KRAS inhibitors and uses thereof

Abstract

Provided are novel compounds useful as inhibitors of KRAS, particularly KRAS G12D and / or other KRAS G12 mutants, as well as pharmaceutical compositions comprising these compounds and methods of treatment by administering these compounds or the pharmaceutical compositions.

Description

Technical Field

[0001] This disclosure generally relates to novel compounds that can be used as inhibitors of KRAS, particularly KRAS G12D and / or other KRAS G12 mutants, as well as pharmaceutical compositions comprising these compounds and methods of treatment by administration of these compounds or said pharmaceutical compositions. Background Technology

[0002] RAS is one of the most well-known proto-oncogenes. Gain-of-function mutations occur in approximately 30% of human cancers. As the most common mutated RAS isotype, KRAS (Kirsten rat sarcoma virus oncogene homolog) has been extensively studied in recent years. KRAS, along with highly associated NRAS and HRAS GTPases, hydrolyzes guanosine triphosphate (GTP) to guanosine diphosphate (GDP). It controls a variety of cellular functions by cycling between the active GTP-binding conformation and the inactive GDP-binding conformation (Hobbs, GA et al., *Journal of Cell Science* 129, 1287-1292 (2016)).

[0003] KRAS is an important oncogene that has been shown to drive tumorigenesis (GG Jinesh et al., Oncogene, Vol. 37, pp. 839-846 (2018)). KRAS also regulates many genetic regulatory mechanisms and forms a large tumorigenetic network. The KRAS gene encodes a 21 kDa protein, known as KRAS, which is part of the RAS / MAPK pathway. The KRAS protein is a GTPase, meaning that it can bind with high affinity to guanosine monophosphate (GDP) and guanosine triphosphate (GTP) and hydrolyze GTP to GDP (Dhirendra K. Simanshu et al., Cell, 29 June 2017; 170(1): 17-33). The GDP / GTP cycle is tightly regulated by several families of multidomain proteins: guanosine monophosphate exchange factors (GEF) and GTPase activators (GAP). GEF stimulates the dissociation of GDP and subsequent GTP association, thereby activating the RAS protein, while GAP accelerates intrinsic GTP hydrolysis, converting RAS to its inactive state (Dhirendra K. Simanshu et al., Cell. 29 June 2017; 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. When the KRAS protein binds to GDP, the protein is shut down (inactivated) and does not relay signals to the nucleus.

[0004] Oncogenic KRAS mutations are most commonly found at codons 12, 13, or 61 (Jozsef Timar et al., Cancer and Metastasis Reviews, Vol. 39, pp. 1029-1038 (2020)). Among these mutation sites, G12 is the most frequently mutated residue (89%), and the most frequently mutated residue is aspartic acid (G12D, 36%), followed by valine (G12V, 23%) and cysteine ​​(G12C, 14%). G12 is located at the active site of the protein and 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 Research, 72, 2457-2467, (2012)). The residues in the active site bind to the phosphate group of GTP and are responsible for the GTPase function of KRAS. The switch regions SI and SII are also responsible for controlling the binding to effector and regulatory proteins. Numerous studies have shown the heterogeneity of KRAS mutations in various aspects, including intrinsic GTPase activity and the affinity of effectors for metastasis sites (Ihle, NT et al., *Journal of the National Cancer Institute*, 104, 228-239 (2012)). A glycine mutation at position 12 in the P-ring to aspartic acid (G12D) impairs GTP hydrolysis and freezes KRAS in its active (GTP-bound) state, resulting in uncontrolled cell growth and escape from apoptosis signals (Malumbres, M. & Barbacid, M., *Nature Reviews Cancer*, 3, 459-465 (2003)). The G12D mutation leads to a population shift in the local conformational state of KRAS, particularly in the switch II (SII) and α3-helical regions, favoring conformations associated with catalytically impaired states through structural changes; this also results in SII motion being inversely correlated with other regions (Sezen Vatansever et al., Sci Rep., August 13, 2019; 9(1):11730).

[0005] Besides the KRAS G12D mutation, other KRAS mutations, 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 that disrupt covalent or potentially non-covalent drug binding, or secondary mutations of KRAS, can be used to illustrate clinical resistance to targeted therapies targeting KRAS mutations (Awad MM et al., *New England Journal of Medicine* 2021;384(25):2382-93.). KRAS gene amplification and overexpression are also associated with tumor progression (E Birkeland et al., *Journal of Cancer*. Dec 4, 2012;107(12):1997-2004). The publication also suggests that wild-type KRAS inhibition may be a viable treatment strategy for KRAS wild-type dependent cancers (Lisa Maria Mustachio et al., Cancers (Basel). March 2021; 13(6): 1204.).

[0006] KRAS mutations (e.g., amino acids G12, G13, Q61, A146) are present in up to 25% of cancers, with oncogenic variants exhibiting varying prevalences across different cancers, including lung, colorectal, and pancreatic cancer (Cox et al., *Nature Reviews Drug Discovery*, 2014, 13(11):825-51). In pancreatic ductal adenocarcinoma cases, the most common KRAS alteration is G12D substitution. G12D variants are also a focus of Mirati's drug discovery efforts, with plans to introduce its lead compound MRTX1133 into clinical trials. Based on epidemiological data and mutation frequencies reported in Globocan 2022 (accessed November 2019), KRAS G12D mutations are estimated to be present in approximately 36% of pancreatic cancers, 4% of colorectal cancers, approximately 6% of endometrial cancers, and approximately 4% of NSCLC. This significant patient population represents a high level of unmet need. The 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 the field (Gongmin Zhu et al., Molecular Cancer. 2021 Nov 6;20(1):143).

[0007] Therefore, there remains an unmet need to develop new compounds that can effectively treat cancers mediated by KRAS (especially KRAS mutated at position 12, such as G12D or 13) and / or cancers mediated by wild-type amplified KRAS. Summary of the Invention

[0008] This article discloses novel compounds capable of inhibiting the KRAS protein. Therefore, the disclosed compounds may be used to treat KRAS-related diseases, such as cancer.

[0009] On the one hand, this disclosure provides a compound having formula (I), formula (II) or formula (III): (I) (II) (III) Or its pharmaceutically acceptable salt. in Ring A is ; X is -C(R) e R f -, -O- or -N(R) X )-; R X It is hydrogen, deuterium, alkyl, or cycloalkyl, wherein the alkyl and the cycloalkyl are optionally substituted with one or more deuterium; Ring E is ; Z is -C(R) j R k -, -O- or -N(R) Z )-; R Z It is hydrogen, deuterium, alkyl, or cycloalkyl, wherein the alkyl and the cycloalkyl are optionally substituted with one or more deuterium; R 1 and R 2 Each is independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, or haloalkyl, wherein the alkyl, the alkoxy, and the haloalkyl are optionally substituted with one or more deuterium; R 3 and R 4 Each is independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, or haloalkyl, wherein the alkyl, the alkoxy, and the haloalkyl are optionally substituted with one or more deuterium atoms; or R 3 and R 4Together with the carbon atoms they are all connected to, they form cycloalkyl or heterocyclic groups, each of which is optionally substituted by one or more groups independently selected from the group consisting of: deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl and alkyl; R 5 and R 6 Each is independently selected from hydrogen, deuterium, alkyl, alkoxy, or haloalkyl, wherein the alkyl, the alkoxy, and the haloalkyl are optionally substituted with one or more deuterium; R 7 and R 8 The components are independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -alkyl-alkoxy, wherein the alkyl, the alkoxy, the haloalkyl, the hydroxyalkyl, and the -alkyl-alkoxy are optionally substituted with one or more deuterium; R 9 and R 10 The components are independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -alkyl-alkoxy, wherein the alkyl, the alkoxy, the haloalkyl, the hydroxyalkyl, and the -alkyl-alkoxy are optionally substituted with one or more deuterium; R a R b R c R d R e and R f Each of these is independently hydrogen, halogen, 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 The two in it are formed together with the spacer atoms , Cycloalkyl or heterocyclic groups, wherein each of the cycloalkyl and heterocyclic groups is optionally substituted by one or more groups independently selected from the group consisting of: deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl and alkyl; The condition is that when 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; R11 and R 12 Each is independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -alkyl-alkoxy, wherein the alkyl, the alkoxy, the haloalkyl, the hydroxyalkyl, and the -alkyl-alkoxy are optionally substituted with one or more deuterium; R 13 and R 14 Each is independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -alkyl-alkoxy, wherein the alkyl, the alkoxy, the haloalkyl, the hydroxyalkyl, and the -alkyl-alkoxy are optionally substituted with one or more deuterium; R s R t R v and R u Each of them is independently hydrogen, halogen, or an alkyl group optionally substituted with one or more deuterium atoms; R j and R k Each of these is independently hydrogen, halogen, or an alkyl group optionally substituted with one or more deuterium atoms; or R j and R k It forms together with the carbon atoms it is attached to. or ; The condition is that when 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 group substituted with one or more deuterium groups; Each R is independently selected from the group consisting of: deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, alkyl, alkenyl, and alkynyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, and haloalkyl are optionally substituted with one or more deuterium groups; Each R' is independently either hydrogen or deuterium; 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.

[0010] On the other hand, this disclosure provides a compound having a formula selected from the following: (Ia) (Ib) (Ic) (Id) (Ie) (If) (IIa) (IIIa) Or its pharmaceutically acceptable salt. in R 5 Selected from alkyl, alkoxy, or haloalkyl, wherein the alkyl, alkoxy, and haloalkyl are optionally substituted with one or more deuterium; Ring B is a cycloalkyl or heterocyclic group, each optionally substituted by one or more groups independently selected from the group consisting of: deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl and alkyl; The condition is R 7 and R 9 At least one of them is not hydrogen; and The condition is R 11 It is an alkyl group substituted with one or more deuterium atoms.

[0011] On the other hand, this disclosure provides a compound selected from any of those shown in Table 1.

[0012] On the other hand, this disclosure provides a pharmaceutical composition comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0013] On the other hand, this disclosure provides a method for inhibiting the activity of wild-type KRas, KRasG12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A and / or KRasQ61H in a subject in need, the method comprising administering to the subject an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0014] On the other hand, this 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, the method comprising administering to a subject in need an effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[0015] On the other hand, this disclosure provides a method for treating cancer in subjects in need, the method comprising: (a) It is known 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; and (b) administering to the subject an effective amount of the compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[0016] On the other hand, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof in the preparation of a medicament for treating cancer.

[0017] On the other hand, this disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof for the treatment of cancer. Detailed Implementation

[0018] Reference will now be made in detail to certain embodiments of this disclosure, examples of which are illustrated in the appended structures and formulas. While this disclosure will be described in conjunction with the enumerated embodiments, it should be understood that it is not intended to limit this disclosure to those embodiments. Rather, this disclosure is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of this disclosure as defined in the claims. Those skilled in the art will recognize that many methods and materials similar to or equivalent to those described herein can be used to practice this disclosure. This disclosure is by no means limited to the methods and materials described. In the event that one or more of the incorporated references and similar materials (including, but not limited to, defined terminology, usage of terminology, described techniques, etc.) differ from or contradict this application, this disclosure shall prevail. All references, patents, and patent applications cited in this disclosure are hereby incorporated in their entirety by reference.

[0019] It should be understood that certain features of this disclosure described in the context of individual embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of this disclosure described in the context of individual embodiments for brevity may also be provided individually or in any suitable sub-combination. It must be noted that, unless the context explicitly indicates otherwise, the singular forms “a,” “an,” and “the” as used in the specification and appended claims include their plural forms. Thus, for example, a reference to “a compound” includes multiple compounds.

[0020] definition The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described herein. In addition, the general principles of organic chemistry, as well as specific functional components and reactivity, are described in the following references: *Organic Chemistry*, Thomas Sorrell, 2nd ed., University Science Books, Sausalito, 2006; Smith and March, *March's Advanced Organic Chemistry*, 6th ed., John Wiley & Sons, Inc., New York, 2007; Larock, *Comprehensive Organic Transformations*, 3rd ed., VCH Publishers, Inc., New York, 2018; Carruthers, *Some Modern Methods of Organic Synthesis*, 4th ed., Cambridge University Press, Cambridge, 2004; the entire contents of each of the above references are incorporated herein by reference.

[0021] Linking substituents are described throughout this disclosure. In particular, each linking substituent includes both the forward and reverse forms of the linking substituent. For example, -NR(CR'R'')- includes both -NR(CR'R'')- and -(CR'R'')NR-. Where the structure explicitly requires a linking group, the Markush variable listed with respect to said group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition of said variable lists "alkyl", then it should be understood that said "alkyl" represents a linked alkylene group.

[0022] When the bond shown to the substituent crosses with the bond of two atoms in the linking ring, such a substituent may bond to any atom in the ring. When the listed substituent does not indicate that the substituent is bonded to any atom in the remaining part of the given compound, then the substituent may be bonded via any atom in the formula. Combinations of substituents and / or variables are permitted, but only if the combination produces a stable compound.

[0023] As used herein, for convenience, a dash “-” is used before or at the end of a chemical group to indicate the connection point of a substituent. For example, -OH is connected via a carbon atom; chemical groups may be depicted with one or more dashes or without one or more dashes without losing their general meaning. Wavy lines drawn through lines in the structure indicate the connection points of groups. The order in which chemical groups are written or named does not indicate or imply directionality unless required by chemistry or structure. As used herein, solid lines emanating from the center of the ring indicate that the connection point of a substituent on the ring can be at any atom of the ring. When a listed substituent does not indicate that the substituent is bonded to an atom of the remainder of a given compound, then the substituent may be bonded via any atom in the formula. Combinations of substituents and / or variables are permissible, but only if such combinations produce a stable compound.

[0024] In any variable (e.g., R) i When a compound appears more than once in any component or formula, its definition for each occurrence is independent of its definition for each subsequent occurrence. Therefore, for example, if the display group is represented by 0-2 R... i In the case of partial substitution, the group may optionally be replaced by up to two R groups. i Partial replacement, and R i Each time it appears, it is independently selected from R. i The definition of [the compound]. Furthermore, combinations of substituents and / or variables are permitted, but only if such combinations produce stable compounds.

[0025] As used herein, the term "KRas G12A" refers to a mutant form of the mammalian KRas protein containing an alanine-glycine substitution at amino acid position 12. The assignment of amino acid codons and residue positions for 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 regulating or inhibiting all or part of the enzymatic activity of Kras G12A. As used herein, "Kras G12A-related disease or condition" refers to a disease or condition associated with, mediated by, or possessing a Kras G12A mutation. A non-limiting example of a Kras G12A-related disease or condition is Kras G12A-related cancer.

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

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

[0028] As used in this article, the term "C" i-j "Indicates a range of carbon atoms, where i and j are integers, and the range includes the endpoints (i.e., i and j) and every integer point in between, where j is greater than i. For example, C..." 1-6The term "C" indicates a range from one to six carbon atoms, including one, two, three, four, five, and six carbon atoms. In some embodiments, the term "C" is used... 1-12 "Indicates 1 to 12 carbon atoms, especially 1 to 10 carbon atoms, especially 1 to 8 carbon atoms, especially 1 to 6 carbon atoms, especially 1 to 5 carbon atoms, especially 1 to 4 carbon atoms, especially 1 to 3 carbon atoms or especially 1 to 2 carbon atoms."

