Heterocyclic compounds, compositions thereof, and methods of treatment using the same

Abstract

This document provides compounds having the following structure (I), wherein substituents are as defined herein; compositions comprising the compounds; and methods for modulating the activity of KRAS G12D.

Description

Technical Field

[0001] This article provides heterocyclic compounds that inhibit KRAS activity, as well as their pharmaceutical compositions and methods of use. Background Technology

[0002] Ras are a class of proteins that associate with the cell membrane via their C-terminal membrane targeting regions, and they are well-known as molecular switches in intracellular signaling networks (Cox AD, Der CJ. Ras history: The saga continues). Small GTPases 2010;1(1):2-27). Ras protein binds to GTP or GDP and switches between "on" and "off" states. By switching to the active state, Ras protein can interact with different downstream proteins and activate related signaling pathways (Berndt N, Hamilton AD, Sebti SM. Targeting protein prenylation for cancer therapy). Nat Rev Cancer . 2011;11(11):775-791). HRas, NRas, and KRas are the most studied proteins in the Ras family because they are among the most common oncogenes in human cancers (O'Bryan JP. Pharmacological targeting of RAS: Recent success with direct inhibitors). Pharmacol Res . 2019;139:503-511).

[0003] KRas is one of the most frequently mutated genes in human cancers.

[0004] Among various cancers, pancreatic cancer is considered the most KRas-dependent type. KRas mutations are found in 94.1% of pancreatic ductal adenocarcinomas (PDAC). The G12D (41%) mutation of KRas is the most prevalent mutation among all KRas-mutant PDACs (Waters AM, Der CJ. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer). Cold Spring Harb Perspect Med . 2018;8(9):a031435).

[0005] Therefore, KRas G12D mutations are highly attractive targets for pancreatic cancer and other cancers with this mutation. Consequently, small molecule therapeutics capable of selectively binding to and inhibiting the function of KRas G12D would be extremely useful.

[0006] No reference or designation in this part of the application shall be construed as an admission that the reference is prior art. Summary of the Invention

[0007] This article provides compounds having formula (I): (I) Or its pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or transisomer. in Ring A is an unsubstituted or substituted aryl group, or an unsubstituted or substituted heteroaryl group; Part of B is an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclic group; L 1 Is it a direct key, or -OR a -, wherein R a C does not exist, is not replaced, or has been replaced. 1-4 Alkylene; R 0 Each of these can be independently H, halogen, -CN, -OH, or unsubstituted or substituted C. 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocyclic groups, or unsubstituted or substituted amino groups; or one or more pairs of the R groups. 0 The groups together with the atoms to which they are attached form unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R 1a R 1b R 2a and R 2b Each is independently H, halogen, or unsubstituted or substituted C. 1-3 Alkyl, or R 1a and R 1b Together they form an oxo- or substituted / unsubstituted cyclopropyl group; m and q are each an integer ranging from 0 to the maximum number of substituents allowed on ring A and ring B, respectively.

[0008] In one embodiment, the compound is selected from Table 2.

[0009] In one embodiment, this document provides a method for inhibiting the activity of a KRAS mutant protein in cells, the method comprising contacting the cells with a compound provided herein or a pharmaceutically acceptable salt thereof, a tautomer, stereoisomer, enantiomer, or transisomer thereof, optionally wherein the KRAS mutant protein is a KRAS G12D mutant protein.

[0010] In one embodiment, this document provides a method for treating or preventing cancer, the method comprising administering to a subject in need a compound provided herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or transisomer thereof, optionally wherein the cancer is caused by a KRAS mutation; preferably mediated by a KRAS G12D mutation. Detailed Implementation

[0011] definition As used in this article, “KRAS gene” refers to the gene selected from the following groups: DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS; RRAS2, and their mutants.

[0012] As used in this article, “KRAS protein” refers to the protein expressed by the KRAS gene or its isoforms (Scolnick EM, Papageoege AG, Shih TY (1979), “Guanine nucleotide-binding activity for srcprotein of rat-derived murine sarcoma viruses,” Proc Natl Acad Sci USA. 76(5): 5355–5559; Kranenburg O (November 2005) “The KRAS oncogene: past, present, and future,” Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1756(2): 81–2).

[0013] As used in this article, "G12D mutation" refers to the mutation of the 12th amino acid residue in the G domain of the KRAS protein from glycine to aspartic acid.

[0014] As used in this article, "KRAS G12D" or "G12D" refers to the KRAS protein with the G12D mutation.

[0015] As used herein, in this specification, and in the appended claims, the indefinite article “a / an” and the definite article “the” include both plural and single indicators, unless the context clearly indicates otherwise.

[0016] As used herein, and unless otherwise specified, the terms “about” and “approximately” when used in conjunction with a dose, amount, or weight percentage of an ingredient in a composition or dosage form mean a dose, amount, or weight percentage that a person skilled in the art would consider to provide an equivalent pharmacological effect to that obtained from a specified dose, amount, or weight percentage. In some embodiments, the terms “about” and “approximately” as used herein cover doses, amounts, or weight percentages within 30%, 20%, 15%, 10%, or 5% of a specified dose, amount, or weight percentage.

[0017] As used herein, and unless otherwise stated, the terms “about” and “approximately” are used in conjunction with providing a range of numerical values ​​or values ​​for characterizing a particular solid form, such as a particular temperature or temperature range, as described in terms of melting, dehydration, desolventizing, or glass transition temperatures; mass variation, such as mass variation with temperature or humidity; solvent or water content, expressed, for example, by mass or percentage; or peak position, as used in conjunction with analyses performed by, for example, IR or Raman spectroscopy or XRPD; indicating that the value or range of values ​​may deviate from what would be reasonable to a person skilled in the art, while still describing the solid form. Techniques used to characterize crystalline and amorphous solids include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, vibrational spectroscopy (e.g., infrared (IR) and Raman spectroscopy), solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies. In some embodiments, the terms "about" and "approximately" used in this context indicate that a numerical value or range of values ​​may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the stated value or range. For example, in some embodiments, the value of the XRPD peak position may vary by up to ±0.2°2θ (or ±0.2 degrees 2θ) while still describing a specific XRPD peak.

[0018] As used herein, and unless otherwise specified, the terms “hydrogen” and “H” are used interchangeably and refer to protium, deuterium, or tritium. In one embodiment, the terms “hydrogen” and “H” refer to protium. In one embodiment, the terms “hydrogen” and “H” refer to deuterium. In one embodiment, the terms “hydrogen” and “H” refer to tritium.

[0019] "Alkyl" is a straight-chain or branched acyclic hydrocarbon having 1 to 10 carbon atoms, typically 1 to 8 carbon atoms, or in some embodiments 1 to 6, 1 to 4, or 2 to 6 carbon atoms, and is either saturated or partially saturated. Representative alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, etc. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH7CH3). Alkyl groups may be substituted or unsubstituted. When the alkyl groups described herein are referred to as “substituted,” they may be substituted by any one or more substituents, such as those seen in the exemplary compounds and embodiments disclosed herein, and halogens (chlorine, iodine, bromine, or fluorine); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; urea; carbamate; oxime; hydroxylamine; alkoxyamine; arylalkoxyamine; N-oxide; hydrazine; acylhydrazine; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2 or O(alkyl)aminocarbonyl.

[0020] "Alkylene" is a saturated, partially saturated, or unsaturated straight-chain divalent group having 1 to 10 carbon atoms, typically 1 to 8 carbon atoms, or in some embodiments 1 to 6, 1 to 4, or 2 to 6 carbon atoms. Representative alkylene groups include -CH2-, -CH2CH2-, -CH(CH3)-, -C(CH3)2-, CH2CH2CH2-, CH(CH3)CH2-, -C=CH2, or -C=CH2-CH2-.

[0021] An "alkenyl" is a straight-chain or branched acyclic hydrocarbon having 2 to 10 carbon atoms, typically 2 to 8, and including at least one carbon-carbon double bond. Representative straight-chain and branched (C2-C8) alkenyl groups include -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutenyl, -1-pentenyl, 2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, 3-octenyl, etc. The double bond in an alkenyl group can be non-conjugated or conjugated with another unsaturated group. The alkenyl group can be unsubstituted or substituted.

[0022] The "alkynyl" group refers to a monovalent hydrocarbon moiety containing at least two carbon atoms and one or more carbon-carbon triple bonds. The alkynyl group may optionally be substituted and may be linear, branched, or cyclic. The alkynyl group includes, but is not limited to, groups having the following carbon atom numbers: 2-20 carbon atoms, i.e., C64-C ... 2-20 Alkynyl group; 2-12 carbon atoms, i.e., C 2-12 Alkynyl group; 2-8 carbon atoms, i.e., C64. 2-8 Alkynyl group; 2-6 carbon atoms, i.e., C64. 2-6 The alkynyl group; and 2-4 carbon atoms, i.e., C 2-4 Alkynyl group. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, and butynyl.

