substituent may be on a tertiary, secondary, or primary carbon. Unless specifically stated otherwise in the specification, an aminylalkyl or aminylalkynyl group is optionally substituted.

[0039] "Aminylalkylaminyl" refers to a group of the formula -NR a R b (In the formula, R a is H or C1-C6 alkyl, R b is an aminylalkyl. Unless specifically stated otherwise in the specification, aminylalkylaminyl groups are optionally substituted.

[0040] "Aminylalkylcarbonyl" is a group of the formula -C(=O)R a NR b R c (In the formula, R a is alkylene, and R b and R c are each independently H or C1-C6 alkyl. Unless specifically stated otherwise in the specification, an aminylalkylcarbonyl group is optionally substituted.

[0041] "Aminylalkoxy" refers to a group of the formula -OR a NH2 (in the formula, R a is alkylene. Unless stated otherwise specifically in the specification, an aminylalkoxy group is optionally substituted.

[0042] "Aminyl alkyl thioether" is a compound of the formula -SR a NR b R c (In the formula, R a is alkylene, and R b and R c are each independently H or alkyl. Unless specifically stated otherwise in the specification, an aminylalkylthioether group is optionally substituted.

[0043] "Alkylcarbonylaminyl" refers to a group of the formula -NR b (C=O)R a (In the formula, R a is an alkyl radical as defined above containing 1 to 12 carbon atoms, R b is H or an alkyl radical as defined above. Unless otherwise specifically stated in the specification, alkylcarbonylaminyl groups are optionally substituted. Alkenylcarbonylaminyl is an alkylcarbonylaminyl that contains at least one carbon-carbon double bond. Alkenylcarbonylaminyl groups are optionally substituted.

[0044] "Aminyl carbonyl" has the formula -C(=O)NR a Rb (In the formula, R a and R b and each independently is H or alkyl. Unless specifically stated otherwise in the specification, an aminylcarbonyl group is optionally substituted.

[0045] "Aminylcarbonylalkyl" refers to a group of the formula -R c C(=O)NR a R b (In the formula, R a and R b are each independently H or alkyl; R c is alkylene. Unless stated otherwise specifically in the specification, aminylcarbonylalkyl groups are optionally substituted.

[0046] "Aminylcarbonylalkoxy" refers to a group of the formula -OR c C(=O)NR a R b (In the formula, R a and R b are each independently H or alkyl; R c is alkylene. Unless stated otherwise specifically in the specification, an aminylcarbonylalkoxy group is optionally substituted.

[0047] "Aminylsulfonyl" has the formula -S(O)NR a R b (In the formula, R a and R b are each independently H or alkyl. Unless specifically stated otherwise in the specification, an aminylsulfonyl group is optionally substituted.

[0048] "Alkylsulfonyl" refers to a group of the formula -S(O)R a (In the formula, R a where R is an alkyl group as defined above. Unless specifically stated otherwise in the specification, alkylsulfonyl groups are optionally substituted.

[0049] "Alkylsulfonylaminyl" refers to a group of the formula -NR a S(O)2R b (wherein Ra is H or alkyl; R b where R is an alkyl group as defined above. Unless specifically stated otherwise in the specification, alkylsulfonyl groups are optionally substituted.

[0050] "Aminylalkylsulfonyl" refers to a group of the formula -S(O)R a NR b R c (In the formula, R a is alkylene, and R b and R c are each independently H or alkyl. Unless specifically stated otherwise in the specification, aminylalkylsulfonyl groups are optionally substituted.

[0051] "Aromatic ring" refers to a cyclic planar portion (i.e., radical) of a molecule having a ring of resonance bonds that exhibit increased stability compared to other bonding arrangements with the same set of atoms. In general, aromatic rings contain a set of covalently bonded coplanar atoms and contain an even number of pi electrons (e.g., alternating double and single bonds) that is not a multiple of four (i.e., 4n+2 pi electrons, n=0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl, and pyrimidonyl. Unless specifically stated otherwise in this specification, "aromatic ring" includes all radicals, optionally substituted.

[0052] "Aryl" refers to a carbocyclic ring system radical containing 6 to 18 carbon atoms and at least one aromatic ring. For purposes of this embodiment, an aryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless specifically stated otherwise in the specification, the term "aryl" or the prefix "ar-" (as in "aralkyl") is meant to include aryl radicals that are optionally substituted.

[0053] An "arylalkyl" is a group of the formula -R b -R c (In the formula, R b is an alkylene chain as defined above, and R c refers to a radical of one or more aryl radicals as defined above, e.g., benzyl, diphenylmethyl, etc. Unless specifically stated otherwise in the specification, arylalkyl groups are optionally substituted.

[0054] "Arylalkyloxy" or "arylalkoxy" refers to an aryl group of the formula -OR b -R c (In the formula, R b is an alkylene chain as defined above, and R c refers to a radical of an aryl radical as defined above, e.g., benzyl, etc. Unless specifically stated otherwise in the specification, an arylalkyloxy group is optionally substituted.

[0055] "Arylalkylaminyl" refers to a group of the formula -N(R a )R b -R c (In the formula, R a is H or C1-C6 alkyl, Rb is an alkylene chain as defined above, and R c refers to a radical of one or more aryl radicals as defined above, e.g., benzyl, diphenylmethyl, etc. Unless specifically stated otherwise in the specification, an arylalkylaminyl group is optionally substituted.

[0056] "Arylaminyl" refers to a group of the formula -N(R a )R b (In the formula, R a is H or C1-C6 alkyl, R b refers to a radical of an aryl radical as defined above, e.g., benzyl, etc. Unless specifically stated otherwise in the specification, an arylaminyl group is optionally substituted.

[0057] "Arylcarbonylaminyl" refers to a group of the formula -N(R a )R b C(=O)R c (In the formula, R a is H or C1-C6 alkyl, R b is an alkylene chain or a direct bond, and R c where R is one or more aryl radicals, as defined above. Unless specifically stated otherwise in the specification, arylcarbonylaminyl groups are optionally substituted.

[0058] A "cyanoalkyl" is a group of the formula -R b -R c (In the formula, R b is an alkylene chain as defined above, and R c is a cyano group, as defined above. Unless specifically stated otherwise in the specification, cyanoalkyl groups are optionally substituted.

[0059] "Carbocyclic" or "carbocycle" refers to a ring system in which each ring atom is carbon.

[0060] "Carboxyalkyl" refers to an alkyl group, as defined herein, containing at least one carboxy substituent. Unless otherwise specifically stated in the specification, a carboxyalkyl group is optionally substituted.

[0061] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic carbocyclic radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, saturated or unsaturated, and attached to the remainder 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, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. "Cycloalkenyl" is a cycloalkyl containing one or more carbon-carbon double bonds in the ring (e.g., cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like). Unless specifically stated otherwise in the specification, cycloalkyl (or cycloalkenyl) groups are optionally substituted.

[0062] "Cycloalkylcarbonyl" refers to a group of the formula -C(=O)R a (In the formula, R a is a cycloalkyl radical, as defined above, containing one to twelve carbon atoms. Unless specifically stated otherwise in the specification, cycloalkylcarbonyl groups are optionally substituted.

[0063] "Cycloalkylalkyl" refers to a group of the formula -R b R d (In the formula, 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, cycloalkylalkyl groups are optionally substituted.

[0064] "Cycloalkylsulfonyl" refers to a group of the formula -S(O)R a (In the formula, R a is cycloalkyl as defined above. Unless specifically stated otherwise in the specification, cycloalkylsulfonyl groups are optionally substituted.

[0065] A "cycloalkyl thioether" is a cycloalkyl thioether of the formula -SR a (In the formula, R a is a cycloalkyl radical, as defined above. Unless specifically stated otherwise in the specification, a cycloalkylthioether group is optionally substituted.

[0066] "Fused" refers to any ring structure described herein that is fused to an existing ring structure in the compounds of the invention. When the fused ring is a heterocyclyl or heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl or heteroaryl ring is replaced with a nitrogen atom.

[0067] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo.

[0068] "Haloalkyl" refers to an alkyl radical as defined above substituted with one or more halo radicals as defined above (e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.). "Perhaloalkyl" refers to an alkyl radical as defined above in which each H atom is replaced with a halogen. Unless otherwise specifically stated in the specification, haloalkyl groups are optionally substituted.

[0069] "Haloalkoxy" refers to a group of the formula -OR a (In the formula, R a is a haloalkyl radical, as defined herein, containing one to twelve carbon atoms. Unless specifically stated otherwise in the specification, a haloalkoxy group is optionally substituted.

[0070] "Heterocyclyl" or "heterocyclic ring" refers to a stable 3- to 18-membered non-aromatic ring radical having 1 to 12 ring carbon atoms (e.g., 2 to 12) and 1 to 6 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless otherwise specifically indicated in the specification, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused, spiro ring systems ("spiro-heterocyclyl"), and / or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical are optionally oxidized; the nitrogen atom is optionally quaternized; and the heterocyclyl radical is partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,2,3,4-tetrahydroquinolinyl, and 1,1-dioxo-thiomorpholinyl. "Heterocyclyloxy" refers to a heterocyclyl group attached to the remainder of the molecule through an oxygen bond (-O-). "Heterocyclylaminyl" refers to a heterocyclyl group attached to the remainder of the molecule through a nitrogen bond (-NR a -(In the formula, R ais H or C1-C6 alkyl). "Heterocyclylcarbonyl" refers to a heterocyclyl group attached to the remainder of the molecule by a carbonyl carbon (-C(=O)-). "Heterocyclylsulfonyl" refers to a heterocyclyl group attached to the remainder of the molecule by a sulfonyl group (-S(O)2-). Unless specifically stated otherwise in the specification, heterocyclyl, heterocyclyloxy and / or heterocyclylaminyl groups are optionally substituted. "Heterocyclenyl" is a heterocyclyl containing one or more carbon-carbon double bonds within the ring. Unless specifically stated otherwise in the specification, heterocyclenyl) groups are optionally substituted. For example, in some embodiments, a heterocyclenyl has the following structure: [ka] (In the formula, R a is H or C1-C6 alkyl.

[0071] A “heterocyclylalkyl” or “heterocycloalkyl” is a heterocyclic group of the formula —R b R e (In the formula, R b is an alkylene chain as defined above, and R e is a heterocyclyl radical, as defined above, where if the heterocyclyl is a nitrogen-containing heterocyclyl, the nitrogen atom of the heterocyclyl is optionally attached to an alkylene chain. Unless otherwise specifically stated in the specification, a heterocyclylalkyl or heterocycloalkyl group is optionally substituted.

[0072] "Heterocyclylalkoxy" refers to a group of the formula -OR b R e (In the formula, R b is an alkylene chain as defined above, and R eis a heterocyclyl radical, as defined above, where if the heterocyclyl is a nitrogen-containing heterocyclyl, the nitrogen atom of the heterocyclyl is optionally bonded to an alkyl radical. Unless specifically stated otherwise in the specification, heterocyclylalkoxy groups are optionally substituted.

[0073] "Heterocyclylalkylaminyl" refers to a heterocyclyl group of the formula -N(R c )R b R e (In the formula, R b is an alkylene chain as defined above, and R e is a heterocyclyl radical as defined above, where if the heterocyclyl is a nitrogen-containing heterocyclyl, the nitrogen atom of the heterocyclyl is optionally attached to an alkyl radical, and R c is H or C1-C6 alkyl. Unless otherwise specifically stated in the specification, heterocyclylalkylaminyl groups are optionally substituted.

[0074] "Heterocyclylcarbonylalkoxy" refers to a heterocyclyl group of the formula -OR c C(=O)R a (In the formula, R a is heterocyclyl as defined above. Unless specifically stated otherwise in the specification, aminylcarbonylalkoxy groups are optionally substituted.

[0075] A "heterocyclyl thioether" is a heterocyclyl thioether of the formula -SR a (In the formula, R a is heterocyclyl as defined above. Unless specifically stated otherwise in the specification, a heterocyclyl thioether group is optionally substituted.

[0076] "Heterocyclylcarbonylaminyl" refers to a heterocyclyl group of the formula -N(R a )R b (C=O)R c (In the formula, R a is H or alkyl, and R b is an alkylene chain or a direct bond, and R cis a heterocyclyl radical as defined above, where, if the heterocyclyl is a nitrogen-containing heterocyclyl, the nitrogen atom of the heterocyclyl is optionally bonded to a carbonyl group. Unless specifically stated otherwise in the specification, heterocyclylcarbonylaminyl groups are optionally substituted.

[0077] "Heteroaryl" refers to a 5-14 membered ring system radical containing a hydrogen atom, 1 to 13 ring carbon atoms, 1 to 6 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring containing a heteroatom. For purposes of this embodiment, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; and the nitrogen atom may be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, 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, indazolyl, isoindolyl, indophenyl, iso ... These include, but are not limited to, linyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl)."Heteroaryloxy" refers to a heteroaryl group attached to the remainder of the molecule via an oxygen bond (-O-). "Heteroarylaminyl" refers to a heteroaryl group attached to the remainder of the molecule via a nitrogen bond (-NR. a -(In the formula, R a is H or C1-C6 alkyl) to the remainder of the molecule. Unless specifically stated otherwise in the specification, heteroaryl, heteroaryloxy, and / or heteroarylaminyl groups are optionally substituted.

[0078] "Heteroarylalkyl" refers to a group of the formula -R b R f (In the formula, 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, heteroarylalkyl groups are optionally substituted.

[0079] "Heteroarylalkyloxy" or "heteroarylalkoxy" refers to a heteroaryl group of the formula -OR b R f (In the formula, R b is an alkylene chain as defined above, and R f is a heteroaryl radical, as defined above, where if the heteroaryl is a nitrogen-containing heteroaryl, a nitrogen atom of the heteroaryl is optionally attached to an alkylene chain. Unless otherwise specifically stated in the specification, a heteroarylalkyloxy or heteroarylalkoxy group is optionally substituted.

[0080] "Heteroarylalkylaminyl" refers to a heteroaryl group of the formula -N(R c )R b R f (In the formula, R b is an alkylene chain as defined above, and R f is a heteroaryl radical, as defined above, where if the heteroaryl is a nitrogen-containing heteroaryl, the nitrogen atom of the heteroaryl is optionally attached to an alkylene chain; R cis H or C1-C6 alkyl. Unless otherwise specifically stated in the specification, heteroarylalkylaminyl groups are optionally substituted.

[0081] "Heteroarylcarbonylaminyl" refers to a heteroaryl group of the formula -N(R c )R b (C=O)R f (In the formula, R b is an alkylene chain or a direct bond as defined above, R f is a heteroaryl radical as defined above, where if the heteroaryl is a nitrogen-containing heteroaryl, the nitrogen atom of the heteroaryl is optionally bonded to a carbonyl group, and R c is H or C1-C6 alkyl. Unless otherwise specifically stated in the specification, heteroarylcarbonylaminyl groups are optionally substituted.

[0082] "Hydroxylalkyl" refers to an alkyl group that contains at least one hydroxyl substituent. The -OH substituent may be on a primary, secondary, or tertiary carbon. Unless otherwise specifically indicated in the specification, hydroxylalkyl groups are optionally substituted.

[0083] "Phosphate" is -OP(=O)(R a )R b group (in the formula, R a OH, O - OR c and R b OH, O - , OR c or additional phosphate groups (e.g., to form a diphosphate or triphosphate), R c refers to the counter ion (e.g., Na+, etc.).

[0084] "Phosphoalkoxy" refers to an alkoxy group, as defined herein, substituted with at least one phosphate group, as defined herein. Unless otherwise specifically indicated in the specification, a phosphoalkoxy group is optionally substituted.

[0085] A "thioalkyl" or "alkyl thioether" is a thiol group of the formula -SR a (In the formula, R a is an alkyl radical, as defined above, containing 1 to 12 carbon atoms. Unless specifically indicated otherwise in the specification, a thioalkyl or alkylthioether group is optionally substituted.

[0086] As used herein, the term "substituted" means that at least one hydrogen atom (e.g., one, two, three, or all hydrogen atoms) has been replaced with a non-hydrogen atom (such as a halogen atom (such as F, Cl, Br, and I); an oxygen atom in groups such as hydroxyl, alkoxy, and ester groups; a sulfur atom in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups;and other heteroatoms in various other groups), any of the above groups (e.g., alkyl, alkenyl, alkynyl, alkylene, alkylcarbonyl, alkoxy, aminylalkyloxy, alkoxyalkyl, alkoxycarbonyl, aryloxy, alkylaminyl, aminoalkyl, aminylalkyl, aminylalkynyl, aminylalkylaminyl, aminylalkylcarbonyl, aminylalkoxy, aminylalkylthioether, alkylcarbonylaminyl, aminylcarbonyl, aminylcarbonylalkyl, aminylcarbonylalkoxy, aminylsulfonyl, alkylsulfonyl, alkylsulfonylaminyl, aminylalkylsulfonyl, aryl, arylalkyl, arylalkyloxy, arylalkylaminyl, arylaminyl, aryl carbonylaminyl, cyanoalkyl, carboxyalkyl, cycloalkyl, cycloalkylene, cycloalkylcarbonyl, cycloalkylalkyl, cycloalkylsulfonyl, cycloalkylthioether, haloalkyl, haloalkoxy, heterocyclyl, heterocyclyloxy, heterocyclylaminyl, heterocyclylcarbonyl, heterocyclylsulfonyl, heterocyclenyl, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkylaminyl, heterocyclylcarbonylalkoxy, heterocyclylthioether, heterocyclylcarbonylaminyl, heteroaryl, heteroarylaminyl, heteroarylalkyl, heteroarylalkyloxy, heteroarylalkylaminyl, heteroarylcarbonylaminyl, hydroxylalkyl, phosphoalkoxy and / or thioalkyl). "Substituted" also refers to any of the above groups in which one or more hydrogen atoms have been replaced by a higher bond (e.g., a double or triple bond) to a heteroatom (such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles). For example, "substituted" includes any group in which one or more hydrogen atoms have been replaced by -NR; g R h , -NRg C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h , -OC(=O)NR g R h , -OR g , -SR g , -SOR g , -SO2R g , -OSO2R g , -SO2OR g , =NSO2R g and -SO2NR g R h "Substituted" also includes any of the above groups in which one or more hydrogen atoms have been replaced with -C(=O)R. g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NR g R h In the above, R g and R hare the same or different and are independently hydrogen, alkyl, alkoxy, alkylaminyl, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. "Substituted" further refers to any of the above groups in which one or more hydrogen atoms are replaced by a bond to an aminyl group, a cyano group, a hydroxyl group, an imino group, a nitro group, an oxo group, a thioxo group, a halo group, an alkyl group, an alkoxy group, an alkylaminyl group, a thioalkyl group, an aryl group, an aralkyl group, a cycloalkyl group, a cycloalkylalkyl group, a haloalkyl group, a heterocyclyl group, a heterocyclylalkyl group, a heteroaryl group, an N-heteroaryl group, and / or a heteroarylalkyl group. Additionally, each of the foregoing substituents may also be optionally substituted with one or more of the above-mentioned substituents.