[0029] As used herein, the term "alkyl," whether used as part of another term or independently, refers to a saturated straight-chain or branched hydrocarbon group that may optionally and independently be substituted by one or more substituents described below. The term "C 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. "C 1-10 Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. "C" 1-6 Examples of "alkyl" are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-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, 3,3-dimethyl-2-butyl, etc.

[0030] As used herein, the term "alkenyl," whether used as part of another term or independently, refers to a straight-chain or branched hydrocarbon group having at least one carbon-carbon double bond that may optionally and independently be substituted by one or more substituents described herein, and includes groups having "cis" and "trans" orientations or alternatively "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, vinyl (ethylenyl or vinyl), propenyl (allyl), butenyl, pentenyl, 1-methyl-2-buten-1-yl, 5-hexenyl, etc.

[0031] As used herein, the term "alkynyl," whether used as part of another term or independently, refers to a straight-chain or branched hydrocarbon group having at least one carbon-carbon triple bond that can be optionally and independently substituted by one or more substituents 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, 2-propynyl, etc.

[0032] As used herein, the term "alkoxy," whether used as part of another term or independently, refers to an alkyl group linked to the parent molecule via an oxygen atom, as previously defined. The term "C..." 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. "C 1-6 Examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, neopentoxy, n-hexyloxy, etc.

[0033] As used herein, the term "amino" refers to the -NH2 group. Amino groups can also be substituted by 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 a monovalent non-aromatic saturated or partially unsaturated monocyclic and polycyclic system in which all ring atoms are carbon, and said system comprises at least three cyclic carbon atoms. In some embodiments, the cycloalkyl group may contain 3 to 12 cyclic carbon atoms, 3 to 10 cyclic carbon atoms, 3 to 9 cyclic carbon atoms, 3 to 8 cyclic carbon atoms, 3 to 7 cyclic carbon atoms, 3 to 6 cyclic carbon atoms, 3 to 5 cyclic carbon atoms, 4 to 12 cyclic carbon atoms, 4 to 10 cyclic carbon atoms, 4 to 9 cyclic carbon atoms, 4 to 8 cyclic carbon atoms, 4 to 7 cyclic carbon atoms, 4 to 6 cyclic carbon atoms, or 4 to 5 cyclic carbon atoms. The cycloalkyl group may be saturated or partially unsaturated. The cycloalkyl group may be substituted. In some embodiments, the cycloalkyl group may be a saturated cyclic alkyl group. In some embodiments, the cycloalkyl group may be a partially unsaturated cycloalkyl group comprising at least one double or triple bond in its ring system. In some embodiments, the cycloalkyl group may be monocyclic or polycyclic. In the case of polycyclic systems, the cycloalkyl group includes fused systems (e.g., one cycloalkyl ring fused to another cycloalkyl ring), spirocyclic systems, and bridged ring systems. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, adamantyl, norbornel, fluorenyl, spiropeptadienyl, spiro[3.6]decyl, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, etc.

[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 iodo).

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

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

[0039] As used herein, the term "heterocyclic group" refers to a saturated or partially unsaturated carbocyclic group, wherein one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, etc., and the remaining ring atoms are carbon, wherein one or more ring atoms may optionally be independently substituted by one or more substituents. In some embodiments, the heterocyclic group is a saturated heterocyclic group. In some embodiments, the heterocyclic group is a partially unsaturated heterocyclic group having one or more double bonds in its ring system. The heterocyclic group can be a monocyclic or polycyclic system. In the case of a polycyclic system, the heterocyclic group can include a fused ring system, a spirocyclic system, or a bridged ring system. For example, a polycyclic heterocyclic group may comprise a heterocyclic ring fused to one or more other rings (such as a cycloalkyl or heterocyclic ring), or a cycloalkyl ring fused to one or more heterocyclic rings. In some embodiments, the heterocyclic group may contain any oxidized form of carbon, nitrogen, or sulfur and any quaternized form of basic nitrogen. Where possible, the heterocyclic group may be carbon-linked or nitrogen-linked. In some embodiments, the heterocycle is carbon-linked. In some embodiments, the heterocycle is nitrogen-linked. For example, the groups derived from pyrrole can be pyrrole-1-yl (nitrogen-linked) or pyrrole-3-yl (carbon-linked).

[0040] In some embodiments, the term "3- to 12-membered heterocyclic group" refers to a 3- to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of heterocyclic groups include, but are not limited to, aziridinyl, aziridine, oxazolidinyl, dioxolanyl, dihydrofuranyl, thiophenyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidyl, oxazolyl, piperidinyl, piperazine, 4-piperidinoneyl, pyrrolyl, pyrazolyl, and quinine cycloesteryl. Thiazolyl, tetrahydrofuranyl, trithienyl, 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-dioxacyclopenten-4-yl, and 2-oxo-1,3-dioxacyclopenten-4-yl.

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

[0042] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups as defined above. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0043] As used in this article, the term "nitro" refers to -NO2.

[0044] As used herein, the term "partially unsaturated" refers to a group comprising at least one double or triple bond. The term "partially unsaturated" is intended to cover rings having multiple unsaturated sites, but is not intended to include aromatic (i.e., completely unsaturated) portions.

[0045] As used herein, the term “substituted,” whether or not preceded by the term “optionally,” means that one or more hydrogen atoms in the specified moiety are replaced by suitable substituents. It should be understood that “substituted” or “replaced by” includes the implicit precondition that such substitution is consistent with the permissible valence of the substituted atom and that the substitution yields a stable or chemically viable compound, e.g., a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, or elimination. Unless otherwise stated, an “optionally substituted” group may have suitable substituents at each substituted position of the group, and where more than one position in any given structure can be substituted by more than one substituent selected from the specified group, the substituents at each position may be the same or different. Those skilled in the art will understand that the substituent itself may be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to the chemical moiety herein should be understood to include substituted variants. For example, references to an “aryl” group or part thereof implicitly include both substituted and unsubstituted variants.

[0046] compound On the one hand, this disclosure provides a compound having formula (I), formula (II) or formula (III): (I) (II) (III) Or its pharmaceutically acceptable salt. in Ring A is ; X is -C(R) e R f -, -O- or -N(R) X )-; R X It is hydrogen, deuterium, alkyl, or cycloalkyl, wherein the alkyl and the cycloalkyl are optionally substituted with one or more deuterium; Ring E is ; Z is -C(R) j R k -, -O- or -N(R) Z )-; R Z It is hydrogen, deuterium, alkyl, or cycloalkyl, wherein the alkyl and the cycloalkyl are optionally substituted with one or more deuterium; R 1 and R 2Each is independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, or haloalkyl, wherein the alkyl, the alkoxy, and the haloalkyl are optionally substituted with one or more deuterium; R 3 and R 4 Each is independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, or haloalkyl, wherein the alkyl, the alkoxy, and the haloalkyl are optionally substituted with one or more deuterium atoms; or R 3 and R 4 Together with the carbon atoms they are all connected to, they form cycloalkyl or heterocyclic groups, each of which is optionally substituted by one or more groups independently selected from the group consisting of: deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl and alkyl; R 5 and R 6 Each is independently selected from hydrogen, deuterium, alkyl, alkoxy, or haloalkyl, wherein the alkyl, the alkoxy, and the haloalkyl are optionally substituted with one or more deuterium; R 7 and R 8 The components are independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -alkyl-alkoxy, wherein the alkyl, the alkoxy, the haloalkyl, the hydroxyalkyl, and the -alkyl-alkoxy are optionally substituted with one or more deuterium; R 9 and R 10 The components are independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -alkyl-alkoxy, wherein the alkyl, the alkoxy, the haloalkyl, the hydroxyalkyl, and the -alkyl-alkoxy are optionally substituted with one or more deuterium; R a R b R c R d R e and R f Each of these is independently hydrogen, halogen, 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 The two in it are formed together with the spacer atoms , Cycloalkyl or heterocyclic groups, wherein each of the cycloalkyl and heterocyclic groups is optionally substituted by one or more groups independently selected from the group consisting of: deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl and alkyl; The condition is that when 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 is independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -alkyl-alkoxy, wherein the alkyl, the alkoxy, the haloalkyl, the hydroxyalkyl, and the -alkyl-alkoxy are optionally substituted with one or more deuterium; R 13 and R 14 Each is independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -alkyl-alkoxy, wherein the alkyl, the alkoxy, the haloalkyl, the hydroxyalkyl, and the -alkyl-alkoxy are optionally substituted with one or more deuterium; R s R t R v and R u Each of them is independently hydrogen, halogen, or an alkyl group optionally substituted with one or more deuterium atoms; R j and R k Each of these is independently hydrogen, halogen, or an alkyl group optionally substituted with one or more deuterium atoms; or R j and R k It forms together with the carbon atoms it is attached to. or ; The condition is that when 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 group substituted with one or more deuterium groups; Each R is independently selected from the group consisting of: deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, alkyl, alkenyl, and alkynyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, and haloalkyl are optionally substituted with one or more deuterium groups; Each R' is independently either hydrogen or deuterium; 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.

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

[0048] In some embodiments of 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 deuterium atoms. In some embodiments, R 3 and R 4 One of them is hydrogen, and the other is C. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl groups, each optionally substituted with one or more deuterium atoms. In some embodiments, R 3 and R 4 One of them is hydrogen, and the other is a methyl group optionally substituted with one or more deuterium atoms. In some embodiments, R 3 and R 4 One of them is hydrogen, and the other is -CH3 or -CD3.

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

[0050] In some embodiments of 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 deuterium atoms, and the other is hydrogen. In some embodiments, R 5 and R 6 One of them is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl groups, each optionally substituted with one or more deuterium atoms, and the other being hydrogen. In some embodiments, R 5 and R 6 One of them 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 It is hydrogen.

[0052] In some embodiments of the compound of formula (I), R 5 and R 6 One of them is an alkyl group optionally substituted with one or more deuterium atoms, and the other is hydrogen, and R 7 R 8 R 9 and R 10 It is hydrogen. In some embodiments, R 5 and R 6 One of them is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl groups, each optionally substituted with one or more deuterium atoms, the other with hydrogen, and R 7 R 8 R 9 and R 10 It is hydrogen.

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

[0054] In some embodiments of the compound of formula (I), R 7 and R8 One of them is an alkyl, alkoxy, -alkyl-alkoxy, hydroxyalkyl, or haloalkyl group, each optionally substituted with one or more deuterium groups, and the other is hydrogen or deuterium. In some embodiments, R 7 and R 8 One of them is C 1-6 Alkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-(C 1-6 alkoxy), C 1-6 Hydroxyalkyl or C 1-6 The alkyl halogroups are each optionally substituted with one or more deuterium atoms, and the other is hydrogen or deuterium. In some embodiments, R 7 and R 8 One of them 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, R 7 and R 8 One of them is an alkyl, alkoxy, -alkyl-alkoxy, hydroxyalkyl, or haloalkyl group, each optionally substituted with one or more deuterium groups, and the other is hydrogen or deuterium. In some embodiments, R 5 and R 6 Both are hydrogen, R 7 and R 8 One of them is C 1-6 Alkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-(C 1-6 alkoxy), C 1-6 Hydroxyalkyl or C 1-6 The alkyl halogroups are each optionally substituted with one or more deuterium atoms, and the other is hydrogen or deuterium. In some embodiments, R 5 and R 6 Both are hydrogen, R 7 and R 8 One of them 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), R 9 and R 10 One of them is hydrogen, and the other is hydrogen or an alkyl group optionally substituted with one or more deuterium atoms. In some embodiments, R 9and R 10 One of them is hydrogen, and the other is hydrogen, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl groups, each optionally substituted with one or more deuterium atoms. In some 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, R 9 and R 10 One of them is hydrogen, and the other is hydrogen or an alkyl group optionally substituted with one or more deuterium atoms. In some embodiments, R 5 and R 6 Both are hydrogen, R 9 and R 10 One of them is hydrogen, and the other is hydrogen, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl groups, each optionally substituted with one or more deuterium atoms. In some embodiments, R 5 and R 6 Both are hydrogen, 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 Together with spacer atoms, they form heterocyclic groups, or R 7 and R a Together with the spacer atoms, they form a heterocyclic group. In some embodiments, ring A is... or .

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

[0060] In some embodiments of the compound of formula (I), R 5 and R 6 Both are hydrogen, R 7 and R 9 Together with spacer atoms, they form heterocyclic groups, or R 7 and R a Together with the spacer atoms, they form heterocyclic groups. In some embodiments, R 5 and R 6 Both are hydrogen, and ring A is... or .

[0061] In some embodiments of the compound of formula (I), X is -C(R) e R f )-, and R a and R e Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, each optionally substituted by one or more groups independently selected from the group consisting of: deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl. In some embodiments, X is -C(R e R f )-, and R a and R e Together with the carbon atom it is attached to, they form C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic groups, each optionally substituted by one or more groups independently selected from the group consisting of: deuterium, 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 , , or .

[0064] In some embodiments of the compound of formula (I), R 5 and R 6 Both are hydrogen, and ring A is... , , or , where R 7 and R 8 One of them is an alkyl, alkoxy, alkyl-alkoxy, or haloalkyl group, each optionally substituted with one or more deuterium groups, and the other is hydrogen or deuterium. In some embodiments, R7 and R 8 One of them is an alkyl group (e.g., C10). 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 One is an alkyl group, and the other is hydrogen or deuterium. In some 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 deuterium, and the other is hydrogen or an alkyl group optionally substituted with one or more deuterium groups (e.g., C10). 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group). In some 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 It forms together with the carbon atoms it is attached to. In some embodiments, each R'' is independently selected from hydrogen or halogen. In some embodiments, one R'' is a halogen and the other is hydrogen. In some embodiments, both R'' are halogens, such as fluorine.

[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 8 One of them is an alkyl, alkoxy, alkyl-alkoxy, or haloalkyl group, each optionally substituted with one or more deuterium groups, and the other is hydrogen or deuterium. In some embodiments, R 7 and R 8 One of them is C 1-6 Alkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-(C 1-6 alkoxy) or C 1-6 The alkyl halogroups are each optionally substituted with one or more deuterium atoms, and the other is hydrogen or deuterium. In some embodiments, R 7 and R8 One of them is -CH3, -CD3, -CH2-OCH3, -CH2-OCD3, -CH2F, -CHF2, or -CF3, and the other is hydrogen or deuterium.