[0023] A “cycloalkyl” group is a saturated, partially saturated, or unsaturated cyclic alkyl group having 3 to 10 carbon atoms, having a monocyclic or multiple fused or bridged rings, which may optionally be substituted with 1 to 3 alkyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups comprising multiple rings can be fused, spirocyclic, or bridged, or combinations thereof. Such cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, etc., or polycyclic or bridged ring structures such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, etc. Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, etc. Cycloalkyl groups can be substituted or unsubstituted. Such substituted cycloalkyl groups include, for example, cyclohexanol.

[0024] A “bridged” bicyclic system comprises two rings sharing three, four, or five adjacent ring atoms. As used herein, the term “bridge” refers to an atom or chain of atoms that connects two different parts of a molecule. The two atoms connected by the bridge (usually, but not always, two tertiary carbon atoms) are called “bridgeheads.” In addition to the bridge, the two bridgeheads are also connected by at least two separate atoms or chains of atoms. Examples of bridged bicyclic systems include adamantyl, norbornel, bicyclic [3.2.1]octyl, bicyclic [2.2.2]octyl, bicyclic [3.3.1]nonyl, bicyclic [3.2.3]nonyl, 2-oxabicyclic [2.2.2]octyl, 1-azabicyclic [2.2.2]octyl, 3-azabicyclic [3.2.1]octyl, and 2, examples including, but not limited to, 6-dioxatricyclic [3.3.1.03,7]nonyl. In one embodiment, the bridge is unsubstituted or substituted -(CH2). n - where n is 1, 2, 3, 4, or 5. In one embodiment, the bridge is -CH2-. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-. A "spirocyclic" bicyclic system shares a ring atom (typically a quaternary carbon atom) between the two rings.

[0025] A "fused atom" is an atom shared by two or more rings in a fused ring system.

[0026] An "aryl" group is an aromatic carbocyclic group containing 6 to 14 carbon atoms, having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthracene). In some embodiments, the aryl group contains 6-14 carbon atoms, and in other embodiments, the ring moiety of the aryl group contains 6 to 12 or even 6 to 10 carbon atoms. Specific aryl groups include phenyl, biphenyl, naphthyl, etc. The aryl group may be substituted or unsubstituted.

[0027] A "heterocyclic group" is an aromatic (also called a heteroaryl) or non-aromatic cycloalkyl group in which one to four ring carbon atoms are independently replaced by heteroatoms from the group consisting of O, S, and N. In some embodiments, the heterocyclic group comprises 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. The heterocyclic group may also be bonded to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocycle). The heterocyclic group may be substituted or unsubstituted. The heterocyclic group may include multiple fused rings, including but not limited to bicyclic, tricyclic, and tetracyclic rings, as well as bridged ring systems or spirocyclic systems. The heterocyclic group encompasses unsaturated, partially saturated, and saturated ring systems, such as imidazolyl, imidazolinyl, and imidazoalkyl (e.g., imidazolidin-4-one or imidazolidin-2,4-diketone). The phrase heterocyclic group includes fused rings, including those containing fused aromatic and non-aromatic groups, such as 1-aminotetrahydronaphthalene and 2-aminotetrahydronaphthalene, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxacyclohexenyl and benzo[1,3]dioxacyclopentenyl. The phrase also includes bridged polycyclic systems containing heteroatoms, such as, but not limited to, quinine cyclic groups. Representative examples of heterocyclic groups include, but are not limited to, aziridine, aziridine-butidine, aziridine-heptidine, oxadiazidine, pyrrolidine, imidazoalkyl (e.g., imidazoline-4-one or imidazoline-2,4-diketone), pyrazolidine, thiazoalkyl, tetrahydrothiophene, tetrahydrofuranyl, dioxacyclopentenyl, furanyl, thiophene, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzo[d]isooxazolyl (e.g., benzo[d]isooxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, and thiomorpholinyl. Tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiaranyl, oxothiacyclohexyl, dioxyl, dithiaalkyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiacyclohexenyl, dihydrodithionyl, 1,4-dioxaspiro[4.5]decyl, 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane, 1-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane, 2-oxo-1-oxa-3,9-diazaspiro[5.5]undecane.5] Undecane, piperazinyl, quinine cycloyl, indoleyl (e.g., indole-2-one or isoindoline-1-one), indolinyl, isoindoline, isoindoline, azaindoline (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazoleyl, inazinyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]... Imidazolyl or 1H-benzo[d]imidazol-2(3H)-keto), benzofuranyl, benzothiophene, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiacyclohexenyl, benzooxazinyl, benzoxazolyl (i.e., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxacyclopentenyl, pyrazolopyridyl (e.g., 1H-pyridyl) Azo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl), imidazopyridyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), triazolopyridyl, isoxazolopyridyl, purine, xanthine, adenine, guanine, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-keto), quinazinyl, quinoxalinyl, quinolineyl Azolinyl, terpineyl, phthalazinyl, naphridinyl, pteridinyl, thianaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxane-hexenyl, tetrahydroindolyl, tetrahydroindazoleyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, tetrahydropyrimidin-2(1H)-one, and tetrahydroquinolinyl. Representative non-aromatic heterocyclic groups do not include fused rings containing fused aromatic groups. Examples of non-aromatic heterocyclic groups include aziridine, aziridine, aziridine-heptidine, pyrrolidinyl, imidazoalkyl (e.g., imidazoline-4-keto or imidazoline-2,4-diketo), pyrazolyl, thiazoalkyl, tetrahydrothiopheneyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-keto), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiaranyl, oxothiocyclohexyl, dithiaalkyl, 1,4-dioxaspiro[4.5]decyl, homopiperazinyl, quininecycloyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclic groups may be monosubstituted or substituted multiple times, for example, but not limited to, pyridinyl or morpholinyl, wherein the group is 2-substituted, 3-substituted, 4-substituted, 5-substituted, or 6-substituted, or disubstituted by various substituents (e.g., those listed below). .

[0028] A "heteroaryl" group is an aryl ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, wherein the remaining atoms are carbon atoms. In some embodiments, the heteroaryl group contains 3 to 6 ring atoms, and in other embodiments, the ring portion of the group contains 6 to 9 or even 6 to 10 atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In some embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, groups such as: pyrrolo, pyrazol, imidazo, triazol, tetrazol, oxazol, isoxazol, benzo[d]isooxazol (e.g., benzo[d]isooxazol), thiazolyl, pyrrolo, pyridazinyl, pyrazinyl, thiophene, benzo[d]thiophene, furanyl, benzofuranyl, indole (e.g., indole-2-one or isoindoline-1-one), azaindole (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), inzol, benzo[d]imidazolyl (e.g., 1H-benzo[d]imidazolyl). ), imidazopyridyl (e.g., azirbenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzooxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthyl, purine, xanthine, adenine, guanine, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-keto), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl.

[0029] As used herein, a "spirocycle" refers to two or more rings in which adjacent rings are linked by a single atom. The rings within a spirocycle may be the same or different. The rings within a spirocycle may be substituted or unsubstituted, and may have different substituents than the other rings within a set of spirocycles.

[0030] The "cycloalkylalkyl" group is a group of the following formula: -alkyl-cycloalkyl, wherein the alkyl and cycloalkyl groups are as defined above. The substituted cycloalkyl group may be substituted at the alkyl, cycloalkyl, or both alkyl and cycloalkyl portions of the group. Representative cycloalkylalkyl groups include, but are not limited to, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, ethylcyclopropyl, ethylcyclobutyl, ethylcyclopentyl, ethylcyclohexyl, propylcyclopentyl, propylcyclohexyl, etc.

[0031] An "aralkyl" group is a group of the following formula: -alkyl-aryl, wherein the alkyl and aryl groups are as defined above. A substituted aralkyl group may be substituted at the alkyl, aryl, or both alkyl and aryl portions of the group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl, as well as fused (cycloalkylaryl)alkyl groups, such as 4-ethyl-indenyl.

[0032] A "heterocyclic alkyl" group is a group of the following formula: -alkyl-heterocyclic, wherein the alkyl and heterocyclic groups are as defined above. The substituted heterocyclic alkyl group may be substituted at the alkyl, heterocyclic, or both alkyl and heterocyclic portions of the group. Representative heterocyclic alkyl groups include, but are not limited to, 4-ethyl-morpholino, 4-propylmorpholino, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indole-2-ylpropyl.

