KRAS inhibitors and their use

Abstract

The present invention provides novel compounds useful as inhibitors of KRAS, particularly KRAS G12D and / or other KRAS G12 variants, pharmaceutical compositions containing these compounds, and therapeutic methods by administering these compounds or the pharmaceutical compositions.

Description

[Technical Field]

[0001] This disclosure generally relates to novel compounds useful as inhibitors of KRAS, particularly KRAS G12D and / or other KRAS G12 variants, pharmaceutical compositions containing these compounds, and therapeutic methods by administering these compounds or the pharmaceutical compositions. [Background technology]

[0002] RAS is one of the best-known proto-oncogenes. Gain-of-function mutations in it occur in approximately 30% of all human cancers. As the most frequently mutated RAS isoform, KRAS (Kirsten rat sarcoma virus oncogene homolog) has been studied intensively in recent years. KRAS and its closely related NRAS and HRAS GTPases hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). They regulate diverse cellular functions by cycling between active GTP-bound conformations and inactive GDP-bound conformations (Hobbs, GA, et al. J. Cell Sci. 129, 1287-1292. (2016)).

[0003] KRAS is a key oncogene proven to drive tumorigenesis (GG Jinesh, et al. Oncogene volume 37, pages 839-846 (2018)). KRAS also regulates numerous gene regulatory mechanisms, forming a large tumorigenic network. The KRAS gene encodes a 21kDa protein called KRAS, which is part of the RAS / MAPK pathway. The KRAS protein is a GTPase, meaning that it binds with high affinity to the guanine nucleotides GDP and guanosine triphosphate (GTP), and can hydrolyze GTP to GDP (Dhirendra K. Simanshu, et al. Cell. 2017 Jun 29; 170(1): 17-33). GDP / GTP cycling is tightly regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), a diverse family of multidomain proteins. GEF stimulates the dissociation of GDP and subsequent association with GTP, activating the RAS protein, while GAP acts to accelerate endogenous GTP hydrolysis, converting RAS to its inactive state (Dhirendra K. Simanshu, et al. Cell. 2017 Jun 29; 170(1): 17-33). The GTP-bound form of KRAS is considered the active form, and downstream signaling effectors specifically bind to this GTP-bound form of KRAS. When the KRAS protein is bound to GDP, it is turned off (inactivated) and does not relay signals to the cell nucleus.

[0004] Cancer-promoting KRAS mutations most commonly occur at codons 12, 13, or 61 (Jozsef Timar, et al. Cancer and Metastasis Reviews volume 39, pages 1029-1038 (2020)). Of these mutation sites, G12 is the most frequently mutated residue (89%), most commonly mutating to aspartic acid (G12D, 36%), followed by valine (G12V, 23%) and cysteine ​​(G12C, 14%). G12 is located in the protein's active site, which consists of a phosphate-binding loop (P-loop, residues 10-17) and two switch regions (Switch I (SI), residues 25-40, and Switch II (SII), residues 60-74) (Prior, IA, et al. Cancer Res 72, 2457-2467, (2012)). The active site residues bind to the phosphate group of GTP, enabling KRAS to perform its GTPase function. The switch regions SI and SII further regulate binding to effector and regulatory proteins. Numerous studies have demonstrated heterogeneity of KRAS mutations in various aspects, including endogenous GTPase activity and affinity between effectors and metastasis sites. A mutation in the P-loop at position 12, replacing glycine with aspartate (G12D), inhibits GTP hydrolysis, fixing KRAS in its active (GTP-bound) state, leading to uncontrolled cell growth and evasion of apoptosis signals (Malumbres, M. & Barbacid, M. Nat Rev Cancer 3, 459-465, (2003)). The G12D mutation causes a shift in the local conformational states of KRAS, particularly in the switch-II (SII) and α3-helix regions, in a population of conformations favoring a catalytically impaired state due to structural changes, and also causes the movement of SII to be inversely correlated with other regions (Sezen Vatansever, et al. Sci Rep. 2019 Aug 13;9(1):11730).

[0005] Other KRAS mutations besides the KRAS G12D mutation, such as KRAS(G12C), KRAS(G12V), KRAS(G12A), KRAS(G12S), or KRAS(G12R), also affect KRAS function and tumor development, progression, or resistance to targeted therapy. Other KRAS mutations or secondary KRAS mutations that inhibit covalent or potentially non-covalent drug binding can be used to indicate clinical resistance to KRAS variant-targeted therapy (Awad MM, et al. N Engl J Med. 2021;384(25):2382-93). KRAS gene amplification and overexpression are also associated with tumor progression (E Birkeland, et al. Br. J Cancer. 2012 Dec 4;107(12):1997-2004). The publication also suggests that inhibiting wild-type KRAS may be a viable therapeutic strategy for treating KRAS wild-type-dependent cancers (Lisa Maria Mustachio, et al. Cancers (Basel). 2021 Mar; 13(6): 1204).

[0006] KRAS mutations (e.g., amino acids G12, G13, Q61, A146) are present in up to 25% of cancers, and their oncogenic variants have different prevalences in various cancers, including lung, colorectal, and pancreatic cancer (Cox et al., Nat, Rev. Drug Discov., 2014, 13(11):825-51). In pancreatic ductal adenocarcinoma, the most common KRAS alteration is the G12D substitution. The G12D variant is also a focus of Mirati's drug discovery efforts, and Mirati plans to introduce its lead compound, MRTX1133, into clinical trials. Based on epidemiological data and mutation-specific frequencies reported in Globocan2022 (accessed November 2019), the KRAS G12D mutation is estimated to be present in approximately 36% of pancreatic cancers, 4% of colorectal cancers, approximately 6% of endometrial cancers, and approximately 4% of NSCLCs. This represents a large patient population with unmet needs. Drug discovery of inhibitors that target KRAS(G12D) while preserving wild-type or other mutant KRAS such as KRAS(G12V) or KRAS(G12S) is a breakthrough in this research area (Gongmin Zhu, et al. Mol Cancer. 2021 Nov 6;20(1):143).

[0007] Therefore, the need to develop novel compounds effective in treating KRAS-mediated cancers, particularly KRAS mutated at position 12 or 13, e.g., G12D, and / or wild-type amplified KRAS-mediated cancers, remains unmet. [Overview of the Initiative]

[0008] This specification discloses novel compounds capable of inhibiting the KRAS protein. As a result, the compounds disclosed herein are useful in the treatment of KRAS-related diseases such as cancer.

[0009] In one embodiment, the present disclosure relates to compounds having formula (I), formula (II), or formula (III). [ka] [ka]

Chem.

Chem.

Chem.

[0010] In another aspect, this disclosure is: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] The expression selected from During the ceremony, R 5 The alkyl, alkoxy, or haloalkyl group is selected from alkyl, alkoxy, or haloalkyl groups, and the alkyl, alkoxy, and haloalkyl groups are optionally substituted with one or more deuterium groups. Ring B is a cycloalkyl or heterocyclyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of deutherium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl. However, R 7 and R 9 At least one of them is not hydrogen, and R 11 is an alkyl group substituted with one or more deuterium atoms. The present invention provides compounds or pharmaceutically acceptable salts thereof.

[0011] In another embodiment, the present disclosure provides compounds selected from any of those shown in Table 1.

[0012] In another embodiment, the Disclosure provides a pharmaceutical composition comprising a compound of the Disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0013] In a further embodiment, the Disclosure provides a method for inhibiting the wild-type KRas, KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, and / or KRas Q61H activity of a subject of interest, the method comprising administering an effective amount of the compound of the Disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the Disclosure to the subject.

[0014] In a further embodiment, the Disclosure provides a method for treating cancers associated with wild-type KRas, KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, and / or KRas Q61H, comprising administering an effective amount of the compound of the Disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the Disclosure to a subject in need.

[0015] In a further aspect, the present disclosure relates to a method for treating a cancer of a particular interest, (a) To obtain findings that the cancer is associated with wild-type KRas, KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, and / or KRas Q61H, (b) A method comprising administering to the subject an effective amount of the compound of the Disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the Disclosure.

[0016] In another aspect, the Disclosure provides the use of the compounds of the Disclosure, pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the Disclosure in the manufacture of pharmaceuticals for the treatment of cancer.

[0017] In another embodiment, the Disclosure provides a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, for use in the treatment of cancer. [Modes for carrying out the invention]

[0018] The following examples refer in detail to specific embodiments of the Disclosure as shown in the attached structures and formulas. While the Disclosure is described in relation to the listed embodiments, it should be understood that they are not intended to limit the Disclosure to those embodiments. On the contrary, the Disclosure seeks to cover all variations, modifications, and equivalents that may be included within the scope of the Disclosure as defined in the claims. Those skilled in the art will recognize a number of methods and materials similar or equivalent to those described herein that may be used in the practice of the Disclosure. The Disclosure is not limited to the methods and materials described herein. If one or more of the incorporated references and similar materials, not limited to defined terms, usage of terms, or the techniques described herein, differ from or conflict with this application, the Disclosure shall prevail. All references, patents, and patent applications cited herein are incorporated herein by reference as a whole.

[0019] For clarity, certain features of this disclosure described in the context of separate embodiments may be provided in combination in a single embodiment. Conversely, various features of this disclosure described in the context of a single embodiment for brevity may be provided separately or in any preferred subcombination. As used in the specification and the appended claims, the singular forms “a, an” and “the” include their plural forms unless otherwise indicated by context. Therefore, note that, for example, a reference to “one compound” includes multiple compounds. definition

[0020] The following provides a more detailed definition of specific functional groups and chemical terms. For the purposes of this disclosure, chemical elements are identified according to the CAS Periodic Table and the back cover of the 75th edition of the Handbook of Chemistry and Physics, and specific functional groups are defined generally as described therein. In addition, general principles of organic chemistry, as well as specific functional parts and reactivity, are incorporated herein by reference in their respective contents, as described in *Organic Chemistry*, Thomas Sorrell, 2 ndEdition, University Science Books, Sausalito, 2006, Smith and March March's Advanced Organic Chemistry, 6 th Edition, John Wiley & Sons, Inc., New York, 2007, Larock, Comprehensive Organic Transformations, 3 rd Edition, VCH Publishers, Inc., New York, 2018, Carruthers, Some Modern Methods of Organic Synthesis, 4 th This is described in Edition, Cambridge University Press, Cambridge, 2004.

[0021] Linked substituents are described in various places in this disclosure. Each linked substituent is particularly intended to include both the forward and backward forms of the linked substituent. For example, -NR(CR'R'')- includes both -NR(CR'R'')- and -(CR'R'')NR-. Where a structure clearly requires a linking group, the Markush variable listed for that group is understood to be the linking group. For example, where a structure requires a linking group and the definition of the Markush group for that variable lists "alkyl", "alkyl" is understood to represent a linked alkylene group.

[0022] If a substituent is shown to be attached across a bond connecting two atoms in a ring, then the substituent can be attached to any atom in the ring. If a substituent is listed without indicating which atom it is attached to the remainder of the compound in a given formula, then the substituent can be attached via any atom in the formula. Combinations of substituents and / or variables are permissible as long as a stable compound is produced.

[0023] When used herein, the dash "-" at the beginning or end of a chemical group is used for convenience to indicate the bonding point of a substituent. For example, -OH is bonded through a carbon atom, and chemical groups may be represented with or without one or more dashes without losing their usual meaning. A wavy line drawn with a single line in the structure indicates the bonding point of a group. Unless chemically or structurally required, direction is neither indicated nor implied by the order in which chemical groups are written or named. When used herein, a solid line emanating from the center of a ring indicates that the bonding point of a substituent on the ring can be on any ring atom. If a substituent is listed without indicating which atom it is bonded to the remainder of the compound in a given formula, the substituent can be bonded through any atom in the formula. Combinations of substituents and / or variables are permissible as long as a stable compound is produced.

[0024] Any variable (e.g., R) can be added to any component or formula of a compound. i If ) appears multiple times, the definition for each appearance is independent of the definition for each other appearance. Therefore, for example, R with 0 to 2 elements i If indicated as partially replaced, the group may optionally have up to two R i It can be replaced in parts, and each occurrence of R i R i The selection is independent of the definition. Furthermore, combinations of substituents and / or variables are permissible as long as a stable compound is produced.

[0025] As used herein, the term “KRas G12A” refers to a variant of the mammalian Kras protein containing an amino acid substitution from alanine to glycine at amino acid position 12. The assignment of amino acid codons and residue positions of human Kras is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, “Kras G12A inhibitor” refers to a compound capable of negatively modulating or inhibiting all or part of the enzymatic activity of Kras G12A. As used herein, “Kras G12A-related disease or disorder” refers to a disease or disorder associated with, mediated by, or having a Kras G12A mutation. A non-limiting example of a Kras G12A-related disease or disorder is Kras G12A-related cancer.

[0026] Similarly, the term "KRas G12C" refers to a variant of the mammalian KRas protein containing an amino acid substitution from cysteine ​​to glycine at amino acid position 12. The term "KRas G12D" refers to a variant of the mammalian KRas protein containing an amino acid substitution from aspartic acid to glycine at amino acid position 12. The term "KRas G12R''" refers to a variant of the mammalian KRas protein containing an amino acid substitution from arginine to glycine at amino acid position 12. The term "KRas G12S" refers to a variant of the mammalian KRas protein containing an amino acid substitution from serine to glycine at amino acid position 12. The term "KRas G12V" refers to a variant of the mammalian KRas protein containing an amino acid substitution from valine to glycine at amino acid position 12. The term "KRas G13D" refers to a variant of the mammalian KRas protein containing an amino acid substitution from aspartic acid to glycine at amino acid position 13. The term "KRas Q61H" refers to a variant of the mammalian KRas protein that contains an amino acid substitution at amino acid position 61, from histidine to glutamine.

[0027] As used herein, the terms “compounds provided herein,” “compounds disclosed herein,” or “compounds of the disclosure” refer to the compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), and certain compounds disclosed herein.

[0028] When used in this specification, the term "C i-j " indicates the range of carbon atoms, where i and j are integers, and the range of carbon atoms includes the endpoints (i.e., i and j) and each integer point between them, where j is greater than i. For example, C 1-6 This refers to a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. In some embodiments, the term "C" is used. 1-12 " represents 1 to 12, especially 1 to 10, especially 1 to 8, especially 1 to 6, especially 1 to 5, especially 1 to 4, especially 1 to 3, or especially 1 to 2 carbon atoms.

[0029] As used herein, the term “alkyl” means a linear or branched hydrocarbon radical, whether used as part of another term or independently, which may optionally be independently substituted with one or more substituents listed below. i-j "Alkyl" refers to an alkyl group having i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms. In some embodiments, the alkyl group contains 1 to 9 carbon atoms. In some embodiments, the alkyl group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. 1-10 Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 1-6Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0030] As used herein, the term “alkenyl,” whether used as part of another term or independently, means a linear or branched hydrocarbon radical having at least one carbon-carbon double bond, which may optionally be independently substituted with one or more substituents as described herein, and which include radicals having “cis” and “trans” orientations, or “E” and “Z” orientations. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkenyl group contains 2 carbon atoms. Examples of alkenyl groups include, but are not limited to, etylene (or vinyl), propenyl, butenyl, pentenyl, 1-methyl-2-buten-1-yl, and 5-hexenyl.

[0031] As used herein, the term “alkynyl,” whether used as part of another term or independently, refers to a linear or branched hydrocarbon radical having at least one carbon-carbon triple bond, which may optionally be independently substituted with one or more substituents as described herein. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkynyl group contains 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, and 2-propynyl.

[0032] As used herein, the term “alkoxy” refers to an alkyl group bonded to a parent molecule via an oxygen atom, as previously defined, whether used as part of another term or independently. i-j "Alkoxy" means that the alkyl portion of the alkoxy group has i to j carbon atoms. In some embodiments, the alkoxy group contains 1 to 10 carbon atoms. In some embodiments, the alkoxy group contains 1 to 9 carbon atoms. In some embodiments, the alkoxy group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. 1-6 Examples of "alkoxys" include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, neopentoxy, and n-hexoxy.

[0033] As used herein, the term "amino" refers to an -NH2 group. The amino group may be substituted with one or more groups, such as alkyl, aryl, carbonyl, or other amino groups.

[0034] As used herein, the term "cyano" refers to -CN.

[0035] As used herein, the term “cycloalkyl,” whether used as part of another term or independently, refers to monovalent non-aromatic saturated or partially unsaturated monocyclic and polycyclic ring systems in which all ring atoms are carbon and which contain at least three ring-forming carbon atoms. In some embodiments, a cycloalkyl may contain 3 to 12 ring-forming carbon atoms, 3 to 10 ring-forming carbon atoms, 3 to 9 ring-forming carbon atoms, 3 to 8 ring-forming carbon atoms, 3 to 7 ring-forming carbon atoms, 3 to 6 ring-forming carbon atoms, 3 to 5 ring-forming carbon atoms, 4 to 12 ring-forming carbon atoms, 4 to 10 ring-forming carbon atoms, 4 to 9 ring-forming carbon atoms, 4 to 8 ring-forming carbon atoms, 4 to 7 ring-forming carbon atoms, 4 to 6 ring-forming carbon atoms, or 4 to 5 ring-forming carbon atoms. A cycloalkyl may be saturated or partially unsaturated. A cycloalkyl may be substituted. In some embodiments, a cycloalkyl may be a saturated cyclic alkyl. In some embodiments, a cycloalkyl may be a partially unsaturated cyclic alkyl containing at least one double or triple bond in the ring system. In some embodiments, the cycloalkyl group may be monocyclic or polycyclic. In the case of polycyclic ring systems, the cycloalkyl group includes fused ring systems (e.g., a cycloalkyl ring fused with another cycloalkyl ring), spirocyclic ring systems, and crosslinked ring systems. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopento-1-enyl, 1-cyclopento-2-enyl, 1-cyclopento-3-enyl, cyclohexyl, 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, 1-cyclohexa-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, adamantyl, norbornyl, fluorenyl, spiropentadienyl, spiro[3,6]decanyl, bicyclo[1,1,1]pentenyl, and bicyclo[2,2,1]heptenyl.

[0036] As used herein, the term "halogen" refers to an atom selected from fluorine (or fluoro), chlorine (or chloro), bromine (or bromo), and iodine (or iod).

[0037] As used herein, the term “haloalkyl” refers to an alkyl group as defined above, substituted with one or more halogens as defined above. Examples of haloalkyls include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0038] As used herein, the term “heteroatom” means nitrogen, oxygen, and sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen (including N-oxides).

[0039] As used herein, the term “heterocyclyl” refers to a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and the remaining ring atoms are carbon, where one or more ring atoms may be independently substituted with one or more substituents. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, the heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in the ring system. The heterocyclyl group may be a monocyclic or polycyclic ring system. In the case of a polycyclic ring system, the heterocyclyl group may include a fused ring system, a spiro-ring system, or a bridging ring system. For example, a polycyclic heterocyclyl may include a heterocyclyl ring fused to one or more additional rings, such as a cycloalkyl ring or a heterocyclyl ring, or a cycloalkyl ring fused to one or more heterocyclyl rings. In some embodiments, the heterocyclyl may contain any oxidized form of carbon, nitrogen, or sulfur, and any quaternized form of basic nitrogen. The heterocyclyl radical may be carbon-bonded or nitrogen-bonded, if possible. In some embodiments, the heterocycle is carbon-bonded. In some embodiments, the heterocycle is nitrogen-bonded. For example, the group derived from pyrrole may be pyrrole-1-yl (nitrogen-bonded) or pyrrole-3-yl (carbon-bonded).

[0040] In some embodiments, the term “3-12 membered heterocyclyl” refers to a 3-12 membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of heterocyclyl free radicals include azilidinyl, azetidinyl, oxetanyl, dioxolanyl, dihydrofuryl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperadinyl, 4-piperidonyl, and pylori. This includes, but is not limited to, dinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianil, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl.

[0041] As used herein, the term "hydroxyl" or "hydroxy" refers to -OH.

[0042] As used herein, the term “hydroxyalkyl” refers to an alkyl free radical as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyls include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0043] As used herein, the term "nitro" refers to -NO2.

[0044] As used herein, the term "partially unsaturated" refers to a radical comprising at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.