[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 deuterium atoms, and the other is hydrogen or deuterium. In some embodiments, R 7 and R 8 One of them is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl groups, each of which is substituted with one or more deuterium atoms, 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 10 One of them is hydrogen or deuterium, and the other is hydrogen or an alkyl group optionally substituted with one or more deuterium atoms. In some embodiments, R 9 and R 10 One of them is hydrogen, and the other is hydrogen, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl groups, each optionally substituted with one or more deuterium atoms. In some embodiments, R 9 and R 10 One of them is hydrogen, and the other is hydrogen, methyl, or CD3. In some embodiments, R 9 and R 10 Both are hydrogen.

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

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

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

[0074] In some embodiments of the compounds of formula (II) or (III), R 5 and R 6 Both are hydrogen, R 13 and R14 One of them is hydrogen, and the other is hydrogen or an alkyl group optionally substituted with one or more deuterium atoms. In some embodiments, R 5 and R 6 Both are hydrogen, R 13 and R 14 One of them is hydrogen, and the other is hydrogen, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl groups, each optionally substituted with one or more deuterium atoms. In some embodiments, both R5 and R6 are hydrogen, one of R13 and R14 is hydrogen, and the other is hydrogen, methyl, or CD3. In some embodiments, R... 5 and R 6 Both are hydrogen, and R 13 and R 14 Both are hydrogen.

[0075] In some embodiments of the compounds of formula (II) or (III), R u and R v One of them is hydrogen, and the other is hydrogen or an alkyl group optionally substituted with one or more deuterium atoms. In some embodiments, R u and R v One of them is hydrogen, and the other is hydrogen, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl groups, each optionally substituted with one or more deuterium atoms. In some 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 compounds of formula (II) or (III), R 5 and R 6 Both are hydrogen, R u and R v One of them is hydrogen, and the other is hydrogen or an alkyl group optionally substituted with one or more deuterium atoms. In some embodiments, R 5 and R 6 Both are hydrogen, R u and R v One of them is hydrogen, and the other is hydrogen, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C1-2 Alkyl groups, each optionally substituted with one or more deuterium atoms. In some embodiments, R 5 and R 6 Both are hydrogen, R u and R v One of them is hydrogen, and the other is hydrogen, methyl, or CD3.

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

[0078] In some embodiments of compounds of formula (II) or (III), Z is -C(R) j R k )-, and R j and R k It forms together with the carbon atoms it is attached to. In some embodiments, one R'' is a halogen and the other is hydrogen. In some embodiments, both R'' are halogens, such as fluorine.

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

[0080] In some embodiments of the compounds of formula (II) or (III), R 11 and R 12 One of them is an alkyl, alkoxy, alkyl-alkoxy, or haloalkyl group, each optionally substituted with one or more deuterium groups, and the other is hydrogen or deuterium. In some embodiments, R 11 and R 12 One of them is C 1-6 Alkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-(C 1-6 alkoxy) or C 1-6 The alkyl halogroups are each optionally substituted with one or more deuterium atoms, and the other is hydrogen or deuterium. In some embodiments, R 11 and R 12 One of them is -CH3, -CD3, -CH2-OCH3, -CH2-OCD3, -CH2F, -CHF2, or -CF3, and the other is hydrogen or deuterium.

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

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

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

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

[0085] In another aspect, this disclosure provides a compound having a formula selected from the following: (Ia) (Ib) (Ic) (Id) (Ie) (If) (IIa) (IIIa) Or its pharmaceutically acceptable salt. in R 5 Selected from alkyl, alkoxy, or haloalkyl, wherein the alkyl, alkoxy, and haloalkyl are optionally substituted with one or more deuterium; Ring B is a cycloalkyl or heterocyclic group, each optionally substituted by one or more groups independently selected from the group consisting of: deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl and alkyl; The condition is R 7 and R 9 At least one of them is not hydrogen; and The condition is R 11 It is an alkyl group substituted with one or more deuterium atoms.

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

[0087] In some embodiments of compounds of formula (I), (II), (III), (Ia), (Ib), (Ic), (Id), (Ie), (If), (IIa), or (IIb), each R is independently selected from cyano, halogen, hydroxyl, amino, haloalkyl, alkyl, or alkynyl, wherein the alkyl or alkynyl group is optionally substituted with one or more deuterium groups. In some embodiments, each R is independently selected from 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 alkynyl group, C 2-5 alkynyl group, C 2-4 alkynyl or C 2-3The alkynyl group, wherein the alkyl group or the alkynyl group is optionally substituted with one or more deuterium groups. In some embodiments, each R is independently selected from fluorine, chlorine, -NH2, -CF3, hydroxyl, ethyl, or ethynyl, wherein the ethyl group or the ethynyl group is optionally substituted with one or more deuterium groups.

[0088] In some embodiments of compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), or formula (If), Choose from the following groups: , , , , , , , , , , and .

[0089] In some embodiments of compounds of formula (II) or (IIa), Choose from the following groups: , and .

[0090] In some embodiments of compounds of formula (III) or (IIIa), Choose from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , and .

[0091] In some embodiments of 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 deuterium.

[0092] In some embodiments of 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 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 deuterium.

[0094] In some embodiments, this disclosure provides a compound having the formula selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Or its pharmaceutically acceptable salt.

[0095] In some embodiments, exemplary compounds of this disclosure are shown in Table 1 below: Table 1. Exemplary Compounds of this Disclosure .

[0096] The compounds described herein are described with reference to both general formulas and specific compounds. Furthermore, the compounds disclosed herein may exist in a variety of different forms or derivatives, including but 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 solvent degradation, yields the desired active compound. Prodrugs include, but are not limited to, esters, amides, carbamates, carbonates, acylureas, solvates, or hydrates of the active compound. Typically, prodrugs are inactive or less active than the active compound, but may provide one or more advantageous disposal, administration, and / or metabolic properties. For example, some prodrugs are esters of the active compound; during metabolism, the ester group is cleaved to produce the active drug. Furthermore, some prodrugs are compounds that are enzymatically activated to produce the active compound or that produce the active compound after further chemical reactions. A prodrug can develop from its prodrug form to its active form in a single step, or it can have one or more intermediate forms that may be active or inactive on their own. The preparation and use of prodrugs are discussed in the following references: T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems”, Volume 14 of the ACS Symposium Series, Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; Prodrugs: Challenges and Rewards, edited by V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley, Springer Verlag New York, 2007. These references are hereby incorporated in full.

[0098] As used herein, the term "soft drug" refers to a compound that exerts a pharmacological effect but breaks down into inactive metabolites and degradation products, resulting in a limited duration of activity. See, for example, "Soft drugs: Principles and methods for the design of safe drugs," Nicholas Bodor, *Medicinal Research Reviews*, Vol. 4, No. 4, pp. 449-469, 1984, which is hereby incorporated in its entirety by reference.

[0099] As used herein, the term "metabolite," such as an active metabolite, overlaps with the prodrug described above. Therefore, such metabolites are pharmacologically active compounds or compounds further metabolized into pharmacologically active compounds, which are derivatives produced by metabolic processes within the body. For example, such metabolites can be generated by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the applied compound or its salt or prodrug. Active metabolites are such pharmacologically active derivatives. For prodrugs, the prodrug compound is typically inactive or less active than the metabolite. For active metabolites, the parent compound can be an active compound or an inactive prodrug.

[0100] Prodrugs and active metabolites can be identified using conventional techniques known in the art. See, for example, Bertolini et al., 1997, *Journal of Medicinal Chemistry* 40:2011-2016; Shan et al., *JPharm Sci* 86:756-757; Bagshawe, 1995, *Drug Dev Res* 34:220-230; Wermuth, ibid.

[0101] As used herein, the term "pharmaceutically acceptable" means that a substance or composition is chemically and / or toxicologically compatible with the other components constituting the formulation and / or the subject being treated.

[0102] As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salt" includes salts that retain the bioavailability of the specified compound as a free acid and base and are not biologically or otherwise undesirable. Contemplated pharmaceutically acceptable salt forms include, but are not limited to, monosalts, disalts, trisalts, tetrasalts, etc. Pharmaceutically acceptable salts are non-toxic at the amount and concentration in which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical properties of the compound without impairing 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 drug concentrations.

[0103] Pharmaceutically acceptable salts include acid addition salts, such as the following: sulfates, chlorides, hydrochlorides, fumarates, maleates, phosphates, aminosulfonates, acetates, citrates, lactates, tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylaminosulfonates, and quinates. Pharmaceutically acceptable salts can be obtained from acids such as: hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, aminosulfonic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylaminosulfonic acid, fumaric acid, and quinates.

[0104] Pharmaceutically acceptable salts also include base addition salts when acidic functional groups such as carboxylic acids or phenols are present, such as those containing: benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines, and zinc. See, for example, Remington's Pharmaceutical Sciences, 19th edition, Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. These salts can be prepared using appropriate corresponding bases.

[0105] Pharmaceutically acceptable salts can be prepared using standard techniques. For example, the free base form of a compound can be dissolved in a suitable solvent (such as an aqueous solution or a water-alcohol solution containing a suitable acid) and then separated by evaporation of the solution. Thus, if a particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, by treating the free base with: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid; pyranoside acids such as glucuronic acid or galacturonic acid; α-hydroxy acids such as citric acid or tartaric acid; amino acids such as aspartic acid or glutamic acid; aromatic acids such as benzoic acid or cinnamic acid; sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid; and so on.

[0106] Similarly, if a particular compound is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, or an alkaline earth metal hydroxide. Illustrative examples of suitable salts include organic salts derived from amino acids such as L-glycine, L-lysine, and L-arginine; ammonia, primary amines, secondary amines, 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] It should also be understood that the compounds disclosed herein may exist in non-solventized, solvated (e.g., hydrated) and solid (e.g., crystalline or polycrystalline) forms, and this disclosure is intended to cover all such forms.

[0108] As used herein, the term "solvent" or "solventized form" refers to a solvation form that includes stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency in their crystalline solid state to trap a fixed molar ratio of solvent molecules, thereby forming a solvate. If the solvent is water, the formed solvate is a hydrate, and if the solvent is an alcohol, the formed solvate is an alcohol. Hydrates are formed by combining one or more water molecules with a molecule of substance in which water retains its molecular state as H₂O. 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 “crystalline form,” “polycrystalline form,” “polymorph,” and “polymorph” are used interchangeably and refer to the crystalline structures in which a compound (or its salts or solvates) can crystallize in different crystalline arrangements, all of which have the same elemental composition. Different crystalline forms typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors may cause one crystalline form to dominate. Crystalline 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 the compounds. Isotopes of atoms include atoms having the same atomic number but different mass numbers. For example, unless otherwise stated, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the compounds of this disclosure are intended to also include their isotopes, such as, but not limited to, those of other atoms. 1 H, 2 H, 3 H, 11 C 12 C13 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 I. In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes... 12 C and 13 C. Isotope-enriched compounds of formula (I), (II), (III), (Ia), (Ib), (Ic), (Id), (Ie), (If), (IIa), or (IIIa) can be prepared without excessive experimentation using conventional techniques well known to those skilled in the art or by methods similar to those described in the embodiments and examples herein, using appropriate isotope-enriching reagents and / or intermediates.

[0111] In some embodiments, this disclosure includes compounds of formula (I), (II), (III), (Ia), (Ib), (Ic), (Id), (Ie), (If), (IIa), or (IIIa), wherein one or more hydrogen atoms bonded to a carbon atom are replaced by deuterium. Such compounds are synthesized by means known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0112] Those skilled in the art will understand that the compounds of this disclosure can exist in different tautomeric forms, and all such forms are covered within the scope of this disclosure. The terms "tautomer" or "tautomeric form" refer to structural isomers of different energies that can interconvert through low energy barriers. The presence and concentration of isomeric forms will depend on the environment in which the compound exists and can vary, for example, whether the compound is a solid or whether it is in an organic or aqueous solution. For example, proton tautomers (also called proton-heterotautomers) include interconversions via proton migration, such as keto-enol, amide-imino, lactam-lactamimide, imine-enamine isomerization, and cyclic forms where protons can occupy two or more positions in a heterocyclic system. Valence tautomers include interconversions via the recombination of some bonding electrons. Tautomers can be in equilibrium or spatially locked into one form through appropriate substitution. Unless otherwise stated, compounds of this disclosure identified by name or structure as a particular tautomeric form are intended to include other tautomeric forms.

[0113] Compound Synthesis The compounds presented in this article can be prepared using any known organic synthesis technique and can be synthesized according to any of a variety of possible synthetic routes.

[0114] 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 are substantially non-reactive to the starting materials (reactants), intermediates, or products at temperatures where the reaction takes place, for example, a range that can be from the solvent's freezing point to its boiling point. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, the solvent suitable for that particular reaction step can be selected by those skilled in the art.

[0115] The preparation of the compounds disclosed herein may involve the protection and deprotection of various chemical groups. Those skilled in the art can readily determine the need for protection and deprotection, as well as the selection of appropriate protecting groups. The chemistry of protecting groups can be found, for example, in the following references: TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, 3rd ed., John Wiley & Son, New York, (1999); P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003; and Peter GM Wuts, Greene's Protective Groups in Organic Synthesis, 5th ed., Wiley, 2014, all of which are incorporated herein by reference in their entirety.

[0116] The reaction can be monitored using any suitable method known in the art. For example, it can be monitored using methods such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) Spectroscopic methods such as infrared spectroscopy, spectrophotometry (e.g., UV-visible), and mass spectrometry, or chromatographic methods such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC) can be used to monitor product formation. Those skilled in the art can purify compounds using 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, cited in full herein) and normal-phase silica gel chromatography.

[0117] Uses of compounds On one hand, this disclosure provides compounds capable of inhibiting KRAS proteins. 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 some embodiments, the KRAS protein is the KRas G12D protein.

[0118] As used herein, the term "therapy" is intended to have its normal meaning, namely, treating a disease to completely or partially alleviate one, some, or all of its symptoms, or to correct or compensate for the underlying pathology, 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, symptom relief, reduction of disease severity, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or mitigation of the disease state, and remission (whether partial or complete), whether detectable or undetectable. "Therapy" may also mean prolonged survival compared to expected survival without therapy. Situations requiring therapy include having a pre-existing condition or symptom, being susceptible to a condition or symptom, or needing to prevent a condition or symptom. Unless specifically indicated to the contrary, the term "therapy" also encompasses prevention. The terms "treatment" and "therapeutic" should be interpreted accordingly.

[0119] As used herein, the term “prevention” is intended to have its normal meaning and includes primary prevention for preventing the development of disease and secondary prevention for protecting patients who have already developed disease from the onset or worsening of the disease or the development of new disease-related symptoms, either temporarily or permanently.

[0120] The terms “treating / treatment” and “therapy” are used synonymously. Similarly, the term “treatment” can be considered as “the application of therapy,” where “therapy” is as defined herein.

[0121] On the other hand, this disclosure provides the use of a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure, for therapeutic purposes, such as for therapies related to 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 some embodiments, the therapy is associated with the KRAS G12D protein.

[0122] On the other hand, this disclosure provides the use of a compound of the disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of a medicament for treating cancer.

[0123] In some embodiments, the cancer is mediated by the KRAS protein. In some embodiments, the 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 some embodiments, the cancer is mediated by the KRAS G12D protein.