[0033] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0034] A “hydroxyalkyl” group is an alkyl group as described above that is replaced by one or more hydroxyl groups.

[0035] The "alkoxy" or "alkoxyl" group is -O- (alkyl), where the alkyl group is as defined above.

[0036] The "alkoxyalkyl" group is -(alkyl)-O-(alkyl), where alkyl is as defined above.

[0037] The "amino" group is a group with the following formula: -NH2.

[0038] The "alkylamino" group is a group of the following formula: -NH-alkyl or –N(alkyl)2, wherein each alkyl group is independently as defined above.

[0039] The "carboxyl" group is a group with the following formula: -C(O)OH.

[0040] The "aminocarbonyl" group is a group with the following formula: -C(O)N(R) # )2、-C(O)NH(R # ) or -C(O)NH2, where each R # Independently defined herein, it is a substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclic or heterocyclic alkyl group.

[0041] The "acylamino" group is a group with the following formula: -NHC(O)(R # ) or -N(alkyl)C(O)(R # ), wherein each alkyl group and R # Independently as defined above.

[0042] The "sulfonylamino" group is a group with the following formula: -NHSO2(R # ) or -N(alkyl)SO2(R # ), wherein each alkyl group and R # As defined above.

[0043] The "urea" group is a group with the following formula: -N(alkyl)C(O)N(R)# )2、-N(alkyl)C(O)NH(R) # -N(alkyl)C(O)NH2, -NHC(O)N(R) # )2、-NHC(O)NH(R # ) or -NH(CO)NHR # Each alkyl group and R # Independently as defined above.

[0044] When the groups described herein (other than alkyl groups) are referred to as “substituted,” they may be substituted by one or more suitable substituents. Illustrative examples of substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogens (chlorine, iodine, bromine, or fluorine); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; urea; carbamate; oxime; hydroxyamine; alkoxyamine; arylalkoxyamine; N-oxide; hydrazine; acylhydrazine; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (═O); B(OH)₂; O(alkyl)aminocarbonyl; cycloalkyl It can be a monocyclic or fused or unfused polycyclic compound (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl); or a heterocyclic compound, which can be a monocyclic or fused or unfused polycyclic compound (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); a monocyclic or fused or unfused polycyclic aryl or heteroaryl compound (e.g., phenyl, naphthyl, pyrrolidinyl, indolyl, furanyl, thiophene, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridineyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophene, or benzofuranyl); aryloxy; arylalkoxy; heterocyclic oxy; and heterocyclic alkoxy.

[0045] As used herein, the term "substituent" refers to an atom or group of atoms that substitutes for a hydrogen atom on a parent molecule. The term "optionally substituted" means that the specified group is not substituted, or is substituted by one or more substituents, which may be independently selected from the possible set of substituents. When indicating the number of substituents, the term "one or more" refers to a range from one substituent to the maximum possible number of substituents, i.e., from one hydrogen atom to all hydrogen atoms being substituted, such as 1 to 8 substituents, 1 to 7 substituents, 1 to 6 substituents, 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 or 2 substituents, or one substituent. Those skilled in the art will understand that any chemical group containing one or more substituents is not intended to introduce any substitution or substitution pattern that is spatially impractical and / or physically infeasible.

[0046] As used herein, the term "one or more pharmaceutically acceptable salts" refers to a salt prepared from a pharmaceutically acceptable, non-toxic acid or base (including inorganic acids and bases as well as organic acids and bases). Suitable pharmaceutically acceptable base addition salts of compounds of formula (I) include, but are not limited to, salts well known in the art, see, for example... Remington’s Pharmaceutical Sciences 18th edition, Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy , 19th edition, Mack Publishing, Easton PA (1995).

[0047] As used herein, and unless otherwise specified, the terms "stereoisomer" or "stereoisopure" mean that one stereoisomer of a compound is substantially free of other stereoisomers of the compound. For example, a stereoisopure compound having one chiral center will substantially free of its opposite enantiomers. A stereoisopure compound having two chiral centers will substantially free of other diastereomers of the compound. Typical stereoisopure compounds contain more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. The compound may have a chiral center and may occur as a racemic mixture, a single enantiomer, or diastereomers, or mixtures thereof. All such isomers are included in the embodiments disclosed herein, including mixtures thereof.

[0048] The use of stereoisomeric pure forms of such compounds, as well as mixtures of these forms, is covered in the embodiments disclosed herein. For example, mixtures comprising equal or unequal amounts of enantiomers of a particular compound can be used in the methods and compositions disclosed herein. These isomers can be synthesized asymmetrically or resolved using standard techniques such as chiral columns or chiral resolving agents. See, for example, Jacques, J. et al. , Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions Page 268 (edited by EL Eliel, Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0049] It should also be noted that the compound may include E and Z isomers, or mixtures thereof, as well as cis and trans isomers, or mixtures thereof. In some embodiments, the compound is isolated as an E or Z isomer. In other embodiments, the compound is a mixture of E and Z isomers.

[0050] As used herein, and unless otherwise specified, "restricted rotation isomer" refers to a stereoisomer produced by restricted rotation about a single bond axis, wherein the rotation barrier is high enough to allow the separation of a single rotation isomer.

[0051] "Tautomers" refer to the isomers of a compound that are in equilibrium with each other. The concentration of the isomers will depend on the environment in which the compound exists and may vary depending on, for example, whether the compound is a solid or in an organic solution or an aqueous solution. For example, in aqueous solution, pyrazole can exhibit the following isomers, which are called tautomers of each other: .

[0052] It will be readily understood by those skilled in the art that various functional groups and other structures can exhibit tautomerism, and that all tautomers of the compound of formula (I) are within the scope of this invention.

[0053] As used herein, “treatment” means the complete or partial relief of a symptom, disease, or ailment, or one or more symptoms associated with a symptom, disease, or ailment, or the slowing or cessation of the further progression or worsening of such symptoms, or the relief or eradication of the cause of the symptom, disease, or ailment itself. In some embodiments, “treatment” means the complete or partial relief of a symptom, disease, or ailment, or the slowing or cessation of the further progression or worsening of such symptoms. In another embodiment, “treatment” means the complete or partial relief of a symptom, disease, or ailment, or symptoms associated with an ailment, wherein the ailment can be treated or prevented by inhibiting KRAS; preferably KRAS G12D.

[0054] As used herein, “prevention” means to completely or partially delay and / or prevent the onset, recurrence, or spread of a symptom, disease, or ailment; to prevent a subject from contracting a symptom, disease, or ailment; or to reduce the risk of a subject contracting a symptom, disease, or ailment. In one embodiment, the ailment is one that can be treated or prevented by inhibiting KRAS; preferably KRAS G12D.

[0055] The term “effective amount” in relation to compounds means the amount that is sufficient to treat or prevent the disease, ailment, or ailment or its symptoms disclosed herein.

[0056] The term "subject" refers to a mammal, and in another implementation, it refers to a human.

[0057] compound This article provides compounds having the following formula (Ia): (Ia) And its pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, or transisomers. in Ring A is an unsubstituted or substituted aryl group, or an unsubstituted or substituted heteroaryl group; Part of B is an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclic group; L 1 Is it a direct key, or -OR a -, wherein R a C does not exist, or has not been replaced or has been replaced. 1-4 Alkylene; R 0 Each can be independently H, halogen, -CN, -OH, or unsubstituted or substituted C. 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclic groups, or unsubstituted or substituted amino groups; or one or more pairs of R 0 The groups together with one or more atoms to which they are attached form unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R 1a R 1b R 2a and R 2b Each is independently H, halogen, or unsubstituted or substituted C. 1-3 Alkyl, or R 1a and R 1b Together they form an oxo- or substituted / unsubstituted cyclopropyl group; m and q are each independent integers ranging from 0 to the maximum number of substituents allowed on ring A and ring B, respectively.

[0058] This article provides compounds having the following formula (I): (I) And its pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, or transisomers. in Ring A is an unsubstituted or substituted aryl group, or an unsubstituted or substituted heteroaryl group; Part of B is an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclic group; L 1 Is it a direct key, or -OR a -, wherein R aC does not exist, is not replaced, or has been replaced. 1-4 Alkylene; R 0 Each of these can be independently H, halogen, -CN, -OH, or unsubstituted or substituted C. 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocyclic groups, or unsubstituted or substituted amino groups; or one or more pairs of the R groups. 0 The groups together with the atoms to which they are attached form unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R 1a R 1b R 2a and R 2b Each is independently H, halogen, or unsubstituted or substituted C. 1-3 Alkyl, or R 1a and R 1b Together they form an oxo- or substituted / unsubstituted cyclopropyl group; m and q are each independent integers ranging from 0 to the maximum allowed number of substituents on ring A and ring B, respectively.