[0087] R 1 , R 2 , R 3a , R 3b , R 3c , R 4a , R 4b , R 5 , L 1 , L 2 , L 3 Each of the options, R and E, unless specifically indicated otherwise, is understood to be optionally substituted as above, provided that all valences are satisfied by substitution. 1 , R 2 , R 3a , R 3b , R 3c , R 4a , R 4b , R 5 , L 1 , L 2 , L 3 and each of the options E, unless specifically stated otherwise, are optionally substituted, provided that such substitution results in a stable molecule (e.g., groups such as H and halo are not optionally substituted).

[0088] An "electrophile" or "electrophilic moiety" is any moiety that can react with a nucleophile (e.g., a moiety having a lone pair of electrons, a negative charge, a partial negative charge, and / or an excess of electrons, e.g., an -SH group). Electrophiles are typically electron deficient or contain an electron deficient atom. In certain embodiments, electrophiles are moieties that contain a positive charge or a partial positive charge, have a resonance structure that contains a positive charge or a partial positive charge, or in which electron delocalization or polarization results in an atom containing one or more positive or partial positive charges. In some embodiments, electrophiles contain conjugated double bonds (e.g., α,β-unsaturated carbonyl compounds or α,β-unsaturated thiocarbonyl compounds).

[0089] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein sufficient to achieve the intended application, including but not limited to disease treatment as defined below. The therapeutically effective amount may vary depending on the intended treatment application (in vivo) or the subject and condition to be treated (e.g., the subject's weight and age, the severity of the condition, and the mode of administration, etc.), and can be easily determined by those skilled in the art. The term also applies to a dose that induces a specific response in target cells (e.g., reduced platelet adhesion and / or cell migration). The specific dose varies depending on the particular compound selected, the administration regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to be administered, and the physical delivery system carried.

[0090] As used herein, "treatment" or "treating" refers to an approach to obtain a beneficial or desired outcome (including, but not limited to, therapeutic benefit and / or prophylactic benefit) with respect to a disease, disorder, or condition. Therapeutic benefit refers to eradication or amelioration of the underlying disorder being treated. Therapeutic benefit is also achieved with eradication or amelioration of one or more physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, even though the subject may still suffer from the underlying disorder. In certain embodiments, for prophylactic benefit, the composition is administered to a subject at risk of developing a particular disease or a subject who has reported one or more physiological symptoms of a disease, even though the disease may not have been diagnosed.

[0091] A "therapeutic benefit," as that term is used herein, includes the therapeutic benefits and / or prophylactic benefits described above. A prophylactic benefit includes delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0092] The terms "co-administration," "administration in combination with," and grammatical equivalents thereof, as used herein, include the administration of two or more agents to an animal (including a human) where both agents and / or their metabolites are present in the subject at the same time. Co-administration includes co-administration of separate compositions, administration of separate compositions at different times, or administration in a composition where both agents are present.

[0093] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0094] "Pharmaceutically acceptable acid addition salts" refer to those acids which retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and which are formed from inorganic acids (e.g., but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid) and organic acids (e.g., 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, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, sucrose ... "acid" refers to salts formed with acids such as, but not limited to, gluconic 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, mucic 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.

[0095] "Pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effectiveness and properties of the free acid and is not biologically or otherwise undesirable. These salts are prepared by the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins (such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins). Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0096] In some embodiments, pharma- ceutically acceptable salts include quaternary ammonium salts, such as quaternary amine alkyl halide salts (eg, methyl bromide).

[0097] The terms "antagonist" and "inhibitor" are used interchangeably, and refer to a compound that has the ability to inhibit the biological function of a target protein by inhibiting the activity or expression of the target protein (such as G12C of KRAS, HRAS, or NRAS). Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. While the preferred antagonists herein specifically interact (e.g., bind) with the target, compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. The preferred biological activity inhibited by antagonists is related to the development, growth, or spread of tumors.

[0098] The term "agonist" as used herein refers to a compound that has the ability to initiate or enhance the biological function of target protein by inhibiting the activity or expression of target protein.Thus, the term "agonist" is defined in the context of the biological role of target polypeptide.While the preferred agonist herein specifically interacts (e.g., binds) with target, compounds that initiate or enhance the biological activity of target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.

[0099] 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 (e.g., 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.

[0100] "Signal transduction" is the process by which stimulatory or inhibitory signals are transmitted in or within a cell to induce an intracellular response. A modulator of a signal transduction pathway refers to a compound that modulates the activity of one or more cellular proteins that map to the same specific signal transduction pathway. Modulators can enhance (agonist) or suppress (antagonist) the activity of a signal transduction molecule.

[0101] "Anti-cancer agent," "anti-tumor agent," or "chemotherapeutic agent" refers to any agent useful in the treatment of a neoplastic condition. One class of anti-cancer agents includes chemotherapy drugs. "Chemotherapy" refers to the administration of one or more chemotherapy drugs and / or other agents to a cancer patient by various methods, including intravenous, oral, intramuscular, intraperitoneal, intracapsular, subcutaneous, transdermal, buccal, or inhalation, or in the form of a suppository.

[0102] The term "cell proliferation" refers to the phenomenon in which a cell changes in number as a result of division. The term also includes cell growth in which the cell changes morphology (e.g., increases in size) in response to a proliferation signal.

[0103] The terms "selective inhibition" or "selectively inhibit" refer to the ability of a biologically active agent to preferentially reduce a target signaling activity through a direct or indirect interaction with the target compared to an off-target signaling activity.

[0104] "Subject" refers to an animal, such as a mammal (e.g., a human). The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is a human.

[0105] "Mammals" includes humans and both domesticated animals, such as laboratory animals and pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals, such as wild animals.

[0106] "Radiotherapy" means exposing a subject to radiation emitters (such as alpha particle-emitting radionuclides (e.g., actinium and thorium radionuclides), low linear energy transfer (LET) radiation emitters (i.e., beta emitters), conversion electron emitters (e.g., strontium-89 and samarium-153-EDTMP), etc.), or high-energy radiation (including, but not limited to, x-rays, gamma rays, and neutrons) using routine methods and compositions known to those of skill in the art.

[0107] "Anti-cancer agent", "anti-tumor agent", or "chemotherapeutic agent" refers to any agent useful in the treatment of a neoplastic condition. One class of anti-cancer agents includes chemotherapeutic agents. "Chemotherapy" refers to the administration of one or more chemotherapeutic and / or other agents to a cancer patient by a variety of methods, including intravenous, oral, intramuscular, intraperitoneal, intracapsular, subcutaneous, transdermal, buccal, or inhalation, or in the form of a suppository.

[0108] "Prodrug" is meant to refer to a compound that can be converted under physiological conditions or by solvolysis into a biologically active compound described herein (e.g., a compound of structure (I)). Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharma- ceutically acceptable. In some embodiments, a prodrug is inactive when administered to a subject, but is converted to an active compound in vivo, e.g., by hydrolysis. Prodrug compounds often confer advantages such as solubility, tissue compatibility, or delayed release in mammals (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Prodrugs are discussed in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," ACS 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 an active compound in vivo when such a prodrug is administered to a mammalian subject. Prodrugs of active compounds are typically prepared by modifying functional groups present in the active compound, as described herein, in such a way that the modification is cleaved to the parent active compound, either by routine manipulation or in vivo. Prodrugs include compounds in which a hydroxy group, an amino group, or a mercapto group is bonded to any group that is cleaved to form a free hydroxy group, a free amino group, or a free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject.Examples of prodrugs include, but are not limited to, active compounds that contain acetate, formate and benzoate derivatives of hydroxy functional groups or acetamide, formamide and benzamide derivatives of amine functional groups.

[0109] In some embodiments, the prodrug includes a compound of structure (I) having a phosphate, phosphoalkoxy, ester, or boronic ester substituent. Without being bound by theory, it is believed that such substituents are converted to a hydroxyl group under physiological conditions. Thus, embodiments include any compound disclosed herein in which a hydroxyl group is replaced with a phosphate, phosphoalkoxy, ester, or boronic ester group, e.g., a phosphate or phosphoalkoxy group. For example, in some embodiments, R 1 The hydroxyl groups on the moiety are replaced with phosphate, phosphoalkoxy, ester, or boronic ester groups, e.g., phosphate or alkoxyphosphate groups. Thus, exemplary prodrugs of certain embodiments include the following substituents: [ka] R replaced by one of 1 Includes parts.

[0110] The term "in vivo" refers to an event that takes place inside a subject's body.

[0111] The embodiments disclosed herein are also meant to include all pharma- ceutically acceptable compounds of structure (I) that are isotopically labeled by replacing one or more atoms with an atom having a different atomic mass or mass number (i.e., "isotopic forms" of the compounds of structure (I)). Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine (respectively, 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, etc. These radiolabeled compounds may be useful, for example, to aid in determining or measuring the effectiveness of a compound by characterizing the site or mode of action, or binding affinity to a pharmacologically important site of action. Certain isotopically labeled compounds of structure (I) (e.g., compounds incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) is particularly useful for this purpose in view of its ease of incorporation and existing means of detection.

[0112] Deuterium (i.e. 2 Substitution with heavier isotopes, such as H, can afford certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances.

[0113] Positron-emitting isotopes ( 11 C. 18 F, 15 O and 13 Substitution with 1,2-dichlorophenyl (such as N) may be useful in positron emission tomography (PET) studies for examination of substrate receptor occupancy. Isotopically labeled compounds of structure (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples below, using an appropriate isotopically labeled reagent in place of the previously used non-labeled reagent.

[0114] Certain embodiments are also meant to include in vivo metabolic products of the disclosed compounds. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, and esterification of the administered compound, primarily by enzymatic processes. Thus, embodiments include compounds produced by a process comprising administering a compound of the present disclosure to a mammal for a period of time sufficient to produce its metabolic products. Such products are typically identified by administering a detectable dose of a radiolabeled compound of the present disclosure to an animal (such as a rat, mouse, guinea pig, monkey, or human), allowing sufficient time for metabolism to occur, and isolating the conversion products from urine, blood, or other biological samples.

[0115] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0116] Often, crystallization produces a solvate of the compound of the present disclosure. As used herein, the term "solvate" refers to an aggregate that contains one or more molecules of the compound of the present disclosure together 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. Thus, the compound of the present disclosure can exist as a hydrate (including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, etc.) and the corresponding solvated forms. In some aspects, the compound of the present disclosure is a true solvate, while in other cases, the compound of the present disclosure only retains extraneous water or is a mixture of water and some extraneous solvent.

[0117] "Optionally" or "optionally" means that the subsequent described circumstantial event may or may not occur, and that the description includes examples in which said event or circumstance occurs and examples in which said event or circumstance does not occur. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted, and that the description includes both substituted and unsubstituted aryl radicals.

[0118] A "pharmaceutical composition" refers to a formulation of a compound of the present disclosure and a medium generally accepted in the art for the delivery of a biologically active compound to a mammal (e.g., a human). Such a medium includes any pharma- ceutically acceptable carrier, diluent, or excipient for the compound.

[0119] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or domestic animals.

[0120] The compounds of the present disclosure (i.e., compounds of structure (I) and embodiments thereof) or pharma- ceutically acceptable salts thereof may contain one or more geometrically asymmetric centers and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms defined in terms of absolute stereochemistry as (R) or (S) forms, or, in the case of amino acids, as (D) or (L) forms. Accordingly, the embodiments 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, may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques (e.g., chromatography and fractional crystallization). Conventional techniques for the preparation / isolation of each enantiomer include chiral synthesis from suitable optically pure precursors, or resolution of the racemates (or racemic salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers, as well as all tautomeric forms.

[0121] The embodiments of the present disclosure include all the modes of rotational isomers and conformational restriction of the compounds of the present invention.Also include atropisomers, which are stereoisomers caused by hindered rotation around a single bond, where the energy difference due to steric strain or other factors creates a sufficiently high rotation barrier to allow each conformer to be isolated.For example, certain compounds of the present disclosure can exist as a mixture of atropisomers, or in the form in which one atropisomer is purified or enriched in its presence.

[0122] 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 S-atropisomer.

[0123] "Stereoisomers" refer to compounds composed of identical atoms joined by the same bonds, but with different, non-interchangeable three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0124] "Tautomer" refers to a proton migration from one atom of a molecule to another atom of the same molecule. Thus, embodiments include tautomers of the disclosed compounds.

[0125] The chemical naming protocol and structure diagrams used herein are modified versions of the IUPAC nomenclature using the ACD / Name version 9.07 software program and / or the ChemDraw Ultra version 11.0.1 software naming program (CambridgeSoft). For complex chemical names used herein, the substituents are typically named before the group to which they are attached. For example, cyclopropylethyl contains an ethyl skeleton with a cyclopropyl substituent. Except as noted below, all bonds are identified in the chemical structure diagrams herein, except for all bonds on some carbon atoms that are believed to be attached to sufficient hydrogen atoms to complete the valence.

[0126] compound In one aspect, the present disclosure provides compounds that can selectively bind to and / or modulate G12C mutant KRAS, HRAS, or NRAS proteins. The compounds can modulate G12C mutant KRAS, HRAS, or NRAS proteins by reacting with amino acids. Without being bound by theory, applicants believe that in some embodiments, the compounds of the present disclosure selectively react with G12C mutant KRAS, HRAS, or NRAS proteins by forming a covalent bond with the cysteine ​​at position 12 of G12C mutant KRAS, HRAS, or NRAS proteins. By binding to cysteine ​​12, the compounds of the present disclosure can confine switch II of G12C mutant KRAS, HRAS, or NRAS in an inactive stage. This inactive stage can be different from that found in KRAS, HRAS, or NRAS bound to GTP and GDP. Some compounds of the present disclosure can also disrupt the conformation of switch I. Some compounds of the present disclosure preferentially bind to KRAS, HRAS, or NRAS bound to GDP rather than GTP, and thus can sequester KRAS, HRAS, or NRAS in the inactive KRAS, HRAS, or NRAS GDP-bound state. Because effector binding to KRAS, HRAS, or NRAS is highly sensitive to the conformation of switches I and II, irreversible binding of these compounds can disrupt downstream signaling of KRAS, HRAS, or NRAS.

[0127] As noted above, in one embodiment of the present invention there is provided a compound having activity as a modulator of a G12C mutant KRAS, HRAS or NRAS protein, the compound having the following structure (I): [ka] (In the formula, A 1 , A 2 , A 3 and A 4 is independently in each occurrence 4a R 4b , O or NR 5and; G 1 and G 2 are each independently CH or N, provided that L 1 is -O-, -S- or -NR 5 - or adjacent A 1 Or A 2 Ga-NR 5 - or -O-, then G 1 is CH, where L 2 Ga-NR 5 - or adjacent A 3 Or A 4 Ga-NR 5 - or -O-, then G 2 is CH; L 1 is a bond, -CR 4a R 4b -, -O-, -S-, -SO2- or -NR 5 - and; G 2 If CH, then L 2 is a bond, C1-C6 alkylene or -NR 5 - and; L 3 is a bond, -CR 4a R 4b -, -O-, -S-, -SO2- or -NR 5 - and; R 1 is aryl, cycloalkyl, heterocyclyl or heteroaryl; R 2 is H, cyano, hydroxyl, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkyl, aminylalkyl, alkylaminyl, aminylcarbonyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl; R 3a , R 3b and R 3cis independently at each occurrence H, halo, hydroxyl, cyano, amino, alkyl, cycloalkyl, cycloalkenyl, heterocyclenyl, haloalkyl, alkynyl, alkenyl, alkoxy, haloalkoxy, aminylcarbonyl, aminylcarbonylalkoxy, aminylsulfonyl, alkylsulfonylaminyl, alkylcarbonyl, aminylalkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, heterocyclylcarbonylalkoxy, alkylsulfonyl, aminylalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, alkylthioether, aminylalkylthioether, cycloalkylthioether, heterocyclyl arylthioether, aminylalkyl, aminylalkynyl, aminylalkylaminyl, aminylalkoxy, alkylcarbonylaminyl, heterocyclyl, heterocyclylaminyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkylaminyl, heterocyclylalkoxy, heterocyclylcarbonylaminyl, aryl, arylalkyl, arylalkylaminyl, arylalkoxy, arylaminyl, arylcarbonylaminyl, heteroaryl, heteroarylaminyl, heteroaryloxy, heteroarylalkyl, heteroarylalkylaminyl, heteroarylalkoxy, or heteroarylcarbonylaminyl; R 4a and R 4b is independently at each occurrence H, -OH, -NH2, -CO2H, halo, cyano, C1-C6 alkyl, cycloalkyl, heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, C1-C6 cyanoalkyl, C1-C6 carboxyalkyl, aminylcarbonylalkyl, aryl, heteroaryl, or aminylcarbonyl; or R 4a and R 4b and when attached to the same carbon, together form an oxo or carbocyclic or heterocyclic ring, or R 3a and R3b and when attached to different carbons, together form a carbocyclic or heterocyclic ring; R 5 is independently at each occurrence H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, C1-C6 haloalkyl, or C3-C8 cycloalkylalkyl; m1, m2, n1 and n2 are independently in each occurrence 1, 2 or 3; and E is an electrophilic moiety. or a pharma- ceutically acceptable salt, isotopic form, stereoisomer or prodrug thereof.

[0128] In some more specific embodiments, the compound of structure (I) has the following structure (I'): [ka] or a pharma- ceutically acceptable salt, isotopic form, stereoisomer or prodrug thereof.