[0045] As used herein, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. It is understood that "substitution" or "substituted with" includes the implicit condition that such substitution is in accordance with the allowed valences of the substituted atom, and that the substitution results in a stable or chemically feasible compound that does not undergo spontaneous transformations such as, for example, rearrangement, cyclization, or elimination. Unless otherwise stated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in a given structure may be substituted with a substituent selected from a specified group, the substituents may be the same or different at each position. One skilled in the art will appreciate that substituents may themselves be optionally substituted. Unless stated otherwise as "unsubstituted", references to chemical moieties herein are understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants. compound

[0046] In one aspect, the present disclosure provides a compound having Formula (I), Formula (II) or Formula (III)

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

[0047] In some embodiments of the compounds of formula (I), formula (II), or formula (III), R 1 and R 2 Both are hydrogen.

[0048] In some embodiments of the compounds of formula (I), formula (II), or formula (III), R 3 and R 4 One of them is hydrogen, and the other is an alkyl group optionally substituted with one or more deutherium atoms. In certain embodiments, R 3 and R 4 One is hydrogen, and the other is C, each optionally substituted with one or more deuterium atoms. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 It is alkyl. In certain embodiments, R 3 and R 4 One of them is hydrogen, and the other is a methyl atom optionally substituted with one or more deutherium atoms. In certain embodiments, R 3 and R4 One of them is hydrogen, and the other is -CH3 or -CD3.

[0049] In some embodiments of the compounds of formula (I), formula (II), or formula (III), R 3 and R 4 Together with the carbon atoms bonded to both of them, they form a cycloalkyl group optionally substituted with one or more groups independently selected from the group consisting of deutherium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl. In some embodiments, R 3 and R 4 C 3-6 Cycloalkyl, C 3-5 Cycloalkyl, or C 3-4 A cycloalkyl group is formed, each of which is optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl. In certain embodiments, R 3 and R 4 Together with the carbon atoms bonded to both of them, they form a cyclopropyl optionally substituted with one or more deutherium atoms.

[0050] In some embodiments of the compounds of formula (I), formula (II), or formula (III), R 5 and R 6 One of them is an alkyl group optionally substituted with one or more deutherium atoms, and the other is hydrogen. In certain embodiments, R 5 and R 6 One of them is C, each arbitrarily substituted with one or more deuteriums. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 One is alkyl, and the other is hydrogen. In certain embodiments, R 5 and R 6one of which is -CH3 or -CD3, and the other is hydrogen.

[0051] In some embodiments of the compound of formula (I), R 7 , R 8 , R 9 and R 10 are hydrogen.

[0052] In some embodiments of the compound of formula (I), R 5 and R 6 one is alkyl optionally substituted with one or more deuterium, and the other is hydrogen, R 7 , R 8 , R 9 and R 10 are hydrogen. In certain embodiments, R 5 and R 6 one of which is C each optionally substituted with one or more deuterium 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, the other is hydrogen, R 7 , R 8 , R 9 and R 10 are hydrogen.

[0053] In some embodiments of the compound of formula (I), formula (II) or formula (III), R 5 and R 6 are both hydrogen.

[0054] In some embodiments of the compound of formula (I), R 7 and R 8 one of which is alkyl, alkoxy, -alkyl-alkoxy, hydroxyalkyl or haloalkyl each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium. In certain embodiments, R 7 and R 8 one of which is C each optionally substituted with one or more deuterium1-6 Alkyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-(C 1-6 Alkoxy), C 1-6 Hydroxyalkyl or C 1-6 One is a haloalkyl group, and the other is hydrogen or deutherium. In certain embodiments, R 7 and R 8 One of the groups is -CH3, -CD3, -CH2-OCH3, -CH2-OCD3, -CH2-OH, -CH2F, -CHF2, or -CF3, and the other is hydrogen or deuterium.

[0055] In some embodiments of the compound of formula (I), R 5 and R 6 Both are hydrogen, and R 7 and R 8 One of them is an alkyl, alkoxy, -alkyl-alkoxy, hydroxyalkyl, or haloalkyl, each optionally substituted with one or more deutherium atoms, and the other is hydrogen or deutherium. In certain embodiments, R 5 and R 6 Both are hydrogen, and R 7 and R 8 One of them is C, each arbitrarily substituted with one or more deuteriums. 1-6 Alkyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-(C 1-6 Alkoxy), C 1-6 Hydroxyalkyl or C 1-6 One is a haloalkyl group, and the other is hydrogen or deutherium. In certain embodiments, R 5 and R 6 Both are hydrogen, and R 7 and R 8 One of the groups is -CH3, -CD3, -CH2-OCH3, -CH2-OCD3, -CH2-OH, -CH2F, -CHF2, or -CF3, and the other is hydrogen or deuterium.

[0056] In some embodiments of the compound of formula (I), R9 and R 10 One of them is hydrogen, and the other is an alkyl group optionally substituted with hydrogen or one or more deutherium atoms. In certain embodiments, R 9 and R 10 One is hydrogen, and the other is C, where each hydrogen is optionally substituted with one or more deuterium atoms. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 It is alkyl. In certain embodiments, R 9 and R 10 One of them is hydrogen, and the other is hydrogen, methyl, or CD3.

[0057] In some embodiments of the compound of formula (I), R 5 and R 6 Both are hydrogen, and R 9 and R 10 One of them is hydrogen, and the other is an alkyl group optionally substituted with hydrogen or one or more deutherium atoms. In certain embodiments, R 5 and R 6 Both are hydrogen, and R 9 and R 10 One is hydrogen, and the other is C, where each hydrogen is optionally substituted with one or more deuterium atoms. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 It is alkyl. In certain embodiments, R 5 and R 6 Both are hydrogen, and R 9 and R 10 One of them is hydrogen, and the other is hydrogen, methyl, or CD3.

[0058] In some embodiments of the compound of formula (I), R 7 and R 9 It forms a heterocycline with the intervening atom, or R 7 and Ra It forms a heterocycline with the intervening atom. In a particular embodiment, ring A is [ka] That is the case.

[0059] In some embodiments of the compound of formula (I), X is -C(R e R f )- and R e and R f One of them is hydrogen, and the other is a halogen. In a particular embodiment, R e and R f One of them is hydrogen, and the other is -F. In a particular embodiment, R e and R f Both are hydrogen.

[0060] In some embodiments of the compound of formula (I), R 5 and R 6 Both are hydrogen, and R 7 and R 9 It forms a heterocycline with the intervening atom, or R 7 and R a It forms a heterocycline with intervening atoms. In certain embodiments, R 5 and R 6 Both are hydrogen, and ring A is [ka] That is the case.

[0061] In some embodiments of the compound of formula (I), X is -C(R e R f )- and R a and R eThese, together with the carbon atoms bonded to them, form cycloalkyl or heterocyclyl groups, each of which is optionally substituted with one or more groups independently selected from the group consisting of deutherium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl groups. In certain embodiments, X is -C(R e R f )- and R a and R e C 3-6 They form cycloalkyl or 3- to 6-membered heterocyclines, each of which is optionally substituted with one or more groups independently selected from the group consisting of deutherium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl.

[0062] In some embodiments of the compound of formula (I), n is 0.

[0063] In some embodiments of the compound of formula (I), when n is 0, ring A is [ka] That is the case.

[0064] In some embodiments of the compound of formula (I), R 5 and R 6 Both are hydrogen, and ring A is [ka] And R 7 and R 8 One of them is an alkyl, alkoxy, -alkyl-alkoxy, or haloalkyl, each optionally substituted with one or more deutherium atoms, and the other is hydrogen or deutherium. In certain embodiments, R 7 and R 8 One of them is alkyl (for example, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C1-3 Alkyl or C 1-2 One is alkyl, and the other is hydrogen or deutherium. In certain embodiments, R 7 and R 8 One of them is -CH3 or -CD3, and the other is hydrogen or deuterium. In some embodiments, R 9 and R 10 One of them is hydrogen or deutherium, and the other is an alkyl (e.g., C) optionally substituted with hydrogen or one or more deutherium atoms. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 It is alkyl. In certain embodiments, R 9 and R 10 Both are hydrogen.

[0065] In some embodiments of the compound of formula (I), X is -C(R e R f )- and R e and R f along with the carbon atoms bonded to them [ka] It forms a . In some embodiments, each R'' is independently selected from hydrogen or halogen. In some embodiments, one of R'' is a halogen and the other is hydrogen. In some embodiments, both R'' are halogens such as fluorocarbons.

[0066] In some embodiments of the compound of formula (I), R 5 and R 6 Both are hydrogen.

[0067] In some embodiments of the compound of formula (I), R 7 and R 8One of them is an alkyl, alkoxy, -alkyl-alkoxy, or haloalkyl, each optionally substituted with one or more deutherium atoms, and the other is hydrogen or deutherium. In certain embodiments, R 7 and R 8 One of them is C, each arbitrarily substituted with one or more deuteriums. 1-6 Alkyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-(C 1-6 Alkoxy) or C 1-6 One is a haloalkyl group, and the other is hydrogen or deutherium. In certain embodiments, R 7 and R 8 One of the molecules is -CH3, -CD3, -CH2-OCH3, -CH2-OCD3, -CH2F, -CHF2, or -CF3, and the other is hydrogen or deutherium.

[0068] In some embodiments of the compound of formula (I), R 7 and R 8 One of them is an alkyl group optionally substituted with one or more deutherium atoms, and the other is hydrogen or deutherium. In certain embodiments, R 7 and R 8 One of them is C, each replaced by one or more deuteria. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 One is alkyl, and the other is hydrogen.

[0069] In some embodiments of the compound of formula (I), R 7 and R 8 One of them is -CH3 or -CD3, and the other is hydrogen or deuterium.

[0070] In some embodiments of the compound of formula (I), R 9 and R 10One of them is hydrogen or deutherium, and the other is an alkyl optionally substituted with hydrogen or one or more deutherium atoms. In certain embodiments, R 9 and R 10 One is hydrogen, and the other is C, where each hydrogen is optionally substituted with one or more deuterium atoms. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 It is alkyl. In certain embodiments, R 9 and R 10 One of them is hydrogen, and the other is hydrogen, methyl, or CD3. In certain embodiments, R 9 and R 10 Both are hydrogen.

[0071] In some embodiments of the compound of formula (II) or formula (III), R 11 and R 12 One of them is an alkyl group substituted with one or more deutherium atoms, and the other is hydrogen or deutherium. In certain embodiments, R 11 and R 12 One of them is C, each replaced by one or more deuteria. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 One is alkyl, and the other is hydrogen. In certain embodiments, R 11 and R 12 One of them is -CD3, and the other is hydrogen.

[0072] In some embodiments of the compound of formula (II) or formula (III), R 5 and R 6 Both are hydrogen, and R 11 and R 12 One of them is an alkyl group substituted with one or more deutherium atoms, and the other is hydrogen or deutherium. In certain embodiments, R 5 and R6 Both are hydrogen, and R 11 and R 12 One of them is C, each replaced by one or more deuteria. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 One is alkyl, and the other is hydrogen. In certain embodiments, R 5 and R 6 Both are hydrogen, and R 11 and R 12 One of them is -CD3, and the other is hydrogen.

[0073] In some embodiments of the compound of formula (II) or formula (III), R 13 and R 14 One of them is hydrogen, and the other is an alkyl group optionally substituted with hydrogen or one or more deutherium atoms. In certain embodiments, R 13 and R 14 One is hydrogen, and the other is C, where each hydrogen is optionally substituted with one or more deuterium atoms. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 It is alkyl. In certain embodiments, R 13 and R 14 One of them is hydrogen, and the other is hydrogen, methyl, or CD3. In certain embodiments, R 13 and R 14 Both are hydrogen.

[0074] In some embodiments of the compound of formula (II) or formula (III), R 5 and R 6 Both are hydrogen, and R 13 and R 14 One of them is hydrogen, and the other is an alkyl group optionally substituted with hydrogen or one or more deutherium atoms. In certain embodiments, R 5 and R 6Both are hydrogen, and R 13 and R 14 One is hydrogen, and the other is C, where each hydrogen is optionally substituted with one or more deuterium atoms. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 It is alkyl. In certain embodiments, R 5 and R 6 Both are hydrogen, and R 13 and R 14 One of them is hydrogen, and the other is hydrogen, methyl, or CD3. In certain embodiments, R 5 and R 6 Both are hydrogen, and R 13 and R 14 Both are hydrogen.

[0075] In some embodiments of the compound of formula (II) or formula (III), R u and R v One of them is hydrogen, and the other is an alkyl group optionally substituted with hydrogen or one or more deutherium atoms. In certain embodiments, R u and R v One is hydrogen, and the other is C, where each hydrogen is optionally substituted with one or more deuterium atoms. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 It is alkyl. In certain embodiments, R u and R v One of them is hydrogen, and the other is hydrogen, methyl, or CD3.

[0076] In some embodiments of the compound of formula (II) or formula (III), R 5 and R 6 Both are hydrogen, and R u and R vOne of them is hydrogen, and the other is an alkyl group optionally substituted with hydrogen or one or more deutherium atoms. In certain embodiments, R 5 and R 6 Both are hydrogen, and R u and R v One is hydrogen, and the other is C, where each hydrogen is optionally substituted with one or more deuterium atoms. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 It is alkyl. In certain embodiments, R 5 and R 6 Both are hydrogen, and R u and R v One of them is hydrogen, and the other is hydrogen, methyl, or CD3.

[0077] In some embodiments of the compound of formula (II) or formula (III), Z is -C(R j R k )- and R j and R k One of them is hydrogen, and the other is a halogen. In a particular embodiment, R j and R k One of them is hydrogen, and the other is -F.

[0078] In some embodiments of the compound of formula (II) or formula (III), Z is -C(R j R k )- and R j and R k along with the carbon atoms bonded to them [ka] It forms a halogen. In some embodiments, one of R'' is a halogen and the other is hydrogen. In some embodiments, both R'' are halogens such as fluorocarbons.

[0079] In some embodiments of the compound of formula (II) or formula (III), R 5 and R 6 Both are hydrogen.

[0080] In some embodiments of the compound of formula (II) or formula (III), R 11 and R 12 One of them is an alkyl, alkoxy, -alkyl-alkoxy, or haloalkyl, each optionally substituted with one or more deutherium atoms, and the other is hydrogen or deutherium. In certain embodiments, R 11 and R 12 One of them is C, each arbitrarily substituted with one or more deuteriums. 1-6 Alkyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-(C 1-6 Alkoxy) or C 1-6 One is a haloalkyl group, and the other is hydrogen or deutherium. In certain embodiments, R 11 and R 12 One of the molecules is -CH3, -CD3, -CH2-OCH3, -CH2-OCD3, -CH2F, -CHF2, or -CF3, and the other is hydrogen or deutherium.

[0081] In some embodiments of the compound of formula (II) or formula (III), R 11 and R 12 One of them is an alkyl group optionally substituted with one or more deutherium atoms, and the other is hydrogen or deutherium. In certain embodiments, R 11 and R 12 One of them is C, each replaced by one or more deuteria. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 One is alkyl, and the other is hydrogen.

[0082] In some embodiments of the compound of formula (II) or formula (III), R 11and R 12 One of them is -CH3 or -CD3, and the other is hydrogen or deuterium.

[0083] In some embodiments of the compound of formula (II) or formula (III), R 13 and R 14 One of them is hydrogen or deutherium, and the other is an alkyl optionally substituted with hydrogen or one or more deutherium atoms. In certain embodiments, R 13 and R 14 One is hydrogen, and the other is C, where each hydrogen is optionally substituted with one or more deuterium atoms. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 It is alkyl. In certain embodiments, R 13 and R 14 One of them is hydrogen, and the other is hydrogen, methyl, or CD3. In certain embodiments, R 13 and R 14 Both are hydrogen.

[0084] In some embodiments of the compounds of formula (II) or formula (III), Z is -O-.

[0085] In a further aspect, this disclosure may include: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] The expression selected from During the ceremony, R 5 The alkyl, alkoxy, or haloalkyl group is selected from alkyl, alkoxy, or haloalkyl groups, and the alkyl, alkoxy, and haloalkyl groups are optionally substituted with one or more deuterium groups. Ring B is a cycloalkyl or heterocyclyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of deutherium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl. However, R 7 and R 9 At least one of them is not hydrogen, and R 11 is an alkyl group substituted with one or more deuterium atoms. The present invention provides compounds or pharmaceutically acceptable salts thereof.

[0086] In some embodiments of the compounds of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (IIa), or formula (IIb), m is 1, 2, 3, or 4. In a particular embodiment, m is 1. In a particular embodiment, m is 2. In a particular embodiment, m is 3. In a particular embodiment, m is 4.

[0087] In some embodiments of the compounds of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (IIa), or formula (IIb), each R is independently selected from cyano, halogen, hydroxyl, amino, haloalkyl, alkyl, or alkynyl, and the alkyl or alkynyl is optionally substituted with one or more deuterium atoms. In some embodiments, each R is cyano, halogen, hydroxyl, amino, C 1-6 Haloalkyl, C 1-5 Haloalkyl, C 1-4 Haloalkyl, C 1-3 Haloalkyl, C 1-2 Haloalkyl, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C 2-6 Alkinyl, C 2-5 Alkinyl, C 2-4 Alkinyl, or C 2-3 The alkyl or alkynyl is independently selected from alkynyl, and the alkyl or alkynyl is optionally substituted with one or more deutherium atoms. In certain embodiments, each R is independently selected from fluoro, chloro, -NH2, -CF3, hydroxyl, ethyl or ethynyl, and the ethyl or ethynyl is optionally substituted with one or more deutherium atoms.

[0088] In some embodiments of compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), or formula (If), [ka] teeth, [ka] It is selected from the group consisting of the following.

[0089] In some embodiments of the compound of formula (II) or formula (IIa), [ka] teeth, [ka] It is selected from the group consisting of the following.

[0090] In some embodiments of the compound of formula (III) or formula (IIIa), [ka] teeth, [ka] It is selected from the group consisting of the following.

[0091] In some embodiments of the compounds of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (IIa), or formula (IIb), each R' is independently hydrogen or deutherium.

[0092] In some embodiments of the compounds of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (IIa), or formula (IIb), each R' is hydrogen.

[0093] In some embodiments of the compounds of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (IIa), or formula (IIb), each R' is deutherium.

[0094] In some embodiments, this disclosure, [ka] [ka] [ka]

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[0095] In certain embodiments, exemplary compounds of this disclosure are shown in Table 1 below. [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]

[0096] The compounds provided herein will be described with reference to both their general formulas and specific compounds. In addition, the compounds of this disclosure may exist in a variety of forms or derivatives, not limited to prodrugs, soft drugs, active metabolic derivatives (active metabolites), and their pharmaceutically acceptable salts, all of which are within the scope of this disclosure.

[0097] As used herein, the term “prodrug” refers to a compound or a pharmaceutically acceptable salt thereof that, when metabolized under physiological conditions or converted by solvolysis, produces a desired active compound. Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of active compounds. Typically, prodrugs are inactive or less active than the active compound, but may offer one or more advantageous handling, administration, and / or metabolic properties. For example, some prodrugs are esters of active compounds, and during metabolism, the ester group is cleaved to obtain the active drug. Also, some prodrugs are enzymatically activated to produce the active compound, or a compound that produces the active compound through further chemical reactions. Prodrugs may progress from the prodrug form to the active form in a single step, or they may have one or more intermediate forms that may themselves be active or inactive. The preparation and use of prodrugs are discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems”, Vol. 14 of the ACS Symposium Series, Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, and Prodrugs: Challenges and Rewards, ed. V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley, Springer-Verlag New York, 2007, both of which are incorporated herein by reference as a whole.

[0098] As used herein, the term “soft drug” refers to a compound that exerts pharmacological effects but has a limited duration of activity due to its breakdown into inactive metabolites. For example, see “Soft drugs: Principles and methods for the design of safe drugs”, Nicholas Bodor, Medicinal Research Reviews, Vol. 4, No. 4, 449–469, 1984, which is incorporated herein by reference in its entirety.

[0099] As used herein, the term “metabolite,” for example, “active metabolite,” overlaps with the term “prodrug” as described above. Therefore, such metabolites are pharmacologically active compounds, or compounds that are further metabolized into pharmacologically active compounds that are derivatives resulting from metabolic processes within the target body. For example, such metabolites may arise from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, and enzymatic degradation of the administered compound, salt, or prodrug. Among these, active metabolites are such pharmacologically active derivative compounds. In the case of prodrugs, the prodrug compound is generally inactive or less active than the metabolite. In the case of active metabolites, the parent compound may be an active compound or an inactive prodrug.