[0059] In some embodiments, the compound is not selected from the compounds in Table 1 of PCT application PCT / CN2023 / 112174.

[0060] Table 1: In some implementations, L 1 Yes -O-.

[0061] In some embodiments, the compound of formula (I) is the compound of formula (IIa): (IIa) The variables are as defined above.

[0062] In some embodiments, part B is a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group containing 1 to 3 heteroatoms independently selected from N or O.

[0063] In some embodiments, part B is a substituted or unsubstituted 4- to 6-membered cycloalkyl group, or a substituted or unsubstituted heterocyclic group containing one oxygen atom.

[0064] In some embodiments, portion B is a substituted or unsubstituted tetrahydro-2H-pyranyl group, or a substituted or unsubstituted furanyl group; preferably a tetrahydro-2H-pyranyl group or a furanyl group, wherein the tetrahydro-2H-pyranyl group or the furanyl group is optionally each surrounded by a C group containing one or more nitrogen atoms. 1-4 Alkylamino or heterocyclic substituted; more preferably tetrahydro-2H-pyranyl substituted with dimethylamino, or furanyl substituted with dimethylamino.

[0065] In some implementation schemes, part B is , , , , , , , , or In some implementations, part B is... , , or .

[0066] In some implementation schemes, part B is , , , or In some implementations, part B is... or .

[0067] In one embodiment, portion B is a substituted or unsubstituted cyclobutyl, a substituted or unsubstituted cyclopentyl, or a substituted or unsubstituted cycloheptyl; preferably a substituted or unsubstituted 2-dimethylaminocyclobutyl, a substituted or unsubstituted 2-heterocyclic cyclobutyl, a substituted or unsubstituted 2-dimethylaminocyclopentyl, a substituted or unsubstituted 2-heterocyclic cyclopentyl, a substituted or unsubstituted 2-dimethylaminocycloheptyl, or a substituted or unsubstituted 2-heterocyclic cycloheptyl, wherein the heterocyclic group is a heterocyclic group containing one or more nitrogen atoms; more preferably, 2-dimethylaminocyclobutyl, 2-dimethylaminocyclopentyl, or 2-dimethylaminocycloheptyl, wherein each of the 2-dimethylaminocyclobutyl, 2-dimethylaminocyclopentyl, and 2-dimethylaminocycloheptyl is optionally substituted with H, F, methoxy, methyl, methyl-d3, methoxy-d3, CF2H, or CF3.

[0068] In some implementation schemes, part B is , , , , , , , , , , , , , or , Where R 11a It is H, F, methoxy, methyl, methyl-d3, methoxy-d3, CF2H, or CF3; and i is 0, 1, 2, 3, or 4. In one implementation, i is 0. In one implementation, i is 1. In one implementation, i is 2. In one implementation, i is 3. In one implementation, i is 4.

[0069] In some implementation schemes, part B is , , , , , , , , or , in R 12a It is H, F, methoxy, methyl, methyl-d3, methoxy-d3, difluoromethyl, or trifluoromethyl; R 12b C is a C that is optionally substituted with one or more substituents. 1-3 Alkyl group, wherein the substituent is selected from methyl, methyl-d3, F, methoxy, or alkenyl; and k is 0, 1, or 2.

[0070] In some implementation schemes, part B is .

[0071] In one implementation, k is 0. In another implementation, k is 1. In yet another implementation, k is 2.

[0072] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0073] In some implementations, L1 It is -OC(R) 3a (R) 3b )-, wherein R 3a and R 3b Each of the following is independently H, F, and C (either substituted or unsubstituted). 1-2 alkyl.

[0074] In some embodiments, the compound of formula (I) is a compound of formula (IIb): (IIb) in R 3a and R 3b Each of the following is independently H, F, and C (either substituted or unsubstituted). 1-2 Alkyl; and Other variables are as defined above.

[0075] In some embodiments, the compound of formula (IIb) is a compound of formula (IIIb): (IIIb) in R a It is methyl, methyl-d3, or Cl; and Other variables are as defined above.

[0076] In some implementation schemes, R 3a It is H, methyl, methyl-d3, difluoromethyl, or trifluoromethyl; and R 3b It is H.

[0077] In some implementation schemes, R 3a and R 3b All are H.

[0078] In some implementation schemes, R 3a and R 3b All are deuterium.

[0079] In some implementation schemes, R 3a It is methyl; R 3b It is H.

[0080] In some implementation schemes, R 3a and R 3b The bonded carbon atom has an R configuration, provided that R... 3a and R 3b They are different substituents.

[0081] In one implementation, R 3a and R 3b The bonded carbon atom has an S configuration, provided that R 3a and R3b They are different substituents.

[0082] In some embodiments, the compound of formula (IIb) is a compound of formula (IIIa): (IIIa) The variables are as defined above.

[0083] In some embodiments, the compound of formula (IIIa) is a compound of formula (IVa): (IVa) The variables are as defined above.

[0084] In some implementations, part B is either replaced or not replaced by C. 3-6 Cycloalkyl, or a substituted or unsubstituted 4- to 6-membered heterocycle containing one or more heteroatoms; preferably cyclopropyl, or a substituted or unsubstituted heterocyclic group containing one or more heteroatoms selected from N or O, wherein the cyclopropyl is optionally substituted by one or more substituents selected from halogens, or substituted or unsubstituted alkyl groups.

[0085] In some embodiments, part B is a cyclopropyl group optionally substituted with one or more substituents selected from halogens, or substituted or unsubstituted alkyl groups.

[0086] In some embodiments, portion B is a cyclopropyl group optionally substituted with one or more substituents selected from halogens or alkyl groups, wherein the alkyl group is optionally substituted or unsubstituted with a 4- to 10-membered heterocyclic group.

[0087] In some implementation schemes, part B is , in R 21a Each is independently either H or halogen; R 22a and R 22b Each is independently H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted heterocyclic group, or R. 22a and R 22b With R 22a and R 22b The atoms that are attached together form substituted or unsubstituted heterocyclic groups; and v can be 0, 1, 2, 3, or 4.

[0088] In one implementation, v is 0. In one implementation, v is 1. In one implementation, v is 2. In one implementation, v is 3. In one implementation, v is 4.

[0089] In some implementation schemes, part B is , in R 23a and R 23b Each is independently either H or halogen; R 22a and R 22b Each is independently H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted heterocyclic group, or R. 22a and R 22b With R 22a and R 22b The atoms that are attached together form a heterocyclic group that is either substituted or unsubstituted.

[0090] In some implementations, with R 22a and R 22b The carbon atom of the cyclopropyl group connected by the branch has an R configuration.

[0091] In some implementations, with R 22a and R 22b The carbon atom of the cyclopropyl group connected by the branch has an S configuration.

[0092] In some implementation schemes, part B is , in R 23a and R 23b Each is independently either H or halogen; R 22a and R 22b Each is independently H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted heterocyclic group, or R. 22a and R 22b With R 22a and R 22b The atoms that are attached together form a heterocyclic group that is either substituted or unsubstituted.

[0093] In some implementation schemes, part B is , in R 23a and R 23b Each is independently either H or halogen; R 22a and R 22b Each is independently H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted heterocyclic group, or R. 22a and R 22b With R22a and R 22b The atoms that are attached together form a heterocyclic group that is either substituted or unsubstituted.

[0094] In some implementation schemes, R 22a and R 22b Each is independently H, a substituted or unsubstituted amino group, or a substituted or unsubstituted C group. 1-3 Alkyl; preferably, R 22a and R 22b Each can be independently H, methyl, or dimethylamino.

[0095] In some implementation schemes, part B is , , , , , , , , , or In some implementations, part B is... , , , , or In some implementations, part B is... or In some implementations, part B is... , , or or In some implementations, part B is... , , or .