[0129] In some of the above embodiments, G 1 and G 2 At least one occurrence of is CH. In some embodiments, 1 is CH. In some embodiments, G 2 is CH. In some embodiments, G 1 and G 2 are each independently CH or N, provided that L 1 , A 1 Or A 2 At least one of the following is NR 5 If G 1 is CH, where L 2 , A 3 Or A 4 At least one of the following is NR 5 If G 2 is CH. In some embodiments, G 1 and G 2are both N. In certain embodiments, A 1 , A 2 , A 3 and A 4 At least one occurrence of CR 4a R 4b In some embodiments, A 1 , A 2 , A 3 and A 4 Each occurrence of CR 4a R 4b It is.

[0130] In some embodiments, E is an electrophilic moiety that can form a covalent bond with the cysteine ​​residue of the target protein.In certain more specific embodiments, the target protein is KRAS, HRAS or NRAS G12C mutant protein.In some embodiments, the cysteine ​​residue is at position 12 of the target protein.In more specific embodiments, the covalent bond with the cysteine ​​residue is at position 12 of the KRAS, HRAS or NRAS G12C mutant protein.

[0131] In some of the foregoing embodiments, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylene, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, C1-C6 cyanoalkyl, C1-C6 carboxyalkyl, aminylsulfonyl, alkylsulfonylaminyl, alkylcarbonyl, aminylalkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, aminylalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, alkylthioether, aminylalkylthioether, cyclo ... The ether, heterocyclylthioether, aminylcarbonylalkyl, aminylcarbonyl, aryl, heteroaryl, aminylalkylaminyl, aminylalkoxy, alkylcarbonylaminyl, heterocyclyl, heterocyclylaminyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkylaminyl, heterocyclylalkoxy, heterocyclylcarbonylaminyl, heteroaryl, heteroarylaminyl, heteroaryloxy, heteroarylalkyl, heteroarylalkylaminyl, heteroarylalkoxy, heteroarylcarbonylaminyl, and each occurrence of carbocyclic and heterocyclic rings are optionally substituted with one or more substituents unless otherwise specified.

[0132] R in the compound of structure (I) 1 , R 2 , R 3a , R 3b , R 3c , R 4a , R 4b , R 5 , L 1 , L 2 , L 3and E are each optionally substituted, unless specifically indicated otherwise or unless substitution would result in an unstable structure or inappropriate valence. For example, in some embodiments, alkyl, alkynyl, alkenyl, alkylene, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, alkylaminyl, haloalkyl, hydroxylalkyl, alkoxy, alkoxyalkyl, haloalkoxy, heterocyclylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonyl, aminylcarbonylalkyl, and each occurrence of carbocyclic and heterocyclic rings are optionally substituted in compounds of structure (I), and are optionally substituted with one or more substituents.

[0133] In some embodiments, A 1 is CR 4a R 4b In another embodiment, A 1 is NR 5 In some embodiments, A 2 is CR 4a R 4b In another embodiment, A 2 is NR 5 In some embodiments, A 3 is CR 4a R 4b In another embodiment, A 3 is NR 5 In some embodiments, A 4 is CR 4a R 4b In another embodiment, A 4 is NR 5 It is.

[0134] In some embodiments, n1 is 1. In some embodiments, n1 is 2. In some embodiments, n1 is 3. In some embodiments, m1 is 1. In some embodiments, m1 is 2. In some embodiments, n2 is 1. In some embodiments, n2 is 2. In some embodiments, n2 is 3.

[0135] In some embodiments, m1 is 1. In some embodiments, m1 is 2. In some embodiments, m1 is 3. In some embodiments, m2 is 1. In some embodiments, m2 is 2. In some embodiments, m2 is 3.

[0136] In some embodiments, m1 is 2 and n1 is 1. In some embodiments, m2 is 1 and n2 is 1. In some embodiments, m2 is 2 and n2 is 1. In some specific embodiments, m1 is 2, n1 is 1, m2 is 1 and n2 is 1. In some embodiments, m1 is 2 and n1 is 2. In some embodiments, n1 is 2, n1 is 2, m2 is 1 and n1 is 1. In some embodiments, m1 is 1 and n1 is 1. In some embodiments, m1 is 1, n1 is 1, m2 is 2 and n2 is 1. In some embodiments, m1 is 2, n1 is 1, m2 is 2 and n2 is 1. In some embodiments, m1 is 1, n1 is 1, m2 is 2 and n2 is 2. In some embodiments, m1 is 2, n1 is 1, m2 is 2 and n2 is 2. In some embodiments, m1 is 2, n1 is 1, m2 is 2, and n2 is 2. In some embodiments, m1 is 3, n1 is 2, m2 is 2, and n2 is 1. In some embodiments, m1 is 1, n1 is 1, m2 is 3, and n2 is 1. In some embodiments, m1 is 1, n1 is 1, m2 is 1, and n2 is 1. In some embodiments, m1 is 2, n1 is 1, m2 is 3, and n2 is 1. In some embodiments, m1 is 3, n1 is 1, m2 is 1, and n2 is 1.

[0137] In some embodiments, the compound has the following structure (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), or (Il): [ka] [ka] has one of the following:

[0138] In some embodiments, the compound has the following structure (I'a), (I'b), (I'c), (I'd), (I'e), (I'f), (I'g), (I'h), (I'i), (I'j), (I'k) or (I'l): [ka] [ka] (In the formula, [ka] represents a double or triple bond; Q is -C(=O)-, -C(=NR 8’ )-, -NR 8 C(=O)-, -S(=O)2- or -NR 8 S(=O)2-; R 8 is H, C1-C6 alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C3-C8 cycloalkyl or heterocyclylalkyl; R 8’ is H, -OH, -CN or C1-C6 alkyl; [ka] If is a double bond, R 9 and R 10 are each independently H, halo, cyano, carboxyl, C1-C6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl, or hydroxylalkyl, or R 9 and R 10 together form a carbocyclic, heterocyclic, or heteroaryl ring; and [ka] If is a triple bond, R 9 does not exist, and R 10 is H, C1-C6 alkyl, aminyl alkyl, alkyl aminyl alkyl or hydroxyl alkyl, wherein each occurrence of alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, cycloalkyl, heterocyclylalkyl, alkoxycarbonyl, heteroaryl, and carbocyclic, heterocyclic, and heteroaryl rings are optionally substituted with one or more substituents unless otherwise specified. has one of the following:

[0139] In other specific embodiments, the compound has the following structure (I'a1), (I'b1), (I'c1), (I'd1), (I'e1), (I'f1), (I'g1), (I'h1), (I'i1), (I'j1), (I'k1) or (I'l1): [ka] [ka] (In the formula, [ka] represents a double or triple bond; Q is -C(=O)-, -C(=NR 8’ )-, -NR 8 C(=O)-, -S(=O)2- or -NR 8 S(=O)2-; R 8 is H, C1-C6 alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C3-C8 cycloalkyl or heterocyclylalkyl; R 8’is H, -OH, -CN or C1-C6 alkyl; [ka] If is a double bond, R 9 and R 10 are each independently H, halo, cyano, carboxyl, C1-C6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl, or hydroxylalkyl, or R 9 and R 10 together form a carbocyclic, heterocyclic, or heteroaryl ring; and [ka] If is a triple bond, R 9 does not exist, and R 10 is H, C1-C6 alkyl, aminyl alkyl, alkyl aminyl alkyl or hydroxyl alkyl, wherein each occurrence of alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, cycloalkyl, heterocyclylalkyl, alkoxycarbonyl, heteroaryl, and carbocyclic, heterocyclic, and heteroaryl rings are optionally substituted with one or more substituents unless otherwise specified. has one of the following:

[0140] In some embodiments, the compound has the following structure (I″a), (I″b), (I″c), (I″d) or (I″e): [ka] [ka] (In the formula, [ka] represents a double or triple bond; Q is -C(=O)-, -C(=NR 8’ )-, -NR 8 C(=O)-, -S(=O)2- or -NR 8 S(=O)2-; R 8 is H, C1-C6 alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C3-C8 cycloalkyl or heterocyclylalkyl; R 8’ is H, -OH, -CN or C1-C6 alkyl; [ka] If is a double bond, R 9 and R 10 are each independently H, halo, cyano, carboxyl, C1-C6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl, or hydroxylalkyl, or R 9 and R 10 together form a carbocyclic, heterocyclic, or heteroaryl ring; and [ka] If is a triple bond, R 9 does not exist, and R 10 is H, C1-C6 alkyl, aminyl alkyl, alkyl aminyl alkyl or hydroxyl alkyl, wherein each occurrence of alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, cycloalkyl, heterocyclylalkyl, alkoxycarbonyl, heteroaryl, and carbocyclic, heterocyclic, and heteroaryl rings are optionally substituted with one or more substituents unless otherwise specified. has one of the following:

[0141] In some embodiments, the compound has the following structure (I'''a), (I'''b), (I'''c), (I'''d) or (I'''e): [ka] (In the formula, [ka] represents a double or triple bond; Q is -C(=O)-, -C(=NR 8’ )-, -NR 8 C(=O)-, -S(=O)2- or -NR 8 S(=O)2-; R 8 is H, C1-C6 alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C3-C8 cycloalkyl or heterocyclylalkyl; R 8’ is H, -OH, -CN or C1-C6 alkyl; [ka] If is a double bond, R 9 and R 10are each independently H, halo, cyano, carboxyl, C1-C6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl, or hydroxylalkyl, or R 9 and R 10 together form a carbocyclic, heterocyclic, or heteroaryl ring; and [ka] If is a triple bond, R 9 does not exist, and R 10 is H, C1-C6 alkyl, aminyl alkyl, alkyl aminyl alkyl or hydroxyl alkyl, wherein each occurrence of alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, cycloalkyl, heterocyclylalkyl, alkoxycarbonyl, heteroaryl, and carbocyclic, heterocyclic, and heteroaryl rings are optionally substituted with one or more substituents unless otherwise specified. has one of the following:

[0142] Without wishing to be bound by theory, Applicants believe that R 1 It is believed that the precise selection of substituents may play a role in the inhibitory activity of the compounds (e.g., against G12C of KRAS, HRAS, or NRAS). 1 R is capable of reversibly interacting with a KRAS, HRAS, or NRAS G12C mutant protein. 1 has high affinity for KRAS, HRAS, or NRAS and exhibits high specificity for KRAS, HRAS, or NRAS at G12C. 1 R can hydrophobically interact with KRAS, HRAS, or NRAS. 1can form hydrogen bonds with various residues of the KRAS, HRAS, or NRAS proteins at G12C.

[0143] In any of the foregoing embodiments, R 1 is aryl, e.g., phenyl or naphthyl. In some such embodiments, R 1 is substituted with one or more substituents. For example, in an exemplary embodiment, R 1 is substituted with halo, amino, hydroxyl, C1-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, etc.), cyano, C1-C6 haloalkyl, C1-C6 alkoxy, alkylaminyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, phosphate, phosphoalkoxy, boronic acid, boronic ester, -OC(=O)R, -C(=O)NH2, or C1-C6 alkylcarbonyloxy, or combinations thereof, where R is C1-C6 alkyl. In other embodiments, R 1 is substituted with fluoro, chloro, hydroxyl, methyl, isopropyl, cyclopropyl, trifluoromethyl or methoxy, or combinations thereof.

[0144] In certain embodiments, R 1 has the following structure: [ka] has one of the following:

[0145] In a specific embodiment, R 1 has the following structure: [ka] has.

[0146] In a different embodiment, R 1 is heteroaryl, such as indazolyl, indolyl, benzimidazolyl, benzotriazolyl, pyrrolopyridyl, or quinolinyl. In some of these embodiments, R1 is substituted with one or more substituents, for example, cyano, nitro, -NH2, -(C=O)NH2, hydroxyl, alkylhydroxy, halo, or C1-C6 alkyl, or combinations thereof.

[0147] In some different embodiments, R 1 has the following structure: [ka] [ka] has one of the following:

[0148] In certain specific embodiments, R 1 has the following structure: [ka] has one of the following:

[0149] In further embodiments, R 1 is a heterocyclyl, e.g., a substituted heterocycle. In some embodiments, the heterocycle is substituted with one or more substituents selected from hydroxyl, hydroxylalkyl, oxo, and aminylcarbonyl.

[0150] In another exemplary embodiment, R 1 has the following structure: [ka] has one of the following:

[0151] In some other embodiments, R 2is H, cyano, hydroxyl, halo, C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkyl, C1-C6 hydroxylalkyl, C3-C8 cycloalkyl, aminylalkyl, alkylaminyl, or aminylcarbonyl. 2 is H. In other embodiments, R 2 has the following structure: [ka] has one of the following:

[0152] In some embodiments, R 2 is cyano. In some embodiments, R 2 is fluoro. In certain embodiments, R 2 is methoxy.

[0153] In some embodiments, R 3a , R 3b and R 3cis independently in each occurrence H, halo, hydroxyl, cyano, amino, alkyl, cycloalkyl, cycloalkenyl, heterocyclenyl, haloalkyl, alkynyl, alkenyl, alkoxy, haloalkoxy, aminylcarbonyl, aminylcarbonylalkoxy, aminylsulfonyl, alkylsulfonylaminyl, alkylcarbonyl, aminylalkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, heterocyclylcarbonylalkoxy, alkylsulfonyl, aminylalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, alkylthioether, aminylalkylthioether, cycloalkylthioether; , heterocyclylthioether, aminylalkyl, aminylalkynyl, aminylalkylaminyl, aminylalkoxy, alkylcarbonylaminyl, heterocyclyl, heterocyclylaminyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkylaminyl, heterocyclylalkoxy, heterocyclylcarbonylaminyl, aryl, arylalkyl, arylalkylaminyl, arylalkoxy, arylcarbonylaminyl, heteroaryl, heteroarylaminyl, heteroaryloxy, heteroarylalkyl, heteroarylalkylaminyl, heteroarylalkoxy or heteroarylcarbonylaminyl.

[0154] In some specific embodiments, R 3a is H. In some embodiments, R 3b is H. In other embodiments, R 3c is H. In some embodiments, R 3b or R 3c are each independently H, alkyl, halo, heterocyclyl, alkoxy, heteroarylalkoxy, heterocyclylalkoxy, or aminylalkoxy. 3b is alkoxy, heterocyclyl, heteroarylalkoxy, heterocyclylalkoxy, or aminylalkoxy. In some embodiments, R 3cis alkyl, halo, or alkoxy. In certain embodiments, R 3b or R 3c each independently have the structure: [ka] has one of the following:

[0155] In some specific embodiments, R 3b or R 3c has the following structure: [ka] [ka] has one of the following:

[0156] In some specific embodiments, R 3b or R 3c has the following structure: [ka] [ka] has one of the following:

[0157] In more embodiments and subembodiments of any of the foregoing compounds of structure (I), R 4a and R 4b is H in each occurrence. In other embodiments, R 4a or R 4b At least one occurrence of is not H. In a different embodiment, occurrence R 4a or R 4b At least one of is C1-C6 alkyl, for example in some embodiments, C1-C6 alkyl is methyl.

[0158] In certain embodiments, R 4a and R 4bis independently at each occurrence H, -OH, -NH2, -CO2H, halo, cyano, hydroxylalkyl, aminylalkyl, cyanoalkyl, carboxyalkyl, or aminylcarbonyl.

[0159] In other embodiments of the above, R 4a and R 4b is independently at each occurrence H, --OH, hydroxylalkyl, cyano, or aminylcarbonyl.

[0160] In certain other embodiments, R 4a and R 4b is independently at each occurrence H, -OH, -NH2, -CO2H, halo, cyano, hydroxylalkyl, aminylalkyl, cyanoalkyl, carboxyalkyl, or aminylcarbonyl.

[0161] In a different embodiment, R 4a and R 4b At least one of is a C1-C6 cyanoalkyl, for example, cyanomethyl.

[0162] In other embodiments, R 4a At least one occurrence of R 4b together with form a carbocyclic or heterocyclic ring;

[0163] In further embodiments, R 4a At least one occurrence of R 4b Together with this, it forms oxo.

[0164] In yet another embodiment, R 4a or R 4b At least one occurrence of is an aminyl carbonyl. For example, in certain embodiments, the aminyl carbonyl is [ka] In another embodiment, R 4a or R 4bAt least one occurrence of R is cyano. 4a or R 4b At least one occurrence of is -OH. In other embodiments, R 4a or R 4b At least one occurrence of is hydroxylalkyl, e.g., hydroxylmethyl.

[0165] In still more of any of the foregoing embodiments, E has the structure: [ka] (In the formula, Q is -C(=O)-, -C(=NR 8’ )-, -NR 8 C(=O)-, -S(=O)2- or -NR 8 S(=O)2-; R 8 is H, C1-C6 alkyl or hydroxylalkyl; R 8’ is H, -OH, -CN or C1-C6 alkyl; and R 9 and R 10 are each independently H, halo, cyano, carboxyl, C1-C6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl, or hydroxylalkyl, or R 9 and R 10 together form a carbocyclic, heterocyclic or heteroaryl ring) has.

[0166] In still other of any of the foregoing embodiments, E has the structure: [ka] (In the formula, Q is -C(=O)-, -NR 8 C(=O)-, -S(=O)2- or -NR 8S(=O)2-; R 8 is H, C1-C6 alkyl or hydroxylalkyl; and R 10 is H, C1-C6 alkyl, aminyl alkyl, alkyl aminyl alkyl or hydroxyl alkyl) has.

[0167] The Q moiety is typically selected to optimize the reactivity (i.e., electrophilicity) of E. In some of the foregoing embodiments, Q is -C(=O)-, -NR 8 C(=O)-, -S(=O)2- or -NR 8 In certain of the above embodiments, Q is -C(=O)-. In other embodiments, Q is -S(=O)-. In still many embodiments, Q is -NR 8 In yet another embodiment, Q is -NR 8 S(=O)2-.

[0168] In other of the foregoing embodiments, Q is -C(=NR 8’ )-(wherein, R 8’ is H, -OH, -CN, or C1-C6 alkyl. For example, in some embodiments, R 8’ is H. In other embodiments, R 8’ is -CN. In another embodiment, R 8’ is -OH.

[0169] In some of the foregoing embodiments, R 8 is H. In other of these embodiments, R 8 is a hydroxylalkyl, for example, in some embodiments, the hydroxylalkyl is a 2-hydroxylalkyl.

[0170] In any one of the preceding embodiments, R 9 or R 10 At least one of R 9 and R10 are H, respectively.

[0171] In other of the aforementioned embodiments, R 10 is alkylaminylalkyl. In some of these embodiments, R 10 has the following structure: [ka] has.

[0172] In other embodiments, R 10 is hydroxylalkyl, for example 2-hydroxylalkyl.