[0100] Prodrugs and active metabolites can be identified using commonly known techniques in this field. See, for example, Bertolini et al, 1997, J Med Chem 40:2011-2016, Shan et al., J Pharm Sci 86:756-757, Bagshawe, 1995, DrugDev Res 34:220-230, and Wermuth, supra.

[0101] As used herein, the term “pharmaceutically acceptable” means that a substance or composition is chemically and / or toxicologically compatible with other components that constitute and / or treat the subject of the preparation.

[0102] As used herein, the term “pharmaceutically acceptable salt” includes, unless otherwise specified, salts that retain the biological effects of the free acids and bases of a particular compound and are not biologically or otherwise undesirable. Forms of pharmaceutically acceptable salts considered include, but are not limited to, mono, bis, tris, and tetrakis. Pharmaceutically acceptable salts are nontoxic at the doses and concentrations administered. The preparation of such salts can facilitate the pharmacological use of a compound by altering its physical properties without interfering with the exertion of its physiological effects. Useful alterations to physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher concentrations of the drug.

[0103] Pharmacopoecitable salts include acid addition salts containing sulfates, chlorides, hydrochlorides, fumarates, maleates, phosphates, sulfamates, acetates, citrates, lactates, tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, and quinates. Pharmacopoecitable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.

[0104] Pharmaceutically acceptable salts also include base addition salts containing acidic functional groups such as carboxylic acids or phenols, such as benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc. For example, Remington's Pharmaceutical Sciences, 19 thSee ed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995, and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using appropriate corresponding bases.

[0105] Pharmacopoeiatically acceptable salts can be prepared by standard techniques. For example, the free base form of a compound can be isolated by dissolving it in a suitable solvent such as an aqueous solution containing a suitable acid or a water-alcohol solution, and then evaporating the solution. Thus, if a particular compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, such as treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, and salicylic acid, a pyranosidylic acid such as glucuronic acid or galacturonic acid, an α-hydroxy acid such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as benzoic acid or cinnamic acid, or a sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid.

[0106] Similarly, if a particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, such as treating the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), alkali metal hydroxide, or alkaline earth metal hydroxide. Examples of suitable salts include organic salts derived from amino acids such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine, or piperazine, as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0107] The compounds of this disclosure can exist in non-solvated, solvated (e.g., hydrated), and solid (e.g., crystalline or polymorphic) forms, and it is understood that this disclosure aims to encompass all such forms.

[0108] As used herein, the terms “solvate” or “solvated form” refer to a solvated form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to form solvates because they capture solvent molecules in a constant molar ratio in their crystalline solid state. When the solvent is water, the solvate formed is a hydrate; when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by a combination of one or more water molecules and one molecule of a substance that holds water in the H2O state. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0109] As used herein, the terms “crystal form,” “crystal shape,” “polymorph,” and “polymorph” are interchangeable and refer to crystalline structures in which a compound (or its salt or solvate) can crystallize in different crystal packing configurations, all having the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability, and solubility. A particular crystalline form may become dominant due to the recrystallization solvent, crystallization rate, storage temperature, and other factors. Crystallographic polymorphs of a compound can be prepared by crystallization under different conditions.

[0110] This disclosure is also intended to include all isotopes of atoms in a compound. An isotope of an atom includes atoms with the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromide, or iodine in the compounds of this disclosure are, for example, 1 H, 2 H, 3 H, 11 C, 12C, 13 C, 14 C, 14 N, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I, 127 I and 131 It is intended to include those isotopes, not limited to I. In some embodiments, hydrogen includes protium, deutherium, and tritium. In some embodiments, carbon is 12 C and 13 Including C. Isotope-enriched compounds of formulas (I), (II), (III), (Ia), (Ib), (Ic), (Id), (Ie), (If), (IIa), or (IIIa) can be prepared without excessive experimentation by using appropriate isotope enrichment reagents and / or intermediates by the prior art well known to those skilled in the art, or by processes similar to those described in the schemes and examples herein.

[0111] In some embodiments, the disclosure includes compounds of formula (I), (II), (III), (Ia), (Ib), (Ic), (Id), (Ie), (If), (IIa), or (IIIa), where one or more hydrogens bonded to a carbon atom are substituted with deutherium. Such compounds are synthesized by means known in the art, for example, by employing starting materials in which one or more hydrogens are substituted with deutherium.

[0112] Those skilled in the art will understand that the compounds of this disclosure may exist in different tautomerized forms, and that all such forms are within the scope of this disclosure. The terms “tautomer” or “tautomerized form” refer to structural isomers of different energies that are interconvertible across a low-energy barrier. The presence and concentration of isomerized forms may depend on the environment in which the compound exists, for example, whether the compound is a solid, an organic solution, or an aqueous solution. As an example, proton tautomers (also known as prototropic tautomers) include interconversions by proton transfer, such as keto-enols, amide-imido acids, lactam-lactimes, and imine-enamine isomerizations, and cyclic forms in which a proton can occupy two or more positions in a heterocyclic system. Valence tautomers include interconversions by rearrangement of some of the bonding electrons. Tautomers can be brought to equilibrium by appropriate substitution or sterically fixed into a single form. Compounds of this disclosure identified by name or structure as a specific tautomer are intended to include other tautomer forms unless otherwise specified. Compound Synthesis

[0113] The compounds provided herein can be prepared by any known organic synthesis technique and can be synthesized according to any of a number of possible synthetic routes.

[0114] The reactions for preparing the compounds of this disclosure can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents may be those that are substantially inactive with the starting materials (reactants), intermediates, or products at the temperature in which the reaction is carried out, for example, in the range from the freezing temperature to the boiling point of the solvent. A given reaction can be carried out in one solvent or a mixture of several solvents. Those skilled in the art can select a solvent suitable for a particular reaction step, depending on that step.

[0115] The preparation of the compounds of this disclosure may involve the protection and deprotection of various chemical groups. Those skilled in the art will readily be able to determine the need for protection and deprotection, and the selection of appropriate protecting groups. For the chemistry of protecting groups, see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003, and Peter GM Wuts, Greene's Protective Groups in Organic Synthesis, 5, all of which are incorporated herein by reference as a whole. th Refer to Edition, Wiley, 2014.

[0116] The reaction can be monitored according to any suitable method known in the art. For example, nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) Product formation can be monitored by spectroscopic means such as infrared spectroscopy, spectrophotometer (e.g., UV-Vis), and mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC). Those skilled in the art can purify the compound by various methods, including high-performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization," Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6(6), 874-883, incorporated herein by reference as a whole), and normal-phase silica chromatography. Use of compounds

[0117] In one embodiment, the present disclosure provides compounds capable of inhibiting the KRAS protein. In some embodiments, the KRAS protein is selected from wild-type KRas, KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, or KRas Q61H proteins. In a particular embodiment, the KRAS protein is the KRas G12D protein.

[0118] As used herein, the term “therapy” is intended to have its ordinary meaning of addressing a disease in order to completely or partially alleviate one, some, or all of the symptoms of the disease, or to correct or compensate for the underlying condition, thereby achieving a beneficial or desired clinical outcome. For the purposes of this disclosure, beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, reduction of the severity of the disease, stabilization (i.e., non-exacerbation) of the disease, delay or slowing of disease progression, improvement or reduction of the disease state, and remission (partial or complete remission), whether detectable or not. “Therapy” may also mean an extension of survival compared to the survival expected without it. Persons requiring therapy include those who already have symptoms or impairments, those who are prone to symptoms or impairments, or those for whom symptoms or impairments can be prevented. Unless otherwise specified, the term “therapy” also includes prevention. The terms “therapeutic” and “therapeutically” should be interpreted in their corresponding manner.

[0119] As used herein, the term “prevention” is intended to have its ordinary meaning and includes primary prevention, which prevents the onset of a disease, and secondary prevention, which protects the patient temporarily or permanently from exacerbation or worsening of the disease or the onset of new symptoms associated with the disease, once the disease has already occurred.

[0120] The term “treatment” is used as a synonym for “therapy.” Similarly, the term “treat” may be considered as “to apply therapy,” where “therapy” is as defined herein.

[0121] In further embodiments, the Disclosure provides therapeutic uses of the compounds of the Disclosure or pharmaceutically acceptable salts thereof or pharmaceutical compositions of the Disclosure, for example, therapeutic uses associated with KRAS proteins. In some embodiments, the therapy is associated with wild-type KRas, KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, or KRas Q61H proteins. In certain embodiments, the therapy is associated with the KRAS G12D protein.

[0122] In a further embodiment, the Disclosure provides the use of the compounds of the Disclosure, pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the Disclosure in the manufacture of pharmaceuticals for the treatment of cancer.

[0123] In some embodiments, cancer is mediated by KRAS proteins. In some embodiments, cancer is mediated by wild-type KRas, KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, or KRas Q61H proteins. In certain embodiments, cancer is mediated by the KRAS G12D protein. Pharmaceutical composition

[0124] In a further embodiment, a pharmaceutical composition is provided comprising one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof.

[0125] In another embodiment, a pharmaceutical composition is provided comprising one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0126] As used herein, the term “pharmaceutical composition” means a preparation containing a molecule or compound of the present disclosure in a form suitable for administration to a subject.

[0127] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is generally safe, non-toxic, and useful for preparing a pharmaceutical composition that is not biologically or otherwise undesirable, and includes excipients that are acceptable for veterinary and human pharmaceutically use. As used herein, “pharmaceutically acceptable excipient” includes one and more such excipients. The term “pharmaceutically acceptable excipient” also includes “pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent.”

[0128] The specific excipients used depend on the means and purpose to which the compounds of this disclosure are applied. Solvents are generally selected based on those that are considered safe for administration to mammals, including humans, and recognized by those skilled in the art. Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and mixtures thereof.

[0129] In some embodiments, suitable excipients include buffers such as phosphoric acid, citrate and other organic acids, antioxidants including ascorbic acid and methionine, preservatives (e.g., octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkylparabens such as methyl or propylparaben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol), low molecular weight (less than about 10 residues) polypeptides, serum albumin, gelatin, or immunoglobulins. It may contain any protein, hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine, monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrin, chelating agents such as EDTA, sugars such as sucrose, mannitol, trehalose, or sorbitol, salt-forming counterions such as sodium, metal complexes (e.g., Zn-protein complexes), and / or nonionic surfactants such as TWEEN®, PLURONICS®, or polyethylene glycol (PEG).

[0130] In some embodiments, suitable excipients may include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, lubricants, processing aids, colorants, sweeteners, flavoring agents, and other known additives for providing a refined appearance to a drug (i.e., a compound of the Disclosure or a pharmaceutical composition thereof) or for assisting in the manufacture of a pharmaceutical product (i.e., a drug). The active pharmaceutical ingredient may also be encapsulated in microcapsules such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules prepared by coacervation technology or interfacial polymerization, colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). Liposomes are vesicles composed of various types of lipids, phospholipids, and / or surfactants that are useful for delivering drugs (e.g., compounds disclosed herein, and optionally, chemotherapeutic agents) to mammals, including humans. The components of liposomes are generally arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.

[0131] The pharmaceutical compositions provided herein may be in any form that enables administration to subjects not limited to humans and can be formulated to suit the intended route of administration.

[0132] Various routes are intended for the pharmaceutical compositions provided herein, and therefore, the pharmaceutical compositions provided herein may be supplied in bulk or in unit dosage forms depending on the intended route of administration. For example, for oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gel caps, and caplets may be accepted as solid dosage forms, and emulsions, syrups, elixirs, suspensions, and solutions may be accepted as liquid dosage forms. For injectable administration, emulsions and suspensions may be accepted as liquid dosage forms, and powders suitable for reconstitution in appropriate solutions may be accepted as solid dosage forms. For inhalation administration, solutions, sprays, dry powders, and aerosols may be accepted dosage forms. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be accepted dosage forms. For vaginal administration, pessaries, tampons, creams, gels, pastes, foams, and sprays may be acceptable dosage forms.

[0133] The amount of active ingredient in a unit dosage form of a composition is the therapeutic dose and varies depending on the specific treatment being addressed. As used herein, the term “therapeutic dose” refers to the amount of a molecule, compound, or composition containing a molecule or compound that treats, improves, or prevents an identified disease or symptom, or exhibits a detectable therapeutic or inhibitory effect. The effect may be detected by any assay method known in the art. The exact effective dose for a subject depends on the subject's weight, size, and health status, the nature and severity of the symptoms, the rate of administration, the therapeutic agent or combination of therapeutic agents selected for administration, and the discretion of the prescribing physician. The therapeutic dose for a given situation may be determined by routine experimentation, within the scope of the clinician's skill and judgment.

[0134] In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of formulations for oral administration.

[0135] In certain embodiments, the pharmaceutical compositions of this disclosure may be in the form of tablets. Suitable pharmaceutically acceptable excipients for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate, or calcium carbonate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid, or talc; preservatives such as ethyl or propyl p-hydroxybenzoate; and antioxidants such as ascorbic acid. The tablet formulations may or may not be coated, or they may be coated using conventional coating agents and procedures well known in the art to modify their disintegration in the gastrointestinal tract and subsequent absorption of the active ingredient, or to improve their stability and / or appearance.

[0136] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.

[0137] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an aqueous suspension containing the active ingredient, generally in fine powder form, together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum, a dispersing and wetting agent, such as lecithin, or a condensation product of alkylene oxide and fatty acid (e.g., polyoxyethylene stearate), or a condensation product of ethylene oxide and long-chain aliphatic alcohol, such as heptadecaethyleneoxycetanol, or a condensation product of ethylene oxide and partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or a condensation product of ethylene oxide and partial esters derived from fatty acids and hexitol anhydride, such as polyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives (e.g., ethyl or propyl p-hydroxybenzoate, antioxidants (e.g., ascorbic acid)), colorants, flavorings, and / or sweeteners (e.g., sucrose, saccharin, or aspartame).

[0138] In certain embodiments, the pharmaceutical compositions of this disclosure may be in the form of an oily suspension containing an active ingredient suspended in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or mineral oil (e.g., liquid paraffin). The oily suspension may also contain thickeners such as beeswax, solid paraffin, or cetyl alcohol. Sweeteners and flavorings as described above may be added to provide an oral preparation with a good taste. These compositions may be preserved by the addition of antioxidants such as ascorbic acid.

[0139] In certain embodiments, the pharmaceutical compositions of this disclosure may be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be, for example, naturally occurring gums such as gum arabic or gum tragacanth, naturally occurring phosphatides such as soybeans and lecithin, esters or partial esters (e.g., sorbitan monooleate) derived from fatty acids and hexitol anhydrides, and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners, flavorings, and preservatives.

[0140] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweeteners such as glycerol, propylene glycol, sorbitol, aspartame, or sucrose, as well as lubricants, preservatives, flavoring agents, and / or coloring agents.

[0141] In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of formulations for injectable administration.

[0142] In certain embodiments, the pharmaceutical compositions of this disclosure may be in the form of sterile injectable preparations, such as sterile injectable aqueous or oily suspensions. These suspensions may be formulated according to known techniques using the preferred dispersing and wetting agents and suspending agents mentioned above. The sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol, or may be prepared as lyophilized powders. Acceptable vehicles and solvents that may be employed include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils may conventionally be employed as solvents or suspension media. For this purpose, any non-irritating non-volatile oil, including synthetic monoglycerides or diglycerides, may be employed. In addition, fatty acids such as oleic acid may similarly be used in the preparation of injectable preparations.

[0143] In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of formulations for inhalation administration.

[0144] In certain embodiments, the pharmaceutical compositions of this disclosure may be in the form of aqueous and non-aqueous (e.g., in fluorocarbon propellants) aerosols containing any suitable solvent and optionally other compounds, not limited to stabilizers, antimicrobial agents, antioxidants, pH adjusters, surfactants, bioavailability adjusters, and combinations thereof. The carriers and stabilizers vary with the requirements of the specific compounds, but typically include nonionic surfactants (Tween, Pluronics, or polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, amino acids such as oleic acid, lecithin, and glycine, buffers, salts, sugars, or sugar alcohols.

[0145] In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of formulations for topical or transdermal administration.

[0146] In certain embodiments, the pharmaceutical compositions provided herein may generally be in the form of creams, ointments, gels, and aqueous or oily liquids or suspensions, which can be obtained by formulating the active ingredient together with conventional topically acceptable excipients, such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0147] In certain embodiments, the pharmaceutical compositions provided herein may be formulated in the form of transdermal patches, which are well known to those skilled in the art.

[0148] In addition to the representative dosage forms described above, pharmaceutically acceptable excipients and carriers are also included in this disclosure as they are generally known to those skilled in the art. Such excipients and carriers are, for example, incorporated herein by reference in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991) and “Remington: The Science and Practice of Pharmacy”, Ed. University of the Sciences in Philadelphia, 21 st This is described in Edition, LWW (2005).

[0149] In some embodiments, the pharmaceutical compositions of this disclosure may be formulated as single dosage forms. The amount of the compound provided herein in a single dosage form will vary depending on the target being treated and the specific method of administration.

[0150] In some embodiments, the pharmaceutical composition of the present disclosure is administered in doses of 0.001 to 1000 mg / kg body weight / day, for example, 0.01 to 800 mg / kg body weight / day, 0.01 to 700 mg / kg body weight / day, 0.01 to 600 mg / kg body weight / day, 0.01 to 500 mg / kg body weight / day, 0.01 to 400 mg / kg body weight / day, 0.01 to 300 mg / kg body weight / day, 0.1 to 200 mg / kg body weight / day, 0.1 to 150 mg / kg body weight / day, or 0.1 to 100 mg / kg body weight / day. The compounds provided herein, or pharmaceutically acceptable salts thereof, may be formulated to be administered in doses of body weight / day, 0.5–100 mg / kg body weight / day, 0.5–80 mg / kg body weight / day, 0.5–60 mg / kg body weight / day, 0.5–50 mg / kg body weight / day, 1–50 mg / kg body weight / day, 1–45 mg / kg body weight / day, 1–40 mg / kg body weight / day, 1–35 mg / kg body weight / day, 1–30 mg / kg body weight / day, and 1–25 mg / kg body weight / day. In some cases, dose levels below the lower limit of the aforementioned ranges may be more than sufficient, while in other cases, even larger doses may be employed without causing adverse side effects, however, such larger doses may first be divided into several smaller doses for administration throughout the day. For detailed information on the route of administration and drug regimen, please refer to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, which is specifically incorporated herein by reference.

[0151] In some embodiments, the pharmaceutical compositions of this disclosure may be formulated as short-acting, fast-release, long-acting, and sustained-release formulations. Accordingly, the pharmaceutical formulations of this disclosure may also be formulated for controlled-release or sustained-release applications.

[0152] In further embodiments, veterinary compositions are also provided, comprising one or more molecules or compounds of the present disclosure or pharmaceutically acceptable salts thereof and a veterinary carrier. The veterinary carrier is a substance useful for administering the composition and may be a solid, liquid, or gaseous substance that is typically inert or acceptable in the veterinary art and compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally, or by any other desired route.

[0153] Pharmaceutical or veterinary compositions may be packaged in various ways depending on the method used to administer the drug. For example, articles for distribution may include containers in which the composition is placed in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, and metal cylinders. Containers may also include tamper-evident assemblies to prevent unauthorized access to the contents of the packaging. In addition, containers are labeled to indicate the contents of the container. Labels may also include appropriate warnings. Compositions may also be packaged in unit or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried state requiring only the addition of a sterile liquid carrier for injection, such as water, immediately before use. Immediate injection solutions and suspensions are prepared from the types of sterile powders, granules, and tablets described above.

[0154] In a further embodiment, a pharmaceutical composition is also provided comprising one or more compounds of the present disclosure as a first active ingredient, or a pharmaceutically acceptable salt thereof, and a second active ingredient.

[0155] In some embodiments, the second active ingredient has complementary activity to the compounds provided herein so as not to adversely affect each other. Such ingredients are preferably present in combination in amounts effective for the intended purpose. Treatment methods for diseases

[0156] In a further embodiment, the Disclosure provides a method for treating cancer, comprising administering an effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof or pharmaceutical composition to a subject in need.

[0157] In some embodiments, the compounds or pharmaceutically acceptable salts and compositions provided herein may be used to treat cancers related to wild-type KRas or KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, KRas Q61H in the subject of interest, the treatment comprising administering to the subject a therapeutically effective amount of the compounds provided herein, pharmaceutically acceptable salts thereof, or a pharmaceutical composition containing such compounds or pharmaceutically acceptable salts thereof.