[0096] In some implementation schemes, R 22b It is H or methyl, and R 22a It is a substituted or unsubstituted heterocyclic group; preferably, R 22b It is H or methyl, and R 22aIt is a substituted or unsubstituted azacyclic butyl group, a substituted or unsubstituted pyrrolidinyl group, a substituted or unsubstituted piperidinyl group, a substituted or unsubstituted 3-azabicyclo[3.1.0]hexyl group, a substituted or unsubstituted 2,5-dihydro-1H-pyrrolidinyl group, a substituted or unsubstituted 6-azaspiro[2.5]octyl group, a substituted or unsubstituted 1,2,3,6-tetrahydropyridyl group, a substituted or unsubstituted morpholinyl group, a substituted or unsubstituted 2-oxa-6-azaspiro[3.3]heptyl group, a substituted or unsubstituted (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptyl group, a substituted or unsubstituted (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptyl group; more preferably, R 22b It is H or methyl, and R 22a It is a substituted or unsubstituted azacyclobutane-1-yl, a substituted or unsubstituted pyrrolidine-1-yl, a substituted or unsubstituted piperidin-1-yl, a substituted or unsubstituted 2,5-dihydro-1H-pyrrolo-1-yl, a substituted or unsubstituted 6-azaspiro[2.5]oct-6-yl, a substituted or unsubstituted 1,2,3,6-tetrahydropyridin-1-yl, a substituted or unsubstituted morpholino-4-yl, a substituted or unsubstituted 2-oxa-6-azaspiro[3.3]hept-6-yl, a substituted or unsubstituted (1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl, a substituted or unsubstituted Substituted (1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl, 2-azaspiro[3.3]hept-2-yl, substituted or unsubstituted 2-azabicyclo[2.2.1]hept-2-yl, substituted or unsubstituted 3-azabicyclo[3.1.1]hept-3-yl, substituted or unsubstituted 2-oxa-6-azaspiro[3.4]oct-6-yl, substituted or unsubstituted 2-oxa-7-azaspiro[4.4]non-7-yl, substituted or unsubstituted 7-oxa-1-azaspiro[4.4]non-1-yl, or substituted or unsubstituted 7-azaspiro[3.5]non-7-yl.

[0097] In some implementation schemes, part B is The ring C is a substituted or unsubstituted 4- to 10-membered heterocyclic group, which optionally contains one or more additional heteroatoms selected from N, O, or S. In some embodiments, the ring C is a substituted or unsubstituted 4- to 7-membered heterocyclic group, which optionally contains one or more additional heteroatoms selected from N, O, or S. In some embodiments, the heterocyclic group is a monocyclic system. In some embodiments, the heterocyclic group is a bridged ring system. In some embodiments, the heterocyclic group is a fused ring system. In some embodiments, the heterocyclic group is a spirocyclic system. In some embodiments, R...22b It is H or methyl. In some embodiments, R 22b It is H. In some implementations, R 22b It is a methyl group.

[0098] In some embodiments, the ring C is optionally substituted with one or more substituents, wherein the substituents are halogens, hydroxyl groups, substituted or unsubstituted C groups. 1-3 Alkoxy, substituted or unsubstituted C 1-3 Alkyl groups, or substituted or unsubstituted C4 groups 3-5 Cycloalkyl, or a pair of substituents together with the atoms to which they are attached, form substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclic groups.

[0099] In some embodiments, the ring C is optionally substituted with one or more substituents, wherein the substituents are H, F, hydroxyl, cyano, methoxy, methyl, methyl-d3, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, difluoromethoxy, cyclopropyl, or oxetane.

[0100] In some embodiments, the ring C is optionally substituted with one or more substituents, wherein a pair of substituents together with the atoms to which they are attached form a substituted or unsubstituted alkenyl group, wherein the alkenyl group is in the ring C (e.g., 2,5-dihydro-1H-pyrrole-1-yl).

[0101] In some implementation schemes, part B is , , , , , , , , , , , , , , , , , , , , , , , , , , , or , where R 23a and R 23b Each independently is H or F; R24a and R 24b Each is independently H, methyl, ethyl, methyl-d3, F, or Cl; and R 24c It is H, F, methoxy, methyl, methyl-d3, ethyl, difluoromethyl, or trifluoromethyl.

[0102] In some implementation schemes, part B is , , , , , , , , , , , , or , where R 24a and R 24b Each independently is H, methyl, ethyl, methyl-d3, F, or Cl; R 24c It is H, F, methoxy, methyl, methyl-d3, ethyl, difluoromethyl or trifluoromethyl; and z is 0, 1 or 2.

[0103] In some implementation schemes, part B is , , , , , , , , , , , , , , , , , , , , or , where R 24a and R 24b Each is independently H, methyl, ethyl, methyl-d3, F, or Cl; and R 24c It is H, F, methoxy, methyl, methyl-d3, ethyl, difluoromethyl, or trifluoromethyl. In some embodiments, part B is... , , , or .

[0104] In some implementation schemes, part B is , , , , , , , , , , , , or , where R 24a and R 24b Each independently is H, methyl, ethyl, methyl-d3, F, or Cl; R 24c It is H, F, methoxy, methyl, methyl-d3, ethyl, difluoromethyl or trifluoromethyl; and z is 0, 1 or 2.

[0105] In some implementation schemes, part B is , , , , , , , , , , , , , , , , , , , , or , where R 24a and R 24b Each is independently H, methyl, ethyl, methyl-d3, F, or Cl; and R 24c It is H, F, methoxy, methyl, methyl-d3, ethyl, difluoromethyl, or trifluoromethyl.

[0106] In some implementation schemes, part B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , where R 24a and R 24b Each is independently H, methyl, ethyl, methyl-d3, F, or Cl; and R 24c It is H, F, hydroxyl, cyano, methoxy, methyl, methyl-d3, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, difluoromethoxy, cyclopropyl, or oxetane.

[0107] In some implementation schemes, part B is , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , or , where R 24a and R 24b Each is independently H, methyl, ethyl, methyl-d3, F, or Cl; and R 24c It is H, F, methoxy, methyl, methyl-d3, ethyl, difluoromethyl, or trifluoromethyl.

[0108] In some implementation schemes, part B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, part B is... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, part B is... , , , , , , , , , , , , , , , , , , , , , , , or .

[0109] In some implementation schemes, R 22a and R 22b With R 22a and R 22b The atoms bonded together form substituted or unsubstituted 5- to 6-membered heterocyclic groups; in some embodiments, R 22a and R 22b With R 22a and R 22b The atoms bonded together form a substituted or unsubstituted pyrrolidinyl group, a substituted or unsubstituted piperidinyl group, or a substituted or unsubstituted morpholinyl group; in some embodiments, R 22a and R 22b With R 22a and R 22b The atoms bonded together form a pyrrolidinyl, piperidinyl, or morpholinyl group, wherein the pyrrolidinyl, piperidinyl, and morpholinyl group are each optionally substituted with H, a halogen, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkyl group.

[0110] In some implementation schemes, part B is , Where R 25a C is a C that is optionally substituted with one or more substituents. 1-3 Alkyl group, wherein the substituent is selected from methyl, methyl-d3, F or alkenyl; R 25b It is H, F, methoxy, methyl, difluoromethyl, or trifluoromethyl; X 1 It is O or C; and r is 0, 1, or 2.

[0111] In some implementation schemes, part B is , , , , , , , or In some implementations, part B is... .

[0112] In some embodiments, part B is a substituted or unsubstituted 4- to 6-membered heterocyclic group containing one or two heteroatoms selected from N or O.

[0113] In some embodiments, part B is a substituted or unsubstituted 4- to 6-membered heterocyclic group containing one oxygen atom; preferably a substituted or unsubstituted oxetane, a substituted or unsubstituted tetrahydrofuranyl, or a substituted or unsubstituted tetrahydro-2H-pyranyl; more preferably a substituted or unsubstituted oxetane-2-yl, a substituted or unsubstituted tetrahydrofuran-3-yl, a substituted or unsubstituted tetrahydrofuran-2-yl, a substituted or unsubstituted tetrahydro-2H-pyran-4-yl, or a substituted or unsubstituted tetrahydro-2H-pyran-3-yl.

[0114] In some embodiments, portion B is 3-dimethylamino-oxetane-2-yl, 4-dimethylamino-tetrahydrofuran-3-yl, 3-dimethylamino-tetrahydrofuran-2-yl, 3-dimethylamino-tetrahydro-2H-pyran-4-yl, or 4-dimethylamino-tetrahydro-2H-pyran-3-yl, wherein each of the 3-dimethylamino-oxetane-2-yl, 4-dimethylamino-tetrahydrofuran-3-yl, 3-dimethylamino-tetrahydrofuran-2-yl, 3-dimethylamino-tetrahydro-2H-pyran-4-yl, and 4-dimethylamino-tetrahydro-2H-pyran-3-yl may optionally be substituted with methyl, F, hydroxyl, methoxy, or difluoromethyl.

[0115] In some implementation schemes, part B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, part B is... , , , , or In some implementations, part B is... , , , , or .

[0116] In one embodiment, portion B is a substituted or unsubstituted pyrrolidinyl; preferably optionally substituted or unsubstituted pyrrolidin-2-yl substituted with one or more substituents selected from H, F, methyl, methyl-d3, difluoromethyl, ethyl, 2-fluoroethyl, 2-(methoxy-d3)ethyl, 1-allyl-2-methyl, methoxy, cyclopropylmethyl, oxetyl, tetrahydrofuranyl, or tetrahydro-2H-pyranyl.