[0173] In some other variations of the above embodiments, R 9 and R 10 and together form a carbocyclic ring. For example, in some of these embodiments, the carbocyclic ring is a cyclopentene, cyclohexene, or phenyl ring. In other embodiments, the carbocyclic ring is a cyclopentene or cyclohexene ring. In other embodiments, the carbocyclic ring is a phenyl ring, such as the following structure: [ka] is a phenyl ring having the following structure:

[0174] In any of the several aforementioned embodiments, E is an electrophile that can bind to KRAS, HRAS or NRAS proteins that contain a G12C mutation. In some embodiments, the electrophile E can form an irreversible covalent bond with the G12C mutant KRAS, HRAS or NRAS protein. In some cases, the 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 aforementioned, E has the following structure: [ka] [ka] has one of the following:

[0175] In some embodiments, E is [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] In certain embodiments, E is [ka] It is.

[0176] In any of the foregoing embodiments, L 1 is a bond. In other embodiments, L 1 -NR 5 -It is.

[0177] L 2 may be selected to provide appropriate spacing and / or orientation for the E groups to form a bond with the KRAS, HRAS or NRAS protein. 2 In other of the above embodiments, L 2 is alkylene.

[0178] In some embodiments, L 3 is a bond.

[0179] Some embodiments of the compounds include more than one stereoisomer. Other embodiments relate to a single stereoisomer. In some embodiments, the compounds are racemic (e.g., a mixture of atropisomers), and in other embodiments, the compounds are substantially a single isomer, e.g., a substantially purified atropisomer. In some embodiments, the compounds are substantially purified S-atropisomers. In some different embodiments, the compounds are substantially purified R-atropisomers.

[0180] In various different embodiments, the compound has one of the structures set forth in Table 1 below. Exemplary compounds in Table 1 are prepared by the methods shown or known in the art and analyzed by mass spectrometry and / or 1 Analyzed by 1 H NMR. Table 1. Representative compounds of structure (I) [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

[0181] It is understood that combinations of substituents and / or variables of the depicted formulae are permissible herein only if such contributions result in stable compounds.

[0182] Additionally, all compounds of the present disclosure that exist in a free base or free acid form can be converted to their pharma- ceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid by methods known to those skilled in the art. Salts of compounds of the present disclosure can be converted to their free base or free acid forms by standard techniques.

[0183] The compound of structure (I) can be prepared according to methods known in the art.For example, the compound of structure (I) can be prepared according to methods similar to those disclosed in International Publication No. 2015 / 054572 (the complete disclosure of which is incorporated herein by reference in its entirety).In general, starting components can be obtained from suppliers such as 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 (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)), or can be prepared as described herein. General Reaction Scheme 1 ("Method A") [ka]

[0184] General Reaction Scheme 1 ("Method A"), where R 1 , L 1 , L 2 , L 3 , A 1 , A 2 , A 3 , A 4 , G 1 , G 2 , E, m1, m2, n1 and n2 are as defined herein), the compounds of structure (I) can be prepared according to the following formula (I): 1 , X 2 , Y 1 , Y 2 and Y 3 is a reactive functional group (e.g., F, Cl, Br, boronic acid / ester, acid chloride, etc.) that is selected based on compatibility with the overall reaction scheme and the desired reaction selectivity and location. PG represents a protecting group (e.g., Boc, Fmoc, etc.), the use of which is known in the art. As shown in General Reaction Scheme 1, compound A-1 is prepared according to known methods or purchased as a commercially available reagent and reacted with an appropriate nucleophile (e.g., Y 1 is coupled with a secondary amine, A-2), to form A-3. 3 -R 1 The substituents can be used in Suzuki coupling (e.g., Y 3 is a boronic acid moiety, and X 1 is Cl) to give A-4. Removal of the protecting group (e.g., removal of Boc with TFA or hydrochloric acid) followed by addition of an appropriately substituted E moiety (e.g., X 3 -E is acryloyl chloride or acrylic anhydride) to give the desired compound of structure (I). Alternatively, the above reaction scheme can be modified at any step to add a substituent (e.g., R 2 , R 3a , R 3b , R 3c etc.) can be added and / or modified. General Reaction Scheme 2 ("Method B") [ka]

[0185] General Reaction Scheme 2 ("Method B"), where R 1 , L 1 , L 2 , L 3 , A 1 , A 2 , A 3 , A 4 , G 1 , G 2 , E, m1, m2, n1 and n2 are as defined herein), the compounds of structure (I) can be prepared according to the following formula (I): 1 , X 2 , Y 1 , Y 2 and Y 3 is a reactive functional group (e.g., F, Cl, Br, boronic acid / ester, acid chloride, etc.) selected based on compatibility with the overall reaction scheme and the desired reaction selectivity and location. PG represents a protecting group (e.g., Boc, Fmoc, etc.), the use of which is known in the art. As shown in General Reaction Scheme 2, compound B-1 is prepared according to known methods or purchased as a commercially available reagent and coupled with a partner (e.g., boronic acid or ester under Suzuki coupling conditions) to form B-2. B-2 is then reacted with B-3 under appropriate conditions (e.g., Pd2(dba)3, BINAP and sodium tert-butoxide) to produce B-4. Removal of the protecting group (e.g., removal of Boc with TFA or hydrochloric acid), followed by addition of an appropriately substituted E moiety (e.g., X 3 -E is acryloyl chloride or acrylic anhydride) to give the desired compound of structure (I).

[0186] Any of the above reaction schemes can be modified at any step to include a substituent (e.g., R 2 , R 3a , R 3b , R 3cThe skilled artisan can add and / or modify substituents (e.g., R 2 , R 3a , R 3b , R 3c It will be appreciated that other elements may be added or modified as appropriate.

[0187] Those skilled in the art will also recognize that in the process of preparing the compounds described herein, it may be necessary to protect the functional groups of intermediate compounds by suitable protecting groups. Such functional groups include, but are not limited to, hydroxy, amino, mercapto, and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, and benzyl, and the like. Suitable protecting groups for amino, amidino, and guanidino include t-butoxycarbonyl and benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(O)-R'', where R'' is alkyl, aryl, or arylalkyl, p-methoxybenzyl, and trityl, and the like. Suitable protecting groups for carboxylic acid include alkyl esters, aryl esters, or arylalkyl esters. Protecting groups are added or removed as necessary according to standard techniques known to those skilled in the art and described herein. The use of protecting groups is described in detail in Green, TW and PGM Hutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill 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.

[0188] Those skilled in the art will also recognize that such protected derivatives of the disclosed compounds may not themselves possess pharmacological activity, but may form pharmacologically active compounds of the disclosed compounds after being administered to a mammal and metabolized in the body. Thus, such derivatives may be described as "prodrugs." Prodrugs of the disclosed compounds are included within the scope of embodiments of the present invention.

[0189] Pharmaceutical Compositions Other embodiments relate to pharmaceutical compositions. The pharmaceutical composition comprises any one (or more) of the aforementioned compounds and a pharma- ceutically 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 (e.g., an anti-cancer agent). Non-limiting examples of such therapeutic agents are described herein below.

[0190] 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.Further, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0191] In certain embodiments, the compounds described herein are administered in a local rather than systemic manner, for example, via direct injection of the compound into an organ, often in a depot preparation or sustained release formulation. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome is targeted to and selectively taken up by the organ. In still other embodiments, the compounds described herein are provided in the form of a rapid release formulation, a long-term release formulation, or a medium-term release formulation. In still other embodiments, the compounds described herein are administered locally.

[0192] The compounds of the present disclosure are effective over a wide dosage range. For example, for treatment of adults, dosages of 0.01-1000 mg / day, 0.5-100 mg / day, 1-50 mg / day, and 5-40 mg / day are examples of dosages used in some embodiments. An exemplary dosage is 10-30 mg / day. The exact dosage will depend 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 preferences and experience of the attending physician.

[0193] In some embodiments, the compound of the present disclosure is administered in a single dose.Typically, such administration is by injection (e.g., intravenous injection) to rapidly introduce the drug.However, other routes are used as necessary.A single dose of the compound of the present disclosure can also be used to treat acute conditions.

[0194] In some embodiments, the compound of the present disclosure is administered in multiple doses. In some embodiments, administration is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, administration is about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the compound of the present disclosure and the other agent are both administered about once a day to about six times a day. In another embodiment, administration of the compound of the present disclosure and the agent continues for less than about 7 days. In yet another embodiment, administration continues for more than about 6 days, 10 days, 14 days, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous administration is performed and administration is maintained as long as necessary.

[0195] The administration of the compound of the present disclosure can be continued as long as necessary.In some embodiments, the compound of the present disclosure is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days.In some embodiments, the compound of the present disclosure is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day.In some embodiments, the compound of the present disclosure is administered continuously and chronically, for example, for treatment to obtain chronic effect.

[0196] In some embodiments, the compound of the present disclosure is administered in multiple dosages.It is known in the art that the pharmacokinetics of the compound varies between subjects, so that individualized administration regimen is required for optimal treatment.The administration regimen of the compound of the present disclosure can be found by routine testing in consideration of the present disclosure.

[0197] In some embodiments, the compound described herein is formulated into pharmaceutical composition.In certain embodiments, the pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate the processing of active compound into medicament-usable preparations.The appropriate formulation depends on the route of administration selected.Any pharmaceutically acceptable technology, carrier, and excipient can be used as appropriate for the formulation of pharmaceutical composition 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;Liberman,HAand Lachman,L.,Eds.,Pharmaceutical Dosage Forms,Marcel Decker,New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0198] Provided herein is a pharmaceutical composition comprising a compound of structure (I) and a pharma- ceutically acceptable diluent, excipient, or carrier.In certain embodiments, the described compound is administered as a pharmaceutical composition in which the compound of structure (I) is mixed with other active ingredients for combination therapy.All combinations of active substances described in the combination therapy section below and throughout this disclosure are included herein.In certain embodiments, the pharmaceutical composition comprises one or more compounds of structure (I).

[0199] Pharmaceutical composition, as used herein, refers to a mixture of a compound of structure (I) with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, in carrying out the methods of treatment or use provided herein, a therapeutically effective amount of a compound of structure (I) provided herein is administered in a pharmaceutical composition 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 varies 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 components of a mixture.

[0200] In one embodiment, one or more compounds of structure (I) are formulated in an aqueous solution. In certain embodiments, the aqueous solution is selected from physiologically compatible buffers, such as, by way of example only, Hank'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, transmucosal formulations include a penetrant appropriate for the barrier to be permeated. In yet other embodiments, in which 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.

[0201] In another embodiment, the compound described herein is formulated for oral administration.The compound described herein is formulated by combining active compound with, for example, pharmaceutically acceptable carrier or excipient.In various embodiments, the compound described herein is formulated in oral dosage form, which includes, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries and suspensions.

[0202] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipients with one or more compounds described herein, grinding the resulting mixture as necessary, and processing the mixture of granules after adding suitable adjuvants as necessary to obtain tablets or dragee cores.Suitable excipients are in particular sugars (including lactose, sucrose, mannitol, or sorbitol); cellulose preparations (e.g., corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.); or other fillers (e.g., polyvinylpyrrolidone (PVP or povidone) or calcium phosphate, etc.).In certain embodiments, disintegrants are added as necessary.Disintegrants include, by way of example only, cross-linked sodium croscarmellose, polyvinylpyrrolidone, agar, or alginic acid or its salts (e.g., sodium alginate).

[0203] In one embodiment, the dosage form (such as dragee core and tablet) is provided with one or more suitable coatings. In a particular embodiment, a concentrated sugar solution is used for coating the dosage form. The sugar solution optionally contains additional components (such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solution, and suitable organic solvent or solvent mixture). 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.

[0204] In certain embodiments, a therapeutically effective amount of at least one compound described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin and sealed soft capsules made of gelatin and plasticizers (such as glycerol or sorbitol). In certain embodiments, the push-fit capsules contain the active ingredient 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, the 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. Additionally, stabilizers are added as necessary.

[0205] In other embodiments, a therapeutically effective amount of at least one compound described herein is formulated for oral or sublingual administration. Formulations suitable for oral or sublingual administration include, by way of example only, tablets, lozenges, or gels. In yet other embodiments, the compounds described herein are formulated for parental injection (including formulations suitable for bolus injection or continuous infusion). In certain embodiments, the formulation for injection is in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are added to the injection formulation as needed. In still other embodiments, the pharmaceutical composition is formulated in a form suitable for parenteral injection as a suspension, solution, or emulsion in a sterile oily or aqueous vehicle. Parenteral injection formulations include formulating agents, such as suspending agents, stabilizing agents, and / or dispersing agents, as needed. In certain embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form. In further embodiments, a suspension of the active compound (e.g., a compound of structure (I)) is prepared as a suitable oily injection suspension. 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 liposomes. In certain specific embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension (such as sodium carboxymethylcellulose, sorbitol, or dextran). If necessary, the suspension contains suitable stabilizers or agents that increase the solubility of the compounds to allow the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle (such as sterile pyrogen-free water) before use.

[0206] In yet another embodiment, 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, balms, creams, or ointments.Such pharmaceutical compositions may optionally include solubilizers, stabilizers, tonicity enhancers, buffers, and preservatives.

[0207] In yet other embodiments, the compounds of structure (I) are formulated for transdermal administration. In certain embodiments, transdermal formulations may be lipophilic emulsions or buffered aqueous solutions 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 agents. In further embodiments, the compounds of structure (I) are delivered transdermally using iontophoretic patches and the like. In certain embodiments, the transdermal patch provides controlled delivery of the compounds of structure (I). In certain embodiments, the absorption rate is reduced by the use of a rate-limiting membrane or by entrapment of the compound within a polymer matrix or gel. In another embodiment, absorption enhancers are used to increase absorption. Absorption enhancers or carriers include pharma- ceutically acceptable absorbent solvents that aid passage through the skin. For example, in one embodiment, the transdermal device is in the form of a bandage that includes a backing member, a reservoir containing the compound, optionally with a carrier, an optional rate-limiting barrier for delivering the compound to the host's skin at a controlled, predetermined rate over an extended period of time, and a means for securing the device to the skin.

[0208] 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, aerosol, mist, or powder.Conveniently, any pharmaceutical composition of any compound of structure (I) is delivered in the form of an aerosol spray provided from a pressurized pack or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas).In certain embodiments, the dosage unit of the pressurized aerosol is determined by providing a valve to deliver a metered amount.In certain embodiments, by way of example only, capsules and cartridges of gelatin or the like are formulated containing a powder mixture of the compound and a suitable powder base (e.g., lactose or starch) for use in an inhaler or insufflator.

[0209] In yet other embodiments, the compounds of structure (I) are formulated in rectal compositions (such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas) containing conventional suppository bases (such as cocoa butter or other glycerides) and synthetic polymers (such as polyvinylpyrrolidone and PEG). In suppository forms 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.

[0210] In certain embodiments, pharmaceutical compositions are formulated into pharmacopoeia-usable preparations in any conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate the processing of active compounds.Suitable formulations depend on the selected route of administration.Any pharmacopoeia-acceptable techniques, carriers, and excipients are used as appropriate, as necessary.The pharmaceutical compositions containing the compound of structure (I) are prepared in a conventional manner (for example, by conventional mixing, dissolving, granulating, dragee-making, wet milling, emulsifying, encapsulating, entrapping, or compressing process, etc.).

[0211] The pharmaceutical compositions comprise at least one pharma- ceutically acceptable carrier, diluent, or excipient and at least one compound of structure (I) as described herein as an active ingredient. The active ingredient is in the form of a free acid or free base or a pharma- ceutically acceptable salt. In addition, 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 tautomers of the compounds described herein are included within the scope of the compounds presented herein. In addition, the compounds described herein include unsolvated forms and solvated forms with pharma- ceutically acceptable solvents (such as water and ethanol). Solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants (such as preservatives, stabilizers, wetting agents, or emulsifiers, dissolution enhancers, salts for adjusting osmotic pressure, buffers, and / or other pharma- ceutical beneficial substances).

[0212] The method of preparing a composition comprising the compounds described herein comprises formulating the compound using one or more inert pharma- ceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid. 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 forms of the pharmaceutical compositions described herein include solutions or suspensions, solids suitable for dissolving or suspending in liquid prior to use, or emulsions. These compositions also optionally contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, and pH buffering agents.

[0213] In some embodiments, pharmaceutical compositions comprising at least one compound of structure (I) are illustratively in the form of a liquid in which the drug is present 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 solution and a second portion of the drug is present in particulate form in suspension in a liquid matrix. In some embodiments, the liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.

[0214] In certain embodiments, useful aqueous suspensions contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers (such as cellulose polymers (e.g., hydroxypropylmethylcellulose)) and water-insoluble polymers (such as cross-linked carboxyl-containing polymers). Certain pharmaceutical compositions described herein contain mucoadhesive polymers selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0215] Useful pharmaceutical compositions also optionally include a solubilizing agent to aid in the solubility of the compound of structure (I). The term "solubilizing agent" generally includes agents that form micellar or true solutions of the drug. Certain acceptable non-ionic surfactants (e.g., polysorbate 80) are useful as solubilizing agents, as are ophthalmically acceptable glycols, polyglycols (e.g., polyethylene glycol 400), and glycol ethers.

[0216] In addition, useful pharmaceutical compositions optionally contain one or more pH adjusting or buffering agents, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0217] In addition, useful compositions also optionally include one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include salts having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions, with suitable salts including sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0218] Other useful pharmaceutical compositions optionally contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances (such as merfen and thiomersal); stabilized chlorine dioxide; and quaternary ammonium compounds (such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride).

[0219] Still other useful compositions include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils (e.g., polyoxyethylene (60) hydrogenated castor oil); and polyoxyethylene alkyl ethers and alkyl phenyl ethers (e.g., octoxynol 10, octoxynol 40).

[0220] Still other useful compositions optionally contain one or more antioxidants to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0221] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers, or, where preservatives are typically included in the composition, multi-dose reclosable containers are used.

[0222] 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, organic solvents such as N-methylpyrrolidone are also used. In further embodiments, the compounds described herein are delivered using sustained release systems, such as semipermeable matrices of solid hydrophobic polymers containing therapeutic agents. A variety of sustained release materials are useful herein. In some embodiments, sustained release capsules release the compounds for several weeks to 100 days. Due to the chemical nature and biological stability of the therapeutic reagent, additional protein stabilization strategies are used.