[0158] In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts and compositions may be used to treat a wide variety of cancers, including, for example, lung, prostate, breast, brain, skin, cervical, and testicular cancers. More specifically, cancers that may be treated with the compounds provided herein or their pharmaceutically acceptable salts and compositions may include, but are not limited to, tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocyte, laryngeal, lung, oral, ovarian, prostate, and thyroid cancers, as well as sarcomas. More specifically, the compounds provided herein or their pharmaceutically acceptable salts and compositions may be used to treat a wide variety of cancers, including, (i) Heart: Sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma, (ii) Lung: bronchogenic carcinoma (squamous, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, cartilaginous hamartoma, mesothelioma, (iii) Gastrointestinal tract: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma), (iv) Urogenital tract: Kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminal epithelium, teratoma, fetal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma), (v) Liver: Hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, (vi) Biliary tract: gallbladder cancer, ampulla cancer, bile duct cancer; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondrosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor, (vii) Nervous system: Skull (osteoma, hemangioma, granuloma, xanthomas, osteoosteitis), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiforme, oligodendroglioma, Schwann cell tumor, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma), (viii) Gynecology: Uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphylosarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma), (ix) Hematology: Blood (myeloleukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma), (x) Skin: Malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentigo, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, and (xi) Adrenal gland: Neuroblastoma It can be used to treat [condition].

[0159] In certain embodiments, cancers that can be treated with the compounds or pharmaceutically acceptable salts and compositions thereof provided herein are non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

[0160] The concentration and route of administration to the target vary depending on the cancer being treated. In certain embodiments, administration is carried out via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasacral, intrathecal, intramuscular, intravitreous, intravenous, intra-arterial, oral, buccal, sublingual, percutaneous, topical, intratracheal, intrarectal, subcutaneous, and topical administration.

[0161] Compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing such compounds and salts may also be co-administered with other antineoplastic compounds, such as chemotherapy, or used in combination with other treatments, such as radiation or surgical interventions, either as pre- or post-operative adjuvants.

[0162] In some embodiments, compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and salts may be administered separately or sequentially, simultaneously with one or more additional therapeutic agents. In certain embodiments, the additional therapeutic agent is selected from an anti-PD-1 antagonist, a MEK inhibitor, an SHP2 inhibitor, a platinum agent, or pemetrexed. In certain embodiments, the anti-PD-1 antagonist is selected from nivolumab, pembrolizumab, or AMB404. In certain embodiments, the MEK inhibitor is trametinib. In certain embodiments, the SHP2 inhibitor is RMC-4630.

[0163] In another aspect, the present disclosure relates to a method for treating a cancer of a particular interest, (a) To obtain findings that cancer is associated with wild-type KRas or KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, KRas Q61H, (b) administering to a subject an effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition, We also provide methods that include this.

[0164] In another aspect, the Disclosure provides a method for inhibiting wild-type KRas or KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, KRas Q61H activity of a target subject of interest, the method comprising administering the compounds of the Disclosure or pharmaceutically acceptable salts thereof or pharmaceutical compositions to a target subject. Examples

[0165] For illustrative purposes, the following embodiments are included. However, it should be understood that these embodiments are not intended to limit the disclosure, but only to suggest ways of putting the disclosure into practice. Example A: Compound Synthesis Intermediate 1 Tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate (intermediate 1) [ka] Step 1: tert-butyl(1S,2S,5R)-2-((S)-1-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidine-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka]

[0166] In a flask containing tert-butyl(1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.92 g, 3.57 mmol) in THF (20 mL), NaH (42.84 g, 10.71 mmol) was added at 0°C, followed by the addition of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine-4-ol (1.0 g, 3.57 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated NH4Cl solution. The aqueous layer was extracted with EA (3 × 10 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The starting material was purified by prep-TLC with elution in a DCM:MeOH ratio of 10:1 to obtain the title compound (1.6 g, 89.4%) as a white solid. LCMS:MS (ESI) m / z: 500 [M+H] + Step 2: tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate [ka]

[0167] To a solution of tert-butyl(1R,2S,5S)-2-((S)-1-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidine-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.6 g, 3.29 mmol) in ACN (40 mL), PyBOP (3.43 g, 6.59 mmol) and TEA (1.37 mL, 9.88 mmol) were added, and the reaction was stirred at 80 °C for 1 hour. The reaction was diluted with EA and water. The organic layer was separated, washed with saturated NaCl solution, and concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain intermediate 1 (1.2 g, 75.6%). LCMS: (M+H) + =482 Example 1 (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphthalene-1-yl)-1-fluoro-5-methyl-12-((R)-2-methyl-3-((R)-3-methylmorpholino)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene (compound 1) [ka] Step 1 (R)-2-methyl-3-((R)-3-methylmorpholino)propan-1-ol [ka]

[0168] (S)-3-bromo-2-methylpropan-1-ol (300 mg, 1.9 mmol) was dissolved in MeCN (6 mL) and (R)-3-methylmorpholine (195 mg, 1.9 mmol), K2CO3 (813 mg, 5.9 mmol), and KI (390 mg, 2.3 mmol) were added. The reaction mixture was stirred overnight at 70 °C. The mixture was then concentrated under vacuum to obtain the residue, which was diluted with H2O (5 ml) and extracted with  (10 ml × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by flash column chromatography (silica gel, 0-10% MeOH in DCM) to obtain the (registered trademark) title product (118 mg, yield 35%) as a pale yellow oil.

[0169] LC-MS (ESI) (m / z): 174 [M+H] + . Step 2: tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate [ka]

[0170] At 0°C, m-CPBA (71 mg, 4.1 mmol) was added in fractions to a solution of tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (100 mg, 2.1 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with aqueous NaHCO3 (1 mL) and H2O (5 mL), and extracted with DCM (5 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to dryness to obtain the title product (105 mg, yield 98%) as a yellow oil.

[0171] LC-MS (ESI) (m / z): 514 [M+H] + Step 3: tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-((R)-2-methyl-3-((R)-3-methylmorpholino)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate [ka]

[0172] (R)-2-methyl-3-((R)-3-methylmorpholino)propan-1-ol (64 mg, 0.37 mmol) and 4A MS (110 mg) in toluene (3 mL) were mixed with t-BuONa (178 mg, 1.85 mmol) at 0°C. The resulting mixture was stirred at room temperature for 30 min, and then tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate (105 mg, 0.20 mmol) was added. After the addition, the reaction was stirred at room temperature overnight. After solvent removal, the residue was purified by silica gel column chromatography (¼) to obtain the title compound (56 mg, yield 43.1%).

[0173] LC-MS (ESI) m / z: 607 [M+H] + . Step 4 tert-butyl(5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-12-((R)-2-methyl-3-((R)-3-methylmorpholino)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate [ka]

[0174] tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-((R)-2-methyl-3-((R)-3-methylmorpholino)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate (56 mg, 0.09 mmol) in a solution of THF (5 mL) and H2O (1 mL) with ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethinyl)triisopropylsilane (63 mg, 0.14 mmol), X-Phos Pd G2 (7 mg, 0.009 mmol) and K3PO4 (59 mg, 0.28 mmol) were added under N2 conditions, and the reaction was stirred at 60°C for 2 hours. After cooling to room temperature, the reaction was diluted with ice water and extracted twice with ethyl acetate. The combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-10% MeOH in DCM) to obtain the title compound (45 mg, yield 54.2%).

[0175] LC-MS (ESI) m / z: 897[M+H] + . Step 5 (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-5-methyl-12-((R)-2-methyl-3-((R)-3-methylmorpholino)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene [ka]

[0176] At 0°C, TMSOTf (14 mg, 0.06 mmol) was added to a solution of tert-butyl(5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-12-((R)-2-methyl-3-((R)-3-methylmorpholino)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate (45 mg, 0.05 mmol) and HMDS (20 mg, 0.12 mmol) in DCM (5 mL), and the resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with an aqueous Na2CO3 solution at 0°C, and then extracted twice with DCM. The combined organic layer was washed with water and brine, dried, and concentrated to obtain the title product (38 mg, 95% yield).

[0177] LC-MS ESI (m / z): 797 [M+H] + . Step 6 (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphthalene-1-yl)-1-fluoro-5-methyl-12-((R)-2-methyl-3-((R)-3-methylmorpholino)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene [ka]

[0178] (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-12-((R)-2-methyl-3-((R)-3-methylmorpholino)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene (38 mg, 0.05 mmol) was dissolved in DMF (5 mL) and CsF (290 mg, 1.91 mmol) was added. The resulting mixture was stirred at 40°C for 1 hour. The reaction was purified by prep-HPLC (chromatographic column: YMC-Actus Triart C18 150*20 mm, mobile phase A: 0.1% NH3 in water, mobile phase B: MeCN, gradient: from 45% B to 95% B in 18 min, flow rate 25 ml / min, wavelength: 220 nm / 254 nm, target retention time: 10.5 min (90% MECN)) to obtain compound 1 (8.5 mg, yield 30.5%).

[0179] LC-MS (ESI) m / z: 641 [M+H] + .

[0180] 1H NMR (400 MHz, CD3OD) δ 8.08 (t, J=7.5 Hz, 2H), 7.70-7.52 (m, 2H), 7.43 (q, J=8.8 Hz, 1H), 5.43 (d, J=13.2 Hz, 1H), 4.57 (dd, J=15.4, 7.6 Hz, 2H), 4.29 (dd, 1H), 4.12 (d, J=9.1 Hz, 1H), 3.76 (dd, 2H), 3.69-3.55 (m, 3H), 3.46 (d, J=11.0 Hz, 1H), 3.24-3.09 (m, 2H), 3.02-2.82 (m, 2H), 2.49-2.35 (m, 1H), 2.34-2.21 (m, 2H), 2.18-2.02 (m, 2H), 1.94-1.76 (m, 3H), 1.58 (t, J=6.8 Hz, 3H), 1.09 (dd, J=6.7, 2.0 Hz, 3H), 0.97 (d, J=6.0Hz, 3H). Example 26 (8S,8aS,9S,12R)-5-(8-ethynyl-7-fluoronaphthalene-1-yl)-4-fluoro-8-methyl-2-((1-(((S)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaza-9,12-methanonaphtho[1,8-ab]heptalene (compound 26) [ka] Step 1: Methyl(S)-1-(3-methylmorpholine-4-carbonyl)cyclopropane-1-carboxylate [ka]

[0181] DMF (0.15 mL, 0.93 mmol) was added to a mixture of 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid (1 g, 6.9 mmol) in DCM (10 mL). The mixture was cooled to 0°C, and then oxalyl dichloride (0.89 mL, 10.4 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum to obtain the residue. The residue was dissolved in DCM (5 mL) and this solution was added dropwise at 0°C under N2 to a solution of (S)-3-methylmorpholine (0.8 mL, 9.7 mmol) and TEA (2.9 mL, 20.8 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 1 hour. The mixture was then quenched with H2O (5 mL) and extracted with DCM (5 ml × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by flash chromatography (silica gel, 0-30% Â in PE) to obtain the title product (720 mg, 48% yield) as a yellow oil. MS(ESI)(m / z): 228 [M+H]+. Step 2 (S)-(1-((3-methylmorpholino)methyl)cyclopropyl)methanol [ka]

[0182] To a solution of methyl(S)-1-(3-methylmorpholine-4-carbonyl)cyclopropane-1-carboxylate (600 mg, 2.6 mmol) in THF (5 mL), LiAlH4 (5.3 mL, 5.3 mmol, 1 M in THF) was added dropwise under N2 at 0°C. The mixture was stirred at room temperature for 1 hour. The mixture was then quenched with H2O (0.1 ml), NaOH (0.1 ml, 15% wt) aqueous solution, and H2O (0.5 ml). The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to obtain the title product (360 mg, yield 74%) as a yellow oil. LC-MS (ESI) (m / z): 186 [M+H] + . Step 3: tert-butyl(8S,8aS,9S,12R)-5-chloro-4-fluoro-8-methyl-2-((1-(((S)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaza-9,12-methanonaphtho[1,8-ab]heptalen-14-carboxylate [ka]

[0183] 4A MS was added to a toluene (5 ml) solution of tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate (100 mg, 1.9 mmol) and (S)-(1-((3-methylmorpholino)methyl)cyclopropyl)methanol (73 mg, 3.9 mmol) and stirred at room temperature for 30 min. Then, sodium 2-methylpropane-2-oleate (98 mg, 9.5 mmol) was added to the reaction mixture at 0°C and stirred at room temperature for 1 hour. The mixture was diluted with water (10 ml) and extracted with ELISA (10 ml x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-30% Â in PE) to obtain the title product (80 mg, yield 67%) as a yellow oil. MS (ESI) (m / z): 619 [M+H] + .

[0184] 1H NMR (400 MHz, CD3OD) δ 8.14 - 8.02 (m, 2H), 7.68 - 7.53 (m, 2H), 7.49 - 7.36 (m, 1H), 4.94 (s, 2H), 4.66 - 4.52 (m, 1H), 4.51 - 4.40 (m, 1H), 4.14-4.10 (m, 1H), 3.75-3.72 (m, 1H), 3.70 - 3.57 (m, 2H), 3.49 - 3.41 (m, 1H), 3.26-3.23 (m, 1H), 3.21 - 3.06 (m, 4H), 3.03 - 2.90 (m, 2H), 2.83-2.81 (m, 1H), 2.64 - 2.42 (m, 2H), 2.12 - 1.99 (m, 1H), 1.98 - 1.89 (m, 2H), 1.89 - 1.77 (m, 2H), 1.61-1.58 (m, 1H). Step 4 tert-butyl(5S,5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-1-fluoro-5-methyl-12-((1-(((S)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate [ka]

[0185] tert-butyl(8S,8aS,9S,12R)-5-chloro-4-fluoro-8-methyl-2-((1-(((S)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaza-9,12-methanonaphtho[1,8-ab]heptalen-14-carboxylate (60 mg, 1.0 mmol) in a solution of tetrahydrofuran (2 mL) and water (0.4 mL) with X-Phos Pd G2 (19.1 mg, 0.25 mmol), tripotassium phosphate (61.2 mg, 3.0 mmol), and ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (52.6 mg, 1.2 mmol) were added. The mixture was stirred at 60°C for 1 hour. The mixture was then quenched with H2O (2 ml) and extracted with DCM (2 ml x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to obtain the title product (50 mg, yield 56.7%) as a yellow oil. LC-MS (ESI) (m / z): 909 [M+H] + . Step 5 (8S,8aS,9S,12R)-4-fluoro-5-(7-fluoro-8-((triisopropylsilyl)ethinyl)naphthalene-1-yl)-8-methyl-2-((1-(((S)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaza-9,12-methanonaphtho[1,8-ab]heptalene [ka]

[0186] 50 mg, 0.06 mmol of tert-butyl(8S,8aS,9S,12R)-4-fluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-((1-(((S)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaza-9,12-methanonaphtho[1,8-ab]heptalen-14-carboxylate (50 mg, 0.06 mmol) was mixed with DCM (2 mL) and HMDS (0.2 mL) and TMSOTf (0.2 mL) at 0°C. The mixture was stirred at room temperature for 1 hour. The mixture was then quenched with H2O (2 mL) and extracted with DCM (2 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated without further purification to obtain the title product (50 mg, crude) as a yellow solid. MS (ESI) (m / z): 809 [M+H] + . Step 6 (8S,8aS,9S,12R)-5-(8-ethynyl-7-fluoronaphthalene-1-yl)-4-fluoro-8-methyl-2-((1-(((S)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaza-9,12-methanonaphtho[1,8-ab]heptalene [ka]

[0187] (8S,8aS,9S,12R)-4-fluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-((1-(((S)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaza-9,12-methanonaphtho[1,8-ab]heptalene (50 mg, 0.06 mmol) was dissolved in DMF (1 mL) and CsF (188 mg, 1.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was then filtered and purified by pre-HPLC to obtain compound 26 (16.9 mg, yield 41%).

[0188] LC-MS (ESI) (m / z): 653 [M+H] + .

[0189] 1 H NMR (400 MHz, CD3OD) δ 8.12-8.04 (m, 2H), 7.67-7.53 (m, 2H), 7.42 (m, 1H), 5.38 (m, 1H), 4.75 (m, 1H), 4.53 (m, 1H), 4.10-3.99 (m, 2H), 3.77-3.46 (m, 6H), 3.41 (dd, J=12.8, 7.6 Hz, 1H), 3.21-3.12 (m, 2H), 3.07 (dd, J=12.0, 2.7 Hz, 1H), 2.37 (dd, J=8.8, 6.1 Hz, 1H), 2.22 (t, J=10.7 Hz, 1H), 2.16 - 2.07 (m, 1H), 1.84 (m, 3H), 1.65 (d, J=12.8 Hz, 1H), 1.57 (dd, J=8.0, 6.5 Hz, 3H), 0.93 (d, J=6.2 Hz, 3H), 0.77-0.70 (m, 1H), 0.67-0.55 (m, 2H), 0.41 (s, 1H). Examples 27 and 28 (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphthalene-1-yl)-1-fluoro-5-methyl-12-((1-(((R)-3-(methyl-d3)morpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene (compound 27) and (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphthalene-1-yl)-1-fluoro-5-methyl-12-((1-(((S)-3-(methyl-d3)morpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene (compound 28) [ka] Step 1: 2-(2-chloroethoxy)acetaldehyde [ka]

[0190] To a solution of (COCl)2 (18.34 g, 144.509 mmol) in anhydrous CH2Cl2 (150 mL), DMSO (18.82 g, 240.848 mmol) was added under N2 conditions at -78 °C. After stirring for 30 min, a solution of 2-(2-chloroethoxy)ethane-1-ol (15.0 g, 120.4 mmol) in anhydrous CH2Cl2 (150 mL) was added dropwise. The mixture was stirred at -78 °C for 30 to 45 min, and then Et3N (83.7 mL, 602.1 mmol) was added dropwise. After stirring at -78 °C for 30 min, the reaction was warmed to room temperature and stirred for 1 hour. The reaction mixture was acidified to pH=5-6 with 2N HCl aqueous solution, and then extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4 and filtered to obtain the crude product as a colorless solution in DCM (200 mL). This product was used directly in the next step without further purification. Step 2 (R)-N-(2-(2-chloroethoxy)ethylidene)-2-methylpropane-2-sulfinamide [ka]

[0191] Anhydrous copper sulfate (38.58 g, 241.730 mmol) was suspended in a solution of (R)-2-methylpropane-2-sulfinamide (10.37 g, 85.581 mmol) and 2-(2-chloroethoxy)acetaldehyde (9.2 g, 75.071 mmol) in dichloromethane (100 mL). The mixture was stirred at room temperature for 16 hours and filtered through a Celite pad. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title product (4.85 g, 28.6%) as a colorless oil.

[0192] LC / MS (ESI) (m / z): 226 [M+H] + . Step 3 (R)-N-(1-(2-chloroethoxy)propan-2-yl-3,3,3-d3)-2-methylpropane-2-sulfinamide [ka]

[0193] Methylmagnesium deuterized iodide (66.5 mL, 66.45 mmol, 1 M in Et2O) was added under N2 conditions to a stirred solution of (R)-N-(2-(2-chloroethoxy)ethylidene)-2-methylpropane-2-sulfinamide (10 g, 44.3 mmol) in anhydrous toluene (150 mL) at -78°C. The reaction mixture was stirred at -78°C for 1-2 hours. TLC and LCMS indicated the completion of the reaction, and the reaction was quenched with saturated NH4Cl (aqueous solution) at -78°C. The mixture was then extracted twice with RINKAN (100 mL). The combined organic phase was washed with saturated NaCl (aqueous solution), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by flash chromatography (silica, hexane / RINKAN, gradient: 0%-75% RINKAN) to obtain the title product (8.0 g, 73.8%) as a yellow oil.

[0194] LC / MS (ESI) (m / z): 245 [M+H] + . Step 4: 4-((R)-tert-butylsulfinyl)-3-(methyl-d3)morpholine [ka]

[0195] 60% w / w NaH in mineral oil (1.44 g, 35.9 mmol, 60% of the oil) was added to a solution of (R)-N-(1-(2-chloroethoxy)propan-2-yl-3,3,3-d3)-2-methylpropane-2-sulfinamide (2.93 g, 12.0 mmol) and 18-crown-6 (1.58 g, 5.99 mmol) in anhydrous THF (50 mL) under N2 conditions at 0°C. The mixture was stirred at room temperature for 2 hours. TLC and LCMS indicated completion of the reaction, and the mixture was quenched with ice water and extracted with Et2O. The combined organic layer was dried over (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title product (1.8 g, 72.3%) as a white solid.