[0117] In some implementation schemes, part B is , in R 26a It is H, methyl, or difluoromethyl; R 26b It is methyl, methyl-d3, ethyl, 2-fluoroethyl, 2-(methoxy-d3)ethyl, 2-methoxyethyl, 1-allyl-2-methyl, cyclopropylmethyl, oxetane, tetrahydrofuranyl or tetrahydro-2H-pyranyl; Each R 26c It is independently H, F, or methoxy, or a pair of R 26c Together with the atoms they are attached to, they form substituted or unsubstituted cyclopropyl groups; and c is 0, 1, or 2.

[0118] In some implementation schemes, R 26a The attached carbon atom has an S configuration.

[0119] In some implementation schemes, R 26a The attached carbon atom has an R configuration.

[0120] In some implementation schemes, part B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , where R 26a It is H, methyl, or difluoromethyl; each R 26b It is independently methoxy, methoxy-d3, fluorine, methyl, fluoromethyl or difluoromethyl.

[0121] In some implementation schemes, part B is , , , , , , , , , , , , , , , , , or In some implementations, part B is... , , , , , , , , or In some implementations, part B is... , , or .

[0122] In some embodiments, part B is a substituted or unsubstituted 6-membered heterocyclic group containing one or two heteroatoms selected from O or N, provided that at least one heteroatom is N; preferably, part B is a substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazineyl.

[0123] In some implementation schemes, part B is , in X 2 It is -CHF-, -CF2-, -CH(CH3)-, N(CH3)-, -CH(OCH3)-, -CH(CHF2)-, -C(=CHF)- or -O-; R 27a It is methyl, ethyl, difluoromethyl, or trifluoromethyl; R 27b It is H, F, methyl, or methoxy; R 27c It is C 1-3 Alkyl, oxetane butyl, tetrahydrofuranyl, or tetrahydropyranyl, wherein the C 1-3 The alkyl group may optionally be substituted with one or more substituents selected from methyl, methyl-d3, F, or alkenyl; and n is 0, 1, 2, 3 or 4.

[0124] In one implementation, n is 0. In one implementation, n is 1. In one implementation, n is 2. In one implementation, n is 3. In one implementation, n is 4.

[0125] In some implementations, connected to R 27a The carbon atom of the cyclopropyl group has an R configuration.

[0126] In some implementations, connected to R 27a The carbon atom of the cyclopropyl group has an S configuration.

[0127] In some implementation schemes, part B is , , , , , , , , , , , , , , , , or , where R 27c It is C 1-3 Alkyl, oxetane butyl, tetrahydrofuranyl, or tetrahydropyranyl, wherein the C 1-3 The alkyl group may optionally be substituted with one or more substituents selected from deuterium, methyl, methyl-d3, F, cyclopropylmethyl, or alkenyl. In some embodiments, part B is... , , , , , , , , , , or In some implementations, part B is... , , , , or In some implementations, part B is... or .

[0128] In one embodiment, part B is a substituted or unsubstituted bicyclic heterocyclic group.

[0129] In some embodiments, portion B is a substituted or unsubstituted bicyclic heterocyclic group containing one or two heteroatoms selected from N or O, provided that at least one fused atom is N; preferably substituted or unsubstituted hexahydro-1H-pyrrolazinyl, substituted or unsubstituted octahydroindazinyl, substituted or unsubstituted hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, or substituted or unsubstituted octahydropyrido[2,1-c][1,4]oxazinyl.

[0130] In some implementation schemes, part B is , , , , , or , in R 28a It is H, methyl, methyl-d3, fluoromethyl, difluoromethyl, or trifluoromethyl; R 28b and R 28c Each is H, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a pair of R groups. 28b Or R 28cTogether with the atoms they are attached to, they form unsubstituted or substituted alkenyl groups, or unsubstituted or substituted cycloalkyl groups; and s and p are each independently 0, 1, 2, 3 or 4.

[0131] In one implementation, s is 0. In one implementation, s is 1. In one implementation, s is 2. In one implementation, s is 3. In one implementation, s is 4. In one implementation, p is 0. In one implementation, p is 1. In one implementation, p is 2. In one implementation, p is 3. In one implementation, p is 4.

[0132] In some implementation schemes, part B is , , , , , , , , , , , , , , or .

[0133] In some implementation schemes, part B is , , , , , or , in R 28a It is H, methyl, methyl-d3, fluoromethyl, difluoromethyl, or trifluoromethyl; R 28b and R 28c Each is H, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a pair of R groups. 28b Or R 28c Together with the atoms they are attached to, they form unsubstituted or substituted alkenyl groups, or unsubstituted or substituted cycloalkyl groups; and s and p are each independently 0, 1, 2, 3 or 4; The premise is that, no .

[0134] In some implementation schemes, part B is .

[0135] In one implementation, s is 0. In one implementation, s is 1. In one implementation, s is 2. In one implementation, s is 3. In one implementation, s is 4. In one implementation, p is 0. In one implementation, p is 1. In one implementation, p is 2. In one implementation, p is 3. In one implementation, p is 4.

[0136] In some implementations, a pair of R 28b Together with the atoms they are attached to, they form vinyl groups. In some embodiments, a pair of R... 28c Together with the atoms they are attached to, they form vinyl groups. In some embodiments, a pair of R... 28c Together with the atoms they are bonded to, they form 2,2-difluorovinyl. In some embodiments, a pair of R... 28b Together with the atoms they are attached to, they form a cyclopropyl group. In some embodiments, a pair of R... 28c Together with the atoms to which they are attached, they form a cyclopropyl group, which may optionally be substituted with one or more fluorine molecules.

[0137] In one implementation, a pair of R 28b Together with the atoms they are attached to, they form unsubstituted or substituted alkenyl groups, wherein the alkenyl group is in R 28b In the connected ring.

[0138] In one implementation, a pair of R 28b Or a pair of R 28c Together with the atoms they are attached to, they form vinyl groups, which may optionally be substituted with one or more F atoms.

[0139] In one implementation, a pair of R 28b Together with the atoms they are attached to, they form cyclopropyl groups.

[0140] In one implementation, a pair of R 28c Together with the atoms they are attached to, they form cyclopropyl groups.

[0141] In one implementation, R 28b and R 28c Each is either F or methoxy.

[0142] In some implementation schemes, part B is , , , , , , , or .

[0143] In some implementation schemes, part B is , , , or , , , or .

[0144] In some implementation schemes, part B is , , , , , or , in R 28a It is H, methyl, methyl-d3, fluoromethyl, difluoromethyl, or trifluoromethyl; R 28b and R 28c Each is H, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a pair of R groups. 28b Or R 28c Together with the atoms they are attached to, they form unsubstituted or substituted alkenyl groups, or unsubstituted or substituted cycloalkyl groups; and s and p are each independently 0, 1, 2, 3 or 4; The premise is that, no , .

[0145] In one implementation, s is 0. In one implementation, s is 1. In one implementation, s is 2. In one implementation, s is 3. In one implementation, s is 4. In one implementation, p is 0. In one implementation, p is 1. In one implementation, p is 2. In one implementation, p is 3. In one implementation, p is 4.

[0146] In some embodiments, portion B is a substituted or unsubstituted bicyclic heterocyclic group containing one or two heteroatoms selected from N or O, provided that both fused atoms are C; preferably substituted or unsubstituted octahydro-1H-cyclopentano[b]pyridyl, substituted or unsubstituted octahydrocyclopentano[b][1,4]oxazinyl, or substituted or unsubstituted octahydrofurano[3,2-b]pyridyl.

[0147] In some implementation schemes, part B is , or , in R 29c It is methyl, methyl-d3, difluoromethyl, or trifluoromethyl; R 29a and R 29b Each is H, a halogen, or a substituted or unsubstituted alkyl group; and t and g are each independently 0, 1, 2, 3 or 4.

[0148] In one implementation, t is 0. In one implementation, t is 1. In one implementation, t is 2. In one implementation, t is 3. In one implementation, t is 4. In one implementation, g is 0. In one implementation, g is 1. In one implementation, g is 2. In one implementation, g is 3. In one implementation, g is 4.

[0149] In some embodiments, portion B is a substituted or unsubstituted cyclobutyl, a substituted or unsubstituted cyclopentyl, or a substituted or unsubstituted cycloheptyl; preferably a substituted or unsubstituted 2-dimethylaminocyclobutyl, a substituted or unsubstituted 2-dimethylaminocyclopentyl, or a substituted or unsubstituted 2-dimethylaminocycloheptyl; more preferably 2-dimethylaminocyclobutyl, 2-dimethylaminocyclopentyl, or 2-dimethylaminocycloheptyl, wherein each of the 2-dimethylaminocyclobutyl, 2-dimethylaminocyclopentyl, and 2-dimethylaminocycloheptyl is optionally substituted with H, a halogen, a methoxy group, or a methoxy-d3 group.