[0223] In certain embodiments, the formulations described herein contain one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general 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 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) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0224] In some embodiments, the concentration of the compound of structure (I) provided in the pharmaceutical composition of the present disclosure is 100%, 90%, 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%, w / w, w / v, or v / v. %, 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 less than 0.0001%.

[0225] In some embodiments, the concentration of the compound of structure (I) provided in the pharmaceutical composition of the present disclosure is 90%, 80%, 70%, 60%, 50%, 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 0.0001%.

[0226] In some embodiments, the concentration of the compound of structure (I) provided in the pharmaceutical composition of the present disclosure is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.0 7% 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 approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10%.

[0227] In some embodiments, the concentration of the compound of structure (I) provided in the pharmaceutical composition of the present disclosure is within the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9%, w / w, w / v, or v / v.

[0228] In some embodiments, the amount of the compound of structure (I) provided in the pharmaceutical composition of the present disclosure is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 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, 0.002 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.

[0229] In some embodiments, the amount of the compound of structure (I) provided in the pharmaceutical composition of the present disclosure 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, 0.0025g, 0.003g, 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025 g, 0.03g, 0.035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0 .08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g , 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 more than 10g.

[0230] In some embodiments, the amount of the compound of structure (I) provided in the pharmaceutical composition of the present disclosure is within the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

[0231] Kits / Products Kits and products are also provided for use in the therapeutic applications described herein.In some embodiments, such kits include carriers, packages, or containers, which are compartmentalized to contain one or more containers, such as vials and tubes, each of which contains one of the individual elements to be used in the methods described herein.Suitable containers include, for example, bottles, vials, syringes, and test tubes.Containers are formed from various materials, such as glass or plastic.

[0232] The products provided herein include packaging materials. Packaging materials used in packaging pharmaceutical products include, for example, packaging materials found in U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging materials appropriate for the selected formulation and intended mode of administration and treatment. For example, the container(s) contain one or more compounds described herein, optionally in a composition or in combination with another agent disclosed herein. The container(s) optionally have a sterile access port (e.g., the container is an intravenous solution bag or vial with a stopper that can be pierced by a hypodermic needle). Such kits optionally contain the compound together with an identifying description or label or instructions for its use in the methods described herein.

[0233] For example, the kit typically includes one or more additional containers, each container having one or more of various materials (reagents and / or devices, optionally in concentrated form) that are desirable from a commercial and user perspective for the use of the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial, and / or tube labels that list the contents and / or instructions for use, and package inserts that include instructions for use. Typically, a set of instructions will also be included. The label is present on or with the container as required. For example, the label is present on the container when the container itself is attached, molded, or etched with letters, numbers, or other symbols that form the label, and the label is present with the container when the label is present in a storage container or carrier that also holds the container, for example, as a package insert. Furthermore, the label is used to indicate that the contents should be used for a specific therapeutic application. Furthermore, the label indicates the use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical composition is present in a pack or dispenser device that contains one or more unit dosage forms containing the compound provided herein. The pack, for example, contains metal or plastic foil (such as a blister pack). Alternatively, the pack or dispenser device is accompanied by administration instructions. Alternatively, the pack or dispenser is accompanied by a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the form of the drug approved by the government agency for administration to humans or animals. Such notice is, for example, a label for prescription drugs approved by the U.S. Food and Drug Administration or an approved product insert. In some embodiments, a composition containing the compound provided herein formulated in a compatible pharmaceutical carrier is prepared, placed in a suitable container, and labeled for treatment of an indicated condition.

[0234] method An embodiment of the present disclosure provides a method for inhibiting RAS-mediated cell signaling, comprising contacting cells with an effective amount of one or more compounds disclosed herein.Inhibition of RAS-mediated signaling can be assessed and demonstrated by a wide variety of methods known in the art.Non-limiting examples include demonstrating: (a) a decrease in the GTPase activity of RAS; (b) a decrease in GTP binding affinity or an increase in GDP binding affinity; (c) a decrease in the K of GTP. off or K of GDP off (d) a decrease in the levels of downstream signaling molecules in the RAS pathway (such as a decrease in pMEK levels); and / or (e) a decrease in binding of the RAS complex to downstream signaling molecules, including but not limited to Raf. Kits and commercially available assays are available for one or more of the above determinations.

[0235] Embodiments also provide methods of using the disclosed compounds or pharmaceutical compositions to treat disease conditions, including but not limited to conditions involving G12C KRAS, HRAS, or NRAS mutations, G12C HRAS mutations and / or G12C NRAS mutations (e.g., cancer).

[0236] In some embodiments, a method of treating cancer is provided, comprising administering to a subject in need of cancer treatment an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of structure (I). In some embodiments, the cancer is mediated by a G12C mutation in KRAS, HRAS, or NRAS. In other embodiments, the cancer is pancreatic cancer, colon cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

[0237] In some embodiments, the disclosure provides a method of treating a disorder in a subject in need thereof, comprising determining whether the subject has a KRAS, HRAS, or NRAS G12C mutation, and administering to the subject a therapeutically effective dose of at least one compound of structure (I), or a pharma- ceutically acceptable salt, ester, prodrug, tautomer, solvate, hydrate, or derivative thereof if the subject is determined to have a KRAS, HRAS, or NRAS G12C mutation.

[0238] The disclosed compounds strongly inhibit anchorage-independent cell growth and therefore may inhibit tumor metastasis. Thus, in another embodiment, the present disclosure provides a method of inhibiting tumor metastasis, comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of any of the compounds disclosed herein and a pharma- ceutically acceptable carrier.

[0239] G12C mutations in KRAS, HRAS, or NRAS have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Accordingly, certain embodiments relate to the administration of the disclosed compounds (e.g., in the form of pharmaceutical compositions) to patients in need of treatment for hematological malignancies. Such malignancies include, but are not limited to, leukemias and lymphomas. For example, the disclosed compounds can be used for the treatment of diseases such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In other embodiments, the compounds are useful for the treatment of lymphomas (such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma).

[0240] Whether a tumor or cancer contains a KRAS, HRAS, or NRAS mutation at G12C can be determined by evaluating the nucleotide sequence encoding the KRAS, HRAS, or NRAS protein, evaluating the amino acid sequence of the KRAS, HRAS, or NRAS protein, or evaluating the characteristics of the predicted mutant protein of KRAS, HRAS, or NRAS. The sequence of wild-type human KRAS, HRAS, or NRAS is known in the art (e.g., accession number NP203524).

[0241] Methods for detecting mutations in the nucleotide sequence of KRAS, HRAS, or NRAS are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assay, real-time PCR assay, PCR sequencing, mutant 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 microarray analysis. In some embodiments, samples are evaluated for KRAS, HRAS, or NRAS mutation of G12C by real-time PCR. In real-time PCR, a fluorescent probe specific for KRAS, HRAS, or NRAS G12C mutation is used. If mutation exists, the probe binds and fluorescence is detected. In some embodiments, the KRAS, HRAS, or NRAS G12C mutation is identified using direct sequencing of a specific region (e.g., exon 2 and / or exon 3) in the KRAS, HRAS, or NRAS gene. This technique identifies all possible mutations in the sequenced region.

[0242] The method of detecting the mutation in KRAS, HRAS or NRAS protein is known to those skilled in the art.These methods include, but are not limited to, the detection of KRAS, HRAS or NRAS mutants using binding agents (e.g., antibodies) specific to mutant proteins, protein electrophoresis, and Western blotting, and direct peptide sequencing.

[0243] The method of determining whether a tumor or cancer contains a G12C KRAS, HRAS, or NRAS mutation can use a variety of samples. In some embodiments, the sample is taken from a subject with a tumor or cancer. In some embodiments, the sample is taken from a subject with 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.

[0244]

[0023] Embodiments of the present disclosure also relate to a method of treating a hyperproliferative disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharma- ceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. In some embodiments, the method relates to the treatment of cancers such as acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoid tumor, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorders (CMD), chronic myeloproliferative disorders (CML ... disorder), colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic cervical squamous cell carcinoma of unknown primary, midline duct carcinoma, oral cancer cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancercancer), oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer (stomach cancer), small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, rare cancer of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer. In some embodiments, the method relates to the treatment of a non-cancerous hyperproliferative disorder, such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hyperplasia (BPH)).

[0245] In certain specific embodiments, the present disclosure relates to a method for treating lung cancer, comprising administering an effective amount of any of the above compounds (or pharmaceutical compositions comprising the above compounds) to a subject in need of lung cancer treatment. In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC) (e.g., adenocarcinoma, squamous cell lung carcinoma, or large cell lung carcinoma). In other embodiments, the lung cancer is small cell lung carcinoma. Other lung cancers that can be treated with the disclosed compounds include, but are not limited to, adenocarcinoma, carcinoid tumor, and undifferentiated carcinoma.

[0246] Subjects who can be treated with the compounds of the invention, or pharma- ceutically acceptable salts, esters, prodrugs, solvates, tautomers, hydrates, or derivatives of said compounds according to the methods of the disclosure, include, for example, subjects who have been diagnosed with acute myeloid leukemia, acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoid tumor, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer. , chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cancer cancer, liver cancer, lobular intraepithelial carcinoma (LCIS), lung cancer, lymphoma, metastatic squamous cell carcinoma of unknown primary site, midline duct carcinoma, mouth cancer, multiple endocrine neoplasia 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, cancer of the nasal cavity and paranasal sinuses, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, cancer of the lip and oral cavitycancer), oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer (stomach cancer), small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, rare cancer of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer. In some embodiments, subjects treated with the compounds of the present disclosure include subjects who have been diagnosed with a non-cancerous hyperproliferative disorder, such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hyperplasia (BPH)).

[0247] The embodiments of the present disclosure further provide a method of modulating G12C mutant KRAS, HRAS, or NRAS protein activity by contacting said protein with an effective amount of a compound of the present disclosure. The modulation can be inhibition or activation of protein activity. In some embodiments, the present disclosure provides a method of inhibiting protein activity by contacting G12C mutant KRAS, HRAS, or NRAS protein with an effective amount of a compound of the present disclosure in solution. In some embodiments, the present disclosure provides a method of inhibiting G12C mutant KRAS, HRAS, or NRAS protein activity by contacting a cell, tissue, or organ expressing the protein of interest. In some embodiments, the present disclosure provides a method of inhibiting protein activity in a subject, including but not limited to rodents and mammals (e.g., humans), by administering an effective amount of a compound of the present invention to the subject. In some embodiments, the modulation rate is more than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the inhibition is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0248] In some embodiments, the present disclosure provides a method for inhibiting the activity of KRAS, HRAS, or NRAS G12C in a cell by contacting the cell with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the cell.In some embodiments, the present disclosure provides a method for inhibiting the activity of KRAS, HRAS, or NRAS G12C in a tissue by contacting the tissue with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the tissue.In some embodiments, the present disclosure provides a method for inhibiting the activity of KRAS, HRAS, or NRAS G12C in an organism by contacting the organism with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the organism. In some embodiments, the present disclosure provides a method of inhibiting the activity of KRAS, HRAS, or NRAS G12C in an animal by contacting the animal with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the animal. In some embodiments, the present disclosure provides a method of inhibiting the activity of KRAS, HRAS, or NRAS G12C in a mammal by contacting the mammal with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the mammal. In some embodiments, the present disclosure provides a method of inhibiting the activity of KRAS, HRAS, or NRAS G12C in a human by contacting the human with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the human. In other embodiments, the present disclosure provides a method of treating a disease mediated by the activity of KRAS, HRAS, or NRAS G12C in a subject in need of such treatment.

[0249] Other embodiments provide methods for combination therapy using agents known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes, in combination with the compounds of the present invention, or pharma- ceutically acceptable salts, esters, prodrugs, solvates, tautomers, hydrates, or derivatives thereof. In one aspect, such therapy includes, but is not limited to, the combination of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation treatments to obtain synergistic or additive therapeutic effects.

[0250] A large number of chemotherapeutic agents are currently known in the art and can be used in combination with the compounds of the present invention. In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.

[0251] Non-limiting examples are chemotherapeutic agents, cytotoxic agents, non-peptide small molecules (such as Gleevec® (imatinib mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and adriamycin), as well as numerous chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents (such as thiotepa and cyclophosphamide (Cytoxan®)); alkyl sulfonates (such as busulfan, improsulfan, and piposulfan); aziridines (such as benzodopa, carboquone, meturedopa, and uredopa); ethylenimines and methylamelamines (altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramine ... amide, and trimethylolomelamine); nitrogen mustards (chlorambucil, chlornaphazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobuenbiquin, phenesterine, prednimustine, trofosfamide, uracil mustard, etc.); nitrosoureas (carmustine, chlorozotocin, fotemustine, lomustine, antibiotics (aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, casodex, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin , marcelomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, keramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, etc.; antimetabolites (such as methotrexate and 5-fluorouracil (5-FU)); folic acid analogs (such as denopterin, methotrexate, pteropterin, trimetrexate, etc.);Purine analogues (such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine); pyrimidine analogues (such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine); androgens (such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone); antiadrenal agents (such as aminoglutethimide, mitotane, trilostane); folic acid supplements (such as floric acid); aceglatone; aldophosphamide Glycosides;Aminolevulinic acid;Amsacrine;Bestravcil;Bisantrene;Edatraxate;Defofamine;Demecolcine;Diazicon;Elfomitin;Elliptinium acetate;Etoglucide;Gallium nitrate;Hydroxyurea;Lentinan;Lonidamine;Mitoguazone;Mitoxantrone;Mopidamol;Nitracrine;Pentostatin;Phenamet;Pirarubicin;Podophyllic acid;2-Ethylhydrazide;Procarbazid and pharmaceuticals such as acetaminophen; PSK®; razoxane; schizofiran; spirogermanium; tenuazonic acid; triazicon; 2,2',2''-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes (e.g., paclitaxel (Taxol™, Bristol-Myers Squibb Oncology, Princeton, NJ) and docetaxel (Taxotere™, Rhone-Poulenc Rorer, Antony, France)); retinoic acid; esperamicin; capecitabine; and pharmaceutical acceptable salts, acids, or derivatives of any of the above. Suitable chemotherapeutic cell modulating agents include antihormonal agents that act to regulate or inhibit hormone action on tumors (antiestrogens (e.g., tamoxifen (Nolvadex™), raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxyphene, keoxyphene, LY 117018, onapristone, and toremifene (Fareston));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); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitors RFS2000;Also included are difluoromethylornithine (DMFO). Optionally, the compounds or pharmaceutical compositions of the present disclosure can be administered in combination with commonly prescribed anti-cancer drugs, such as Herceptin (registered trademark), Avastin (registered trademark), Erbitux (registered trademark), Rituxan (registered trademark), Taxol (registered trademark), Arimidex (registered trademark), Taxotere (registered trademark), ABVD, AVICINE, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharadin, albocidin, bu, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antineoplastic drugs, antitumorigenic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW2992, biricoderl, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, cell cycle nonspecific antineoplastic agents, dichloroacetic acid, discodermolide, elsamitre Synth, enocitabine, epothilone, eribulin, everolimus, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, lanicuidar, larotaxel, lenalidomide, lucantone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixa It may be used in combination with any of the following: introne, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, or zosuquidar;

[0252] The embodiments further relate to the method of using the compounds or pharmaceutical compositions provided herein in combination with radiation therapy for inhibiting abnormal cell growth or treating hyperproliferative disorders in mammals.Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein.The administration of the compounds of the present disclosure in this combination therapy can be determined as described herein.

[0253] Radiation therapy can be administered by one of several methods or a combination of methods, including but not limited to external beam radiation therapy, internal radiation therapy, interstitial radiation therapy, stereotactic radiosurgery, total body radiation therapy, radiation therapy, and continuous or temporary interstitial brachytherapy. The term "brachytherapy" as used herein refers to radiation therapy delivered by spatially restricted radioactive material inserted at or near the affected site of tumor or other proliferative tissue in the body. This term is intended to include, but is not limited to, exposure to radioisotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioisotopes of Lu). Radiation sources suitable for use as cell conditioning agents of the present disclosure include both solid and liquid. As non-limiting examples, the radiation source can be a radionuclide (I-125 as a solid source, I-131, Yb-169, Ir-192, I-125 as a solid source, etc.) or other radionuclides that emit photons, beta particles, gamma rays, or other therapeutic radiation. The radioactive material can also be a fluid made from any radionuclide solution (e.g., a solution of I-125 or I-131), or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of a solid radionuclide (Au-198, Y-90, etc.). Additionally, the radionuclide can be incorporated into a gel or radioactive microspheres.

[0254] Without being limited to any theory, the compounds of the present disclosure can make abnormal cells more sensitive to treatment with irradiation for killing and / or inhibiting the growth of such cells.Therefore, the present disclosure further relates to a method for increasing the sensitivity of abnormal cells in a mammal to treatment with irradiation, comprising administering to the mammal a compound of the present disclosure or its pharma- ceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative in an amount effective to increase the sensitivity of abnormal cells to treatment with irradiation.The amount of the compound, salt or solvate in the method can be determined according to the means for identifying an effective amount of such compounds described herein.

[0255] The compounds or pharmaceutical compositions of the present disclosure can be used in combination with an amount of one or more agents selected from an antiangiogenic agent, a signal transduction inhibitor, an antiproliferative agent, a glycolysis inhibitor, or an autophagy inhibitor.

[0256] Antiangiogenic agents, such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors, can be used in conjunction with the disclosed compounds and pharmaceutical compositions described herein. Antiangiogenic agents include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include Celebrex™ (alecoxib), valdecoxib, and rofecoxib.Examples of useful matrix metalloproteinase inhibitors are disclosed in WO 96 / 33172 (published October 24, 1996), WO 96 / 27583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed July 8, 1997), European Patent Application No. 99308617.2 (filed October 29, 1999), WO 98 / 07697 (published February 26, 1998), WO 98 / 03516 (published February 26, 1998), and WO 98 / 03516 (published March 7, 1996). No. (published January 29, 1998), WO98 / 34918 (published August 13, 1998), WO98 / 34915 (published August 13, 1998), WO98 / 33768 (published August 6, 1998), WO98 / 30566 (published July 16, 1998), European Patent Publication No. 606,046 (published July 13, 1994), European Patent Publication No. 931,788 (published July 28, 1999), WO90 / No. 05719 (published 31 May 1990), WO99 / 52910 (published 21 October 1999), WO99 / 52889 (published 21 October 1999), WO99 / 29667 (published 17 June 1999), PCT International Application No. PCT / IB98 / 01113 (filed 21 July 1998), European Patent Application No. 99302232.1 (filed 25 March 1999), UK Patent Application No. 991 No. 2961.1, filed June 3, 1999, U.S. Provisional Patent Application No. 60 / 148,464, filed August 12, 1999, U.S. Patent No. 5,863,949, issued January 26, 1999, U.S. Patent No. 5,861,510, issued January 19, 1999, and European Patent Publication No. 780,386, published June 25, 1997, all of which are incorporated herein by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no MMP-1 inhibitory activity. More preferred are inhibitors that selectively inhibit MMP-2 and / or MMP-9 relative to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).Some specific examples of MMP inhibitors useful in the present disclosure are AG-3340, RO32-3555, and RS13-0830.