[0124] Pharmaceutical Composition On the other hand, pharmaceutical compositions are provided that comprise one or more compounds disclosed herein or pharmaceutically acceptable salts thereof.

[0125] On the other hand, a pharmaceutical composition is provided comprising one or more of the compounds disclosed herein or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0126] As used herein, the term "pharmaceutical composition" refers to a formulation of the molecules or compounds included in this disclosure in a form suitable for administration to a subject.

[0127] As used herein, the term "pharmaceuticalally acceptable excipient" means an excipient that can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, and biologically and otherwise desirable, and includes excipients that are acceptable for both veterinary and human pharmaceutical use. As used herein, "pharmaceuticalally acceptable excipient" includes one or more such excipients. The term "pharmaceuticalally acceptable excipient" also covers "pharmaceuticalally acceptable carriers" and "pharmaceuticalally acceptable diluents."

[0128] The specific excipients used will depend on the means and purpose of applying the compounds disclosed herein. Solvents are typically selected based on those deemed safe by those skilled in the art for use in mammals, including humans. Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), and mixtures thereof.

[0129] In some embodiments, suitable excipients may include buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethyl ammonium chloride; benzalkonium chloride; benzyl chloride; phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoate, such as methyl or propyl p-hydroxybenzoate; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) peptides; proteins, such as serum albumin, gelatin, or... Immunoglobulins; 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 dextran; 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, flow aids, processing aids, colorants, sweeteners, flavorings, and other known additives to provide the optimal presentation of the drug (i.e., the compounds of this disclosure or pharmaceutical compositions thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a drug). The active pharmaceutical ingredient may also be encapsulated in microcapsules, for example, prepared by coagulation techniques or by interfacial polymerization, such microcapsules being, for example, hydroxymethyl cellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in crude emulsions. Such techniques are disclosed in Remington’s Pharmaceutical Sciences, 16th edition, Osol, A. (1980). “Liposomes” are small vesicles containing various types of lipids, phospholipids, and / or surfactants that can be used to deliver drugs (such as the compounds disclosed herein and optionally chemotherapeutic agents) to mammals, including humans. The components of liposomes are usually arranged in a bilayer, similar to the lipid arrangement of biological membranes.

[0131] The pharmaceutical compositions provided herein may be administered to subjects, including but not limited to humans, and may be formulated into any form compatible with the intended route of administration.

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

[0133] The amount of active ingredient in a unit dosage form of a composition is a therapeutically effective amount and varies depending on the specific treatment involved. As used herein, the term "therapeuticly effective amount" refers to the amount of a molecule, compound, or composition containing said molecule or compound that treats, improves, or prevents an identified disease or symptom or exhibits detectable therapeutic or inhibitory effects. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, body type, and health status; the nature and severity of the symptom; the rate of administration; the choice of the therapeutic agent or combination of therapeutic agents used for administration; and the judgment of the prescribing physician. The therapeutically effective amount in a given situation can be determined by routine testing within the skill and judgment of a clinician.

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

[0135] In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of tablet formulations. Pharmaceutically acceptable excipients suitable for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate, or calcium carbonate; granulating and disintegrants such as corn starch or alginate; binders such as starch; lubricants such as magnesium stearate, stearic acid, or talc; preservatives such as ethylparaben or propylparaben; and antioxidants such as ascorbic acid. Tablet formulations may be uncoated or coated to regulate their disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability and / or appearance; in either case, conventional coating agents and procedures well known in the art are used.

[0136] In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of hard gelatin capsules, wherein 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, wherein the active ingredient is mixed with water or oil, such as peanut oil, liquid paraffin or olive oil.

[0137] In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of an aqueous suspension, which typically comprises an active ingredient in fine powder form and one or more suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; dispersants or wetting agents, such as lecithin or condensation products of olefins and fatty acids (e.g., polyoxyethylene stearate); or condensation products of ethylene oxide and long-chain fatty alcohols, such as heptadecetylated cetyl alcohol; or condensation products of ethylene oxide and esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate; or condensation products of ethylene oxide and esters derived from fatty acids and hexitol anhydrides, such as polyvinyl sorbitan monooleate. Aqueous suspensions may also include one or more preservatives (such as ethylparaben or propylparaben), antioxidants (such as ascorbic acid), colorants, flavorings and / or sweeteners (such as sucrose, saccharin or aspartame).

[0138] In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of an oily suspension, which typically contains a suspended active ingredient in a vegetable oil (such as peanut oil, castor oil, olive oil, sesame oil, or coconut oil) or a mineral oil (such as liquid paraffin). The oily suspension may also include a thickener, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (such as those described above) and flavoring agents may be added to provide a palatable oral formulation. These compositions may be preserved by adding antioxidants (such as ascorbic acid).

[0139] In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil; or a mineral oil, such as liquid paraffin; or any mixture of these oils. Suitable emulsifiers may be, for example, naturally occurring gums, such as gum arabic or tragacanth; naturally occurring phospholipids, such as soybean, lecithin, esters or metaesters derived from fatty acids and hexadiol anhydrides (e.g., sorbitan monooleate), and condensation products of said metaesters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also include sweeteners, flavoring agents, and preservatives.

[0140] In some embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may include sweeteners such as glycerin, propylene glycol, sorbitol, aspartame, or sucrose; modifiers; preservatives; flavoring agents and / or coloring agents.

[0141] In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of a formulation for injection.

[0142] In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of sterile injectable formulations, such as sterile injectable aqueous or oily suspensions. Such suspensions may be formulated using suitable dispersants or wetting agents and suspending agents mentioned above, according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol or prepared as lyophilized powders. Acceptable mediators and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile non-volatile oils may conventionally be used as solvents or suspension media. For this purpose, any mild non-volatile oil may be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid may also be used in the preparation of injectable formulations.

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

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

[0145] In some embodiments, the pharmaceutical compositions disclosed herein may be in the form of formulations for topical or transdermal application.

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

[0147] In some embodiments, the pharmaceutical compositions provided herein can be formulated in the form of transdermal patches, as is well known to those skilled in the art.

[0148] In addition to the representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in this disclosure. Such excipients and carriers are described, for example, in: “Remington’s Pharmaceutical Sciences”, Mack Pub. Co., New Jersey (1991); “Remington: The Science and Practice of Pharmacy”, edited by University of the Sciences in Philadelphia, 21st edition, LWW (2005), the references of which are incorporated herein by reference.

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

[0150] In some embodiments, the pharmaceutical compositions of this disclosure can be formulated such that they can be administered at doses ranging from 0.001 mg / kg body weight / day to 1000 mg / kg body weight / day, for example, 0.01 mg / kg body weight / day to 800 mg / kg body weight / day, 0.01 mg / kg body weight / day to 700 mg / kg body weight / day, 0.01 mg / kg body weight / day to 600 mg / kg body weight / day, 0.01 mg / kg body weight / day to 500 mg / kg body weight / day, 0.01 mg / kg body weight / day to 400 mg / kg body weight / day, 0.01 mg / kg body weight / day to 300 mg / kg body weight / day, 0.1 mg / kg body weight / day to 200 mg / kg body weight / day, 0.1 mg / kg body weight / day to 150 mg / kg body weight / day, 0.1 mg / kg body weight / day to 100 mg / kg body weight / day, 0.5 mg / kg body weight / day to 100 mg / kg body weight / day. The compounds described herein, or their pharmaceutically acceptable salts, may be administered at doses ranging from 0.5 mg / kg body weight / day to 80 mg / kg body weight / day, from 0.5 mg / kg body weight / day to 60 mg / kg body weight / day, from 0.5 mg / kg body weight / day to 50 mg / kg body weight / day, from 1 mg / kg body weight / day to 50 mg / kg body weight / day, from 1 mg / kg body weight / day to 45 mg / kg body weight / day, from 1 mg / kg body weight / day to 40 mg / kg body weight / day, from 1 mg / kg body weight / day to 35 mg / kg body weight / day, from 1 mg / kg body weight / day to 30 mg / kg body weight / day, and from 1 mg / kg body weight / day to 25 mg / kg body weight / day. In some cases, dose levels below the lower limit of the foregoing ranges may be sufficient, while in other cases, larger doses may be used without causing any adverse side effects, provided that such larger doses are first divided into several smaller doses for administration throughout the day. Further information regarding the route of administration and dosage regimen can be found in Comprehensive Medicinal Chemistry, Volume 5, Chapter 25.3 (Corwin Hansch; Chairman of the Editorial Board), Pergeman Publishers, 1990, and the references cited herein are specifically incorporated by way of citation.

[0151] In some embodiments, the pharmaceutical compositions of this disclosure can be formulated into short-acting, rapid-release, long-acting, and sustained-release forms. Therefore, the pharmaceutical formulations of this disclosure can also be formulated for controlled or slow release.

[0152] On the other hand, veterinary compositions are also provided, comprising one or more molecules or compounds disclosed herein, or pharmaceutically acceptable salts thereof, and a veterinary carrier. The veterinary carrier is a material suitable for the purpose of administering the composition and may be a solid, liquid, or gaseous material that is otherwise inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally, or via any other desired route.

[0153] Pharmaceutical or veterinary compositions may be packaged in various ways depending on the method of administration. For example, articles for dispensing may include containers containing the composition in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), capsules, ampoules, plastic bags, metal tubes, etc. Containers may also include tamper-evident components to prevent easy access to the contents of the package. Additionally, the container is labeled with a description of its contents. The label may also include appropriate warnings. The composition may also be packaged in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored under lyophilized (freeze-dried) conditions, requiring only immediate addition of a sterile liquid carrier (e.g., water for injection) for injection before use. Temporary injectable solutions and suspensions are prepared from sterile powders, granules, and tablets of the types previously described.

[0154] On the other hand, 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 an activity complementary to that of the compounds provided herein, such that they do not adversely affect each other. Such ingredients are suitably present in a combination of amounts effective for the intended purpose.

[0156] Methods of treating diseases On the other hand, this disclosure provides a method for treating cancer, the method comprising administering to a subject in need an effective amount of the compound provided herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0157] In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts and the compositions provided herein may be used to treat cancers associated with wild-type KRas or KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, KRas Q61H in subjects of need, including administering a therapeutically effective amount of the compounds provided herein, their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the compounds or their pharmaceutically acceptable salts to the subjects.

[0158] In some embodiments, the compounds or pharmaceutically acceptable salts and compositions thereof provided herein can be used to treat a variety of cancers, including tumors such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, and testicular cancer. More specifically, cancers that can be treated by the compounds or pharmaceutically acceptable salts and compositions thereof provided herein include, but are not limited to, the following tumor types: astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, and sarcomas. More specifically, the compounds or pharmaceutically acceptable salts and compositions thereof provided herein can be used to treat: (i) Cardiac cancer: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; (ii) Lung cancer: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, mesothelioma; (iii) Gastrointestinal cancers: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (tubular adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, angiotensinoma), small bowel cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); (iv) Urogenital tract cancers: kidney cancer (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminomatous seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma-like tumor, lipoma); (v) Liver cancer: liver cancer (hepatocellular carcinoma), bile duct carcinoma, hepatoblastic carcinoma, angiosarcoma, hepatocellular adenoma, hemangioma; (vi) Biliary tract cancer: gallbladder cancer, ampullary cancer, bile duct cancer; bone cancer: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma and giant cell tumor; (vii) Cancers of the nervous system: Skull cancer (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningeal cancer (meningioma, meningeal sarcoma, glioma), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); (viii) Gynecological cancers: Uterine cancer (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulomatous cell tumor, Seylebsiella pneumoniae, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube cancer (cancer); (ix) Blood cancers: Blood cancers (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); (x) Skin cancers: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and (xi) Adrenal carcinoma: neuroblastoma.

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

[0160] The dosage and route of administration will vary depending on the cancer to be treated. In some embodiments, the administration is carried out via a route selected from the group consisting of: parenteral, intraperitoneal, intradermal, intracardiac, intravenous, intracranial, intraspinal, intrasynovial, intrathecal, intrathecal, intramuscular, intravitreal, intravenous, intra-arterial, oral, oral, sublingual, percutaneous, local, intratracheal, intrarectal, subcutaneous, and local administration.

[0161] Compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions containing such compounds and salts may also be administered in combination with other antitumor compounds, such as chemotherapy, or in combination with other treatments, such as radiation or surgical interventions, as adjuvant therapy before or after surgery.

[0162] In some embodiments, the compound, its pharmaceutically acceptable salt, and pharmaceutical compositions comprising such compounds and salts may be administered simultaneously, alone, or sequentially with one or more additional therapeutic agents. In some embodiments, the additional therapeutic agents are selected from anti-PD-1 antagonists, MEK inhibitors, SHP2 inhibitors, platinum preparations, or pemetrexed. In some embodiments, the anti-PD-1 antagonist is selected from nivolumab, pembrolizumab, or AMB 404. In some embodiments, the MEK inhibitor is trametinib. In some embodiments, the SHP2 inhibitor is RMC-4630.

[0163] On the other hand, this disclosure also provides a method for treating cancer in subjects in need, the method comprising: (a) It is known that the cancer is associated with wild-type KRas or KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, or KRas Q61H; and (b) administering to the subject an effective amount of the compound of this disclosure or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0164] On the other hand, this disclosure provides a method for inhibiting the activity of wild-type KRas or KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, KRas Q61H in a subject in need, the method comprising administering to the subject a compound of the disclosure or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0165] Example The following embodiments are included for illustrative purposes. However, it should be understood that these embodiments do not limit this disclosure and are merely intended to illustrate the methods of practicing this disclosure.

[0166] Example A: Synthesis of the compound Intermediate 1 (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-bridged methylenenaphtho[1,8-ab]heptanronene-14-carboxylic acid tert-butyl ester (intermediate 1) Step 1. (1S,2S,5R)-2-((S)-1-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyridino[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester At 0 °C, NaH (42.84 g, 10.71 mmol) was added to a flask containing (1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.92 g, 3.57 mmol) in THF (20 mL), followed by the addition of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.0 g, 3.57 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution. The aqueous layer was extracted with EA (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified by preparative TLC with elution of DCM:MeOH = 10:1 to give the title compound (1.6 g, 89.4%) as a white solid. LCMS:MS (ESI) m / z: 500 [M+H] + Step 2. (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-bridged methylenenaphtho[1,8-ab]heptanronene-14-carboxylic acid tert-butyl ester PyBOP (3.43 g, 6.59 mmol) and TEA (1.37 mL, 9.88 mmol) were added to a solution of (1R,2S,5S)-2-((S)-1-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.6 g, 3.29 mmol) in ACN (40 mL), and the reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture 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 give intermediate 1 (1.2 g, 75.6%). LCMS: (M+H) + = 482 Example 1 (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphth-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-bridged methylenenaphtho[1,8-ab]heptanronene (compound 1) Step 1. (R)-2-methyl-3-((R)-3-methylmorpholino)prop-1-ol Add (R)-3-methylmorpholine (195 mg, 1.9 mmol), K₂CO₃ (813 mg, 5.9 mmol), and KI (390 mg, 2.3 mmol) to a solution of (S)-3-bromo-2-methylprop-1-ol (300 mg, 1.9 mmol) in MeCN (6 mL). Stir the reaction mixture overnight at 70 °C. Then concentrate the mixture under vacuum to obtain a residue, which is diluted with H₂O (5 mL) and extracted with EtOAc (10 mL × 3). Dry the combined organic layers over anhydrous Na₂SO₄, filter, concentrate, and purify the residue by rapid column chromatography (silica gel, 0–10% MeOH in DCM) to give the ® title product (118 mg, 35% yield) as a pale yellow oil.