[0150] In some implementation schemes, part B is , in R 20 It is H, halogen, methyl, methyl-d3, methoxy, or methoxy-d3; and h can be 1, 2, or 3.

[0151] In some embodiments, the compound of formula (IIb) is the same as the compound of formula (IVb): (IVb) in The ring C is a substituted or unsubstituted 4- to 7-membered heterocyclic group that optionally contains one or more additional heteroatoms selected from N or O; R c Each of these can be independently H, halogen, amino, -OH, -CN, or unsubstituted or substituted C. 1-4 Alkyl, or unsubstituted or substituted C 1-4 alkoxy, or a pair of said R cThe groups together with the atoms they are attached to form unsubstituted or substituted bridges, unsubstituted or substituted cycloalkyl groups, or unsubstituted or substituted heterocyclic groups; u is an integer ranging from 0 to the maximum allowed number of substituents on ring C; and Other variables are as defined above.

[0152] In some embodiments, the compound of formula (IVb) is the same as the compound of formula (Vb): (Vb) in R a It is methyl, methyl-d3, or Cl.

[0153] The ring C is a substituted or unsubstituted 4- to 7-membered heterocyclic group that optionally contains one or more additional heteroatoms selected from N, O or S; R c Each of these can be independently H, halogen, amino, -OH, -CN, or unsubstituted or substituted C. 1-4 Alkyl, or unsubstituted or substituted C 1-4 alkoxy, or a pair of said R c The groups together with the atoms they are attached to form unsubstituted or substituted bridges, unsubstituted or substituted cycloalkyl groups, or unsubstituted or substituted heterocyclic groups; u is an integer ranging from 0 to the maximum allowed number of substituents on ring C; and Other variables are as defined above.

[0154] In some embodiments, the ring C is an unsubstituted or substituted azacyclobutane, an unsubstituted or substituted pyrrolidinyl, an unsubstituted or substituted piperidinyl, an unsubstituted or substituted morpholinyl, an unsubstituted or substituted thiomorpholinyl, or an unsubstituted or substituted 1,4-oxazacycloheptyl-4-yl.

[0155] In some implementation schemes, R c Each of them independently is H, methyl, methoxy, F, trifluoromethyl, hydroxy, or hydroxymethyl.

[0156] In some implementations, a pair of said R c Groups together with the atoms they are attached to form unsubstituted or substituted bridges, and the bridges are -CH2- or -CH2-CH2-.

[0157] In some implementations, a pair of said R cThe groups, together with the atoms to which they are attached, form an unsubstituted or substituted cyclopropyl group, an unsubstituted or substituted tetrahydrofuran group, an unsubstituted or substituted imidazolyl group, or an unsubstituted or substituted 1,2,4-triazolyl group, wherein the tetrahydrofuranyl group, imidazolyl group, and 1,2,4-triazolyl group are fused with a cyclic C.

[0158] In some implementations, a pair of said R c The groups, together with the atoms to which they are attached, form unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted oxacyclobutane, unsubstituted or substituted tetrahydrofuranyl, and unsubstituted or substituted tetrahydro-2H-pyranyl.

[0159] In some implementation schemes, R c Each of them is independently F, methyl, trifluoromethyl, hydroxy, methoxy, or hydroxymethyl.

[0160] In some implementations, u is 0. In some implementations, u is 1. In some implementations, u is 2. In some implementations, u is 3.

[0161] In some implementation schemes, yes , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0162] In some implementation schemes, yes , , , , , , , or .

[0163] In some implementation schemes, yes , , , , , or .

[0164] In some implementation schemes, yes , , , , or .

[0165] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0166] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0167] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0168] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0169] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0170] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0171] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0172] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0173] In some implementation schemes, yes ; yes And R 1a R 1b R2a and R 2b Both are H.

[0174] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0175] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0176] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0177] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0178] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0179] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0180] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0181] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0182] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0183] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0184] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0185] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0186] In some implementation schemes, yes ; yes And R1a R 1b R 2a and R 2b Both are H.

[0187] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0188] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0189] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0190] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0191] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0192] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0193] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0194] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0195] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0196] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0197] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0198] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0199] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0200] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0201] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0202] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0203] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0204] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0205] In some implementation schemes, yes ; yes And R 1a R 1b R2a and R 2b Both are H.

[0206] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0207] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0208] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0209] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0210] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0211] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0212] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0213] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0214] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0215] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0216] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0217] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0218] In some implementation schemes, yes ; yes And R1a R 1b R 2a and R 2b Both are H.

[0219] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0220] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0221] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0222] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0223] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0224] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0225] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0226] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0227] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0228] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0229] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0230] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0231] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0232] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0233] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0234] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0235] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0236] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0237] In some implementation schemes, yes ; yes And R 1a R 1b R2a and R 2b Both are H.

[0238] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0239] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0240] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0241] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0242] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0243] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0244] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0245] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0246] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0247] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0248] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0249] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0250] In some implementation schemes, yes ; yes And R1a R 1b R 2a and R 2b Both are H.

[0251] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0252] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0253] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0254] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0255] In some implementation schemes, yes ; yes ;R 1a R 1b R 2a and R 2b Both are H; and R 3a and R 3b Both are H, where H refers to deuterium.

[0256] In some implementation schemes, yes ; yes ;R 1a R 1bR 2a and R 2b Both are H; and R 3a and R 3b Both are H, where H refers to deuterium.

[0257] In some implementation schemes, yes ; yes ;R 1a R 1b R 2a and R 2b Both are H; and R 3a and R 3b Both are H, where H refers to deuterium.

[0258] In some implementation schemes, yes ; yes ;R 1a R 1b R 2a and R 2b Both are H; and R 3a and R 3b Both are H, where H refers to deuterium.

[0259] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0260] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0261] In some implementation schemes, yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0262] In some implementation schemes, yes ; yes ;R 1a R 1b R 2a and R 2b Both are H; and R 3a and R 3b Both are H, where H refers to deuterium.

[0263] In some implementation schemes, yes ; yes ;R 1a R 1b R 2a and R 2b Both are H; and R 3a and R 3b Both are H, where H refers to deuterium.

[0264] In some implementation schemes, yes ; yes ;R 1a R 1b R 2a and R 2b Both are H; and R 3a and R 3b Both are H, where H refers to deuterium.

[0265] In some implementation schemes, yes ; yes ;R 1a It is methyl; and R 1b R 2a and R 2b Both are H.

[0266] In some implementations, L 1 It is a direct key.

[0267] In some embodiments, part B is a substituted or unsubstituted azacyclobutyl, a substituted or unsubstituted diazaspiro[3.3]heptyl, a substituted or unsubstituted diazaspiro[3.4]octyl, or a substituted or unsubstituted diazaspiro[3.5]nonyl; preferably a substituted or unsubstituted 1,6-diazaspiro[3.3]hept-6-yl, a substituted or unsubstituted 2,5-diazaspiro[3.4]oct-2-yl, or a substituted or unsubstituted 2,5-diazaspiro[3.5]non-2-yl.

[0268] In some implementation schemes, part B is , or , where R 31 It is H or C that has been substituted or not substituted. 1-4 alkyl.

[0269] In some implementation schemes, R 31 It is H, methyl, methyl-d3, or ethyl.

[0270] In some embodiments, the compound of formula (I) is a compound of formula (IIc): (IIc) in R 32a and R 32b Each is independently H, or C that has been substituted or has been substituted. 1-4 Alkyl groups, unsubstituted or substituted amino groups, or unsubstituted or substituted heterocyclic groups; and Other variables are as defined above.

[0271] In some embodiments, the compound of formula (I) is the compound of formula (IIIc): (IIIc) in R a It is methyl, methyl-d3, or Cl; and Other variables are as defined above.

[0272] In some implementation schemes, R 32a It is dimethylamino, ethyl(methyl)amino, diethylamino, aziridine-1-yl, 3-fluoroaziridine-1-yl, 3-methoxyaziridine-1-yl, pyrrolidine-1-yl, 2-fluoropyrrolidine-1-yl, 2-methoxypyrrolidine-1-yl, piperidin-1-yl, 2-fluoropiperidin-1-yl, 3-fluoropiperidin-1-yl, 2-methoxypiperidin-1-yl, 3-methoxypiperidin-1-yl, morpholino, 3-oxa-6-azabicyclo[3.1.1]hept-6-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3 -yl, (1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl, 3-oxa-8-azabicyclo[3.2.1]oct-8-yl, 8-azabicyclo[3.2.1]oct-8-yl, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, 3-azabicyclo[3.1.1]hept-3-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl or 6-azabicyclo[3.1.1]hept-6-yl.