[0257] Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, autophagy-inhibiting algal toxins that inhibit protein phosphatase type 2A or type 1, analogs of cAMP, and drugs that increase cAMP levels (such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine). Additionally, antisense or siRNA that inhibit the expression of proteins, including, but not limited to, ATG5 (involved in autophagy), can also be used.

[0258] Embodiments also relate to methods and pharmaceutical compositions for the treatment of cardiovascular disease in a mammal comprising an amount of a compound of the invention, or a pharma- ceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate, or derivative thereof, or an isotopically labeled derivative thereof, and an amount of one or more therapeutic agents for the treatment of cardiovascular disease.

[0259] Exemplary agents for use in cardiovascular disease are antithrombotic agents (e.g., prostacyclin and salicylates), thrombolytic agents (e.g., streptokinase, urokinase, tissue plasminogen activator (TPA), and anisoylated plasminogen-streptokinase activator complex (APSAC)), antiplatelet agents (e.g., acetyl-salicylic acid (ASA) and clopidogrel), vasodilators (e.g., nitrates), calcium channel blockers, antiproliferative agents (e.g., colchicine and alkylating agents), intercalating agents, growth regulators (interleukins, transforming growth factor-β, and congeners of platelet-derived growth factor, monoclonal antibodies directed against growth factors, etc.), anti-inflammatory agents (both steroidal and nonsteroidal), and other agents that can modulate vascular tone, function, arteriosclerosis, and healing responses to vascular or organ injury following intervention. Antibiotics can also be included in the combinations or coatings encompassed by the present invention. Additionally, the coatings can be used to deliver therapeutic agents locally within the vessel wall by incorporating the active agent into a swellable polymer, which is released upon swelling of the polymer.

[0260] In some embodiments, the compounds described herein are formulated or administered in conjunction with liquid or solid tissue barriers known as lubricants.Examples of tissue barriers include, but are not limited to, polysaccharides, polyglycans, seprafilm, interceed, and hyaluronic acid.

[0261] In some embodiments, pharmaceutical agents administered in conjunction with the compounds described herein include any suitable drug that is usefully delivered by inhalation, including, for example, analgesics (e.g., codeine, dihydromorphine, ergotamine, fentanyl, or morphine); angina preparations (e.g., diltiazem); antiallergy drugs (e.g., cromoglycate, ketotifen, or nedocromil); anti-infectives (e.g., cephalosporins, penicillins, streptomycin, sulfonamides, tetracyclines, , or pentamidine); antihistamines (e.g., methapyrilene); anti-inflammatory drugs (e.g., beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide, or fluticasone); antitussives (e.g., noscapine); bronchodilators (e.g., ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, sarbutinol ... lumeterol, terbutaline, isoetharine, tulobuterol, orciprenaline, or (-)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol; diuretics (e.g., amiloride); anticholinergics (e.g., ipratropium, atropine, or oxitropium); hormones (e.g., cortisone, hydrocortisone, or prednisolone); xanthines (e.g., aminophylline, co phosphate theophyllinate, lysine theophyllinate, or theophylline; and therapeutic proteins and peptides (e.g., insulin or glucagon). It will be apparent to those skilled in the art that, where appropriate, drugs may be used in the form of a salt (e.g., as an alkali metal or amine salt or as an acid addition salt), or as an ester (e.g., a lower alkyl ester), or as a solvate (e.g., a hydrate) to optimize activity and / or stability of the drug.

[0262] Other exemplary therapeutic agents useful in combination therapy include the above-mentioned radiation therapy agents, hormone antagonists, hormones and their releasing factors, thyroid and antithyroid agents, estrogens and progestins, androgens, adrenocorticotropic hormones; corticosteroids and their synthetic analogs; corticosteroid synthesis and action, insulin, oral hypoglycemic agents, and inhibitors of the pharmacological action of the endocrine pancreas, agents affecting mineralization and bone turnover: calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitamins (water soluble), These include, but are not limited to, vitamins such as soluble vitamins, vitamin B complex, ascorbic acid, fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines, chemokines, muscarinic receptor agonists and antagonists; anticholinesterase agents; agents acting at the neuromuscular junction and / or autonomic ganglia; catecholamine, sympathomimetic, and adrenergic receptor agonists or antagonists; and 5-hydroxytryptamine (5-HT, serotonin) receptor agonists and antagonists.

[0263] Therapeutic drugs include drugs for pain and inflammation (such as histamine and histamine antagonists, brandykinin and brandykinin antagonists, 5-hydroxytryptamine (serotonin)), lipid substances produced by biotransformation of selective hydrolysis products of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatory drugs, analgesic-antipyretics, drugs that inhibit the synthesis of prostaglandins and thromboxanes, selective inhibitors of inducible cyclooxygenase Inhibitors, selective inhibitors of inducible cyclooxygenase-2, autacoids, paracrine hormones, 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, membrane stabilizers, and leukotriene inhibitors.

[0264] Additional therapeutic agents contemplated herein include diuretics, vasopressin, agents affecting water retention in the kidney, rennin, angiotensin, agents useful in the treatment of myocardial ischemia, antihypertensive agents, angiotensin-converting enzyme inhibitors, β-adrenergic receptor antagonists, agents for the treatment of hypercholesterolemia, and agents for the treatment of dyslipidemia.

[0265] Other therapeutic agents contemplated include drugs used for controlling gastric acidity, drugs for treating peptic ulcers, drugs for treating gastroesophageal reflux disease, gastrointestinal motility agents, 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 disease, drugs used for pancreatic disease, drugs used to treat protozoal infections, drugs used to treat malaria, amebiasis, giardiasis, trichomoniasis, trypanosomatosis, and / or leishmaniasis, and / or drugs used in chemotherapy of helminthiasis. Other therapeutic agents include antibacterial agents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, and agents for urinary tract infections, beta-lactam antibiotics such as penicillins, cephalosporins, agents containing aminoglycosides, protein synthesis inhibitors, agents used in chemotherapy for tuberculosis, Mycobacterium avium complex disease, and leprosy, antifungals, and antivirals (including nonretrovirals and antiretrovirals).

[0266] Examples of therapeutic antibodies that can be combined with the compounds of the present disclosure include, but are not limited to, anti-receptor tyrosine kinase antibodies (cetuximab, panitumumab, trastuzumab), anti-CD20 antibodies (rituximab, tositumomab), and other antibodies (such as alemtuzumab, bevacizumab, and gemtuzumab).

[0267] Additionally, therapeutic agents used for immunomodulation, such as immunomodulators, immunosuppressants, tolerogens, and immunostimulants, are contemplated in the methods herein, as well as therapeutic agents acting on blood and blood-forming organs, hematopoietic agents, growth factors, minerals, and vitamins, anticoagulants, thrombolytic agents, and antiplatelet agents.

[0268] For the treatment of renal cancer, the compound of the present disclosure can be combined with sorafenib and / or avastin.For the treatment of endometrial disorders, the compound of the present disclosure can be combined with doxorubicin, taxotere (taxol), and / or cisplatin (carboplatin).For the treatment of ovarian cancer, the compound of the present disclosure can be combined with cisplatin (carboplatin), taxotere, doxorubicin, topotecan, and / or tamoxifen.For the treatment of breast cancer, the compound of the present disclosure can be combined with taxotere (taxol), gemcitabine (capecitabine), tamoxifen, letrozole, tarceva, lapatinib, PD0325901, avastin, herceptin, OSI-906, and / or OSI-930. For the treatment of lung cancer, compounds of the present disclosure can be combined with Taxotere (Taxol), Gemcitabine, Cisplatin, Pemetrexed, Tarceva, PD0325901, and / or Avastin.

[0269] In other embodiments, agents useful in the methods for combination therapy with one or more compounds of structure (I) include erlotinib, afatinib, Iressa, GDC0941, MLN1117, BYL719 (alpelisib), BKM120 (buparlisib), CYT387, GLPG0634, baricitinib, lestaurtinib, momelotinib, pacritinib, ruxolitinib, TG101348, crizotinib, tivantinib, AMG337, cabozantinib, foretinib, onartuzumab, NVP-AEW541, dasatinib, ponatinib, saracatinib, bosutinib, thrombin ... These include, but are not limited to, lametinib, selumetinib, cobimetinib, PD0325901, RO5126766, axitinib, bevacizumab, bosutinib, cetuximab, crizotinib, fostamatinib, gefitinib, imatinib, lapatinib, lenvatinib, ibrutinib, nilotinib, panitumumab, pazopanib, pegaptanib, ranibizumab, ruxolitinib, sorafenib, sunitinib, SU6656, trastuzumab, tofacitinib, vandetanib, vemurafenib, irinotecan, taxol, docetaxel, rapamycin, or MLN0128.

[0270] Additional therapeutic agents that can be combined with the compounds of the present disclosure are found in Goodman and Gilman's "The Pharmacological Basis of Therapeutics" Tenth Edition edited by Hardman, Limbird and Gilman, or the Physician's Desk Reference, both of which are incorporated by reference herein in their entireties.

[0271] The compounds described herein can be used in combination with the agents disclosed herein or other suitable agents depending on the condition to be treated. Thus, in some embodiments, one or more compounds disclosed herein are co-administered with the other agents described above. When used in combination therapy, the compounds described herein are administered simultaneously or separately with the second agent. This combined administration can include simultaneous administration of the 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 agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds disclosed herein and any of the agents described above can be administered simultaneously, present in separate formulations. In another alternative method, any of the agents described above can be administered immediately after the administration of the compounds disclosed herein, or vice versa. In some embodiments of the separate administration protocol, the compounds disclosed herein and any of the agents described above are administered minutes, hours, or days apart.

[0272] The examples and preparations provided below further illustrate and illustrate the compounds of the present disclosure and the preparation methods of such compounds.It should be understood that the scope of the present disclosure 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 with a single stereocenter exist as racemic mixtures unless otherwise stated.Molecules with two or more stereocenters exist as racemic mixtures of diastereomers unless otherwise stated.Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art. EXAMPLES

[0273] The following examples are provided for illustrative purposes: Methods for preparing compounds of structure (I) are known in the art or can be derived by those of skill in the art. Example 1 Biochemical assay of compounds

[0274] Test compounds were prepared as 10 mM stock solutions in DMSO (Fisher catalog number BP-231-100). KRAS G12C 1-169 (his-tagged protein, GDP-loaded) was diluted to 2 μM or 0.5 μM in buffer (20 mM Hepes, 150 mM NaCl, 1 mM MgCl2). Compounds were tested for activity as follows.

[0275] Compounds were diluted in DMSO to 50x the final test concentration in a 96-well storage plate. Compound stock solutions were vortexed before use and carefully observed for any signs of precipitation. Dilutions were made as follows: · To achieve a final compound concentration of 32 μM, compounds were diluted to 1600 μM (3 μL of 10 mM compound stock solution + 15.75 μL of DMSO) and mixed thoroughly by pipetting. · To achieve a final compound concentration of 8 μM, compounds were diluted to 400 μM (2 μL of 10 mM compound stock solution + 48 μL of DMSO) and mixed thoroughly by pipetting.

[0276] 49 μL of protein stock solution was added to each well of a 96-well PCR plate (Fisher Catalog No. 1423027). 1 μL of 50× diluted compound was added to the appropriate well in the PCR plate using a 12-channel pipettor. The reactions were carefully and thoroughly mixed by pipetting up and down using a 200 μL multichannel pipettor. The plate was thoroughly sealed with an aluminum plate seal and the protein and compound were allowed to react for the desired time. The reaction was then quenched by adding 5 μL of 2% formic acid (Fisher Catalog No. A117) in deionized H2O to each well followed by mixing using a pipette. The plate was then resealed with an aluminum seal and stored frozen on dry ice until analysis as described below.

[0277] The assays were analyzed by mass spectrometry according to one of two following procedures. RapidFire / TOF Assay:

[0278] The MS instrument was set to positive polarity, 2 GHz resolution, and low mass (1700) mode and equilibrated for 30 minutes. The instrument was then calibrated, switched to acquisition mode, and the appropriate method was loaded.

[0279] After an additional 30 min equilibration time, a blank batch (i.e., buffer) was run to ensure the instrument was working properly. Samples were thawed at 37°C for 10 min, centrifuged briefly, and transferred to the benchtop. Wells A1 and H12 were spiked with 1 μL of 500 μM internal standard peptide, and the plate was centrifuged at 2000×g for 5 min. The method was then run and the mass of each well recorded.

[0280] The mass of each well (integrated data desired) was pasted into the plate map and exported from the analysis. The mass of the internal standard was also exported. Data at 50 ppm was extracted for charge state +19 and the identity of well A1 was assigned using the internal standard spike and integrated. Peak data was exported as a TOF list and the above process was repeated for charge states +20, +21, +22, +23, +24, and +25, respectively. Q-Exactive Assay:

[0281] The mass and peak intensity of the KRAS G12C protein species were analyzed using a Dionex coupled to a Q Exactive Plus mass spectrometer (Thermo Scientific). Measurements were performed using an RSLC Nano system (Thermo Scientific).

[0282] 20 μL of the sample was diluted with 80% solvent A (0.1% formic acid in HO) and 20% solvent B (0.1% formic acid in acetonitrile) at 40 °C for 600 h. μL / 分The sample was loaded onto an Aeris™ 3.6 μm WIDEPORE C4 200 Å, LC Column 50×2.1 mm column, maintained at a flow rate of 600 rpm. Liquid chromatography conditions were 20% solvent B for 1 min, 20% to 60% solvent B for 1.5 min, 60% to 90% solvent B for 0.5 min, 90% solvent B for 0.2 min, 90% to 20% solvent B for 0.2 min, then equilibrated for 1.6 min before subsequent sample injection. The flow rate was maintained at 600 rpm throughout the sample run. μL / 分 was maintained.

[0283] The mass spectrometer was operated with a maximum injection time of 50 ms and a 1 × 10 6 AGC target of 17500 resolution, 5 microscan operating in profile mode, 800 to 1850 m / z The entire mass range of was recorded. For optimal ion transfer and maximum sensitivity, the intact protein mode was applied. The method of ionization was electrospray ionization, with a spray voltage of 4 kV, sheath gas flow set at 50 AU, auxiliary gas flow set at 10 AU and sweep gas flow set at 1 AU. The capillary ion transfer temperature was 320°C and the S-lens RF level was set at 50 voltage. For quantitative deconvolution of the charge envelope of each protein species in the sample, Protein Deconvolution software (Thermo Scientific) was used to determine the mass and intensity of each parent species (modified or unmodified protein). The modification percentage was calculated based on the deconvoluted peak intensity. Other in vitro analyses are as follows:

[0284] Inhibition of cell growth: The ability of the compounds of the present invention to inhibit RAS-mediated cell growth is assessed and demonstrated as follows: Cells expressing wild-type 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, after which a compound disclosed herein is added. After a period of time (e.g., after 24, 48, or 72 hours of cell growth), cell proliferation is determined by measuring total ATP content using Cell Titer Glo reagent (Promega) according to the manufacturer's instructions. Proliferative EC 50 is determined by analysis of an eight-point compound dose response decreasing in half-log intervals from 100 μM.

[0285] Inhibition of RAS-mediated signaling: The ability of the compounds disclosed herein to inhibit RAS-mediated signal transduction 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) a compound of the present invention. The inhibition of RAS signal transduction by one or more compounds of the present invention is demonstrated by the decrease in the steady-state levels of phosphorylated MEK, phosphorylated ERK, phosphorylated RSK, and / or Raf binding in cells treated with one or more compounds of the present invention compared to control cells.