[0196] LC / MS (ESI) (m / z): 209 [M+H]+ . Step 5: 3-(methyl-d3)morpholine [ka]

[0197] To a solution of 4-((R)-tert-butylsulfinyl)-3-(methyl-d3)morpholine (200 mg, 0.96 mmol) in DCM (1 mL), HCl / dioxane (5 mL, 4 mol / L) was added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to obtain the title product (100 mg) as a yellow solid, which was used directly in the next step.

[0198] LC / MS (ESI) (m / z): 105 [M+H] + . Step 6: Methyl 1-(3-(methyl-d3)morpholine-4-carbonyl)cyclopropane-1-carboxylate [ka]

[0199] Cyclopropane-1,1-dicarboxylate methyl ester (200 mg, 1.4 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0°C. N,N-dimethylformamide (1 drop) and oxalyl dichloride (0.22 g, 1.8 mmol) were added. The reaction was stirred at room temperature for 1 hour, and the reaction solution was concentrated to dryness. The residue was diluted with dichloromethane (10 mL), and the resulting solution was added dropwise to a solution of 3-(methyl-d3)morpholine (100 mg, 1 mmol) and Et3N (200 mg, 2 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours and concentrated to obtain the residue. The residue was purified by silica gel column chromatography to obtain the title product (150 mg, 67.9%).

[0200] LC / MS (ESI) (m / z): 231[M+H] + . Step 7 (1-((3-(methyl-d3)morpholino)methyl)cyclopropyl)methanol [ka]

[0201] A 20 mL LTF solution of methyl 1-(3-(methyl-d3)morpholine-4-carbonyl)cyclopropane-1-carboxylate (150 mg, 9.8 mmol) was cooled to 0°C. A 20 mL, 1 M lithium aluminum hydride THF solution was slowly added under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 3 hours. 500 mg of sodium sulfate decahydrate was added to the reaction mixture in portions at 0°C to obtain a white suspension. 25 mL of ethyl acetate was added, and the suspension was stirred at room temperature for approximately 18 hours. The resulting suspension was filtered and washed with diethyl ether. The combined filtrate was concentrated to obtain the crude product (120 mg), which was used directly in the next step without further purification.

[0202] LC / MS (ESI) (m / z): 189[M+H] + . Step 8: tert-butyl(8S,8aS,9S,12R)-5-chloro-4-fluoro-8-methyl-2-((1-((3-(methyl-d3)morpholino)methyl)cyclopropyl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaza-9,12-methanonaphtho[1,8-ab]heptalen-14-carboxylate [ka]

[0203] Sodium tert-butoxide (375 mg, 3.9 mmol) and 4A molecular sieve (100 mg) were added to a toluene (5 mL) solution of (1-((3-(methyl-d3)morpholino)methyl)methanol (165 mg, 0.58 mmol). The mixture was stirred at room temperature for 20 mins, and then a toluene (5 mL) solution of tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (200 mg, 0.39 mmol) was added dropwise, and the mixture was stirred at room temperature under N2 for 2 hours. The mixture was filtered, and the filtrate was concentrated. The residue was placed on a silica gel plate. The plate was eluted with EA:PE=1:1 to obtain the title product (120 mg, 50% yield) as a white solid.

[0204] MS (ESI) m / z: 622[M+H] + . Step 9 tert-butyl(5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-12-((1-((3-(methyl-d3)morpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate [ka]

[0205] tert-butyl(8S,8aS,9S,12R)-5-chloro-4-fluoro-8-methyl-2-((1-((3-(methyl-d3)morpholino)methyl)cyclopropyl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaza-9,12-methanonaphtho[1,8-ab]heptalen-14-carboxyle To a solution of (120 mg, 0.19 mmol) and ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (175 mg, 0.38 mmol) in THF (2 mL) and water (0.4 mL), K3PO4 (121 mg, 0.57 mmol) was added, followed by the addition of cataCXium(R) A Pd G3 (29 mg, 0.04 mmol). The mixture was refluxed at 80°C under an N2 atmosphere for 1.5 hours. The reaction mixture was concentrated under vacuum. The crude product was chromatographically analyzed on silica gel (DCM / MeOH 10 / 1) to obtain the title product (100 mg, yield 56.8%) as a white solid.

[0206] MS (ESI) m / z: 912 [M+H] + . Step 10 (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-5-methyl-12-((1-((3-(methyl-d3)morpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene [ka]

[0207] To a solution of tert-butyl(5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-12-((1-((3-(methyl-d3)morpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate (100 mg, 0.11 mmol) in DCM (3 mL), HMDS (0.2 mL) and TMSOTf (0.1 mL) were added at 0°C, and the reaction was stirred at room temperature for 1 hour. Saturated NaHCO3 was added to the reaction, extracted with DCM, dried, and concentrated under vacuum to obtain the title product (80 mg, 90% yield) without further purification.

[0208] LC / MS ESI (m / z): 812 [M+H] + Step 11 (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphthalene-1-yl)-1-fluoro-5-methyl-12-((1-((3-(methyl-d3)morpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene [ka]

[0209] (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-12-((1-((3-(methyl-d3)morpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene (80 mg, 0.1 mmol) was added to a flask, followed by the addition of N,N-dimethylmethaneamide (3 mL), and then CsF (608 mg, 4 mmol). The mixture was stirred at 40°C under N2 for 2 hours. The mixture was filtered, and the filtrate was purified by prep-HPLC (chromatographic column: YMC-Actus Triart, 50*250 mm, 7 μm, mobile phase A: 0.1% NH3 in water, mobile phase B: CH3CN, gradient: from 35% B to 95% B in 30 min, flow rate 25 mL / min, UV wavelength: 220 / 254 nm) to obtain a crude product (60 mg, yield 95%) as a white solid.

[0210] LC / MS (ESI) m / z: 656 [M+H] + .

[0211] The crude product (60 mg) was further purified by chiral preparation (preparative separation method: apparatus: Shimadzu LC-20AT, column: CHIRALCEL OD-H (ODH0CE-KJ063), 0.46 cm ID × 25 cm L, mobile phase A: MeCN, mobile phase B: MEOH + 0.1% MEA), flow rate: 1.0 mL / min, gradient: isocratic 30% B, column temperature (°C): 35, wavelength: 214 nm) to obtain compound 28 (19 mg, retention time: 5.01 min) and compound 27 (22 mg, retention time: 5.93 min), respectively. Compound 27:

[0212] 11H NMR (400 MHz, CD3OD) δ 8.16 - 8.01 (m, 2H), 7.68 - 7.53 (m, 2H), 7.45 (m, 1H), 5.50 (d, J=12.3 Hz, 1H), 4.73 - 4.53 (m, 3H), 4.21 (t, J=16.5 Hz, 2H), 3.99 (d, J=43.1 Hz, 2H), 3.82 (s, 1H), 3.78 - 3.43 (m, 4H), 3.17 - 2.99 (m, 2H), 2.27 - 2.18 (m, 1H), 2.14 - 1.89 (m, 4H), 1.60 (t, J=6.8 Hz, 3H), 1.30 (t, J=7.3 Hz, 3H), 0.77 (d, J=42.3 Hz, 3H), 0.53 (s, 1H).

[0213] LC / MS (ESI) m / z: 656 [M+H] + . Compound 28:

[0214] 1 1H NMR (400 MHz, CD3OD) δ 8.13 - 8.06 (m, 2H), 7.66 - 7.64 (m, 1H), 7.59 (m, 7.3 Hz, 1H), 7.44 (m, 1H), 5.48 (d, J=13.6 Hz, 1H), 4.74 - 4.55 (m, 3H), 4.23 (d, J=8.5 Hz, 1H), 4.21 - 4.10 (m, 1H), 4.04 (s, 1H), 3.93 (s, 1H), 3.76 (m, 4H), 3.46 (d, J=11.7 Hz, 1H), 3.04 (m, 2H), 2.25 (s, 1H), 2.12 - 1.84 (m, 4H), 1.63 - 1.57 (m, 3H), 1.30 (t, J=7.3 Hz, 3H), 0.78 (d, J=45.9 Hz, 3H), 0.53 (s, 1H).

[0215] LC / MS (ESI) m / z: 656 [M+H] + . Example 30 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-5-methyl-12-((1-(((S)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-Hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol (Compound 30) [ka] Step 1: tert-butyl(5S,5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-1-fluoro-5-methyl-12-((1-(((S)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate [ka]

[0216] X-PhosPd is added to a solution of tert-butyl(8S,8aS,9S,12R)-5-chloro-4-fluoro-8-methyl-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaza-9,12-methanonaphtho[1,8-ab]heptalen-14-carboxylate (65 mg, 1.05 mmol) in tetrahydrofuran (2 mL) and water (0.4 mL). G2 (20.1 mg, 0.25 mmol), tripotassium phosphate (66.8 mg, 3.15 mmol), and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (45.4 mg, 1.26 mmol) were added. The mixture was stirred at 60°C for 1 hour. The mixture was then quenched with H2O (5 ml) and extracted with DCM (5 ml x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to obtain tert-butyl(5S,5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-1-fluoro-5-methyl-12-((1-(((S)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate (50 mg, yield 58.3%) as a yellow oil. MS(ESI) (m / z): 817[M+H] + . Step 2 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-5-methyl-12-((1-(((S)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-Hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol [ka]

[0217] To a solution of tert-butyl(5S,5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5-methyl-12-((1-(((S)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate (50 mg, 0.06 mmol) in 2 mL of dry DCM, TFA (1 mL) was added and the mixture was stirred at room temperature for 1 hour. The mixture was then quenched with H2O (2 mL) and extracted with DCM (2 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and purified by pre-HPLC to obtain compound 30 (3.5 mg, yield 8.5%).

[0218] LC / MS (ESI) m / z: 673 [M+H] + .

[0219] 1H NMR (400 MHz, CD3OD) δ 7.69 - 7.62 (m, 1H), 7.28 (t, J=2.7 Hz, 1H), 7.23 (dd, J=13.2, 5.3 Hz, 1H), 7.03 (dd, J=52.9, 2.6 Hz, 1H), 4.71 - 4.63 (m, 2H), 4.21 (dd, J=19.9, 9.7 Hz, 2H), 4.00 (s, 1H), 3.87 (dd, J=10.8, 5.9 Hz, 2H), 3.82 - 3.77 (m, 1H), 3.70 (dd, J=20.8, 11.1Hz, 3H), 3.23 - 3.18 (m, 2H), 2.45 (s, 2H), 2.24 - 2.15 (m, 2H), 1.98 (dd, J=26.7, 7.2 Hz, 3H), 1.58 (d, J=6.3 Hz, 3H), 1.31 (d, J=17.9 Hz, 4H), 1.03 (d, J=5.5 Hz, 3H), 0.98 - 0.88 (m, 2H), 0.80 (d, J=7.3 Hz, 2H), 0.70 (s, 2H). Example 38 (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphthalene-1-yl)-1-fluoro-5-methyl-12-((1-(((S)-2-methylpiperidine-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene (compound 38) [ka] Step 1: Methyl(S)-1-(2-methylpiperidine-1-carbonyl)cyclopropane-1-carboxylate [ka]

[0220] 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid (280 mg, 1.9 mmol) was dissolved in DCM (5 mL) and oxalyl dichloride (493 mg, 3.9 mmol) and a catalytic amount of DMF were added at 0°C. The mixture was stirred at 25°C for 1 hour. The reaction was concentrated. The residue was dissolved in DCM (5 mL) and the solution was added dropwise at 0°C to a solution of (S)-2-methylpiperidine (289 mg, 2.9 mmol) and Et3N (589 mg, 5.8 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (10 mL) and extracted with DCM (5 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / Â(9:1~4:1) to obtain the title product (350 mg, yield 80%) as a yellow oil.

[0221] LCMS (ESI) (m / z): 226 [M+H] + . Step 2 (S)-(1-((2-methylpiperidine-1-yl)methyl)cyclopropyl)methanol [ka]

[0222] To a solution of methyl(S)-1-(2-methylpiperidine-1-carbonyl)cyclopropane-1-carboxylate (350 mg, 1.55 mmol) in THF (10 mL), LiAlH4 (118 mg, 3.1 mmol) was added under N2 conditions at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched at 0°C with an aqueous solution of NaOH (15% wt) (0.6 mL). After stirring at 0°C for 15 minutes, the mixture was filtered through a Celite pad, and the filtrate was concentrated to obtain the title product (250 mg, yield 87%) as a yellow oil.

[0223] LCMS (ESI) (m / z): 184 [M+H] + . Step 3 tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-((1-(((S)-2-methylpiperidine-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate. [ka]

[0224] To a solution of (S)-(1-((2-methylpiperidine-1-yl)methyl)cyclopropyl)methanol (78 mg, 0.4 mmol) in toluene (5 mL), sodium tert-butoxide (617 mg, 6.4 mmol) and 4A molecular sieve (600 mg) were added, and the reaction was stirred at room temperature for 10 minutes. Then, a solution of tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate (110 mg, 0.2 mmol) in toluene (0.5 mL) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction was immediately filtered, and the filtrate was concentrated. The residue was purified by prep-HPLC (DCM / MeOH = 15:1) to obtain the title product (70 mg, yield 53%) as a yellow oil.

[0225] LCMS (ESI) (m / z): 617 [M+H] + . Step 4 tert-butyl(5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-5-methyl-12-((1-(((S)-2-methylpiperidine-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate [ka]

[0226] tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-((1-(((S)-2-methylpiperidine-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate (70 mg, 0.14 mmol) in THF / water (5 mL / 1 mL) solution with ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethinyl)triisopropylsilane (92 mg, 0.21 mmol), X-Phos Pd G2 (24 mg, 0.03 mmol) and K3PO4 (86 mg, 0.41 mmol) were added. The mixture was stirred at 60°C under N2 for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-TLC (DCM / MeOH = 15:1) to obtain the title product (60 mg, yield 49%) as a yellow solid.

[0227] LCMS (ESI) (m / z): 907 [M+H] + . Step 5 (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-5-methyl-12-((1-(((S)-2-methylpiperidine-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene [ka]

[0228] To a solution of tert-butyl(5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-12-((1-(((S)-2-methylpiperidine-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate (60 mg, 0.07 mmol) in DCM (2 mL), HMDS (0.2 mL) and TMSOTF (0.1 mL) were added under N2 conditions at 0°C, and the mixture was stirred at 0°C for 30 min. The mixture was injected into saturated NaHCO3 (10 mL) and extracted with DCM (5 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain the title product (50 mg, yield 94%) as a yellow solid.

[0229] LCMS (ESI) (m / z): 807 [M+H] + Step 6 (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphthalene-1-yl)-1-fluoro-5-methyl-12-((1-(((S)-2-methylpiperidine-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene [ka]

[0230] (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-12-((1-(((S)-2-methylpiperidine-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene (40 mg, 0.05 mmol) was dissolved in DMF (1.5 mL) and cesium fluoride (301 mg, 1.98 mmol) was added, and the mixture was stirred at room temperature for 30 min. The mixture was purified by prep-HPLC (chromatographic column: YMC-Actus Triart C18 150*20 mm, mobile phase A: 0.1% NH3 in water, mobile phase B: MeCN, gradient: from 20% B to 95% B in 18 min, flow rate 25 ml / min, wavelength: 220 nm / 254 nm, target retention time: 9 min (75% MECN)) to obtain compound 38 (5.5 mg, yield 17%).

[0231] LC / MS (ESI) (m / z): 651 [M+H] + .

[0232] 1 H NMR (400 MHz, CD3OD) δ 8.08 (m, 2H), 7.69 - 7.53 (m, 2H), 7.42 (m, 1H), 5.43 - 5.34 (m, 1H), 4.71 - 4.63 (m, 2H), 4.53 (m, 2H), 4.16 - 4.05 (m, 2H), 3.77 - 3.46 (m, 3H), 3.22 - 3.08 (m, 2H), 2.31 (s, 1H), 2.15 (m, 7.3 Hz, 2H), 1.91 - 1.74 (m, 4H), 1.57 (m, 8H), 1.05 (d, J=6.0 Hz, 3H), 0.67 (m, 2H), 0.51 (d, J=56.0 Hz, 2H). Example 86 (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphthalene-1-yl)-1-fluoro-12-((1-(((R)-3-fluoropyrrolidine-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene (compound 86) [ka] Step 1 (S)-2-methyl-3-morpholinopropan-1-ol [ka]

[0233] (R)-3-bromo-2-methylpropan-1-ol (1 g, 6.5 mmol) was mixed with MeCN (10 mL) and K2CO3 (2.72 g, 19.7 mmol), KI (1.3 g, 7.9 mmol), and morpholine (0.68 g, 7.9 mmol). The reaction mixture was stirred overnight at 80°C. The mixture was then filtered. The filtrate was concentrated and purified by flash chromatography (silica gel, siRNA:PE = 1:1) to obtain the title product (840 mg, yield 80%) as a colorless oil. LC-MS (ESI) (m / z): 160 [M+H] + . Step 2: tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-((S)-2-methyl-3-morpholinopropoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate [ka]

[0234] A 4A molecular sieve and sodium (S)-(1-((3-methylmorpholino)methyl)cyclopropyl)methanol (121 mg, 4 mmol) were added to a three-necked flask. The mixture was heated to maintain dryness, and (S)-2-methyl-3-morpholinopropan-1-ol (80 mg, 10 mmol) in dry toluene (5 mL) was added at 0°C. After stirring at 0°C for 20 minutes, tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate (100 mg, 2.0 mmol) in dry toluene (5 mL) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes. LC-MS indicated completion of the reaction. The mixture was quenched with H2O (5 mL) and extracted with DCM (5 mL x 3). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting starting material was purified by flash chromatography (silica gel, DCM:MeOH = 20:1) to obtain the desired product (70 mg, yield 60.8%) as a yellow oil.

[0235] LC-MS (ESI) (m / z): 593 [M+H] + . Step 3: tert-butyl(5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-12-((S)-2-methyl-3-morpholinopropoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate [ka]

[0236] X-PhosPd is added to a solution of tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-((S)-2-methyl-3-morpholinopropoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate (70 mg, 1.2 mmol) in tetrahydrofuran (4 mL) and water (0.8 mL). G2 (16.7 mg, 0.3 mmol), tripotassium phosphate (53.6 mg, 3.6 mmol), and ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (46 mg, 2.4 mmol) were added. The mixture was stirred at 60°C for 1 hour. The mixture was then quenched with H2O (4 mL) and extracted with DCM (4 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by flash chromatography (silica gel, DCM:MeOH = 20:1) to obtain the title product (60 mg, yield 57.6%) as a yellow oil.

[0237] LC-MS (ESI) (m / z): 883 [M+H] + . Step 4 (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-5-methyl-12-((S)-2-methyl-3-morpholinopropoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene [ka]

[0238] To a solution of tert-butyl(5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-12-((S)-2-methyl-3-morpholinopropoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate (60 mg, 0.068 mmol) in DCM (2 mL), HMDS (0.2 mL) and TMSOTf (0.1 mL) were added at 0°C. The mixture was stirred at room temperature for 1 hour. Then, the mixture was quenched with H2O (2 ml) and extracted with DCM (2 ml x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated without further purification to obtain the title product (60 mg, crude) as a yellow solid.

[0239] LC-MS (ESI) (m / z): 783 [M+H] + . Step 5 (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphthalene-1-yl)-1-fluoro-5-methyl-12-((S)-2-methyl-3-morpholinopropoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene [ka]

[0240] (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-12-((S)-2-methyl-3-morpholinopropoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene (60 mg, 0.076 mmol) was dissolved in DMF (1 mL) and CsF (282 mg, 27.6 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was then filtered and purified by pre-HPLC to obtain compound 86 (21.4 mg, yield 44.6%).

[0241] LC-MS (ESI) (m / z): 627 [M+H] + .