[0167] LC-MS (ESI) (m / z): 174 [M+H] + .

[0168] Step 2. (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methanesulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-bridged methylenenaphtho[1,8-ab]heptanronene-14-carboxylic acid tert-butyl ester At 0 °C, m-CPBA (71 mg, 4.1 mmol) was added fractionally to a solution of (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-pentazaza-6,9-bridged methylenenaphthalene[1,8-ab]heptannin-14-carboxylic acid tert-butyl ester (100 mg, 2.1 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with an aqueous solution of NaHCO3 (1 mL), H2O (5 mL), and extracted with DCM (5 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title product (105 mg, 98% yield) as a yellow oil.

[0169] LC-MS (ESI) (m / z): 514 [M+H] + Step 3. (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-bridged methylenenaphtho[1,8-ab]heptanronene-14-carboxylic acid tert-butyl ester t-BuONa (178 mg, 1.85 mmol) was added to a mixture of (R)-2-methyl-3-((R)-3-methylmorpholino)prop-1-ol (64 mg, 0.37 mmol) and 4 ÅMS (110 mg) in toluene (3 mL) at 0 °C. The resulting mixture was stirred at room temperature for 30 min, followed by the addition of (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methanesulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-bridged methylenenaphtho[1,8-ab]heptanronen-14-carboxylic acid tert-butyl ester (105 mg, 0.20 mmol). After the addition, the reaction mixture was stirred overnight at room temperature. After solvent removal, the residue was purified by silica gel column chromatography (EtOAc) to give the title compound (56 mg, 43.1% yield).

[0170] LC-MS (ESI) m / z: 607 [M+H] + .

[0171] Step 4. (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-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-bridged methylenenaphtho[1,8-ab]heptanronen-14-carboxylic acid tert-butyl ester Under N2, (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-bridged methylenenaphthalo[1,8-ab]heptanronen-14-carboxylic acid tert-butyl ester (56 mg, 0.09 mmol) was added to a solution of (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-bridged methylenenaphthalo[1,8-ab]heptanronen-14-carboxylic acid tert-butyl ester (56 mg, 0.09 mmol) in THF (5 mL) and H2O (1 mL). Then, ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphthyl)ethynyl)triisopropylsilane (63 mg, 0.14 mmol) and X-Phos Pd G2 (7 The reaction mixture was prepared with 0.009 mg (59 mg, 0.28 mmol) and K3PO4 (59 mg, 0.28 mmol), and stirred at 60 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ice water and extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by rapid column chromatography (silica gel, 0-10% MeOH in DCM) to give the title compound (45 mg, 54.2% yield).

[0172] LC-MS (ESI) m / z: 897 [M+H] + .

[0173] Step 5. (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-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-bridged methylenenaphtho[1,8-ab]heptanronene At 0 °C, TMSOTf (14 mg, 0.06 mmol) was added to a solution of (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-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-bridged methylenenaphthalene[1,8-ab]heptanronen-14-carboxylic acid tert-butyl ester (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 mixture was quenched at 0°C with an aqueous solution of Na₂CO₃, and then extracted twice with DCM. The combined organic layers were washed with water and brine, dried, and concentrated to give the title product (38 mg, 95% yield).

[0174] LC-MS ESI (m / z): 797 [M+H] + .

[0175] Step 6. (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphth-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-bridged methylenenaphtho[1,8-ab]heptanronene CsF (290 mg, 1.91 mmol) was added to a solution of (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-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-bridged methylenenaphtho[1,8-ab]heptanronne (38 mg, 0.05 mmol) in DMF (5 mL). The resulting mixture was stirred at 40 °C for 1 hour. The reaction solution was purified by preparative HPLC (column: YMC-Actus Triart C18 150 * 20 mm; mobile phase A: 0.1% NH3 in water, mobile phase B: MeCN; gradient: 45% B to 95% B over 18 min; flow rate: 25 ml / min; wavelength: 220 nm / 254 nm; target retention time: 10.5 min (90% MECN)) to give compound 1 (8.5 mg, 30.5% yield).

[0176] LC-MS (ESI) m / z: 641 [M+H] + .

[0177] 1 H 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 = 6.0 Hz, 3H).

[0178] Example 26 (8S,8aS,9S,12R)-5-(8-ethynyl-7-fluoronaphth-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-bridged methylenenaphtho[1,8-ab]heptanronene (compound 26) Step 1: (S)-1-(3-methylmorpholine-4-carbonyl)cyclopropane-1-carboxylic acid methyl ester 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 chloride (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 a residue. A solution of the residue dissolved in DCM (5 mL) 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 layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by rapid chromatography (silica gel, 0-30% EtOAc in PE) to give the title product (720 mg, 48% yield) as a yellow oil. MS (ESI) (m / z): 228 [M+H]+.

[0179] Step 2: (S)-(1-((3-methylmorpholino)methyl)cyclopropyl)methanol At 0 °C under N2, LiAlH4 (5.3 mL, 5.3 mmol, 1 M in THF) was added dropwise to a solution of (S)-1-(3-methylmorpholino-4-carbonyl)cyclopropane-1-carboxylate (600 mg, 2.6 mmol) in THF (5 mL). The mixture was stirred at room temperature for 1 hour. The mixture was then quenched with H2O (0.1 mL), NaOH aqueous solution (0.1 mL, 15% wt), and H2O (0.5 mL). The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by rapid chromatography (silica gel, 0-10% MeOH in DCM) to give the title product (360 mg, 74% yield) as a yellow oil. LC-MS (ESI) (m / z): 186 [M+H] + .

[0180] Step 3: (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-bridged methylenenaphthalo[1,8-ab]heptanronene-14-carboxylic acid tert-butyl ester A solution of (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methanesulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentazaza-6,9-bridged methylenenaphtho[1,8-ab]heptanronen-14-carboxylic acid tert-butyl ester (100 mg, 1.9 mmol) and (S)-(1-((3-methylmorpholino)methyl)cyclopropyl)methanol (73 mg, 3.9 mmol) in toluene (5 ml) was added to 4 Å MS and stirred at room temperature for 30 min. Then, sodium 2-methylprop-2-ol (98 mg, 9.5 mmol) was added to the reaction mixture at 0 °C and stirred at room temperature for 1 h. The mixture was diluted with water (10 ml) and extracted with EtOAc (10 ml × 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by rapid chromatography (silica gel, 0-30% EtOAc in PE) to give the title product (80 mg, 67% yield) as a yellow oil. MS (ESI) (m / z): 619 [M+H] + .

[0181] 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).

[0182] Step 4. (5S,5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-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-bridged methylenenaphtho[1,8-ab]heptan-14-carboxylic acid tert-butyl ester Add X-Phos Pd G2 (19.1 mg, 0.25 mmol) and tripotassium phosphate (61.2 mg, 3.0 mmol) to a solution of (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-bridged methylenenaphthalo[1,8-ab]heptanronne-14-carboxylic acid tert-butyl ester (60 mg, 1.0 mmol) in tetrahydrofuran (2 mL) and water (0.4 mL). 1.2 mmol) and ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (52.6 mg, 1.2 mmol). 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 × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by rapid chromatography (silica gel, 0-10% MeOH in DCM) to give the title product (50 mg, 56.7% yield) as a yellow oil. LC-MS (ESI) (m / z): 909 [M+H] + .

[0183] Step 5. (8S,8aS,9S,12R)-4-fluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-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-bridged methylenenaphtho[1,8-ab]heptanronene At 0 °C, HMDS (0.2 mL) and TMSOTf (0.2 mL) were added to a solution of (8S,8aS,9S,12R)-4-fluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-8-methyl-2-((1-(((S)-3-methylmorpholino)methyll)cyclopropyl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaza-9,12-bridged methylenenaphthalene[1,8-ab]heptanronne-14-carboxylic acid tert-butyl ester (50 mg, 0.06 mmol) in DCM (2 mL). 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 × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated. No further purification was required to obtain the title product (50 mg crude) as a yellow solid. MS (ESI) (m / z): 809 [M+H] + .

[0184] Step 6. (8S,8aS,9S,12R)-5-(8-ethynyl-7-fluoronaphth-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-bridged methylenenaphtho[1,8-ab]heptanronene CsF (188 mg, 1.1 mmol) was added to a solution of (8S,8aS,9S,12R)-4-fluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-8-methyl-2-((1-(((S)-3-methylmorpholino)methyll)cyclopropyl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaza-9,12-bridged methylenenaphtho[1,8-ab]heptanronne (50 mg, 0.06 mmol) in DMF (1 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was then filtered and purified by preparative HPLC to give compound 26 (16.9 mg, 41% yield).

[0185] LC-MS (ESI) (m / z): 653 [M+H] + .

[0186] 1H 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).

[0187] Examples 27 and 28 (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphth-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-bridged methylenenaphtho[1,8-ab]heptanronene (compound 27) And (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphth-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-bridged methylenenaphtho[1,8-ab]heptanronene (compound 28) Step 1. 2-(2-Chloroethoxy)acetaldehyde DMSO (18.82 g, 240.848 mmol) was added to a solution of (COCl)₂ (18.34 g, 144.509 mmol) in anhydrous CH₂Cl₂ (150 mL) at -78 °C under N₂. After stirring for 30 min, 2-(2-chloroethoxy)ethanol-1-ol (15.0 g, 120.4 mmol) was added dropwise to the solution of anhydrous CH₂Cl₂ (150 mL). 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 mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was acidified to pH 5-6 with 2 N HCl aqueous solution and then extracted with CH₂Cl₂. The combined organic layers were dried over anhydrous MgSO4 and filtered to obtain a crude product that was a colorless solution in DCM (200 mL). The crude product could be used directly in the next step without further purification.

[0188] Step 2. (R)-N-(2-(2-chloroethoxy)ethylidene)-2-methylpropane-2-sulfinamide 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 100 mL of dichloromethane. The mixture was stirred at room temperature for 16 hours and filtered through a diatomaceous earth mat. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title product (4.85 g, 28.6%) as a colorless oil.

[0189] LC / MS (ESI) (m / z): 226 [M+H] + .

[0190] Step 3. (R)-N-(1-(2-chloroethoxy)propyl-2-yl-3,3,3-d3)-2-methylpropane-2-sulfinamide At -78 °C and under N2, deuterated methylmagnesium iodide (66.5 mL, 66.45 mmol, 1 M in Et2O) was added to (R)-N-(2-(2-chloroethoxy)ethylidene)-2-methylpropane-2-sulfinamide (10 g, 44.3 mmol) in a stirred solution of anhydrous toluene (150 mL). The reaction mixture was stirred at -78 °C for 1–2 h. The reaction was considered complete by TLC and LCMS, and the reaction mixture was quenched at -78 °C with saturated NH4Cl (aqueous solution). The mixture was then extracted twice with EtOAc (100 mL). The combined organic phases were washed with saturated NaCl (aqueous solution), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by rapid chromatography (silica gel, hexane / EtOAc, gradient: 0% to 75% EtOAc) to give the title product (8.0 g, 73.8%) as a yellow oil.

[0191] LC / MS (ESI) (m / z): 245 [M+H] + .

[0192] Step 4. 4-((R)-tert-butylsulfinyl)-3-(methyl-d3)morpholine At 0 °C and under N2, 60% w / w NaH (1.44 g, 35.9 mmol, 60% in oil) dissolved in mineral oil was added to a solution of (R)-N-(1-(2-chloroethoxy)propyl-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). The mixture was stirred at room temperature for 2 hours. The reaction was shown to be complete by TLC and LCMS. The mixture was quenched with ice water and extracted with Et2O. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography to give the title product (1.8 g, 72.3%) as a white solid.

[0193] LC / MS (ESI) (m / z): 209 [M+H] + .

[0194] Step 5. 3-(methyl-d3)morpholine HCl / dioxane (5 mL, 4 mol / L) was added to a solution of 4-((R)-tert-butylsulfinyl)-3-(methyl-d3)morpholine (200 mg, 0.96 mmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to give the title product (100 mg) as a yellow solid, which was used directly in the next step.

[0195] LC / MS (ESI) (m / z): 105 [M+H] + .

[0196] Step 6. Methyl 1-(3-(methyl-d3)morpholine-4-carbonyl)cyclopropane-1-carboxylate Methyl cyclopropane-1,1-dicarboxylate (200 mg, 1.4 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 °C, and N,N-dimethylformamide (1 drop) and oxalyl chloride (0.22 g, 1.8 mmol) were added. After stirring at room temperature for 1 hour, the reaction solution was concentrated to dryness. The residue was diluted with dichloromethane (10 mL), and the resulting solution was added dropwise at 0 °C to a solution of 3-(methyl-d3)morpholine (100 mg, 1 mmol) and Et3N (200 mg, 2 mmol). 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 give the title product (150 mg, 67.9%).

[0197] LC / MS (ESI) (m / z): 231 [M+H] + .

[0198] Step 7. (1-((3-(methyl-d3)morpholino)methyl)cyclopropyl)methanol A solution of methyl 1-(3-(methyl-d3)morpholine-4-carbonyl)cyclopropane-1-carboxylate (150 mg, 9.8 mmol) in 20 mL of THF was cooled to 0 °C. A solution of lithium aluminum hydride in THF (20 mL, 1 M) was slowly added under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 3 hours. Sodium sulfate decahydrate (500 mg) was added in portions to the reaction mixture at 0 °C to give a white suspension. Ethyl acetate (25 mL) 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 filtrates were concentrated to obtain a crude product (120 mg), which could be used directly in the next step without further purification.

[0199] LC / MS (ESI) (m / z): 189 [M+H] + .

[0200] Step 8. (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-bridged methylenenaphthalo[1,8-ab]heptanronene-14-carboxylic acid tert-butyl ester Sodium tert-butoxide (375 mg, 3.9 mmol) and 4 Å molecular sieve (100 mg) were added to a solution of (1-((3-(methyl-d3)morpholino)methyl)cyclopropyl)methanol (165 mg, 0.58 mmol) in toluene (5 mL). The mixture was stirred at room temperature for 20 min, and then (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methanesulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentazaza-6,9-bridged methylenenaphtho[1,8-ab]heptan-14-carboxylic acid tert-butyl ester (200 mg, 0.39 mmol) in toluene (5 mL) was added dropwise, and the mixture was stirred at room temperature under N2 for 2 h. The mixture was filtered, and the filtrate was concentrated. The residue was loaded onto a silica gel plate. The plate was eluted with EA:PE = 1:1 to give the tert-butyl title product as a white solid (120 mg, 50% yield).