[0286] Representative compounds from Table 1 were tested according to the above method and found to covalently bind to KRAS G12C. Representative data are provided in Table 2. Table 2. Modulation activity of representative compounds* [Table 2] *Compounds were tested at 32 μM unless otherwise indicated. - indicates compound not tested + indicates binding activity above 0% up to 50% ++ indicates 50-75% binding activity +++ indicates binding activity of more than 75% ‡ Tested at a concentration of 8 μM Example 2 Synthesis of compound I-7 [ka] 2,6-Dichloro-4-morpholinobenzonitrile

[0287] To a solution of 4-bromo-2,6-dichlorobenzonitrile (251 mg, 1 mmol) in NMP (15 mL) was added DIEA (645 mg, 5 mmol) and morpholine (87 mg, 1 mmol). The resulting mixture was stirred at 110° C. overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (20% EA / PE) to give the desired product (110 mg, 43%). ESI-MS m / z: 257.3 [M+H] + . tert-Butyl 6-(3-chloro-2-cyano-5-morpholinophenyl)-2,6-diazaspiro[3.4]octane-2-carboxylate

[0288] To a solution of 2,6-dichloro-4-morpholinobenzonitrile (514 mg, 2 mmol) in toluene (25 mL) was added tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (424 mg, 2 mmol), sodium 2-methylpropan-2-olate (288 mg, 3 mmol), BINAP (80 mg) and Pd2(dba)3 (80 mg) under argon. The resulting mixture was stirred at 110° C. overnight. The solvent was removed and the residue was purified by silica gel flash column chromatography (50% EA / PE) to give the desired product (430 mg, 50%). ESI-MS m / z: 433.2 [M+H] + . tert-Butyl 6-(2-cyano-3-(5-methyl-1H-indazol-4-yl)-5-morpholinophenyl)-2,6-diazaspiro[3.4]octane-2-carboxylate

[0289] To a solution of tert-butyl 6-(3-chloro-2-cyano-5-morpholinophenyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (50 mg, 0.115 mmol) and (5-methyl-1H-indazol-4-yl)boronic acid (40 mg, 0.23 mmol) in toluene (15 mL) was added Pd2(dba)3 (10 mg), Na2CO3 (61 mg, 0.58 mmol) and S-phos (10 mg) under argon. The resulting mixture was stirred at 110 °C overnight. The solvent was removed and the residue was purified by silica gel flash column chromatography (5% MeOH / DCM) to give the desired product (50 mg, 82%). ESI-MS m / z: 529.3 [M+H] + . 2-(2-Acryloyl-2,6-diazaspiro[3.4]octan-6-yl)-6-(5-methyl-1H-indazol-4-yl)-4-morpholinobenzonitrile

[0290] To a solution of tert-butyl 6-(2-cyano-3-(5-methyl-1H-indazol-4-yl)-5-morpholinophenyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (50 mg, 0.095 mmol) in DCM (8 mL) was added TFA (2 mL). The resulting mixture was stirred at room temperature for 2 h. The solvent was removed. The residue was partitioned between 10% Et3N / DCM and aqueous NaHCO3. To the organic layer was added acryloyl chloride (27 mg, 0.3 mmol) at 0 °C and the resulting mixture was stirred for 10 min. The mixture was partitioned between water and dichloromethane. The organic layer was concentrated in vacuo. The residue was dissolved in THF (5 mL), cooled to 0 °C, and LiOH (21 mg, 0.5 mmol) and H2O (5 mL) were added. The mixture was stirred at 0 °C for 20 min. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by preparative TLC plate to give the desired product (13 mg, 28.4%). ESI-MS m / z: 483.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ: 13.04 (s, 1H), 7.6(s, 1H), 7.45 (dd, J=8.4 Hz, 1H), 7.28 (dd, J = 8.4 Hz, 1H), 6.4-6.2 (m, 2H), 6.15-6.05 (m, 2H), 5.68 (dd, J = 2.0, 10.4 Hz, 1H), 4.4-4.2 (m, 1H), 4.18 (d, J=8.4 Hz, 1H), 4.0-3.9 (m, 2H), 3.8-3.75 (m,2H), 3.75-3.6.5 (m, 4H), 3.65-3.6 (m, 2H), 3.4-3.2 (m, 4H), 2.3-2.1 (m, 5H). Example 3 Synthesis of compound I-14 [ka] 2,6-Dichloro-4-methoxybenzaldehyde

[0291] To a solution of 2,6-dichloro-4-hydroxybenzaldehyde (18 g, 95.23 mmol) in DMF (150 mL) was added K2CO3 (39.49 g, 285.69 mmol) and iodomethane (14.87 g, 104.76 mmol). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (20% EA / PE) to give the desired product (18 g, 100%). ESI-MS m / z: 203.9 [M+H] + . 2,6-Dichloro-4-methoxybenzonitrile

[0292] To a solution of 2,6-dichloro-4-methoxybenzaldehyde (10 g, 49.26 mmol) in H2O (100 mL) was added PhI(OAc)2 (23.8 g, 73.8 mmol), NHOAc (5.67 g, 73.8 mmol), and sodium tridecyl sulfate (2.84 g, 9.85 mmol). The resulting mixture was stirred at 70 °C for 3 h. The mixture was cooled to room temperature, Na2S2O3 (18.33 g, 73.89 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo by silica gel flash column chromatography to give the desired product (10 g, 55%). ESI-MS m / z: 200.9 [M+H] + . tert-Butyl 6-(3-chloro-2-cyano-5-methoxyphenyl)-2,6-diazaspiro[3.4]octane-2-carboxylate

[0293] To a solution of 2,6-dichloro-4-methoxybenzonitrile (100 mg, 0.5 mmol) and tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (136 mg, 0.64 mmol) in NMP (50 mL) was added DIEA (193.5 mg). The resulting mixture was stirred at 50° C. for 1 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (25% PE / EA) to give the desired product (100 mg, 100%). ESI-MS m / z: 377.1 [M+H] + . tert-Butyl 6-(2-cyano-5-methoxy-3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octane-2-carboxylate

[0294] To a solution of tert-butyl 6-(3-chloro-2-cyano-5-methoxyphenyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (100 mg, 0.28 mmol) in dioxane / H2O (20 / 6 mL) was added 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (177.8 mg, 0.52 mmol), Pd(PPh3)4 (36.65 mg, 0.03 mmol) and Na2CO3 (82.68 mg, 0.78 mmol) under argon. The resulting mixture was stirred at 120 °C overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give the desired product (90 mg, 90%). ESI-MS m / z: 557.3 [M+H] + . 4-Methoxy-2-(5-methyl-1H-indazol-4-yl)-6-(2,6-diazaspiro[3.4]octan-6-yl)benzonitrile

[0295] To a solution of tert-butyl 6-(2-cyano-5-methoxy-3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (90 mg, 0.16 mmol) in MeOH was added HCl. The resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the desired product (50 mg, 55%). ESI-MS m / z: 373.1 [M+H] + . 2-(2-Acryloyl-2,6-diazaspiro[3.4]octan-6-yl)-4-methoxy-6-(5-methyl-1H-indazol-4-yl)benzonitrile

[0296] To a solution of 4-methoxy-2-(5-methyl-1H-indazol-4-yl)-6-(2,6-diazaspiro[3.4]octan-6-yl)benzonitrile (50 mg, 0.13 mmol) in dichloromethane (10 mL) was added triethylamine (2 mL). Then acryloyl chloride (12 mg) was added. The resulting mixture was stirred at room temperature for 15 min. The solvent was removed. The residue was partitioned between dichloromethane and aqueous NaHCO3. The organic layer was concentrated in vacuum. The residue was purified by preparative TLC plate to give the desired product (18 mg, 36%). ESI-MS m / z: 427.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ: 13.08 (m, 1H), 7.58 (m, 1H),7.50-7.48 (m, 1H), 7.31-7.29 (m, 1H), 6.36-6.29 (m, 3H), 6.14-6.09 (m, 1H), 5.70-5.67 (m, 1H), 3.99-3.97 (m, 1H), 3.92-3.90 (m, 1H), 3.83 (m, 3H), 3.80-3.75 (m, 2H), 3.66-3.63 (m, 2H), 2.23-2.19 (m, 5H), 1.24 (m, 2H). Example 4 Synthesis of Compound I-2 [ka] 4-(3-bromo-2-methoxyphenyl)-5-methyl-1H-indazole

[0297] To a stirred solution of 1,3-dibromo-2-methoxybenzene (527 mg, 2 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was added (5-methyl-1H-indazol-4-yl)boronic acid (350 mg, 2 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) and Na2CO3 (636 mg, 6 mmol). The mixture was degassed and backfilled with argon (several cycles) and then stirred at 100 °C overnight. The mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (20% EA / PE) to give the desired product (450 mg, 71% yield). tert-Butyl 6-(2-methoxy-3-(5-methyl-1H-indazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octane-2-carboxylate

[0298] To a stirred solution of 4-(3-bromo-2-methoxyphenyl)-5-methyl-1H-indazole (450 mg, 1.42 mmol) in toluene (10 mL) was added tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (451 mg, 2.1 mol), Pd2(dba)3 (130 mg, 0.14 mmol) and BINAP (87 mg, 0.14 mmol) and sodium tert-butoxide (336 mg, 3.5 mmol). The mixture was degassed and backfilled with nitrogen (several cycles) and then stirred at 100° C. overnight. The mixture was concentrated in vacuo and the residue was purified by silica gel flash chromatography (20% EA / PE) to give the desired product (330 mg, 51.8% yield). ESI-MS m / z: 449 [M+H] + . 4-(2-Methoxy-3-(2,6-diazaspiro[3.4]octan-6-yl)phenyl)-5-methyl-1H-indazole

[0299] To a stirred solution of tert-butyl 6-(2-methoxy-3-(5-methyl-1H-indazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (330 mg, 0.73 mmol) in DCM (4 mL) at 0° C., trifluoroacetic acid (2 mL) was added and the resulting mixture was stirred at room temperature for 45 min. The mixture was concentrated in vacuo to remove the solvent and then slowly poured into ice-H2O. The mixture was extracted with ethyl acetate, washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product (250 mg, 98% yield). ESI-MS m / z: 349 [M+H] + . 1-(6-(2-methoxy-3-(5-methyl-1H-indazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octan-2-yl)prop-2-en-1-one

[0300] The title compound was prepared according to the procedure described in the final step of Example 2. ESI-MS m / z: 403 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 12.96 (s, 1H), 7.51 (s, 1H), 7.42 (d, 1H), 7.272 (d, 1H), 7.07 (t, 1H), 6.79 (d, 1H), 6.62~6.60 (m, 1H), 6.37~6.29 (m, 1H), 6.13~6.09 (m, 1H), 5.69~5.65 (m, 1H), 4.27~4.16 (m, 2H), 4.04~3.88 (m, 2H), 3.58~3.48 (m, 2H), 3.44~3.33 (m, 2H), 3.08 (s, 3H), 2.19 (s, 3H), 2.18~2.13 (m, 2H). Example 5 Synthesis of compound I-25 [ka] 2-Bromo-6-fluoro-3-methylbenzaldehyde

[0301] To a 250 mL three neck was added 2-bromo-4-fluoro-1-methylbenzene (5 g, 26.4 mmol) and THF (50 mL), the mixture was purged with nitrogen three times, cooled to -78°C, and LDA (26.4 mL, 52.8 mmol) was added. The mixture was stirred at -78°C for 1 h, then DMF (5.78 g, 79.2 mmol) was added. The resulting mixture was stirred at -78°C for 1 h, then warmed to room temperature. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was concentrated in vacuo to give the desired product (4.5 g, 78%). ESI-MS m / z: 217.04 [M+H] + . 2-Bromo-6-fluoro-3-methylbenzonitrile

[0302] A solution of 2-bromo-6-fluoro-3-methylbenzaldehyde (4.5 g, 20.7 mmol) in HO (50 mL) was reacted with PhI(OAc) (10 g, 31 mmol), NHOAc (7.9 g, 10.4 mmol) and Me(CH 11 SO3Na (1.19 g, 4.1 mmol) was added. The mixture was stirred at 70° C. for 2 h and then cooled to room temperature. Na2S2O3.5H2O (7.7 g, 31 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. The mixture was extracted with ethyl acetate and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (PE) to give the desired product (3 g, 68%). ESI-MS m / z: 214.4 [M+H] + . tert-Butyl 6-(3-bromo-2-cyano-4-methylphenyl)-2,6-diazaspiro[3.4]octane-2-carboxylate

[0303] To a solution of 2-bromo-6-fluoro-3-methylbenzonitrile (500 mg, 2.34 mmol) and tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (522 mg, 2.5 mmol) in NMP (15 mL) was added DIEA (0.8 mL, 4.7 mmol), and the resulting mixture was stirred at 100° C. for 1 h. The mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuum, and the residue was purified by silica gel flash column chromatography (PE / EA=5:1) to give the desired product (300 mg, 31.4%). ESI-MS m / z: 406.23 [M+H] + . tert-Butyl 6-(2-cyano-4-methyl-3-(5-methyl-1H-indazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octane-2-carboxylate

[0304] To a solution of tert-butyl 6-(3-bromo-2-cyano-4-methylphenyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (150 mg, 0.37 mmol) in dioxane (20 mL) and H2O (5 mL) was added (5-methyl-1H-indazol-4-yl)boronic acid (130 mg, 0.74 mmol), Na2CO3 (118 mg, 1.11 mmol) and Pd(PPh3)4 (43 mg, 0.037 mmol). The mixture was stirred overnight at 100 °C under nitrogen. The solvent was removed in vacuum. The residue was purified by silica gel flash column chromatography (PE:EA=4:1) to give the desired product (30 mg, 17%). ESI-MS m / z: 457.58 [M+H] + . 3-Methyl-2-(5-methyl-1H-indazol-4-yl)-6-(2,6-diazaspiro[3.4]octan-6-yl)benzonitrile

[0305] To a solution of tert-butyl 6-(2-cyano-4-methyl-3-(5-methyl-1H-indazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (30 mg, 0.066 mmol) in dichloromethane (20 mL) was added TFA (5 mL) and the resulting mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo to give the crude product (40 mg). ESI-MS m / z: 357.46 [M+H] + . 6-(2-Acryloyl-2,6-diazaspiro[3.4]octan-6-yl)-3-methyl-2-(5-methyl-1H-indazol-4-yl)benzonitrile

[0306] To a solution of 3-methyl-2-(5-methyl-1H-indazol-4-yl)-6-(2,6-diazaspiro[3.4]octan-6-yl)benzonitrile (40 mg) in THF (20 mL) was added 2N NaOH (5 mL) followed by acryloyl chloride (5.9 mg, 0.066 mmol). The mixture was stirred at room temperature for 10 min. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by preparative TLC plate to give the desired product (10 mg, 21.7%). ESI-MS m / z: 411.51 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ: 13.09 (s, 1H), 7.51-7.4 (m, 3H), 7.35-7.33 (d, 1H), 6.84-6.82 (d, 1H), 6.35-6.82 (m, 1H), 6.14-6.09 (dd, 1H), 5.69-5.66 (dd, 1H), 4.26-4.16 (m, 2H), 3.94-3.91 (m, 2H), 3.70-3.69 (m, 2H), 3.60-3.57 (m, 2H), 2.20-2.18 (m, 2H), 2.09-2.09 (d, 3H), 1.749 (s, 3H). Example 6 Synthesis of compound I-50 [ka] (3,5-Dichlorophenoxy)triisopropylsilane

[0307] To a solution of 3,5-dichlorophenol (10 g, 6.13 mmol) in DCM (150 mL) was added 2,6-dimethylpyridine (19.67 g, 18.39 mmol). The resulting mixture was stirred at 0° C. for 15 min under argon. TIPSOTF was then added dropwise. The resulting mixture was stirred at 0° C. for 2 h. The mixture was washed with NH4Cl(aq) and brine, and extracted with dichloromethane. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (100% PE) to give the desired product (18.0 g, 92%). ESI-MS m / z: 320.3 [M+H] + . 2,6-Dichloro-4-hydroxybenzaldehyde

[0308] To a stirred solution of (3,5-dichlorophenoxy)triisopropylsilane (10 g, 31.35 mmol) in THF (100 mL). The mixture was cooled to -78 °C under argon. n-BuLi (24 mL, 1.6 M) was added dropwise. The resulting mixture was stirred at -78 °C for 1 h. Then DMF (3.44 g, 47.02 mmol) was added dropwise. The resulting mixture was stirred at -78 °C for 3 min and then warmed to room temperature. 1N HCl (150 mL) was added. The resulting mixture was stirred at room temperature for 1 h. NH4Cl (aq, 50 mL) was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. Dichloromethane was added and the solid was collected by filtration to give the desired product (4.67 g, 78%). ESI-MS m / z: 192 [M+H] + . 2,6-Dichloro-4-(pyridin-2-ylmethoxy)benzaldehyde

[0309] To a solution of 2,6-dichloro-4-hydroxybenzaldehyde (2.1 g, 11.05 mmol) in THF (50 mL) was added Ph3P (4.34 g, 16.57 mmol) and pyridin-2-ylmethanol (1.44 g, 13.26 mmol). The resulting mixture was stirred at 0 °C under argon for 1 h. Then DIAD (3.34 g, 16.57 mmol) was added dropwise. The resulting mixture was stirred at 0 °C to room temperature under argon overnight. The reaction mixture was extracted with ethyl acetate, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (30% PE / EA) to give the desired product (2.9 g, 89%). ESI-MS m / z: 282 [M+H] + . (E)-2,6-Dichloro-4-(pyridin-2-ylmethoxy)benzaldehyde oxime

[0310] To a stirred solution of 2,6-dichloro-4-(pyridin-2-ylmethoxy)benzaldehyde (3.7 g 13.12 mmol) in MeOH (50 mL) was added K2CO3 (5.43 g, 39.36 mmol). The mixture was stirred at reflux under argon overnight. The mixture was concentrated to remove MeOH. The mixture was extracted with ethyl acetate, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (30% PE / EA) to give the desired product (3.7 g, 95%). ESI-MS m / z: 297 [M+H] + . 2,6-Dichloro-4-(pyridin-2-ylmethoxy)benzonitrile

[0311] To a stirred solution of (E)-2,6-dichloro-4-(pyridin-2-ylmethoxy)benzaldehyde oxime (3.7 g, 12.46 mmol) in dichloromethane (40 mL) was added SOCl2 (4 mL, 37.91 mmol) and the mixture was stirred at reflux under argon for 2.5 h. The mixture was poured into ice water and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (50% PE / EA) to give the desired product (3.1 g, 90%). ESI-MS m / z: 279 [M+H] + . tert-Butyl 7-(3-chloro-2-cyano-5-(pyridin-2-ylmethoxy)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0312] To a solution of 2,6-dichloro-4-(pyridin-2-ylmethoxy)benzonitrile (300 mg, 1.07 mmol) in toluene (30 mL) was added tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (194 mg, 0.86 mmol), t-BuONa (310 mg, 3.22 mmol), BINAP (67 mg, 0.12 mmol) and Pd2(dba)3 (98 mg, 0.12 mmol). The resulting mixture was stirred under argon at 110° C. for 3 h. The solvent was removed and the residue was purified by silica gel flash column chromatography (75% EA / PE) to give the desired product (160 mg, 32%). ESI-MS m / z: 469.2 [M+H] + . tert-Butyl 7-(2-cyano-3-(5-methyl-1H-indazol-4-yl)-5-(pyridin-2-ylmethoxy)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0313] To a solution of tert-butyl 7-(3-chloro-2-cyano-5-(pyridin-2-ylmethoxy)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (160 mg, 0.34 mmol) and (5-methyl-1H-indazol-4-yl)boronic acid (240 mg, 1.36 mmol) in dioxane (20 mL) and H2O (5 mL) was added Pd2(dba)3 (32 mg, 0.04 mmol), Na2CO3 (180 mg, 1.7 mmol) and S-phos (14 mg, 0.04 mmol). The resulting mixture was stirred overnight at 110 °C under argon. The mixture was extracted with ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (5% MeOH / DCM) to give the desired product (173 mg, 90%). ESI-MS m / z: 565.3 [M+H] + . 2-(5-Methyl-1H-indazol-4-yl)-4-(pyridin-2-ylmethoxy)-6-(2,7-diazaspiro[3.5]nonan-7-yl)benzonitrile