[0242] 1 H NMR (400 MHz, CD3OD) δ 8.08 (q, J=6.5 Hz, 2H), 7.66 - 7.53 (m, 2H), 7.43 (q, J=8.9 Hz, 1H), 5.39 (d, J=13.5 Hz, 1H), 4.55 (dd, J=12.6, 8.0 Hz, 2H), 4.29 (dd, J=18.9, 8.3 Hz, 1H), 4.09 (d, J=9.1 Hz, 1H), 3.64 (d, J=26.3 Hz, 6H), 3.48 (s, 1H), 3.17 (d, J=11.2 Hz, 1H), 2.47 (d, J=16.1 Hz, 5H), 2.27 (d, J=8.0 Hz, 2H), 2.08 (s, 1H), 1.82 (d, J=20.5 Hz, 3H), 1.58 (t, J=7.1 Hz, 3H), 1.09 (dd, J=6.1, 3.4 Hz, 3H). Example 87 (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphthalene-1-yl)-1-fluoro-5-methyl-12-((R)-2-methyl-3-(piperidine-1-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene (compound 87) [ka] Step 1 (R)-2-methyl-3-(piperidine-1-yl)propan-1-ol [ka]

[0243] (S)-3-bromo-2-methylpropan-1-ol (300 mg, 1.9 mmol) was mixed with MeCN (6 mL) and piperidine (217 mg, 2.6 mmol), K2CO3 (813 mg, 5.9 mmol), and NaI (353 mg, 2.4 mmol). The reaction mixture was stirred overnight at 70°C. The mixture was then concentrated under vacuum to obtain the residue, which was diluted with H2O (5 mL) and extracted with  (10 mL × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by flash column chromatography (silica gel, 0-10% MeOH in DCM) to obtain the title product (243 mg, yield 79%) as a pale yellow oil.

[0244] LC-MS (ESI) (m / z): 158 [M+H] + . Step 2: tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-((R)-2-methyl-3-(piperidine-1-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate [ka]

[0245] (R)-2-methyl-3-(piperidine-1-yl)propan-1-ol (46 mg, 0.3 mmol) and 4A MS (80 mg) in toluene (3 mL) were mixed with t-BuONa (141 mg, 1.47 mmol) at 0°C. The resulting mixture was stirred at room temperature for 30 min, and then tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate (100 mg, 0.19 mmol) was added. The reaction was stirred overnight at room temperature. After solvent removal, the residue was purified by silica gel column chromatography (¼) to obtain the title compound (52 mg, yield 30.1%).

[0246] LC-MS (ESI) m / z: 591 [M+H] + . Step 3: tert-butyl(5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-5-methyl-12-((R)-2-methyl-3-(piperidine-1-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate [ka]

[0247] tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-((R)-2-methyl-3-(piperidine-1-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate (52 mg, 0.09 mmol) in a solution of THF (5 mL) and H2O (1 mL) with ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethinyl)triisopropylsilane (42 mg, 0.09 mmol), X-Phos Pd G2 (7 mg, 0.009 mmol) and K3PO4 (54 mg, 0.25 mmol) were added under N2 conditions, and the reaction was stirred at 60°C for 2 hours. The reaction was diluted with ice water and then extracted twice with ethyl acetate. The combined organic layer was washed with water and brine, dried, and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain the title compound (40 mg, yield 66.7%).

[0248] LC-MS (ESI) m / z: 881 [M+H] + . Step 4 (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-5-methyl-12-((R)-2-methyl-3-(piperidine-1-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene [ka]

[0249] To a solution of tert-butyl(5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-12-((R)-2-methyl-3-(piperidine-1-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylate (40 mg, 0.04 mmol) and HMDS (20 mg, 0.12 mmol) in DCM (5 mL), TMSOTf (14 mg, 0.06 mmol) was added at 0°C, and the resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with an aqueous Na2CO3 solution at 0°C, and then extracted twice with DCM. The combined organic layer was washed with water and brine, dried, and concentrated to obtain the title product (35 mg, 98% yield).

[0250] LC-MS ESI (m / z): 781 [M+H] + . Step 5 (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphthalene-1-yl)-1-fluoro-5-methyl-12-((R)-2-methyl-3-(piperidine-1-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene [ka]

[0251] (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-12-((R)-2-methyl-3-(piperidine-1-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanonaphtho[1,8-ab]heptalene (35 mg, 0.04 mmol) was dissolved in DMF (5 mL) and CsF (234 mg, 1.54 mmol) was added. The mixture was stirred at 40°C for 1 hour. The reaction was purified by prep-HPLC (chromatographic column: YMC-Actus Triart C18 150*20 mm, mobile phase A: 0.1% NH3 in water, mobile phase B: MeCN, gradient: from 35% B to 95% B in 18 min, flow rate 25 ml / min, wavelength: 220 nm / 254 nm, target retention time: 13 min (85% MECN)) to obtain compound 87 (6.2 mg, yield 31%).

[0252] LC-MS (ESI) m / z: 625 [M+H] + .

[0253] 1 H NMR (400 MHz, CD3OD) δ 8.14 - 8.03 (m, 2H), 7.74 - 7.51 (m, 2H), 7.43 (q, J=9.0 Hz, 1H), 5.44 - 5.35 (m, 1H), 4.57 - 4.45 (m, 2H), 4.26 (s, 1H), 4.08 (d, J=8.6 Hz, 1H), 3.78 - 3.47 (m, 3H), 3.21 - 3.13 (m, 1H), 2.43 (d, J=83.2 Hz, 7H), 2.07 (s, 1H), 1.90 - 1.75 (m, 3H), 1.67 - 1.55 (m, 7H), 1.48 (s, 2H), 1.14 - 1.07 (m, 3H).

[0254] The following compounds were prepared using different starting materials according to the method described above. [Table 2-1] Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 Table 2-24 Table 2-25 Table 2-26 Table 2-27 Table 2-28 Table 2-29 Table 2-30 Table 2-31 Table 2-32 Table 2-33 Table 2-34 Table 2-35 Table 2-36 Table 2-37 Table 2-38 Table 2-39 Table 2-40 Table 2-41 Table 2-42 Table 2-43 Table 2-44 Table 2-45 Table 2-46 Table 2-47 Table 2-48 Table 2-49 Table 2-50 Table 2-51 Table 2-52 Table 2-53 Table 2-54 Example 2

[0255] 1 H NMR (400 MHz, CD3OD) δ 8.08 (q, J=6.2 Hz, 2H), 7.69-7.53 (m, 2H), 7.43 (q, J=9.0 Hz, 1H), 5.40 (d, J=13.4 Hz, 1H), 4.58-4.53 (m, 1H), 4.46-4.38 (m, 1H), 4.35-4.26 (m, 1H), 4.14-4.08 (m, 1H), 3.78-3.47 (m, 1H), 3.77-3.70 (m, 2H), 3.70-3.59 (m, 3H), 3.26-3.13 (m, 2H), 2.87-2.78 (m, 1H), 2.73-2.63 (m, 1H), 2.48-2.37 (m, 1H), 2.34-2.15 (m, 3H), 2.13-2.04 (m, 1H), 1.93-1.76 (m, 3H), 1.58 (t, J=6.9 Hz, 3H), 1.10 (dd, J=6.6, 1.9 Hz, 3H), 1.00 (d, J=6.3 Hz, 3H). Example 13

[0256] 1H NMR: (400 MHz, CD3OD) δ 8.15-8.03 (m, 2H), 7.69-7.52 (m, 2H), 7.49-7.36 (m, 1H), 5.45-5.34 (m, 1H), 4.60-4.47 (m, 2H), 4.40-4.25 (m, 1H), 4.09 (d, J=8.6 Hz, 1H), 3.82-3.40 (m, 7H), 3.26-3.00 (m, 3H), 2.49-2.29 (m, 2H), 2.24-2.03 (m, 2H), 2.01-1.93 (m, 2H), 1.91-1.72 (m, 5H), 1.58 (t, J=6.9 Hz, 3H), 1.10 (dd, J=6.7, 2.4 Hz, 3H). Example 25

[0257] 1 H NMR: (400 MHz, CD3OD) δ 8.07 (dd, J=9.0, 6.4 Hz, 2H), 7.65-7.53 (m, 2H), 7.42 (q, J=9.1 Hz, 1H), 5.39 (dd, J=13.3, 2.8 Hz, 1H), 4.73-4.68 (m, 1H), 4.56-4.50 (m, 1H), 4.10 (s, 1H), 4.07 (s, 1H), 3.78-3.73 (m, 1H), 3.70 (s, 1H), 3.63 (d, J=10.6 Hz, 1H), 3.59 (s, 2H), 3.46 (d, J=16.2 Hz, 1H), 3.38 (d, J=12.9 Hz, 1H), 3.21-3.13 (m, 2H), 3.07 (d, J=11.5 Hz, 1H), 2.37 (s, 1H), 2.22 (s, 1H), 2.07 (s, 1H), 1.88-1.75 (m, 3H), 1.68 (d, J=14.2 Hz, 1H), 1.60-1.55 (m, 3H), 0.94 (dd, J=6.2, 2.1 Hz, 3H), 0.73 (d, J=9.7 Hz, 1H), 0.66-0.55 (m, 2H), 0.41 (s, 1H). Example 29

[0258] 1 H NMR: (400 MHz, CD3OD) δ 7.64 (dd, J=9.2, 5.6 Hz, 1H), 7.27 (t, J=2.6 Hz, 1H), 7.25-7.18 (m, 1H), 7.03 (dd, J=53.2, 2.5 Hz, 1H), 5.44-5.34 (m, 1H), 4.77-4.70 (m, 1H), 4.58-4.52 (m, 1H), 4.14-4.04 (m, 2H), 3.73 (d, J=16.8 Hz, 2H), 3.61 (t, J=12.9 Hz, 3H), 3.38 (d, J=12.6 Hz, 1H), 3.24-3.14 (m, 2H), 3.08 (d, J=11.8 Hz, 1H), 2.53-2.35 (m, 2H), 2.32-2.00 (m, 3H), 1.90-1.75 (m, 3H), 1.68 (d, J=12.9 Hz, 1H), 1.56 (d, J=6.3 Hz, 3H), 0.93 (dd, J=14.8, 6.7 Hz, 4H), 0.77 (dd, J=15.0, 7.6 Hz, 3H), 0.67-0.55 (m, 2H), 0.45-0.38 (m, 1H). Example 33

[0259] 1H NMR: (400 MHz, MeOD) δ 8.24-7.90 (m, 2H), 7.78-7.51 (m, 2H), 7.48-7.36 (m, 1H), 5.36 (d, 1H), 4.59-4.43 (m, 2H), 4.46-4.28 (m, 3H), 4.08 (d, J=8.8 Hz, 1H), 3.96 (d, J=7.7 Hz, 1H), 3.78-3.48 (m, 5H), 3.22-3.13 (m, 1H), 2.94 (d, J=10.1 Hz, 1H), 2.84-2.72 (m, 1H), 2.65 (d, J=12.9 Hz, 2H), 2.26-1.93 (m, 2H), 1.82-1.65 (m, 3H), 1.60-1.52 (m, 3H), 0.68 (d, 2H), 0.54 (d, J=22.5 Hz, 2H). Example 37

[0260] 1 H NMR: (400 MHz, CD3OD) δ 8.21-7.99 (m, 2H), 7.74-7.50 (m, 2H), 7.42 (m, 1H), 5.51-5.26 (m, 1H), 4.82-4.38 (m, 4H), 4.31-4.01 (m, 2H), 3.81-3.40 (m, 3H), 3.22-3.05 (m, 2H), 2.26-1.94 (m, 2H), 1.89-1.59 (m, 7H), 1.57 (t, J=6.8 Hz, 3H), 1.45-1.25 (m, 3H), 1.21-0.99 (m, 3H), 0.84-0.40 (m, 4H). Example 85

[0261] 1H NMR: (400 MHz, CD3OD) δ 8.17-7.99 (m, 2H), 7.70-7.50 (m, 2H), 7.43 (q, J=9.0 Hz, 1H), 5.44-5.30 (m, 1H), 4.62-4.45 (m, 3H), 4.25 (m, 1H), 4.08 (d, J=8.7 Hz, 1H), 3.82-3.43 (m, 7H), 3.22-3.10 (m, 1H), 2.60-2.36 (m, 5H), 2.33-2.22 (m, 2H), 2.11-2.00 (m, 1H), 1.93-1.73 (m, 3H), 1.63-1.52 (m, 3H), 1.09 (dd, J=6.3, 2.8 Hz, 3H). Example 90 1 H NMR: (400 MHz, CD3OD) δ 7.67 (m, 1H), 7.33 (m, 2H), 7.15-6.98 (m, 2H), 5.39 (m, 1H), 4.70 (d, J=10.8 Hz, 1H), 4.50 (m, 1H), 4.07 (d, J=10.1 Hz, 2H), 3.71 (d, J=9.5 Hz, 2H), 3.65-3.57 (m, 3H), 3.38-2.95 (m, 2H), 3.22-3.15 (m, 2H), 3.07 (d, J=12.1 Hz, 1H), 2.36 (s, 1H), 2.23 (s, 1H), 2.06 (s, 1H), 1.82 (m, 3H), 1.68 (d, J=13.9 Hz, 1H), 1.57 (t, J=6.6 Hz, 3H), 0.74 (s, 1H), 0.60 (m, 2H), 0.41 (s, 1H). Example 92

[0262] 1¹H NMR: (400 MHz, CD₃OD) δ 7.64 (m, 1H), 7.29-7.18 (m, 2H), 7.04 (m, 1H), 5.38 (m, 1H), 4.78-4.53 (m, 3H), 4.14-4.04 (m, 2H), 3.76-3.68 (m, 2H), 3.65-3.56 (m, 3H), 3.38 (d, J=12.8 Hz, 1H), 3.22-3.12 (m, 2H), 3.07 (m, 1H), 2.53-2.45 (m, 1H), 2.35 (dd, J=8.8, 3.2 Hz, 1H), 2.23 (m, 1H), 2.09-2.02 (m, 1H), 1.82-1.75 (m, 2H), 1.67 (d, J=12.8 Hz, 1H), 1.56 (dd, J=6.4, 1.9 Hz, 3H), 0.98-0.76 (m, 5H), 0.67-0.56 (m, 2H), 0.45-0.38 (m, 1H). Example 97a

[0263] 1 ¹H NMR: (400 MHz, CD₃OD) δ 8.16-8.01 (m, 2H), 7.70-7.52 (m, 2H), 7.42 (q, J=9.0 Hz, 1H), 5.48-5.32 (m, 1H), 4.67 (t, J=10.6 Hz, 1H), 4.60-4.35 (m, 2H), 4.19-4.02 (m, 2H), 3.78-3.43 (m, 3H), 3.41-3.33 (m, 1H), 3.24-3.11 (m, 1H), 2.30 (s, 1H), 2.13-1.64 (m, 9H), 1.57 (t, J=6.9 Hz, 3H), 1.45-1.22 (m, 2H), 1.08 (d, J=10.7 Hz, 3H), 0.81-0.41 (m, 4H). Example 97b

[0264] 1H NMR: (400 MHz, CD3OD) δ 8.14-8.02 (m, 2H), 7.69-7.51 (m, 2H), 7.42 (q, J=9.2 Hz, 1H), 5.50-5.27 (m, 1H), 4.76-4.43 (m, 3H), 4.23-4.03 (m, 2H), 3.84-3.41 (m, 3H), 3.27-2.95 (m, 3H), 2.54 (d, J=94.8 Hz, 2H), 2.14-1.99 (m, 1H), 1.96-1.68 (m, 7H), 1.57 (t, J=7.0 Hz, 4H), 1.04 (s, 3H), 0.81-0.36 (m, 4H). Example 102a

[0265] 1 H NMR (400 MHz, CD3OD) δ 8.12-8.04 (m, 2H), 7.68-7.53 (m, 2H), 7.42 (q, J=9.1 Hz, 1H), 5.44-5.34 (m, 1H), 4.77-4.37 (m, 3H), 4.13-3.99 (m, 2H), 3.79-3.33 (m, 5H), 3.23-3.11 (m, 1H), 2.30-2.22(m, 1H), 2.12-1.64 (m, 9H), 1.61-1.54 (m, 3H), 1.45-1.28 (m, 1H), 0.78-0.70 (m, 1H), 0.69-0.61 (m, 1H), 0.60-0.53 (m, 1H), 0.47-0.38 (m, 1H). Example 102b

[0266] 11H NMR (400 MHz, CD3OD) δ 8.12-8.03 (m, 2H), 7.68-7.53 (m, 2H), 7.42 (m, 1H), 5.44-5.34 (m, 1H), 4.67 (m, 1H), 4.58-4.36 (m, 2H), 4.08 (m, 2H), 3.77-3.44 (m, 1H), 3.68 (d, J=5.6 Hz, 1H), 3.59 (d, J=4.8 Hz, 1H), 3.40-3.33 (m, 1H), 3.18 (dd, J=12.9, 8.9 Hz, 1H), 2.26 (d, J=10.2 Hz, 1H), 2.11-2.02 (m, 2H), 1.98-1.62 (m, 7H), 1.61-1.53 (m, 3H), 1.45-1.31 (m, 1H), 0.78-0.70 (m, 1H), 0.68-0.60 (m, 1H), 0.60-0.53 (m, 1H), 0.47-0.39 (m, 1H). Example 103a

[0267] 1 1H NMR (400 MHz, CD3OD) δ 7.74-7.66 (m, 1H), 7.21 (m, 1H), 7.17-7.04 (m, 2H), 5.37 (m, 1H), 4.83-4.67 (m, 1H), 4.64-4.56 (m, 1H), 4.54-4.44 (m, 1H), 4.15 (m, 1H), 4.09-4.02 (m, 1H), 3.67 (d, J=5.7 Hz, 1H), 3.58 (m, 1H), 3.64-3.22 (m, 1H), 3.16 (m, 1H), 3.08-2.97 (m, 1H), 2.63 (d, J=8.1 Hz, 1H), 2.47-2.36 (m, 1H), 2.10-2.03 (m, 1H), 1.93-1.70 (m, 7H), 1.63-1.43 (m, 4H), 0.77-0.69 (m, 1H), 0.69-0.61 (m, 1H), 0.60-0.53 (m, 1H), 0.48-0.40 (m, 1H). Example 103b

[0268] 1 H NMR (400 MHz, CD3OD) δ7.70 (m, 1H), 7.21 (m, 1H), 7.17-7.04 (m, 2H), 5.38 (m, 1H), 4.66 (m, 6.6 Hz, 1H), 4.58-4.36 (m, 2H), 4.08 (m, 2H), 3.68 (d, J=5.7 Hz, 1H), 3.65-3.32 (m, 3H), 3.17 (m, 1H), 2.26 (d, J=10.1 Hz, 1H), 2.10-1.61 (m, 10H), 1.56 (m, 3H), 1.44-1.32 (m, 1H), 0.77-0.70 (m, 1H), 0.68 -0.60 (m, 1H), 0.60-0.52 (m, 1H), 0.47-0.38 (m, 1H). Example 116a

[0269] 1 H NMR (400 MHz, CD3OD) δ 8.11-8.04 (m, 2H), 7.67-7.53 (m, 2H), 7.42 (dd, J=18.5, 9.2 Hz, 1H), 5.42-5.35 (m, 1H), 4.79 (d, J=10.8 Hz, 1H), 4.57-4.48 (m, 1H), 4.08 (d, J=8.7 Hz, 1H), 3.98 (dd, J=10.8, 6.0 Hz, 1H), 3.77-3.42 (m, 6H), 3.23-3.10 (m, 6H), 2.22-2.14 (m, 1H), 2.10-2.02 (m, 1H), 1.91-1.72 (m, 4H), 1.60-1.54 (m, 3H), 1.41 (dd, J=12.8, 4.6 Hz, 1H), 1.11 (d, J=6.3 Hz, 3H), 0.91 (dd, J=6.2, 2.8 Hz, 3H), 0.80-0.72 (m, 1H), 0.66-0.57 (m, 2H), 0.43-0.35 (m, 1H). Example 116b

[0270] 1¹H NMR (400 MHz, CD₃OD) δ 8.08 (q, J=6.2 Hz, 2H), 7.67-7.62 (m, 1H), 7.62-7.53 (m, 1H), 7.42 (q, J=9.0 Hz, 1H), 5.40-5.34 (m, 1H), 4.56-4.48 (m, 2H), 4.30 (dd, J=10.7, 3.9 Hz, 1H), 4.08 (d, J=8.8 Hz, 1H), 3.79-3.45 (m, 6H), 3.17 (dd, J=12.8, 9.4 Hz, 1H), 2.84 (dd, J=6.0, 3.0 Hz, 1H), 2.74-2.57 (m, 2H), 2.36-2.28 (m, 2H), 2.12-2.02 (m, 1H), 1.91-1.74 (m, 3H), 1.57 (dd, J=8.0, 6.6 Hz, 3H), 1.12 (d, J=6.2 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.73-0.62 (m, 2H), 0.51-0.44 (m, 2H). Example 117a