[0201] MS (ESI) m / z: 622 [M+H] + .

[0202] Step 9. (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-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-bridged methylenenaphtho[1,8-ab]heptanronen-14-carboxylic acid tert-butyl ester Add K3PO4 (121 mmol) to a solution of (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-bridged methylenenaphthalo[1,8-ab]heptannin-14-carboxylic acid tert-butyl ester (120 mg, 0.19 mmol) and ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (175 mg, 0.38 mmol) in THF (2 mL) and water (0.4 mL). The first step was to add cataCXium(R)A Pd G3 (29 mg, 0.04 mmol). The mixture was refluxed at 80 °C for 1.5 h under N2 atmosphere. The reaction mixture was concentrated under vacuum. The crude product was analyzed by chromatography on silica gel (DCM / MeOH 10 / 1) to give the title product (100 mg, 56.8% yield) as a white solid.

[0203] MS (ESI) m / z: 912 [M+H] + .

[0204] Step 10. (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-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-bridged methylenenaphtho[1,8-ab]heptanronene At 0 °C, HMDS (0.2 mL) and TMSOTf (0.1 mL) were added to a solution of (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-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-bridged methylenenaphthalene[1,8-ab]heptanronen-14-carboxylic acid tert-butyl ester (100 mg, 0.11 mmol) in DCM (3 mL), and the reaction mixture was stirred at room temperature for 1 hour. Saturated NaHCO3 was added to the reaction solution, extracted with DCM, dried and concentrated under vacuum to give the title product (80 mg, 90% yield), which required no further purification.

[0205] LC / MS ESI (m / z): 812 [M+H] + Step 11. (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphth-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-bridged methylenenaphtho[1,8-ab]heptanronene N,N-dimethylformamide (3 mL) was added to a flask containing (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-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-bridged methylenenaphtho[1,8-ab]heptanronne (80 mg, 0.1 mmol), followed by 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 preparative HPLC (column: YMC-ActusTriart, 50 * 250 mm, 7 μm; mobile phase A: 0.1% NH3 in water, mobile phase B: CH3CN; gradient: 35% B to 95% B over 30 min; flow rate: 25 mL / min; UV wavelength: 220 / 254 nm) to provide a crude product (60 mg, 95% yield) as a white solid.

[0206] LC / MS (ESI) m / z: 656 [M+H] + .

[0207] The crude product (60 mg) was further purified by chiral preparation (preparative separation method: instrument: Shimadzu LC-20AT; column: CHIRALCEL OD-H (ODH0CE-KJ063), 0.46 cm inner diameter × 25 cm length; 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.

[0208] Compound 27: 1 H 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).

[0209] LC / MS (ESI) m / z: 656 [M+H] + .

[0210] Compound 28: 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).

[0211] LC / MS (ESI) m / z: 656 [M+H] + .

[0212] 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-bridged methylenenaphthalo[1,8-ab]heptanen-2-yl)naphth-2-ol (Compound 30) Step 1: (5S,5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-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-bridged methylenenaphtho[1,8-ab]heptan-14-carboxylic acid tert-butyl ester Add X-Phos Pd G2 (20.1 mg, 0.25 mmol) and tripotassium phosphate (66.8 mg, 3.15 mmol) to a solution of (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-bridged methylenenaphthalo[1,8-ab]heptanen-14-carboxylic acid tert-butyl ester (65 mg, 1.05 mmol) in tetrahydrofuran (2 mL) and water (0.4 mL). 1.26 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (45.4 mg, 1.26 mmol). 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 × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by rapid chromatography (silica gel, 0-10% MeOH in DCM) to obtain a yellow oily substance, (5S,5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-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-bridged methylenenaphtho[1,8-ab]heptanronne-14-carboxylic acid tert-butyl ester (50 mg, 58.3% yield). MS (ESI) (m / z): 817 [M+H] + .

[0213] 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-bridged methylenenaphthalo[1,8-ab]heptan-2-yl)naphth-2-ol TFA (1 mL) was added to a solution of (5S,5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-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-bridged methylenenaphtho[1,8-ab]heptanronne-14-carboxylic acid tert-butyl ester (50 mg, 0.06 mmol) in dry DCM (2 mL), 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 × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and purified by preparative HPLC to give compound 30 (3.5 mg, 8.5% yield).

[0214] LC / MS (ESI) m / z: 673 [M+H] + .

[0215] 1 H 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, 11.1 Hz, 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).

[0216] Example 38 (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphth-1-yl)-1-fluoro-5-methyl-12-((1-(((S)-2-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-bridged methylenenaphtho[1,8-ab]heptanronene (compound 38) Step 1. Methyl (S)-1-(2-methylpiperidin-1-carbonyl)cyclopropane-1-carboxylate. At 0 °C, oxaloyl chloride (493 mg, 3.9 mmol) and a catalytic amount of DMF were added to a solution of 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid (280 mg, 1.9 mmol) in DCM (5 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated. At 0 °C, a solution of the residue dissolved in DCM (5 mL) was added dropwise 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 × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography with PE / EtOAc (9:1-4:1) elution to obtain the title product (350 mg, 80% yield) as a yellow oil.

[0217] LCMS(ESI) (m / z): 226 [M+H] + .

[0218] Step 2. (S)-(1-((2-methylpiperidin-1-yl)methyl)cyclopropyl)methanol. LiAlH4 (118 mg, 3.1 mmol) was added to a solution of (S)-1-(2-methylpiperidin-1-carbonyl)cyclopropane-1-carboxylate (350 mg, 1.55 mmol) in THF (10 mL) at 0 °C under N2. 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 diatomaceous earth mat, and the filtrate was concentrated to give the title product (250 mg, 87% yield) as a yellow oil.

[0219] LCMS(ESI) (m / z): 184 [M+H] + .

[0220] Step 3. (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-((1-(((S)-2-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-bridged methylenenaphthalo[1,8-ab]heptanronene-14-carboxylic acid tert-butyl ester. Sodium tert-butoxide (617 mg, 6.4 mmol) and 4 Å molecular sieve (600 mg) were added to a solution of (S)-(1-((2-methylpiperidin-1-yl)methyl)cyclopropyl)methanol (78 mg, 0.4 mmol) in toluene (5 mL), and the reaction mixture was stirred at room temperature for 10 min. Then, (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methanesulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentazaza-6,9-bridged methylenenaphtho[1,8-ab]heptanronne-14-carboxylic acid tert-butyl ester (110 mg, 0.2 mmol) was added to a solution of toluene (0.5 mL), and the mixture was stirred at room temperature for 20 min. The reaction mixture was filtered immediately, and the filtrate was concentrated. The residue was purified by preparative HPLC (DCM / MeOH = 15:1) to give the title product (70 mg, 53% yield) as a yellow oil.

[0221] LCMS(ESI) (m / z): 617 [M+H] + .

[0222] Step 4. (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-5-methyl-12-((1-(((S)-2-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-bridged methylenenaphtho[1,8-ab]heptanronen-14-carboxylic acid tert-butyl ester. Add ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-1-yl)naphthyl)ethynyl)triisopropylsilane (92 mg, 0.21 mmol) and X-Phos Pd G2 (24 mmol) to a solution of (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-((1-(((S)-2-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-bridged methylenenaphtho[1,8-ab]heptan-14-carboxylic acid tert-butyl ester (70 mg, 0.14 mmol) in THF / water (5 mL / 1 mL) to a solution of (2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphthyl)ethynyl)triisopropylsilane (92 mg, 0.21 mmol) and X-Phos Pd G2 (24 mmol) to a solution of (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-((1-(((S)-2-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-bridged methylenena-naphthyl)[(((S)-2-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-ox The mixture was prepared with 86 mg (0.03 mmol) and K3PO4 (86 mg, 0.41 mmol). 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 × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 15:1) to give the title product (60 mg, 49% yield) as a yellow solid.

[0223] LCMS(ESI) (m / z): 907 [M+H] + .

[0224] Step 5. (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-5-methyl-12-((1-(((S)-2-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-bridged methylenenaphtho[1,8-ab]heptanronene At 0°C and under N2, HMDS (0.2 mL) and TMSOTF (0.1 mL) were added to a solution of (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-5-methyl-12-((1-(((S)-2-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-bridged methylenenaphthalene[1,8-ab]heptanronne-14-carboxylic acid tert-butyl ester (60 mg, 0.07 mmol) in DCM (2 mL), and the mixture was stirred at 0°C for 30 minutes. The mixture was poured into saturated NaHCO3 (10 mL) and extracted with DCM (5 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give the title product as a yellow solid (50 mg, 94% yield).

[0225] LCMS(ESI) (m / z): 807 [M+H] + Step 6. (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphth-1-yl)-1-fluoro-5-methyl-12-((1-(((S)-2-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-bridged methylenenaphtho[1,8-ab]heptanronene Add cesium fluoride (301 mg, 1.98 mmol) to a solution of (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-5-methyl-12-((1-(((S)-2-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-bridged methylenenaphtho[1,8-ab]heptanronne (40 mg, 0.05 mmol) in DMF (1.5 mL) and stir the mixture at room temperature for 30 minutes. The mixture was purified by preparative HPLC (column: YMC-Actus Triart C18 150 * 20 mm; mobile phase A: 0.1% NH3 in water, mobile phase B: MeCN; gradient: 20% B to 95% B over 18 min; flow rate: 25 ml / min; wavelength: 220 nm / 254 nm; target retention time: 9 min (75% MECN)) to give compound 38 (5.5 mg, 17% yield).

[0226] LC / MS (ESI) (m / z): 651 [M+H] + .

[0227] 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).

[0228] Example 86 (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphth-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-bridged methylenenaphtho[1,8-ab]heptanronene (compound 86) Step 1. (S)-2-methyl-3-morpholinopropan-1-ol To a mixture of (R)-3-bromo-2-methylprop-1-ol (1 g, 6.5 mmol) and MeCN (10 mL), K₂CO₃ (2.72 g, 19.7 mmol), KI (1.3 g, 7.9 mmol), and morpholine (0.68 g, 7.9 mmol) were added. The reaction mixture was stirred overnight at 80 °C. The mixture was then filtered. The filtrate was concentrated and purified by rapid chromatography (silica gel, EtOAc:PE = 1:1) to give the title product (840 mg, 80% yield) as a colorless oil. LC-MS (ESI) (m / z): 160 [M+H] + .

[0229] Step 2. (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-bridged methylenenaphtho[1,8-ab]heptanronene-14-carboxylic acid tert-butyl ester Add 4 Å molecular sieve and sodium (S)-(1-((3-methylmorpholino)methyl)cyclopropyl)methoxide (121 mg, 4 mmol) to a three-necked flask. Heat the mixture to keep it dry, and add (S)-2-methyl-3-morpholinoprop-1-ol (80 mg, 10 mmol) dissolved in anhydrous toluene (5 mL) at 0 °C. After stirring at 0 °C for 20 minutes, add dropwise (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methanesulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentazaza-6,9-bridged methylenenaphtho[1,8-ab]heptanronne-14-carboxylic acid tert-butyl ester (100 mg, 2.0 mmol) dissolved in anhydrous toluene (5 mL). The resulting mixture was stirred at room temperature for 30 minutes. LCMS showed the reaction was complete. The mixture was quenched with H2O (5 mL) and extracted with DCM (5 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting crude material was purified by rapid chromatography (silica gel, DCM:MeOH = 20:1) to give the desired product (70 mg, 60.8% yield) as a yellow oil.

[0230] LC-MS (ESI) (m / z): 593 [M+H] + .

[0231] Step 3. (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-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-bridged methylenenaphtho[1,8-ab]heptanronene-14-carboxylic acid tert-butyl ester Add X-Phos Pd G2 (16.7 mg, 0.3 mmol) and tripotassium phosphate (53.6 mg, 3.6 mmol) to a solution of (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-pentazaza-6,9-bridged methylenenaphthalo[1,8-ab]heptanronen-14-carboxylic acid tert-butyl ester (70 mg, 1.2 mmol) in tetrahydrofuran (4 mL) and water (0.8 mL). (mmol) and ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (46 mg, 2.4 mmol). 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 × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by rapid chromatography (silica gel, DCM:MeOH = 20:1) to give the title product (60 mg, 57.6% yield) as a yellow oil.

[0232] LC-MS (ESI) (m / z): 883 [M+H] + .

[0233] Step 4. (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-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-bridged methylenenaphtho[1,8-ab]heptanronene At 0 °C, HMDS (0.2 mL) and TMSOTf (0.1 mL) were added to a solution of (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-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-bridged methylenenaphthalene[1,8-ab]heptanronne-14-carboxylic acid tert-butyl ester (60 mg, 0.068 mmol) in DCM (2 mL). 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 × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. Without further purification, the title product (60 mg crude) was obtained as a yellow solid.

[0234] LC-MS (ESI) (m / z): 783 [M+H] + .

[0235] Step 5. (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphth-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-bridged methylenenaphtho[1,8-ab]heptanronene CsF (282 mg, 27.6 mmol) was added to a solution of (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-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-bridged methylenenaphtho[1,8-ab]heptanronne (60 mg, 0.076 mmol) in DMF (1 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was then filtered and purified by preparative HPLC to give compound 86 (21.4 mg, 44.6% yield).

[0236] LC-MS (ESI) (m / z): 627 [M+H] + .

[0237] 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).

[0238] Example 87 (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphth-1-yl)-1-fluoro-5-methyl-12-((R)-2-methyl-3-(piperidin-1-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-bridged methylenenaphtho[1,8-ab]heptanronene (compound 87) Step 1. (R)-2-methyl-3-(piperidin-1-yl)prop-1-ol To a mixture of (S)-3-bromo-2-methylprop-1-ol (300 mg, 1.9 mmol) and MeCN (6 mL), piperidine (217 mg, 2.6 mmol), K₂CO₃ (813 mg, 5.9 mmol), and NaI (353 mg, 2.4 mmol) were added. The reaction mixture was stirred overnight at 70 °C. The mixture was then concentrated under vacuum to obtain a residue, which was diluted with H₂O (5 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by rapid column chromatography (silica gel, 0–10% MeOH in DCM) to give the title product (243 mg, 79% yield) as a pale yellow oil.

[0239] LC-MS (ESI) (m / z): 158 [M+H] + .

[0240] Step 2. (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-((R)-2-methyl-3-(piperidin-1-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-bridged methylenenaphtho[1,8-ab]heptan-14-carboxylic acid tert-butyl ester t-BuONa (141 mg, 1.47 mmol) was added to a mixture of (R)-2-methyl-3-(piperidin-1-yl)prop-1-ol (46 mg, 0.3 mmol) and 4 Å MS (80 mg) in toluene (3 mL) at 0 °C. The resulting mixture was stirred at room temperature for 30 min, and then (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methanesulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-bridged methylenenaphtho[1,8-ab]heptanronen-14-carboxylic acid tert-butyl ester (100 mg, 0.19 mmol) was added. The reaction mixture was stirred at room temperature overnight. After solvent removal, the residue was purified by silica gel column chromatography (EtOAc) to give the title compound (52 mg, 30.1% yield).