[0314] To a solution of tert-butyl 7-(2-cyano-3-(5-methyl-1H-indazol-4-yl)-5-(pyridin-2-ylmethoxy)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (94 mg, 0.17 mmol) in dichloromethane (15 mL) was added TFA (4 mL). The resulting mixture was stirred at room temperature for 30 min. The mixture was concentrated in vacuo to give the desired product (55 mg, 71%). ESI-MS m / z: 465.3 [M+H] + . 2-(2-Acryloyl-2,7-diazaspiro[3.5]nonan-7-yl)-6-(5-methyl-1H-indazol-4-yl)-4-(pyridin-2-ylmethoxy)benzonitrile

[0315] The title compound was prepared according to the procedure described in the final step of Example 5. ESI-MS m / z: 518.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ: 13.1 (s, 1H), 8.57 (s, 1H), 7.86 (s, 1H), 7.5 (m, 3H), 7.36 (m, 2H), 6.83 (s, 1H), 6.68 (s, 1H), 6.33 (m, 1H), 6.1 (d, 1H), 5.68 (d, 1H), 5.3 (s, 2H), 3.9 (s, 2H), 3.7 (s, 3H), 3.15 (d, 4H), 2.17 (s, 3H), 2.0 (s, 3H). Example 7 Synthesis of compound I-84 [ka] 1,3-Dichloro-5-fluoro-2-methoxybenzene

[0316] To a solution of 2,6-dichloro-4-fluorophenol (2 g, 11 mmol) in DMF was added K2CO3 (3 g, 22 mmol) and MeI (2.3 g, 16.6 mmol). The resulting mixture was stirred at room temperature for 30 min. The mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the product (1 g, 47.6%). ESI-MS m / z: 195 [M+H] + . 2,4-Dichloro-6-fluoro-3-methoxybenzaldehyde

[0317] To a solution of 1,3-dichloro-5-fluoro-2-methoxybenzene (1 g, 5.1 mmol) in THF (20 mL) at -78°C, LDA (5.1 mL, 10.2 mmol) was added under nitrogen and the resulting mixture was stirred at -78°C for 1 h. DMF (1.1 g, 15.8 mmol) was added. The mixture was stirred at -78°C for 1 h and then warmed to room temperature. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was concentrated in vacuo to give the desired product (713 mg, 62%). ESI-MS m / z: 195 [M+H] + . 2,4-Dichloro-6-fluoro-3-methoxybenzonitrile

[0318] A solution of 2,4-dichloro-6-fluoro-3-methoxybenzaldehyde (713 mg, 20.7 mmol) in HO (15 mL) was reacted with PhI(OAc) (1.54 g, 3.32 mol), NHOAc (1.23 g, 11.07 mmol) and Me(CH 11 SO3Na (184 mg, 0.44 mmol) was added. The mixture was stirred at 70° C. for 2 h and then cooled to room temperature. Na2S2O3.5H2O (1.2 g, 3.32 mmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water. The organic layer was concentrated in vacuo to give the desired product (880 mg). ESI-MS m / z: 220.02 [M+H] + . tert-Butyl 7-(3,5-dichloro-2-cyano-4-methoxyphenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0319] To a solution of 2,4-dichloro-6-fluoro-3-methoxybenzonitrile (880 mg, 4 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (1.35 g, 6 mmol) in NMP (20 mL) was added DIEA (1.5 g, 12 mmol), and the resulting mixture was stirred at 100° C. for 1 h. The mixture was partitioned between ethyl acetate and water. The organic layer was concentrated in vacuum, and the residue was purified by silica gel column chromatography (PE / EA=5:1) to give the desired product (300 mg, 17.6%). ESI-MS m / z: 426.34 [M+H] + . tert-Butyl 7-(3-chloro-2-cyano-4-methoxy-5-morpholinophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0320] To a solution of tert-butyl 7-(3,5-dichloro-2-cyano-4-methoxyphenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (150 mg, 0.71 mmol) in toluene (16 mL) was added morpholine (49 mg, 0.56 mmol), BINAP (87 mg, 0.14 mmol), Pd2(dba)3 (64 mg, 0.071 mmol) and t-BuONa (171 mg, 1.76 mmol). The mixture was stirred under nitrogen at 100° C. for 3 h. The mixture was concentrated in vacuo and the residue was purified by silica gel flash column chromatography (PE:EA=4:1) to give the desired product (156 mg, 46.4%). ESI-MS m / z: 477 [M+H] + . tert-Butyl 7-(2-cyano-4-methoxy-3-(5-methyl-1H-indazol-4-yl)-5-morpholinophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0321] To a solution of tert-butyl 7-(3-chloro-2-cyano-4-methoxy-5-morpholinophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (20 mg, 0.04 mmol) in toluene (8 mL) was added (5-methyl-1H-indazol-4-yl)boronic acid (14.7 mg, 0.084 mmol), Na2CO3 (13 mg, 0.12 mmol), Pd2(dba)3 (4 mg, 0.004 mmol), s-phos (2 mg, 0.004 mmol) and H2O (1 mL). The mixture was stirred overnight at 100 °C under nitrogen. The mixture was concentrated in vacuum and the residue was purified by silica gel flash column chromatography (PE:EA=1:1) to give the desired product (16 mg, 66.7%). ESI-MS m / z: 572.71 [M+H] + . 3-Methoxy-2-(5-methyl-1H-indazol-4-yl)-4-morpholino-6-(2,7-diazaspiro[3.5]nonan-7-yl)benzonitrile

[0322] To a solution of tert-butyl 7-(2-cyano-4-methoxy-3-(5-methyl-1H-indazol-4-yl)-5-morpholinophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (16 mg, 0.028 mmol) in DCM (20 mL) was added TFA (5 mL) and the resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to give the desired product (20 mg). ESI-MS m / z: 461.61 [M+H] + . 6-(2-Acryloyl-2,7-diazaspiro[3.5]nonan-7-yl)-3-methoxy-2-(5-methyl-1H-indazol-4-yl)-4-morpholinobenzonitrile

[0323] The title compound was prepared according to the procedure described in the final step of Example 5. ESI-MS m / z: 515.66 [M+H] + ; 1 H NMR (CD3OD, 400 MHz) δ: 7.52-7.51 (d, 2H), 7.38-7.36 (d, 1H), 6.73 (s, 1H), 6.41-6.34 (m, 1H), 6.27-6.23 (dd, 1H), 5.76-5.73 (dd, 1H), 4.072 (s, 2H), 3.85-3.84 (m, 6H), 3.36-3.34 (m, 5H), 3.27-3.23 (m, 2H), 3.16-3.15 (m, 4H), 2.22 (s, 3H), 2.04-1.98 (m, 4H).

[0324] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent literature mentioned in this specification and in the accompanying Application Data Sheets are hereby incorporated by reference in their entirety to the extent not inconsistent herewith.

[0325] U.S. Provisional Application No. 62 / 750,009 (filed October 24, 2018) is hereby incorporated by reference in its entirety.

[0326] From the foregoing, it will be appreciated that, although specific embodiments of the present disclosure have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the present disclosure is not limited except as by the appended claims. The present invention provides, for example, the following items. (Item 1) The structure (I) is: [ka] [In the formula, A 1 、A 2 、A 3 and A 4 is independently in each occurrence 4a R 4b , O or NR 5 and; G 1 and G 2 are each independently CH or N, provided that L 1 is -O-, -S- or -NR 5 - or adjacent A 1 Or A 2 Ga-NR 5 - or -O-, then G 1 is CH, where L 2 Ga-NR 5 - or adjacent A 3 Or A 4 Ga-NR 5 - or -O-, then G 2 is CH; L 1 is a bond, -CR 4a R 4b -, -O-, -S-, -SO 2 -OR-NR 5 - and; L 2 is a bond, C 1 ~C 6 Alkylene or -NR 5 - and; L 3 is a bond, -CR 4a R 4b -, -O-, -S-, -SO 2 -OR-NR 5 - and; R 1 is aryl, cycloalkyl, heterocyclyl or heteroaryl; R 2 is H, cyano, hydroxyl, halo, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Hydroxyl alkyl, C 1 ~C 6 Cyanoalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, C 1 ~C 6 Haloalkyl, aminylalkyl, alkylaminyl, aminylcarbonyl, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, or heteroaryl; R 3a 、R 3b and R 3c is independently at each occurrence H, halo, hydroxyl, cyano, amino, alkyl, cycloalkyl, cycloalkenyl, heterocyclenyl, haloalkyl, alkynyl, alkenyl, alkoxy, haloalkoxy, aminylcarbonyl, aminylcarbonylalkoxy, aminylsulfonyl, alkylsulfonylaminyl, alkylcarbonyl, aminylalkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, heterocyclylcarbonylalkoxy, alkylsulfonyl, aminylalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, alkylthioether, aminylalkylthioether, cycloalkylthioether, heterocyclyl arylthioether, aminylalkyl, aminylalkynyl, aminylalkylaminyl, aminylalkoxy, alkylcarbonylaminyl, heterocyclyl, heterocyclylaminyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkylaminyl, heterocyclylalkoxy, heterocyclylcarbonylaminyl, aryl, arylalkyl, arylalkylaminyl, arylalkoxy, arylaminyl, arylcarbonylaminyl, heteroaryl, heteroarylaminyl, heteroaryloxy, heteroarylalkyl, heteroarylalkylaminyl, heteroarylalkoxy, or heteroarylcarbonylaminyl; R 4a and R 4b is independently in each occurrence H, -OH, -NH 2 , -CO 2 H, halo, cyano, C 1 ~C 6 Alkyl, cycloalkyl, heterocyclyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Haloalkoxy, C 1~C 6 Hydroxyl alkyl, alkoxy alkyl, aminyl alkyl, alkyl aminyl alkyl, C 1 ~C 6 Cyanoalkyl, C 1 ~C 6 carboxyalkyl, aminylcarbonylalkyl, aryl, heteroaryl, or aminylcarbonyl, or R 4a and R 4b and when attached to the same carbon, together form an oxo or carbocyclic or heterocyclic ring, or R 3a and R 3b and when attached to different carbons, together form a carbocyclic or heterocyclic ring; R 5 independently in each occurrence: H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Hydroxyl alkyl, C 1 ~C 6 Cyanoalkyl, C 1 ~C 6 Haloalkyl or C 3 ~C 8 cycloalkylalkyl; m1, m2, n1 and n2 are independently in each occurrence 1, 2 or 3; and E is an electrophilic moiety. or a pharma- ceutically acceptable salt, isotopic form, stereoisomer or prodrug thereof. (Item 2) G 1 or G 2 The compound according to item 1, wherein at least one occurrence of is CH. (Item 3) G 1 and G 2 The compound according to any one of items 1 or 2, wherein (Item 4) A 1 、A 2 、A 3 and A 4 At least one occurrence of 4a R 4b The compound according to any one of items 1 to 3, (Item 5) The compound has the following structure (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik) or (Il):

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Claims

1. The following structure (I): 【Chemistry 88】 [In the formula, A １ , A ２ , A ３ and A ４ represents, independently at each occurrence, ４ａ R ４ｂ , O or NR ５ and G １ and G ２ are each independently CH or N, provided that L １ is -O-, -S- or -NR ５ -, or adjacent A １ Or A ２ -NR ５ - or -O-, then G １ is CH, where L ２ -NR ５ -, or adjacent A ３ Or A ４ -NR ５ - or -O-, then G ２ is CH; L １ is a bond; L ２ is a bond, C １ ~C ６ Alkylene or -NR ５ - and L ３ is a bond; R １ is aryl, cycloalkyl, heterocyclyl or heteroaryl; R ２ is H, cyano, hydroxyl, halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Hydroxyl alkyl, C １ ~C ６ Cyanoalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, C １ ~C ６ Haloalkyl, aminylalkyl, alkylaminyl, aminylcarbonyl, C ３ ~C ８ Cycloalkyl, C ３ ~C ８ heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, or heteroaryl; R ３ａ , R ３ｂ and R ３ｃ is independently at each occurrence H, halo, hydroxyl, cyano, amino, alkyl, cycloalkyl, cycloalkenyl, heterocyclenyl, haloalkyl, alkynyl, alkenyl, alkoxy, haloalkoxy, aminylcarbonyl, aminylcarbonylalkoxy, aminylsulfonyl, alkylsulfonylaminyl, alkylcarbonyl, aminylalkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, heterocyclylcarbonylalkoxy, alkylsulfonyl, aminylalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, alkylthioether, aminylalkylthioether, cycloalkylthioether, heterocyclyl arylthioether, aminylalkyl, aminylalkynyl, aminylalkylaminyl, aminylalkoxy, alkylcarbonylaminyl, heterocyclyl, heterocyclylaminyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkylaminyl, heterocyclylalkoxy, heterocyclylcarbonylaminyl, aryl, arylalkyl, arylalkylaminyl, arylalkoxy, arylaminyl, arylcarbonylaminyl, heteroaryl, heteroarylaminyl, heteroaryloxy, heteroarylalkyl, heteroarylalkylaminyl, heteroarylalkoxy, or heteroarylcarbonylaminyl; R ４ａ and R ４ｂ is independently at each occurrence H, —OH, —NH ２ , -CO ２ H, halo, cyano, C １ ~C ６ Alkyl, cycloalkyl, heterocyclyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, C １ ~C ６ Hydroxyl alkyl, alkoxy alkyl, aminyl alkyl, alkyl aminyl alkyl, C １ ~C ６ Cyanoalkyl, C １ ~C ６ carboxyalkyl, aminylcarbonylalkyl, aryl, heteroaryl or aminylcarbonyl, or R ４ａ and R ４ｂ and, when attached to the same carbon, are taken together to form oxo; R ５ is independently in each occurrence H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Hydroxyl alkyl, C １ ~C ６ Cyanoalkyl, C １ ~C ６ Haloalkyl or C ３ ~C ８ cycloalkylalkyl; m １ , m ２ , n １ and n ２ is independently in each occurrence 1, 2 or 3; and E has the following structure: 【Chemistry 89】 having Where: 【Chemistry 90】 represents a double or triple bond; Q is -C(=O)-, -C(=NR ８’ ) -, -NR ８ C(=O)-, -S(=O) ２ -or-NR ８ S (=O) ２ - and R ８ is H, C １ ~C ６ Alkyl, hydroxyl alkyl, amino alkyl, alkoxy alkyl, aminyl alkyl, alkyl aminyl alkyl, cyano alkyl, carboxy alkyl, aminyl carbonyl alkyl, C ３ ~C ８ cycloalkyl or heterocyclylalkyl; R ８’ is H, -OH, -CN or C １ ~C ６ is alkyl; 【Chemistry 91】 is a double bond, R ９ and R １０ are each independently H, halo, cyano, carboxyl, C １ ~C ６ alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, or hydroxylalkyl; and 【Chemistry 92】 is a triple bond, R ９ does not exist, and R １０ is H, C １ ~C ６ alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl; wherein each occurrence of alkyl, alkynyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, cycloalkyl, heterocyclylalkyl, alkoxycarbonyl, heteroaryl, and carbocyclic, heterocyclic, and heteroaryl rings are optionally substituted with one or more substituents, unless otherwise specified. or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof.

2. G １ and G ２ or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof.

3. The compound has the following structure (I'a), (I'b), (I'c), (I'd), (I'e), (I'f), (I'g), (I'h), (I'i), (I'j), (I'k) or (I'l): 【Chemistry 93】 【Chemistry 94】 【Chemistry 95】 2. The compound of claim 1, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, having one of the following:

4. The compound has the following structure (I'a1), (I'b1), (I'c1), (I'd1), (I'e1), (I'f1), (I'g1), (I'h1), (I'i1), (I'j1), (I'k1) or (I'l1): 【Chemistry 96】 【Chemistry 97】 【Chemistry 98】 4. The compound of claim 3, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, having one of the following:

5. R １ halo, amino, hydroxyl, C １ ~C ６ Alkyl, Cyano, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, alkylaminyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, phosphate, phosphoalkoxy, boronic acid, boronic ester, -OC(=O)R or C １ ~C ６ alkylcarbonyloxy or a combination thereof; R is C １ ~C ６ 5. The compound of claim 4, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, wherein R is an alkyl group.

6. R １ has the following structure: 【Chemistry 99】 【Chemistry 100】 2. The compound of claim 1, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, having one of the following:

7. R １ has the following structure: 【Chemistry 101】 【Chemistry 102】 【Chemistry 103】 2. The compound of claim 1, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, having one of the following:

8. R １ has the following structure: 【Chemistry 104】 2. The compound of claim 1, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, having one of the following:

9. R ２ H, cyano, hydroxyl, halo, C １ ~C ６ Alkyl, C １ ~C ６ Cyanoalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyl alkyl, C ３ ~C ８ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, which is cycloalkyl, aminylalkyl, alkylaminyl, or aminylcarbonyl.

10. R ２ has the following structure: 【Chemistry 105】 2. The compound of claim 1, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, having one of the following:

11. R ３ａ is H, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof.

12. R ３ｂ Or R ３ｃ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, wherein each is independently H, alkyl, halo, heterocyclyl, alkoxy, heteroarylalkoxy, heterocyclylalkoxy, or aminylalkoxy.

13. R ３ｂ Or R ３ｃ each independently having the structure: 【Chemistry 106】 【Chemistry 107】 12. The compound of claim 11, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, having one of the following:

14. R ３ｂ Or R ３ｃ has the following structure: 【Chemistry 108】 【Chemistry 109】 2. The compound of claim 1, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, having one of the following:

15. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, wherein Q is -C(=O)-.

16. E has the following structure: 【Chemistry 110】 2. The compound of claim 1, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, having one of the following:

17. L ２ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, wherein is a bond.

18. The compound has the following structure: 【Chemistry 111】 【Chemistry 112】 【Chemistry 113】 【Chemistry 114】 【Chemistry 115】 【Chemistry 116】 【Chemistry 117】 【Chemistry 118】 【Chemistry 119】 【Chemistry 120】 【Chemistry 121】 【Chemistry 122】 【Chemistry 123】 【Chemistry 124】 【Chemistry 125】 【Chemistry 126】 【Chemistry 127】 【Chemistry 128】 【Chemistry 129】 【Chemistry 130】 【Chemistry 131】 【Chemistry 132】 2. The compound of claim 1, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, having one of the following:

19. 13. A pharmaceutical composition comprising a compound of claim 1, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

20. 20. The pharmaceutical composition of claim 19 for the treatment of cancer.

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