[0271] 1 ¹H NMR (400 MHz, CD₃OD) δ 8.13-8.04 (m, 2H), 7.67-7.52 (m, 2H), 7.42 (q, J=9.1 Hz, 1H), 5.43-5.35 (m, 1H), 4.76-4.61 (m, 1H), 4.56-4.49 (m, 1H), 4.08 (d, J=8.1 Hz, 2H), 3.77-3.42 (m, 5H), 3.14 (m, 1H), 2.14-1.98 (m, 2H), 1.88-1.53 (m, 11H), 1.35-1.32 (m, 1H), 1.08 (s, 3H), 1.01-0.93 (m, 1H), 0.90-0.85 (m, 3H), 0.82-0.39 (m, 4H). Example 117b

[0272] 1 ¹H NMR (400 MHz, CD₃OD) δ 8.13-8.02 (m, 2H), 7.68-7.52 (m, 2H), 7.42 (q, J=8.9Hz, 1H), 5.41-5.34 (m, 1H), 4.56-4.32 (m, 3H), 4.08 (d, J=8.6Hz, 1H), 3.78-3.40 (m, 4H), 3.26-3.12 (m, 2H), 2.65-2.51 (m, 2H), 2.40-2.26 (m, 1H), 2.09-2.04 (m, 1H), 1.89-1.65 (m, 5H), 1.60-1.55 (m, 3H), 1.53-1.42 (m, 2H), 1.34 (dd, J=3.7, 2.2Hz, 1H), 1.06-0.95 (m, 3H), 0.91 (dd, J=6.4, 2.6Hz, 3H), 0.75-0.64 (m, 2H), 0.59-0.41(m, 2H). Example 118

[0273] 1 1H NMR (400 MHz, Methanol-d4) δ 8.08 (q, J=6.6 Hz, 2H), 7.68-7.52 (m, 2H), 7.42 (q, J=9.2 Hz, 1H), 5.39 (d, J=13.4 Hz, 1H), 4.69-4.51 (m, 2H), 4.22-4.12 (m, 1H), 4.09 (d, J=8.7 Hz, 1H), 3.80-3.55 (m, 7H), 3.55-3.42 (m, 3H), 3.19 (t, J=12.3 Hz, 1H), 3.05 (d, J=12.0 Hz, 1H), 2.37 (d, J=34.5 Hz, 2H), 2.11-1.97 (m, 2H), 1.93-1.76 (m, 3H), 1.57 (t, J=7.1 Hz, 3H), 0.71 (s, 1H), 0.65 (dd, J=9.5, 4.6 Hz, 1H), 0.57 (d, J=4.0 Hz, 1H), 0.44 (d, J=3.9 Hz, 1H). Example 119a

[0274] 1 H NMR (400 MHz, CD3OD) δ 8.08 (q, J=6.2 Hz, 2H), 7.68-7.51 (m, 2H), 7.42 (q, J=9.0 Hz, 1H), 5.43-5.34 (m, 1H), 4.71-4.52 (m, 3H), 4.18-4.03 (m, 2H), 3.78-3.39 (m, 4H), 3.21-2.95 (m, 3H), 2.67 (s, 1H), 2.43 (s, 1H), 2.10 (t, J=9.9 Hz, 1H), 1.92-1.71 (m, 7H), 1.56 (d, J=6.6 Hz, 3H), 1.02 (dd, J=23.5, 6.8 Hz, 3H), 0.80-0.41 (m, 4H). Example 119b

[0275] 1 H NMR (400 MHz, CD3OD) δ 8.09 (q, J=6.2 Hz, 2H), 7.66-7.53 (m, 2H), 7.43 (q, J=9.1 Hz, 1H), 5.43-5.35 (m, 1H), 4.56 (d, J=14.9 Hz, 3H), 4.12 (d, J=8.8 Hz, 2H), 3.77-3.47 (m, 4H), 3.20 (d, J=10.2 Hz, 1H), 2.21-1.97 (m, 7H), 1.94-1.68 (m, 5H), 1.60-1.56 (m, 3H), 1.23-1.11 (m, 3H), 0.85-0.47 (m, 4H). Example 120

[0276] 11H NMR (400 MHz, CD3OD) δ 7.75-7.67 (m, 1H), 7.26-7.03 (m, 3H), 5.41-5.34 (m, 1H), 4.53-4.40 (m, 2H), 4.36 (d, J=10.9 Hz, 1H), 4.07 (d, J=8.7 Hz, 1H), 3.72-3.62 (m, 6H), 3.59 (s, 1H), 3.21-3.12 (m, 1H), 2.54-2.37 (m, 6H), 2.07 (s, 1H), 1.93-1.76 (m, 3H), 1.59-1.54 (m, 3H), 0.71 (s, 2H), 0.50 (s, 2H). Example 121

[0277] 1 1H NMR (400 MHz, CD3OD) δ 7.67 (t, J=7.5 Hz, 1H), 7.42-7.34 (m, 1H), 7.29 (dd, J=16.4, 8.1 Hz, 1H), 7.13 (d, J=2.3 Hz, 1H), 7.05 (dd, J=38.1, 2.4 Hz, 1H), 5.36 (dd, J=8.8, 4.7 Hz, 1H), 4.47 (m, 2H), 4.36 (dd, J=10.9, 2.7 Hz, 1H), 4.07 (d, J=8.7 Hz, 1H), 3.71-3.58 (m, 6H), 3.17 (dd, J=13.0, 7.7 Hz, 1H), 2.49 (d, J=12.9 Hz, 4H), 2.45-2.38 (m, 2H), 2.19-2.01 (m, 2H), 1.89-1.73 (m, 3H), 1.56 (t, J=7.0 Hz, 3H), 0.70 (s, 2H), 0.50 (s, 2H). Example 122

[0278] 11H NMR (400 MHz, CD3OD)δ 7.84-7.75 (m, 1H), 7.26 (dt, J=13.6, 6.0 Hz, 2H), 7.15 (dd, J=40.9, 2.5 Hz, 1H), 5.41-5.34 (m, 1H), 4.52 (dt, J=8.8, 6.3 Hz, 1H), 4.45 (dd, J=10.9, 6.7 Hz, 1H), 4.36 (dd, J=10.9, 2.8 Hz, 1H), 4.07 (d, J=8.8 Hz, 1H), 3.65 (d, J=4.6 Hz, 3H), 3.59 (s, 1H), 3.50-3.32 (m, 1H), 3.17 (dd, J=13.2, 7.7 Hz, 1H), 2.50 (s, 3H), 2.41 (dd, J=18.3, 7.7 Hz, 2H), 2.07 (s, 1H), 1.90-1.74 (m, 3H), 1.57 (t, J=6.9 Hz, 3H), 1.28 (s, 3H), 0.71 (d, J=6.4 Hz, 2H), 0.49 (d, J=4.8 Hz, 2H). Example 123

[0279] 1 1H NMR (400 MHz, CD3OD) δ 7.70-7.59 (m, 1H), 7.29-7.17 (m, 2H), 7.03 (dd, J=52.0, 2.6 Hz, 1H), 5.42 (d, J=13.2 Hz, 1H), 4.59 (s, 2H), 4.44 (q, J=10.2, 9.6 Hz, 2H), 4.17-4.10 (m, 1H), 3.82 (s, 1H), 3.78-3.69 (m, 2H), 3.67 (t, J=4.4 Hz, 4H), 3.25 (d, J=13.7 Hz, 1H), 2.62-2.49 (m, 6H), 2.21-2.11 (m, 2H), 1.90-1.82 (m, 2H), 1.57 (d, J=6.3 Hz, 3H), 0.98-0.78 (m, 3H), 0.74 (d, J=5.1 Hz, 2H), 0.54 (s, 2H). Example 128

[0280] 1 H NMR (400 MHz, CD3OD) δ6.34 (s, 1H), 5.36 (m, 1H), 4.70 (d, J=10.6 Hz, 1H), 4.55-4.49 (m, 1H), 4.11-4.06 (m, 2H), 3.75-3.60 (m, 5H), 3.49-3.37 (m, 1H), 3.21-3.07 (m,4H), 2.53 (d, J=2.0 Hz, 3H), 2.39 (s, 1H), 2.26 (s, 1H), 2.06 (s, 1H), 1.78 (d, J=6.9 Hz, 3H), 1.57 (d, J=6.4 Hz, 3H), 0.74 (d, J=8.9 Hz, 1H), 0.67-0.58 (m, 2H), 0.43 (s, 1H). Example 162

[0281] 1 H NMR (400 MHz, CD3OD) δ 7.77-7.67 (m, 1H), 7.27-7.03 (m, 3H), 5.43-5.31 (m, 1H), 4.82-4.68 (m, 1H), 4.54-4.45 (m, 1H), 4.13-3.98 (m, 2H), 3.77-3.67 (m, 2H), 3.64-3.57 (m, 3H), 3.43-3.40 (m, 1H), 3.24-3.00 (m, 4H), 2.38-2.30 (m, 1H), 2.28-2.17 (m, 1H), 2.16-2.06 (m, 1H), 1.93-1.74 (m, 3H), 1.70-1.59 (m, 1H), 0.79-0.69 (m, 1H), 0.69-0.53 (m, 2H), 0.46-0.35 (m, 1H). Example 163

[0282] 1H NMR (400 MHz, CD3OD) δ 8.12-8.04 (m, 2H), 7.68-7.53 (m, 2H), 7.42 (m, 1H), 5.44-5.34 (m, 1H), 4.77-4.37 (m, 3H), 4.13-3.99 (m, 2H), 3.79-3.33 (m, 5H), 3.23-3.11 (m, 1H), 2.30-2.22(m, 1H), 2.12-1.64 (m, 9H), 1.61-1.54 (m, 3H), 1.45-1.28 (m, 1H), 0.78-0.70 (m, 1H), 0.69-0.61 (m, 1H), 0.60-0.53 (m, 1H), 0.47-0.38 (m, 1H). Example 164

[0283] 1 H NMR (400 MHz, CD3OD) δ7.74-7.67 (m, 1H), 7.22 (m, 1H), 7.17-7.04 (m, 2H), 5.43-5.32 (m, 1H), 4.76-4.62 (m, 1H), 4.59-4.37 (m, 2H), 4.13-3.99 (m, 2H), 3.70 (s, 1H), 3.64-3.35 (m, 3H), 3.23-3.11 (m, 1H), 2.29 (d, J=9.6 Hz, 1H), 2.15-1.63 (m, 9H), 1.60-1.54 (m, 3H), 1.45-1.27 (m, 2H), 0.78-0.71 (m, 1H), 0.69-0.61 (m, 1H), 0.61-0.54 (m, 1H), 0.47-0.39 (m, 1H). Example B: Biological assay

[0284] The effects of the compounds disclosed herein were measured by the following assay. Phospho-ERK 1 / 2 assay:

[0285] PNAC-1 cells were grown in T75 flasks using standard tissue culture procedures in DMEM and 10% single fetal bovine serum (FCS, Gibco®) until a colony density of ~80% was achieved. On day 1, 6000 cells / well were seeded into 384-well plates and incubated at 37°C and 5% CO2. Diluted compounds were added by Echo550 to a final DMSO concentration of 0.5%, and the cells were incubated at 37°C and 5% CO2 for 3 hours. The medium was then removed, and the cells were fixed with 3.7% formaldehyde in PBS (PFA) using Apricot. They were washed once with PBS. The cells were permeabilized with cold 100% methanol, and washed once again with PBS. Li-Cor blocking buffer was added to each well, and incubated at RT for 1.5 hours. The blocking buffer was removed, and a primary antibody mixture (rabbit anti-pERK, mouse anti-GAPDH) was added. Incubated overnight at 4°C. On day 2, the plates were washed a total of three times with PBST (Tween-20 in PBS), then the secondary antibody mixture (goat anti-rabbit 800CW (diluted 1:800 in combination solution) and goat anti-mouse 680RD (diluted 1:800 in combination solution)) was added, and the plates were incubated at RT for 60 minutes, away from light. Washing with PBST was repeated three times. After the final wash, the plates were inverted and centrifuged at 1000 rpm to completely remove the washing solution from the wells. To avoid possible interference during scanning, the bottom plate surface and the Odyssey® Imager scan bed (if applicable) were cleaned with a damp lint-free tissue before scanning the plates. The plates were scanned by detection on both 700 and 800 nm channels.

[0286] The results of phospho-ERK 1 / 2 assays of some exemplary compounds of this disclosure are shown in Table 2 below. [Table 3-1] [Table 3-2]

[0287] GDP-loaded KRAS(G12D) was thawed on ice and diluted to 500 nM with RBD-RAS binding buffer. A master mixture (6 μl) was prepared: 96 wells × (1 μl diluted GDP-loaded KRAS(G12D), 500 nM + 5 μl RBD-RAS binding buffer). 6 μl of the master mixture was added to each well. Serial dilutions of the test compound were prepared at 200X test concentrations with DMSO. Subsequently, the compound was diluted 20-fold with deionized water to prepare a 10X intermediate solution. For the positive and negative controls, 5% DMSO in water was used as the 10X intermediate, so that all wells contained the same amount of DMSO. 1 μl of the 10X intermediate solution of the test compound was added to the test wells. 1 μl of 5% DMSO was added to the positive and negative control wells. The plate was gently centrifuged and incubated at room temperature for 30 minutes. GTP (10 mM) and SOS1 were thawed on ice. SOS1 was diluted to 5 μM with RBD-RAS binding buffer. GTP (10 mM) and diluted SOS1 (5 μM) were combined in a 1:1 ratio. The exchange reaction was started by adding 2 μl of the GTP / SOS1 mixture to the test wells and positive control wells. RBD-cRAF was thawed and diluted to 25 nM with RBD-RAS binding buffer. After incubation with SOS1 / GTP (RBD-RAS buffer for negative control) for 30 minutes, 1 μl of diluted RBD-cRAF (25 nM) was added to all wells. The plate was gently centrifuged and incubated at room temperature for 30 minutes. 1X Immuno buffer was prepared by diluting 3X Immuno Buffer with deionized water. 1 volume of 3X Immuno Buffer was added to 2 volumes of deionized water. Glutathione acceptor beads (PerkinElmer #AL109C) and nickel chelate donor beads (PerkinElmer #AS101D) were diluted in 1x Immuno buffer at 1:500 and 1:250, respectively. 20 μl of the acceptor / donor bead mixture needed to be added per well. Therefore, 16 μl of glutathione acceptor beads and 32 μl of nickel chelate donor beads were added to 8 mL of 1x Immuno buffer.The samples were incubated at room temperature for 30 minutes. Alpha counts were read using a compatible plate reader. KRAS G12D 2D CellTiter-Glo® Proliferation Assay:

[0288] AsPC-1 (ATCC CRL-1682) and LS513 (ATCC CRL-2134) cells were purchased from ATCC, GP2D (Cobioer CBP60010), AGS (Cobioer CBP60476), and SW1990 (Cobioer CBP60691) cells were purchased from Cobioer Biosciences Co., Ltd., and MKN-1 (JCRB, JCRB0252) cells were purchased from the JCRB Cell Bank. Each cell type was cultured in medium supplemented with 10% fetal bovine serum (FBS) according to the manufacturer's recommended protocol. Cells were seeded at 800 cells / well in 384-well plates (Corning) and incubated at 37°C and 5% CO2 for 18 hours. Serially diluted compounds were added to the cells, and the plates were incubated at 37°C and 5% CO2 for 72 hours. Cell viability was measured using the CellTiter-Glo® luminescent cell viability assay kit (Promega) according to the manufacturer's protocol. KRAS G12D 3D CellTiter-Glo® Proliferation Assay

[0289] Panc-1 (ATCC CRL-1469), HPAC (ATCC CRL-2119), Panc0403 (ATCC CRL-2555), and AsPC-1 (ATCC CRL-1682) cells were purchased from ATCC; GP2D (Cobioer CBP60010), AGS (Cobioer CBP60476), and SW1990 (Cobioer CBP60691) cells were purchased from Cobioer Biosciences Co., Ltd.; and MKN-1 (JCRB, JCRB0252) cells were purchased from the JCRB Cell Bank. Each cell type was cultured in medium supplemented with 10% fetal bovine serum (FBS) according to the manufacturer's recommended protocol. Serially diluted compounds were added to 384-well ultra-low adhesion round-bottom plates (Corning). 400 cells / well were seeded into plates and incubated at 37°C and 5% CO2 for 7 days. Cell viability was measured using the CellTiter-Glo® 3D cell viability assay kit (Promega) according to the manufacturer's protocol, as shown in Table 3. [Table 4]

[0290] Other compounds in this disclosure include ICs with a concentration of 0.5 to 5000 nM. 50 The values ​​are shown. Some of the compounds in this disclosure have ICs of 1 to 4000 nM. 50 The values ​​are shown. Some of the compounds in this disclosure have IC50 values ​​of 1 to 3000 nM. 50 The values ​​are shown. Some of the compounds in this disclosure have IC50 values ​​of 1 to 2000 nM. 50 The values ​​are shown. Some of the compounds in this disclosure have IC50 values ​​of 1 to 1000 nM. 50 The values ​​are shown. Some of the compounds in this disclosure have IC500 to 1-500 nM. 50 Show the value. DMPK assay Caco-2 cell monolayer permeability

[0291] Cells were incubated at 37°C for 120 minutes at a concentration of 10 μM and pH 6.5 / 7.4 (apical / basal) in the presence of the efflux inhibitors zoskidal, benzbromarone, and KO-143. Samples were taken at 45 and 120 minutes to assess recovery. All incubations were performed once. Lucifer yellow was used as a marker to confirm the integrity of the cell monolayer after 120 min incubation. Compound concentrations in the incubation medium of the donor and receiver compartments were quantified using UPLC-MS / MS. The apparent permeability after 120 min incubation was calculated using the concentration data. The results are shown in Table 4. [Table 5]

[0292] P-glycoprotein (Pgp)-mediated efflux transport was evaluated using MDCK-MDR1 cells. The final concentrations of the test and control compounds were 1 μM. Multiwell insert plates were incubated at 37°C for 2 hours. To ensure accurate measurement of passive permeability coefficients, Pexact, which automatically corrects for compound loss, was reported. The results are shown in Table 5. [Table 6]

[0293] Single doses of the test compound were administered to female Balb / c mice according to the following methods: IV bolus administration (1 mg / kg, 0.2 mg / mL in 1% DMSO water, 99% SBE-β-CD (10% w / v)) and forced oral administration (10 mg / kg to 60 mg / kg). Blood samples were collected at 2 min, 5 min, 10 min, 30 min, 1 hr, 2 hr, 4 hr, 8 hr, and 24 hr (further 32 hr and 48 hr for MRTX1133) after the IV bolus, and at 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, and 24 hr (further 32 hr and 48 hr for MRTX1133) after PO administration. Plasma concentrations of the compound were determined by UPLC-MS / MS. The results are shown in Table 6. [Table 7]

[0294] Single doses of the test compound were administered to female SD rats via IV infusion (1 mg / kg, 0.25 mg / mL) and forced oral administration (5 mg / kg to 60 mg / kg). Blood samples were collected 10 min, 30 min, 1 hr, 1.25 hr, 1.5 hr, 2 hr, 4 hr, 8 hr, and 24 hr after IV infusion, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, and 24 hr after PO administration. Plasma concentrations of the compound were determined by UPLC-MS / MS. The results are shown in Table 7. [Table 8]

[0295] Mice were reared under pathogen-free conditions and given free access to food and water. 5.0 × 10⁶ HPAC (ATCC, CRL-2119) cells in 100 μl of PBS were placed in the right posterior flank of 6-8 week old female BALB / c nude mice (Anikeeper, Beijing, China). 6 Individual subcutaneous injections were administered. 1.0 × 10⁶ cells of Panc-1 (ECACC, 87092802) in 100 μl of PBS were injected into the right posterior flank of a 6-8 week old female CB17 SCID (Vital River, Beijing, China). 7Individual subcutaneous injections were administered. 200 μl of SW1990 (ATCC, CRL-2172) cells in PBS and Matrigel matrix (1:1) were injected into the right posterior flank of a 6-8 week old female CB17 SCID (Vital River, Beijing, China) in 5.0 × 10⁶ cells. 6 Individual subcutaneous injections were administered. The health status of the mice was monitored daily, and caliper measurements were started when the tumors became palpable. Formula 0.5 × L × W 2 The tumor volume is measured using the following formula, where L represents the length of each tumor and W represents the width of each tumor. The average tumor volume is 100-200 mm². 3 When the optimal treatment time was reached, the mice were randomly divided into treatment groups. Mice were treated with forced oral administration of a vehicle consisting of 10% sorbitol + 90% water or 20-120 mg / kg BID of compounds in the vehicle. Animals were monitored daily, tumors were measured 2 or 3 times per week, and body weight was measured 2 or 3 times per week. Data are expressed as mean ± standard error. Statistical analysis of intergroup differences in tumor volume and tumor weight was performed using data obtained at the optimal treatment time. One-way ANOVA was performed to compare tumor volume and tumor weight between groups. If a significant F-statistic (ratio of treatment variance to error variance) was obtained, intergroup comparisons were performed using the Games-Howell test; otherwise, Dunnett's (two-sided) test was applied. Significance between two groups was analyzed by a t-test. All data were analyzed using SPSS 17.0 (IBM, Armonk, New York). p<0.05 was considered a statistically insignificant difference, and p<0.01 was considered statistically significant. The results are shown in Tables 8 and 9.