[0241] LC-MS (ESI) m / z: 591 [M+H] + .

[0242] Step 3. (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-5-methyl-12-((R)-2-methyl-3-(piperidin-1-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-bridged methylenenaphtho[1,8-ab]heptanronen-14-carboxylic acid tert-butyl ester Under N2, a solution of (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-((R)-2-methyl-3-(piperidin-1-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentazaza-6,9-bridged methylenenaphthalo[1,8-ab]heptanronen-14-carboxylic acid tert-butyl ester (52 mg, 0.09 mmol) in THF (5 mL) and H2O (1 mL) was prepared by adding ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (42 mg, 0.09 mmol) and X-Phos Pd G2 (7 mg, 0.009 mmol) to a solution of (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-((R)-2-methyl-3-(piperidin-1-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentazaza-6,9-bridged methylenenaphthalo[1,8-ab]heptanronen-14-carboxylic acid tert-butyl ester (52 mg, 0.09 mmol) in THF (5 mL) and H2O (1 mL). The reaction mixture was prepared with 54 mg (0.25 mmol) of K₃PO₄ and stirred at 60 °C for 2 hours. The reaction mixture was diluted with ice water and then extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried, and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give the title compound (40 mg, 66.7% yield).

[0243] LC-MS (ESI) m / z: 881 [M+H] + .

[0244] Step 4. (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-5-methyl-12-((R)-2-methyl-3-(piperidin-1-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-bridged methylenenaphtho[1,8-ab]heptanronene At 0 °C, TMSOTf (14 mg, 0.06 mmol) was added to a solution of (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-5-methyl-12-((R)-2-methyl-3-(piperidin-1-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-bridged methylenenaphtho[1,8-ab]heptanronne-14-carboxylic acid tert-butyl ester (40 mg, 0.04 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 mixture was quenched with aqueous Na2CO3 solution at 0 °C and then extracted twice with DCM. The combined organic layers were washed with water and brine, dried and concentrated to give the title product (35 mg, 98% yield).

[0245] LC-MS ESI (m / z): 781 [M+H] + .

[0246] Step 5. (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphth-1-yl)-1-fluoro-5-methyl-12-((R)-2-methyl-3-(piperidin-1-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-bridged methylenenaphtho[1,8-ab]heptanronene CsF (234 mg, 1.54 mmol) was added to a solution of (5S,5aS,6S,9R)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-5-methyl-12-((R)-2-methyl-3-(piperidin-1-yl)propoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-bridged methylenenaphtho[1,8-ab]heptanronne (35 mg, 0.04 mmol) in DMF (5 mL). The mixture was stirred at 40 °C for 1 hour. The reaction solution was purified by preparative HPLC (column: YMC-Actus Triart C18 150 * 20 mm; mobile phase A: 0.1% NH3 in water, mobile phase B: MeCN; gradient: 35% B to 95% B over 18 min; flow rate: 25 ml / min; wavelength: 220 nm / 254 nm; target retention time: 13 min (85% MECN)) to provide compound 87 (6.2 mg, 31% yield).

[0247] LC-MS (ESI) m / z: 625 [M+H] + .

[0248] 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).

[0249] The following compounds were prepared using different starting materials according to the method described above. Example 2 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).

[0250] Example 13 1 H 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).

[0251] Example 25 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).

[0252] Example 29 [[ID=2三十三]] 1 1H 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, It should be noted that there seems to be an incorrect "三十三" in the original text which is likely a typo. I've translated it as "Example 29" for the relevant part. If this is not what you intended, please clarify. Also, the chemical shift values and NMR data translation are presented as is, and it's recommended to double-check with a chemistry expert for accurate interpretation in a real chemical context.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).

[0253] Example 33 1 H 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).

[0254] Example 37 1H 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).

[0255] Example 85 1 H 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).

[0256] 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= 10.1Hz, 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).

[0257] Example 92 1 H 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).

[0258] Example 97a 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).

[0259] Example 97b 1 H 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).

[0260] Example 102a 11H 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).

[0261] Example 102b 1 1H 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 J = 5.6 Hz, 1H), 3.59 (d, J J = 4.8 Hz, 1H), 3.40 - 3.33 (m, 1H), 3.18 (dd, J J = 12.9, 8.9 Hz, 1H), 2.26 (d, J 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).

[0262] Example 103a 11H 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 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 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).

[0263] Example 103b 1 1H NMR (400 MHz, CD3OD) δ 7.70 (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 J = 5.7 Hz, 1H), 3.65 - 3.32 (m, 3H), 3.17 (m, 1H), 2.26 (d, J 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).

[0264] Example 116a 11H NMR (400 MHz, CD3OD) δ 8.11 - 8.04 (m, 2H), 7.67 - 7.53 (m, 2H), 7.42 (dd, J J = 18.5, 9.2 Hz, 1H), 5.42 - 5.35 (m, 1H), 4.79 (d, J J = 10.8 Hz, 1H), 4.57 - 4.48 (m, 1H), 4.08 (d, J J = 8.7 Hz, 1H), 3.98 (dd, J 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 J = 12.8, 4.6 Hz, 1H), 1.11 (d, J J = 6.3 Hz, 3H), 0.91 (dd, J 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).

[0265] Example 116b 1 1H NMR (400 MHz, CD3OD) δ 8.08 (q, J J = 6.2 Hz, 2H), 7.67 - 7.62 (m, 1H), 7.62 - 7.53 (m, 1H), 7.42 (q, J J = 9.0 Hz, 1H), 5.40 - 5.34 (m, 1H), 4.56 - 4.48 (m, 2H), 4.30 (dd, J J = 10.7, 3.9 Hz, 1H), 4.08 (d, J J = 8.8 Hz, 1H), 3.79 - 3.45 (m, 6H), 3.17 (dd, J J = 12.8, 9.4 Hz, 1H), 2.84 (dd, J= 6.0, 3.0Hz, 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).

[0266] Example 117a 1 H 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).

[0267] Example 117b 1 H 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= 8.6 Hz, 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, 2.2 Hz, 1H), 1.06 - 0.95 (m, 3H), 0.91 (dd, J = 6.4, 2.6 Hz, 3H), 0.75 - 0.64 (m, 2H), 0.59 - 0.41 (m, 2H).

[0268] Example 118 1 H NMR (400 MHz, methanol - d 4) 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).

[0269] Example 119a 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).

[0270] Example 119b 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).

[0271] Example 120 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).

[0272] Example 121 1 1H NMR (400 MHz, CD3OD) δ 7.67 (t, J J = 7.5 Hz, 1H), 7.42 - 7.34 (m, 1H), 7.29 (dd, J J = 16.4, 8.1 Hz, 1H), 7.13 (d, J J = 2.3 Hz, 1H), 7.05 (dd, J J = 38.1, 2.4 Hz, 1H), 5.36 (dd, J J = 8.8, 4.7 Hz, 1H), 4.47 (m, 2H), 4.36 (dd, J J = 10.9, 2.7 Hz, 1H), 4.07 (d, J J = 8.7 Hz, 1H), 3.71 - 3.58 (m, 6H), 3.17 (dd, J J = 13.0, 7.7 Hz, 1H), 2.49 (d, J 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 J = 7.0 Hz, 3H), 0.70 (s, 2H), 0.50 (s, 2H).

[0273] Example 122 11H NMR (400 MHz, CD3OD) δ 7.84 - 7.75 (m, 1H), 7.26 (dt, J J = 13.6, 6.0Hz, 2H), 7.15 (dd, J J = 40.9, 2.5 Hz, 1H), 5.41 - 5.34 (m, 1H), 4.52 (dt, J J =8.8, 6.3 Hz, 1H), 4.45 (dd, J J = 10.9, 6.7 Hz, 1H), 4.36 (dd, J J = 10.9, 2.8Hz, 1H), 4.07 (d, J J = 8.8 Hz, 1H), 3.65 (d, J J = 4.6 Hz, 3H), 3.59 (s, 1H),3.50 - 3.32 (m, 1H), 3.17 (dd, J J = 13.2, 7.7 Hz, 1H), 2.50 (s, 3H), 2.41 (dd, J J = 18.3, 7.7 Hz, 2H), 2.07 (s, 1H), 1.90 - 1.74 (m, 3H), 1.57 (t, J J = 6.9Hz, 3H), 1.28 (s, 3H), 0.71 (d, J J = 6.4 Hz, 2H), 0.49 (d, J J = 4.8 Hz, 2H).

[0274] Example 123 1 1H NMR (400 MHz, CD3OD) δ 7.70 - 7.59 (m, 1H), 7.29 - 7.17 (m, 2H),7.03 (dd, J J = 52.0, 2.6 Hz, 1H), 5.42 (d, J J = 13.2 Hz, 1H), 4.59 (s, 2H),4.44 (q, J 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).

[0275] Example 128 1 H NMR (400 MHz, CD3OD) δ6.34 (s, 1H), 5.36 (m, 1H), 4.70 (d, J = 10.6Hz, 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).

[0276] Example 162 1H 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).

[0277] Example 163 1 H 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).

[0278] Example 164 1H 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).

[0279] Example B: Biological assay The following measurements were used to measure the effects of the compounds disclosed herein.

[0280] Determination of phosphate-ERK 1 / 2: Using standard tissue culture procedures, PNAC-1 cells were grown in T75 flasks in DMEM and 10% fetal bovine serum (FCS; Gibco®) until approximately 80% confluence was reached. On Day 1, 6000 cells / well were seeded in 384-well plates and incubated at 37°C and 5% CO2. Diluted compounds were added via Echo 550 to a final DMSO concentration of 0.5%, and cells were incubated at 37°C and 5% CO2 for 3 hours. The medium was then removed, and cells were fixed with PBS (PFA) containing 3.7% formaldehyde using Apricot. Cells were washed once with PBS. Cells were permeated with cold 100% methanol and washed once more with PBS. Li-Cor blocking buffer was added to each well, and cells were 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. Cells were incubated overnight at 4°C. On day 2, the plates were washed a total of 3 times with PBST (PBS containing Tween-20), and then the secondary antibody mixture (goat anti-rabbit 800CW (at a 1:800 dilution in combinatorial solution) and goat anti-mouse 680RD (at a 1:800 dilution in combinatorial solution) were added. The plates were incubated at RT for 60 minutes in the dark. Washing was repeated 3 times with PBST. After the final wash, the plates were centrifuged inverted mode at 1000 rpm to completely remove the wash solution from the wells. The plates and Odyssey plates were cleaned with moistened, lint-free tissue prior to plate scanning. ® Imager scanning bed (if applicable) to avoid any obstructions during scanning. Scanning plate for detection in 700 nm and 800 nm channels.

[0281] The phosphate-ERK 1 / 2 determination results of some exemplary compounds of this disclosure are shown in Table 2 below.

[0282] Table 2. KRAS(G12D):SOS1 Nucleotide Exchange Binding Assay Thaw the GDP-loaded KRAS (G12D) on ice and dilute it to 500 nM in RBD-RAS binding buffer. Prepare the master mixture (6 µl): 96 wells × (1 µl diluted GDP-loaded KRAS (G12D), 500 nM + 5 µl RBD-RAS binding buffer). Add 6 µl of the master mixture to each well. Prepare a series of dilutions of the test compound at a 200X test concentration in DMSO. Then dilute the compound 20-fold in deionized water to prepare a 10X intermediate solution. For positive and negative controls, use water containing 5% DMSO as the 10X intermediate, ensuring all wells contain the same amount of DMSO. Add 1 µl of the 10X intermediate solution of the test compound to the test well. Add 1 µl of 5% DMSO to the positive and negative control wells. Briefly centrifuge the plate and incubate at room temperature for 30 minutes. Thaw GTP (10 mM) and SOS1 on ice. Dilute SOS1 at 5 µM in RBD-RAS binding buffer. Mix GTP (10 mM) and diluted SOS1 (5 µM) at a 1:1 ratio. Initiate the exchange reaction by adding 2 µl of the GTP / SOS1 mixture to the test wells and positive control wells. Thaw RBD-cRAF and dilute it at 25 nM in RBD-RAS binding buffer. After incubating with SOS1 / GTP (RBD-RAS buffer for negative control) for 30 min, add 1 µl of diluted RBD-cRAF (25 nM) to all wells. Briefly centrifuge the plate and incubate at room temperature for 30 min. Dilute 3X immunobuffer in deionized water to prepare 1X immunobuffer. Add one volume of 3X immunobuffer to two volumes of deionized water. Dilute glutathione receptor beads (PerkinElmer #AL109C) and nickel chelate donor beads (PerkinElmer #AS101D) at 1:500 and 1:250, respectively, in 1X immunobuffer. Add 20 µl of the receptor / donor bead mixture to each well. Therefore, add 16 µl of glutathione receptor beads and 32 µl of nickel donor beads to 8 mL of 1X immunobuffer. Incubate at room temperature for 30 minutes. Read the α count using a compatible plate reader.

[0283] KRAS G12D 2D CellTiter-Glo® proliferation assay: AsPC-1 (ATCC CRL-1682) and LS513 (ATCC CRL-2134) cells were purchased from ATCC; GP2D (CBP60010), AGS (CBP60476), and SW1990 (CBP60691) cells were purchased from Cobioer Biosciences CO., LTD; and MKN-1 (JCRB, JCRB0252) cells were purchased from the JCRB cell bank. Each cell 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, 5% CO2 for 18 hours. Serially diluted compounds were added to the cells, and the plates were incubated at 37°C, 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.

[0284] KRAS G12D 3D CellTiter-Glo® Proliferation Assay 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 (CBP60010), AGS (CBP60476), and SW1990 (CBP60691) cells were purchased from CBP Biosciences Ltd.; and MKN-1 (JCRB, JCRB0252) cells were purchased from the JCRB Cell Bank. Each cell 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 surface circular plates (Corning). 400 cells / well were seeded into the 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.

[0285] Table 3 Other compounds disclosed herein exhibit IC50 values ​​ranging from 0.5 nM to 5000 nM. 50 Value. Some compounds disclosed herein exhibit IC50 values ​​of 1–4000 nM. 50 Value. Some compounds disclosed herein exhibit IC50 values ​​of 1–3000 nM.50 Value. Some compounds disclosed herein exhibit IC50 values ​​of 1-2000 nM. 50 Value. Some compounds disclosed herein exhibit IC50 values ​​of 1–1000 nM. 50 Value. Some compounds disclosed herein exhibit IC50 values ​​of 1-500 nM. 50 value.