[0296] [Mathematics 1] TGI(%)=(1-(T n -T0) / (C n -C0))*100%

[0297] Tn: Mean tumor volume of the treatment group on day n

[0298] T0: Mean tumor volume of the treatment group on day 0

[0299] Cn: Mean tumor volume of the vehicle control group on day n

[0300] C0: Mean tumor volume of the vehicle control group on day 0. [Table 9] [Table 10]

[0301] In vivo pharmacological studies were conducted to evaluate the efficacy of the test compound after oral administration in human pancreatic cancer cell Panc-1 and / or SW1990 and / or HPAC subcutaneous transplantation models. The test compound significantly inhibited tumor growth in all models. Mice with tumors showed good tolerability at all test doses of the test compound. hERG inhibition test

[0302] In HEK293 cell lines that stably express hERG, inhibition of hERG channels was performed by manual patch-clamp.

[0303] hERG inhibition tests were performed with the compounds disclosed herein. In vitro Hep Clint assay

[0304] The test compound at a concentration of 1 μM was incubated with cryopreserved hepatocytes for various time points up to 120 minutes. The disappearance of the test compound was quantified by LC-MS / MS. The metabolic stability of the test compound in hepatocytes was evaluated by calculating the intrinsic clearance (Clint) and half-life (T1 / 2). A positive control was included in each assay to validate the performance of the test system.

[0305] The above description is intended solely to illustrate the principles of this disclosure. Furthermore, since numerous modifications and variations are readily apparent to those skilled in the art, it is undesirable to limit the present invention to the specific configurations and processes described above. Accordingly, all suitable modifications and equivalents can be considered to fall within the scope of the present invention as defined by the following claims.

Claims

1. Compounds having formula (I), formula (II), or formula (III): 【Chemistry 1】 【Chemistry 2】 【Transformation 3】 (In the formula, Ring A is, 【Chemistry 4】 And, X is -C(R ｅ R ｆ )-, -O- or -N(R Ｘ ) - and R Ｘ is hydrogen, deutherium, alkyl, or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more deutherium atoms. Ring E is, 【Transformation 5】 And, Z is -C(R ｊ R ｋ )-, -O- or -N(R Ｚ ) - and R Ｚ is hydrogen, deutherium, alkyl, or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more deutherium atoms. R １ and R ２ are each independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy or haloalkyl, and said alkyl, alkoxy and haloalkyl are optionally substituted with one or more deuterium atoms, R ３ and R ４ Each is independently selected from hydrogen, deutherium, halogen, alkyl, alkoxy, or haloalkyl, and the alkyl, alkoxy, and haloalkyl are optionally substituted with one or more deutherium atoms, or R ３ and R ４ These, together with the carbon atoms bonded to both, form cycloalkyl or heterocyclyl groups, each of which is optionally substituted with one or more groups independently selected from the group consisting of deutherium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl groups. R ５ and R ６ Each is independently selected from hydrogen, deutherium, alkyl, alkoxy, or haloalkyl, and the alkyl, alkoxy, and haloalkyl are optionally substituted with one or more deutherium atoms. R ７ and R ８ is independently selected from hydrogen, deutherium, alkyl, alkoxy, haloalkyl, hydroxyalkyl or -alkyl-alkoxy, and the alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy are optionally substituted with one or more deutherium atoms. R ９ and R １０ is independently selected from hydrogen, deutherium, alkyl, alkoxy, haloalkyl, hydroxyalkyl or -alkyl-alkoxy, and the alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy are optionally substituted with one or more deutherium atoms. R ａ , R ｂ , R ｃ , R ｄ , R ｅ , and R ｆ Each of them is independently a hydrogen atom, a halogen atom, or an alkyl group optionally substituted with one or more deuterium atoms, or R ７ , R ８ , R ９ , R １０ , R ａ , R ｂ , R ｃ , R ｄ , R ｅ , R ｆ , and R Ｘ These two, along with the intervening atom 【Transformation 6】 A cycloalkyl or heterocyclyl is formed, and each of the cycloalkyl and heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of deutherium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl. However, if the compound has formula (I), R ５ , R ６ , R ７ , R ８ , R ９ and R １０ At least one of them is not hydrogen, R １１ and R １２ Each of these is independently selected from hydrogen, deutherium, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -alkyl-alkoxy, and the alkyl, alkoxy, haloalkyl, hydroxyalkyl, and -alkyl-alkoxy are optionally substituted with one or more deutherium atoms. R １３ and R １４ Each of these is independently selected from hydrogen, deutherium, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -alkyl-alkoxy, and the alkyl, alkoxy, haloalkyl, hydroxyalkyl, and -alkyl-alkoxy are optionally substituted with one or more deutherium atoms. R ｓ , R ｔ , R ｖ , and R ｕ Each of them is independently an alkyl group optionally substituted with hydrogen, a halogen, or one or more deuterium atoms. R ｊ and R ｋ Each of them is independently a hydrogen atom, a halogen atom, or an alkyl group optionally substituted with one or more deuterium atoms, or R ｊ and R ｋ along with the carbon atoms bonded to them 【Transformation 7】 Forming, However, if the compound has formula (II) or formula (III), R ５ , R ６ , R １１ , R １２ , R １３ and R １４ At least one of them is an alkyl, alkoxy, haloalkyl, hydroxyalkyl, and -alkyl-alkoxy element substituted with one or more deuterium atoms. Each R is independently selected from the group consisting of deutherium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, alkyl, alkenyl, and alkynyl, and the alkyl, alkenyl, alkynyl, alkoxy, and haloalkyl are optionally substituted with one or more deutherium atoms. Each R' is independently either hydrogen or deutherium. Each R'' is independently hydrogen, deuterium, or halogen. m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2 or 3, and p is 0, 1, 2, or 3. or a pharmaceutically acceptable salt thereof.

2. R １ and R ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein both are hydrogen.

3. R ３ and R ４ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is hydrogen and the other is an alkyl group optionally substituted with one or more deutherium atoms.

4. R ３ and R ４ The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is hydrogen and the other is a methyl atom optionally substituted with one or more deutherium atoms.

5. R ３ and R ４ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the carbon atoms bonded to both of them form a cycloalkyl group optionally substituted with one or more groups independently selected from the group consisting of deutherium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl.

6. R ３ and R ４ The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein the carbon atoms bonded to both of them form a cyclopropyl optionally substituted with one or more deutherium atoms.

7. R ５ and R ６ A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is an alkyl group optionally substituted with one or more deutherium atoms, and the other atom is hydrogen.

8. R ５ and R ６ One of them is -CH ３ or -CD ３ The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein the other is hydrogen.

9. The compound has formula (I), R ７ , R ８ , R ９ and R １０ The compound according to claim 7 or 8, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

10. R ５ and R ６ A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein both are hydrogen.

11. The compound has formula (I), R ７ and R ８ The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein one of the members is an alkyl, alkoxy, -alkyl-alkoxy, hydroxyalkyl, or haloalkyl, each optionally substituted with one or more deutherium atoms, and the other member is hydrogen or deutherium.

12. R ７ and R ８ one of which is -CH ３ , -CD ３ , -CH ２ -OCH ３ , -CH ２ -OCD ３ , -CH ２ -OH, -CH ２ F, -CHF ２ or -CF ３ , and the other is hydrogen or deuterium. The compound according to claim 11, or a pharmaceutically acceptable salt thereof.

13. R ９ and R １０ A compound according to any one of claims 11 to 12, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is hydrogen and the other is an alkyl atom optionally substituted with hydrogen or one or more deutherium atoms.

14. R ９ and R １０ One is hydrogen, and the other is hydrogen, methyl or CD ３ The compound according to claim 13, or a pharmaceutically acceptable salt thereof.

15. The compound has formula (I), R ７ and R ９ It forms a heterocycline with the intervening atom, or R ７ and R ａ The compound according to claim 10, or a pharmaceutically acceptable salt thereof, which forms a heterocycline with an intervening atom.

16. Ring A is, 【Transformation 8】 The compound according to claim 15, or a pharmaceutically acceptable salt thereof.

17. The compound has formula (I), where X is -C(R ｅ R ｆ ) - and R ｅ and R ｆ A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is hydrogen and the other is a halogen.

18. R ｅ and R ｆ The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is hydrogen and the other is -F.

19. R ｅ and R ｆ The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein both are hydrogen.

20. The compound has formula (I), where X is -C(R ｅ R ｆ ) - and R ａ and R ｅ The compounds according to any one of claims 1 to 6, or pharmaceutically acceptable salts thereof, wherein the carbon atoms bonded thereto form a cycloalkyl or heterocyclyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of deutherium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl.

21. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein n is 0.

22. Ring A is, 【Chemistry 9】 The compound according to claim 21, or a pharmaceutically acceptable salt thereof.

23. R ５ and R ６ The compound according to claim 22, or a pharmaceutically acceptable salt thereof, wherein both are hydrogen.

24. R ７ and R ８ The compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein one of the members is an alkyl, alkoxy, -alkyl-alkoxy, or haloalkyl, each optionally substituted with one or more deutherium atoms, and the other is hydrogen or deutherium.

25. R ７ and R ８ The compound according to claim 24, or a pharmaceutically acceptable salt thereof, wherein one of the members is an alkyl group optionally substituted with one or more deutherium atoms, and the other member is hydrogen or deutherium.

26. R ７ and R ８ One of them is -CH ３ or -CD ３ The compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein the other is hydrogen or deutherium.

27. R ９ and R １０ A compound according to any one of claims 22 to 26, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is hydrogen or deutherium, and the other is an alkyl group optionally substituted with hydrogen or one or more deutherium atoms.

28. R ９ and R １０ The compound according to claim 27, or a pharmaceutically acceptable salt thereof, wherein both are hydrogen.

29. The compound has formula (I), where X is -C(R ｅ R ｆ ) - and R ｅ and R ｆ along with the carbon atoms bonded to them 【Chemistry 10】 A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, which forms a compound.

30. R ５ and R ６ The compound according to claim 29, or a pharmaceutically acceptable salt thereof, wherein both are hydrogen.

31. R ７ and R ８ The compound according to claim 29 or 30, or a pharmaceutically acceptable salt thereof, wherein one of the members is an alkyl, alkoxy, -alkyl-alkoxy or haloalkyl, each optionally substituted with one or more deutherium atoms, and the other is hydrogen or deutherium.

32. R ７ and R ８ The compound according to claim 31, or a pharmaceutically acceptable salt thereof, wherein one of the members is an alkyl group optionally substituted with one or more deutherium atoms, and the other member is hydrogen or deutherium.

33. R ７ and R ８ One of them is -CH ３ or -CD ３ The compound according to claim 32, or a pharmaceutically acceptable salt thereof, wherein the other is hydrogen or deutherium.

34. R ９ and R １０ A compound according to any one of claims 29 to 33, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is hydrogen or deutherium, and the other is an alkyl group optionally substituted with hydrogen or one or more deutherium atoms.

35. R ９ and R １０ The compound according to claim 34, or a pharmaceutically acceptable salt thereof, wherein both are hydrogen.

36. The aforementioned compound has formula (II) or formula (III), R １１ and R １２ The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein one of the members is an alkyl group substituted with one or more deutherium atoms, and the other is hydrogen or deutherium.

37. R １１ and R １２ One of them is -CD ３ The compound according to claim 36, or a pharmaceutically acceptable salt thereof, wherein the other is hydrogen or deutherium.

38. R １３ and R １４ The compound according to claim 36 or 37, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is hydrogen and the other is an alkyl group optionally substituted with hydrogen or one or more deutherium atoms.

39. R １３ and R １４ One is hydrogen, and the other is hydrogen, methyl or CD ３ The compound according to claim 38, or a pharmaceutically acceptable salt thereof.

40. R １３ and R １４ The compound according to claim 36 or 37, or a pharmaceutically acceptable salt thereof, wherein both are hydrogen.

41. R ｕ and R ｖ The compound according to claim 36 or 37, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is hydrogen and the other is an alkyl group optionally substituted with hydrogen or one or more deutherium atoms.

42. R ｕ and R ｖ One is hydrogen, and the other is hydrogen, methyl or CD ３ The compound according to claim 41, or a pharmaceutically acceptable salt thereof.

43. The compound has formula (II) or formula (III), where Z is -C(R ｊ R ｋ ) - and R ｊ and R ｋ A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is hydrogen and the other is a halogen.

44. R ｊ and R ｋ The compound according to claim 43, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is hydrogen and the other is -F.

45. The compound has formula (II) or formula (III), where Z is -C(R ｊ R ｋ ) - and R ｊ and R ｋ along with the carbon atoms bonded to them 【Chemistry 11】 A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, which forms a compound.

46. R ５ and R ６ The compound according to claim 45, or a pharmaceutically acceptable salt thereof, wherein both are hydrogen.

47. R １１ and R １２ The compound according to claim 45 or 46, or a pharmaceutically acceptable salt thereof, wherein one of the members is an alkyl, alkoxy, -alkyl-alkoxy or haloalkyl, each optionally substituted with one or more deutherium atoms, and the other is hydrogen or deutherium.

48. R １１ and R １２ The compound according to claim 47, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is an alkyl group optionally substituted with one or more deutherium atoms, and the other atom is hydrogen or deutherium.

49. R １１ and R １２ One of them is -CH ３ or -CD ３ The compound according to claim 48, or a pharmaceutically acceptable salt thereof, wherein the other is hydrogen or deutherium.

50. R １３ and R １４ A compound according to any one of claims 45 to 49, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is hydrogen or deutherium, and the other is an alkyl group optionally substituted with hydrogen or one or more deutherium atoms.

51. R １３ and R １４ The compound according to claim 50, or a pharmaceutically acceptable salt thereof, wherein both are hydrogen.

52. The compound according to any one of claims 1 to 6, wherein the compound has formula (II) or formula (III), and Z is -O-, or a pharmaceutically acceptable salt thereof. 【Request Item 53】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 The expression selected from During the ceremony, R ５ The alkyl, alkoxy, or haloalkyl group is selected from alkyl, alkoxy, or haloalkyl groups, and the alkyl, alkoxy, and haloalkyl groups are optionally substituted with one or more deuterium groups. Ring B is a cycloalkyl or heterocyclyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of deutherium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl. However, R ７ and R ９ At least one of them is not hydrogen, and R １１ is an alkyl group substituted with one or more deutherium atoms. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

54. The compound according to any one of the claims, or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3, or 4.

55. Each R is independently selected from cyano, halogen, hydroxyl, amino, haloalkyl, alkyl, or alkynyl, and the alkyl or alkynyl is optionally substituted with one or more deuterium atoms, the compound according to claim 54, or a pharmaceutically acceptable salt thereof.

56. Each R is fluoro, chloro, hydroxyl, -NH ２ , -CF ３ The compound according to claim 55, or a pharmaceutically acceptable salt thereof, independently selected from ethyl or ethynyl, wherein the ethyl or ethynyl is optionally substituted with one or more deuterium atoms.

57. The compound has formula (I), 【Chemistry 20】 teeth, 【Chemistry 21】 A compound according to any one of claims 1 to 28 and 53 to 56, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

58. The aforementioned compound has formula (II), 【Chemistry 22】 teeth, 【Chemistry 23】 A compound according to any one of claims 1 to 8 and 36 to 56, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

59. The aforementioned compound has formula (III), 【Chemistry 24】 teeth, 【Chemistry 25】 A compound according to any one of claims 1 to 8 and 36 to 56, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

60. Each R' is hydrogen, the compound according to any one of the claims, or a pharmaceutically acceptable salt thereof.

61. Each R' is deutherium, the compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof. 【Request Item 62】 【Chemistry 26-1】 【Chemistry 26-2】 【Chemistry 26-3】 【Chemistry 26-4】 【Chemistry 26-5】 【Chemistry 26-6】 【Chemistry 26-7】 【Chemistry 26-8】 【Chemistry 26-9】 【Chemistry 26-10】 【Chemistry 26-11】 【Chemistry 26-12】 【Chemistry 26-13】 [Chemistry 26-14] 【Chemistry 26-15】 【Chemistry 26-16】 [Chemistry 26-17] [Chemistry 26-18] [Chemistry 26-19] 【Chemistry 26-20】 【Chemistry 26-21】 [Chemistry 26-22] [Chemistry 26-23] [Chemistry 26-24] [Chemistry 26-25] 【Chemistry 26-26】 [Chemistry 26-27] [Chemistry 26-28] [Chemistry 26-29] [Chemistry 26-30] [Chemistry 26-31] [Chemistry 26-32] [Chemistry 26-33] [Chemistry 26-34] [Chemistry 26-35] [Chemistry 26-36] [Chemistry 26-37] [Chemistry 26-38] [Chemistry 26-39] [Chemistry 26-40] [Chemistry 26-41] [Chemistry 26-42] [Chemistry 26-43] A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

63. A pharmaceutical composition comprising a compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

64. A method for inhibiting the wild-type KRas, Kras G12D, Kras G12C, Kras G12V, Kras G13D, Kras G12R, Kras G12S, Kras G12A, and / or Kras Q61H activity of a target of interest, comprising administering to the target an effective amount of a compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 63.

65. A method for treating cancers associated with wild-type KRas, KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, and / or KRas Q61H, comprising administering an effective amount of a compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 63 to a subject in need.

66. The aforementioned cancer is (i) Heart: Sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma, (ii) Lung: bronchogenic carcinoma (squamous epithelial, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, cartilaginous hamartoma, mesothelioma, (iii) Digestive tract: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma), (iv) Urogenital tract: Kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminocarcinoma, teratoma, fetal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma), (v) Liver: Hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, (vi) Biliary tract: gallbladder cancer, ampulla cancer, bile duct cancer; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondrosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor, (vii) Nervous system: Skull (osteoma, hemangioma, granuloma, xanthomas, degenerative osteitis), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiforme, oligodendroglioma, Schwann cell tumor, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma) (viiii) Gynecology: Uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma), (ix) Hematology: Blood (myeloleukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma), (x) Skin: Malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentigo, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, and (xi) Adrenal gland: Neuroblastoma The method according to claim 65, selected from the group consisting of the following.

67. The method according to claim 65, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

68. A method for treating a target cancer, comprising: (a) obtaining the finding that the cancer is associated with wild-type KRas or KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, KRas Q61H; and (b) administering to the target an effective amount of a compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 63.

69. The method according to any one of claims 64 to 68, wherein the administration is carried out via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasacral, intrathecal, intramuscular, intravitreous, intravenous, intra-arterial, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous, and topical administration.

70. The method according to any one of claims 64 to 68, wherein the compound is administered separately or sequentially, simultaneously with one or more additional therapeutic agents.

71. The method according to claim 70, wherein the one or more additional therapeutic agents are selected from anti-PD-1 or PD-L1 antagonists, MEK inhibitors, CDK4 / CDK6 inhibitors, EGFR inhibitors, ERK inhibitors, SHP2 inhibitors, platinum agents, SMARCA2 inhibitors, or pemetrexed.

72. Use of a compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 63, in the manufacture of a pharmaceutical for the treatment of cancer.

73. A compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 63, for use in the treatment of cancer.

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