[0286] DMPK Measurement Caco-2 cell monolayer permeability In the presence of efflux inhibitors Zosuquidar, Benzbromarone, and KO-143, a 10 μM inlet concentration and pH 6.5 / 7.4 (top / substrate lateral) were used. Incubation was performed at 37 °C with shaking at 480 rpm on a rotary shaker for 120 min, and samples were collected at 45 min and 120 min to assess recovery. All incubations were performed in singlet state. Fluorescein was used as a label to confirm the integrity of the cell monolayer after 120 min of incubation. UPLC-MS / MS was used to quantify the concentrations of compounds in the incubation medium in the donor and recipient compartments. Concentration data were used to calculate apparent permeability after 120 min of incubation. Results are shown in Table 4.

[0287] Table 4 MDCK-MDR1 Pgp Evaluation Efflux transport mediated by P-glycoprotein (Pgp) was assessed using MDCK-MDR1 cells. The final concentrations of the test and control compounds were 1 μM. The well plates were incubated at 37°C for 2 hours. Pexact, which automatically corrects for compound loss, was used to reliably measure passive osmotic coefficients. Results are shown in Table 5.

[0288] Table 5 In vivo mouse PK Balb / c female mice were administered the test compound via single-dose administration following an IV bolus (1 mg / kg, 0.2 mg / mL in 1% DMSO, 99% SBE-β-CD (10% w / v) in water) and oral bolus feeding (10 mg / kg to 60 mg / kg). Blood samples were collected at 2, 5, 10, 30, 1, 2, 4, 8, and 24 hours after IV bolus administration (32 and 48 hours for MRTX1133), and at 15, 30, 1, 1.5, 2, 3, 4, 8, and 24 hours after PO administration (32 or 48 hours for MRTX1133). Plasma concentrations of the compound were determined by UPLC-MS / MS. Results are shown in Table 6.

[0289] Table 6 In vivo rat PK Male SD rats were administered the test compounds via single-dose administration following intravenous infusion (1 mg / kg, 0.25 mg / mL) and oral bolus feeding (5 mg / kg–60 mg / kg). Blood samples were collected at 10 min, 30 min, 1 h, 1.25 h, 1.5 h, 2 h, 4 h, 8 h, and 24 h after intravenous infusion, and at 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 8 h, and 24 h after oral administration. Plasma concentrations of the compounds were determined by UPLC-MS / MS. The results are shown in Table 7.

[0290] Table 7 Antitumor activity in human tumor xenografts Mice were kept under pathogen-free conditions and provided with free access to food and water. 6-8 week old female BALB / c nude mice (Anikeeper, Beijing, China) were subcutaneously injected with 100 μl of HPAC (ATCC, CRL-2119) cells in PBS (5.0 × 10⁶ cells per ... 6 1.0 × 10⁶ cells. 100 μl of Panc-1 (ECACC, 87092802) cells in PBS were subcutaneously injected into the right posterior flank of 6-8 week old female CB17 SCID (Vital River, Beijing, China). 7Cells. SW1990 (ATCC, CRL-2172) cells in PBS and Matrigel matrix (1:1) were subcutaneously injected into the right posterior flank of 6-8 week old female CB17 SCID (Vitol Biosciences, Beijing, China). 5.0 × 10⁶ cells 6 Cells. Mice were monitored daily for health, and caliper measurements were initiated when tumors became palpable. The formula 0.5 × L × W was used. 2 Determine the tumor volume measurement, where L refers to the length of each tumor and W refers to the width of each tumor. When the tumor reaches 100-200 mm... 3 Mice were randomly assigned to treatment groups when the mean tumor volume was determined. Mice were treated orally via tube feeding at a dose of 20–120 mg / kg BID with a mordant consisting of 10% Solutol + 90% water or a test compound in the mordant. Animals were monitored daily, with tumor volume measured 2 or 3 times per week and body weight measured 2 or 3 times per week. Data are presented as mean ± SEM. Statistical analysis was performed on the differences in tumor volume and tumor weight between groups based on data obtained at the optimal treatment time. One-way ANOVA was performed to compare tumor volume and tumor weight between groups, and the Games-Howell test was used for comparisons between groups when a significant F-statistic (the ratio of treatment variance to error variance) was obtained; otherwise, the Dunnet (2-sided) test was used. Significance between groups was analyzed using a t-test. All data were analyzed using SPSS 17.0 (IBM, Armonk, New York). p < 0.05 was considered statistically significant, and p < 0.01 was considered statistically significant. The results are shown in Tables 8 and 9.

[0291] TGI (%) = (1-(T n -T0) / (C n -C0))*100% Tn: Mean tumor volume in the treatment group on day n; T0: Mean tumor volume in the treatment group on day 0; Cn: Mean tumor volume in the catalyst group on day n; C0: Mean tumor volume in the catalyst group on day 0.

[0292] Table 8. Panc-1 pancreatic xenograft model Table 9. SW1990 pancreatic xenograft model In vivo pharmacology was performed to evaluate the efficacy of the test compound in human pancreatic cancer cell models Panc-1 and / or SW1990 and / or HPAC subcutaneous xenograft models after oral administration. The test compound significantly inhibited tumor growth in all models. Tumor-bearing mice tolerated all tested doses of the test compound well.

[0293] hERG inhibition study hERG channels were inhibited in the HEK 293 cell line, which stably expresses hERG channels, by manual patch clamping.

[0294] hERG inhibition studies were conducted using the compounds disclosed herein.

[0295] In vitro Hep Clint assay The test compound at a concentration of 1 µM was incubated with cryopreserved hepatocytes for various time points, up to a maximum of 120 minutes. Consumption of the test compound was quantified using LC-MS / MS. The metabolic stability of the test compound in hepatocytes was assessed by calculating the intrinsic clearance (Clint) and half-life (T1 / 2). A positive control was included in each assay run to validate the performance of the assay system.

[0296] The foregoing description is intended to be merely illustrative of the principles of this disclosure. Furthermore, since many modifications and variations will be apparent to those skilled in the art, it is not intended to limit the invention to the exact constructions and processes described above. Therefore, all suitable modifications and equivalents can be considered to fall within the scope of the invention as defined by the appended claims.

Claims

1. A compound having formula (I), formula (II) or formula (III): （I） (II) (III) Or its pharmaceutically acceptable salt. in Ring A is ; X is -C(R) e R f -, -O- or -N(R) X )-; R X It is hydrogen, deuterium, alkyl, or cycloalkyl, wherein the alkyl and the cycloalkyl are optionally substituted with one or more deuterium; Ring E is ; Z is -C(R) j R k -, -O- or -N(R) Z )-; R Z It is hydrogen, deuterium, alkyl, or cycloalkyl, wherein the alkyl and the cycloalkyl are optionally substituted with one or more deuterium; R 1 and R 2 Each is independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, or haloalkyl, wherein the alkyl, the alkoxy, and the haloalkyl are optionally substituted with one or more deuterium; R 3 and R 4 Each is independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, or haloalkyl, wherein the alkyl, the alkoxy, and the haloalkyl are optionally substituted with one or more deuterium atoms; or R 3 and R 4 Together with the carbon atoms they are all connected to, they form cycloalkyl or heterocyclic groups, each of which is optionally substituted by one or more groups independently selected from the group consisting of: deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl and alkyl; R 5 and R 6 Each is independently selected from hydrogen, deuterium, alkyl, alkoxy, or haloalkyl, wherein the alkyl, the alkoxy, and the haloalkyl are optionally substituted with one or more deuterium; R 7 and R 8 The components are independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -alkyl-alkoxy, wherein the alkyl, the alkoxy, the haloalkyl, the hydroxyalkyl, and the -alkyl-alkoxy are optionally substituted with one or more deuterium; R 9 and R 10 The components are independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -alkyl-alkoxy, wherein the alkyl, the alkoxy, the haloalkyl, the hydroxyalkyl, and the -alkyl-alkoxy are optionally substituted with one or more deuterium; R a R b R c R d R e and R f Each of these is independently hydrogen, halogen, 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 The two in it are formed together with the spacer atoms , Cycloalkyl or heterocyclic groups, wherein each of the cycloalkyl and heterocyclic groups is optionally substituted by one or more groups independently selected from the group consisting of: deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl and alkyl; The condition is that when 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 is independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -alkyl-alkoxy, wherein the alkyl, the alkoxy, the haloalkyl, the hydroxyalkyl, and the -alkyl-alkoxy are optionally substituted with one or more deuterium; R 13 and R 14 Each is independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -alkyl-alkoxy, wherein the alkyl, the alkoxy, the haloalkyl, the hydroxyalkyl, and the -alkyl-alkoxy are optionally substituted with one or more deuterium; R s R t R v and R u Each of them is independently hydrogen, halogen, or an alkyl group optionally substituted with one or more deuterium atoms; R j and R k Each of these is independently hydrogen, halogen, or an alkyl group optionally substituted with one or more deuterium atoms; or R j and R k It forms together with the carbon atoms it is attached to. or ; The condition is that when 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 group substituted with one or more deuterium groups; Each R is independently selected from the group consisting of: deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, alkyl, alkenyl, and alkynyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, and haloalkyl are optionally substituted with one or more deuterium groups; Each R' is independently either hydrogen or deuterium; 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.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Both are hydrogen.

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

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 One of them is hydrogen, and the other is a methyl group optionally substituted with one or more deuterium atoms.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Together with the carbon atoms they are all connected to, they form a cycloalkyl group which is optionally substituted by one or more groups independently selected from the group consisting of: deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl and alkyl.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Together with the carbon atoms to which they are attached, they form a cyclopropyl group that is optionally substituted with one or more deuterium atoms.

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

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 One of them is -CH3 or -CD3, and the other is hydrogen.

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

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

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I), and R 7 and R 8 One of them is an alkyl, alkoxy, -alkyl-alkoxy, hydroxyalkyl, or haloalkyl group, each optionally substituted with one or more deuterium groups, and the other is hydrogen or deuterium.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 One of them is -CH3, -CD3, -CH2-OCH3, -CH2-OCD3, -CH2-OH, -CH2F, -CHF2, or -CF3, and the other is hydrogen or deuterium.

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

14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 One of them is hydrogen, and the other is hydrogen, methyl, or CD3.

15. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I), and R 7 and R 9 Together with spacer atoms, they form heterocyclic groups, or R 7 and R a Together with the spacer atoms, they form heterocyclic groups.

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein ring A is or .

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

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

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

20. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I), and X is -C(R) e R f )-, and R a and R e Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, each of which is optionally substituted by one or more groups independently selected from the group consisting of: deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl and alkyl.

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

22. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein ring A is , , or .

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

24. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 One of them is an alkyl, alkoxy, -alkyl-alkoxy, or haloalkyl group, each optionally substituted with one or more deuterium groups, and the other is hydrogen or deuterium.

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

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 One of them is -CH3 or -CD3, and the other is hydrogen or deuterium.

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

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

29. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I), and X is -C(R) e R f )-, and R e and R f It forms together with the carbon atoms it is attached to. .

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

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

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

33. The compound of claim 32 or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 One of them is -CH3 or -CD3, and the other is hydrogen or deuterium.

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

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

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

37. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 One of them is -CD3, and the other is hydrogen or deuterium.

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

39. The compound of claim 38 or a pharmaceutically acceptable salt thereof, wherein R 13 and R 14 One of them is hydrogen, and the other is hydrogen, methyl, or CD3.

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

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

42. The compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein R u and R v One of them is hydrogen, and the other is hydrogen, methyl, or CD3.

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

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

45. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II) or formula (III), and Z is -C(R j R k )-, and R j and R k It forms together with the carbon atoms it is attached to. .

46. ​​The compound of claim 45 or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 Both are hydrogen.

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

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

49. The compound of claim 48 or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 One of them is -CH3 or -CD3, and the other is hydrogen or deuterium.

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

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

52. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the compound has formula (II) or formula (III), and Z is -O-.

53. The compound according to claim 1, having a formula selected from the following: (It) (One) (Ic) (Id) (Ie) (If) (IIa) (IIIa) Or its pharmaceutically acceptable salt. in R 5 Selected from alkyl, alkoxy, or haloalkyl, wherein the alkyl, alkoxy, and haloalkyl are optionally substituted with one or more deuterium; Ring B is a cycloalkyl or heterocyclic group, each optionally substituted by one or more groups independently selected from the group consisting of: deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl and alkyl; The condition is R 7 and R 9 At least one of them is not hydrogen; and The condition is R 11 It is an alkyl group substituted with one or more deuterium atoms.

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

55. The compound of claim 54 or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from cyano, halogen, hydroxyl, amino, haloalkyl, alkyl or ynyl, wherein the alkyl or ynyl group is optionally substituted with one or more deuterium groups.

56. The compound of claim 55 or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from fluorine, chlorine, hydroxyl, -NH2, -CF3, ethyl or ethynyl, wherein the ethyl or ethynyl is optionally substituted with one or more deuterium groups.

57. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28 and 53 to 56, wherein the compound has formula (I), and Choose from the following groups: , , , , , , , , , , and .

58. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 and 36 to 56, wherein the compound has formula (II), and Choose from the following groups: , and .

59. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 and 36 to 56, wherein the compound has formula (III), and Choose from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , and .

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

61. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 60, wherein each R' is deuterium.

62. A compound selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or its pharmaceutically acceptable salt.

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 activity of wild-type KRas, Kras G12D, Kras G12C, Kras G12V, Kras G13D, Kras G12R, Kras G12S, Kras G12A and / or Kras Q61H in a subject in need, the method comprising administering to the subject 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, the method comprising administering to a subject in need 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.

66. The method of claim 65, wherein the cancer is selected from the group consisting of: (i) Cardiac cancer: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; (ii) Lung cancer: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, mesothelioma; (iii) Gastrointestinal cancers: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (tubular adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, angiotensinoma), small bowel cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); (iv) Urogenital tract cancers: kidney cancer (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminomatous seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma-like tumor, lipoma); (v) Liver cancer: liver cancer (hepatocellular carcinoma), bile duct carcinoma, hepatoblastic carcinoma, angiosarcoma, hepatocellular adenoma, hemangioma; (vi) Biliary tract cancer: gallbladder cancer, ampullary cancer, bile duct cancer; bone cancer: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma and giant cell tumor; (vii) Cancers of the nervous system: Skull cancer (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningeal cancer (meningioma, meningeal sarcoma, glioma), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); (viii) Gynecological cancers: Uterine cancer (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulomatous cell tumor, Seylebsiella pneumoniae, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube cancer (cancer); (ix) Blood cancers: Blood cancers (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma). (x) Skin cancers: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and (xi) Adrenal carcinoma: neuroblastoma.

67. The method of 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 cancer in a subject in need, the method comprising: (a) learning 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 subject an effective amount of the compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof or the 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, intravenous, intracranial, intraspinal, intrasynovial, intrathecal, intrathecal, intramuscular, intravitreal, intravenous, intra-arterial, oral, oral, sublingual, percutaneous, local, tracheal, rectal, subcutaneous, and local administration.

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

71. The method of 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-based agents, SMARCA2 inhibitors, or pemetrexed.

72. Use of the compound of any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 63 in the preparation of a medicament for treating cancer.

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

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