[0273] In some implementation schemes, R 32bIt is H, methyl, methyl-d3, fluoromethyl, methoxymethyl or ethyl; preferably H, methyl or methyl-d3.

[0274] In some implementation schemes, yes , , , , , , , , , , , , , , , , , , , , , , , , , , , or , where R 32b It is H, methyl, methyl-d3, fluoromethyl, methoxymethyl, or ethyl; and R 33b It is H, methyl, methyl-d3, or ethyl. In some embodiments, yes or .

[0275] In some implementation schemes, yes , , , , , , , , , , , , , , , , , , , , , , , , , , , or , Where R 33a It is H, methyl, methyl-d3, fluoromethyl, methoxymethyl, or ethyl; and R 33b It is H, methyl, methyl-d3, or ethyl.

[0276] In some implementation schemes, R 1a R 1b R 2a and R 2b Each is independently H or methyl, or R 1a and R 1b Together they form oxygen.

[0277] In some implementation schemes, R 1a R 1b R 2a and R 2b Both are H.

[0278] In some embodiments, ring A is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted naphthyl group; preferably, ring A is a phenyl or naphthyl group, wherein the phenyl and naphthyl groups are optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of amino, -Cl, -F, cyano, ethyl, methyl, trifluoromethyl, cyclopropyl, hydroxy or 1,1-difluoroethyl.

[0279] In some embodiments, ring A is a phenyl group optionally substituted with 1, 2, 3, or 4 substituents, said substituents being independently selected from amino, hydroxy, -Cl, -F, ethyl, methyl, methyl-d3, trifluoromethyl, or cyclopropyl; preferably, it is an aminophenyl group optionally substituted with 1, 2, 3, or 4 substituents, said substituents being independently selected from -Cl, -F, ethyl, methyl, methyl-d3, trifluoromethyl, or cyclopropyl.

[0280] In some implementation schemes, yes , , , , , , , , or .

[0281] In some embodiments, ring A is a naphthyl group optionally substituted with 1, 2, 3 or 4 substituents, said substituents being independently selected from -Cl, -F, vinyl, ethyl, cyclopropyl or hydroxy; preferably, it is a hydroxynaphthyl group optionally substituted with 1, 2, 3 or 4 substituents, said substituents being independently selected from -Cl, -F, vinyl, ethyl or cyclopropyl.

[0282] In some implementation schemes, yes , , , , , or .

[0283] In some implementation schemes, yes , , , , , , , , , , , , , , , , , or .

[0284] In some embodiments, the compound is selected from one of the compounds in Table 2.

[0285] This document provides a pharmaceutical composition comprising the compound provided herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or transisomer thereof, and a pharmaceutically acceptable carrier, excipient, or mediator.

[0286] This document provides a method for inhibiting the activity of a KRAS mutant protein in cells, the method comprising contacting the cells with a compound provided herein or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer, an enantiomer, or a transtransisomer thereof, optionally wherein the KRAS mutant protein is a KRAS G12D mutant protein.

[0287] This document provides a method for treating or preventing cancer, the method comprising administering to a subject in need a compound provided herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or transisomer thereof, optionally wherein the cancer is a KRAS mutation; preferably mediated by a KRAS G12D mutation. This document also provides a method for treating or preventing cancer, the method comprising administering to a subject in need a compound provided herein.

[0288] This document provides a method for modulating the activity of KRAS G12D, the method comprising contacting the cells with the compound provided herein or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, enantiomer or transisomer.

[0289] This document provides a kit for treating cancer, the kit comprising (a) a pharmaceutical composition containing the compounds provided herein; and (b) instructions for use in treating an individual’s cancer by administering the pharmaceutical composition containing the KRAS G12D inhibitor provided herein.

[0290] Implementation plan with numbering 1. A compound having formula (I): (I) Or its pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or transisomer. in Ring A is an unsubstituted or substituted aryl group, or an unsubstituted or substituted heteroaryl group; Part of B is an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclic group; L 1 Is it a direct key, or -OR a -, wherein R a C does not exist, is not replaced, or has been replaced. 1-4 Alkylene; R 0 Each of these can be independently H, halogen, -CN, -OH, or unsubstituted or substituted C. 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocyclic groups, or unsubstituted or substituted amino groups; or one or more pairs of the R groups. 0The groups together with the atoms to which they are attached form unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R 1a R 1b R 2a and R 2b Each is independently H, halogen, or unsubstituted or substituted C. 1-3 Alkyl, or R 1a and R 1b Together they form an oxo- or substituted / unsubstituted cyclopropyl group; m and q are each independent integers ranging from 0 to the maximum number of substituents allowed on ring A and ring B, respectively; The premise is that the compound is not one of the compounds in Table 1.

[0291] 2. The compound as described in embodiment 1, wherein L 1 Yes -O-.

[0292] 3. The method as described in embodiment 1, wherein the compound of formula (I) is a compound of formula (IIa): (IIa).

[0293] 4. The compound as described in any of embodiments 1 to 3, wherein part B is a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group containing 1 to 3 heteroatoms selected from N or O.

[0294] 5. The compound as described in any of embodiments 1 to 3, wherein part B is a substituted or unsubstituted 4- to 6-membered cycloalkyl group, or a substituted or unsubstituted heterocyclic group containing one oxygen atom.

[0295] 6. The compound as described in any of embodiments 1 to 4, wherein part B is a substituted or unsubstituted tetrahydro-2H-pyranyl group, or a substituted or unsubstituted furanyl group; preferably a tetrahydro-2H-pyranyl group or a furanyl group, wherein the tetrahydro-2H-pyranyl group or the furanyl group is optionally each substituted by a C group containing one or more nitrogen atoms. 1-4 Alkylamino or heterocyclic substituted; more preferably tetrahydro-2H-pyranyl substituted with dimethylamino, or furanyl substituted with dimethylamino.

[0296] 7. The compound as described in any of embodiments 1 to 6, wherein part B is , , , , , , , , or .

[0297] 8. The compound as described in any of embodiments 1 to 6, wherein part B is , , , or .

[0298] 9. The compound as described in any of embodiments 1 to 5, wherein part B is a substituted or unsubstituted cyclobutyl, a substituted or unsubstituted cyclopentyl, or a substituted or unsubstituted cycloheptyl; preferably a substituted or unsubstituted 2-dimethylaminocyclobutyl, a substituted or unsubstituted 2-heterocyclic cyclobutyl, a substituted or unsubstituted 2-dimethylaminocyclopentyl, a substituted or unsubstituted 2-heterocyclic cyclopentyl, a substituted or unsubstituted 2-dimethylaminocycloheptyl, or a substituted or unsubstituted 2-heterocyclic cycloheptyl, wherein the heterocyclic group is a heterocyclic group containing one or more nitrogen atoms; more preferably 2-dimethylaminocyclobutyl, 2-dimethylaminocyclopentyl, or 2-dimethylaminocycloheptyl, wherein each of the 2-dimethylaminocyclobutyl, 2-dimethylaminocyclopentyl, and 2-dimethylaminocycloheptyl is optionally substituted with H, F, methoxy, methyl, methyl-d3, methoxy-d3, CF2H, or CF3.

[0299] 10. The compound as described in any of embodiments 1 to 5 and 9, wherein part B is , , , , , , , , , , , , , or , Where R 11a It is H, F, methoxy, methyl, methyl-d3, methoxy-d3, CF2H, or CF3; and i can be 0, 1, 2, 3 or 4.

[0300] 11. The compound as described in any of embodiments 1 to 5 and 9, wherein part B is , , , , , , , , or , Where R 12a It is H, F, methoxy, methyl, methyl-d3, methoxy-d3, difluoromethyl, or trifluoromethyl; R 12b C is a C that is optionally substituted with one or more substituents. 1-3 Alkyl group, wherein the substituent is selected from methyl, methyl-d3, F, methoxy, or alkenyl; and k is 0, 1, or 2.

[0301] 12. The compound as described in embodiment 11, wherein part B is .

[0302] 13. The compound as described in any one of embodiments 1 to 5, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0303] 14. The compound as described in embodiment 1, wherein L 1 It is -OC(R) 3a (R) 3b )-, wherein R 3a and R 3b Each of the following is independently H, F, and C (either substituted or unsubstituted). 1-2 alkyl.

[0304] 15. The compound as described in Embodiment 1, wherein the compound of formula (I) is a compound of formula (IIb): (IIb) in R 3a and R 3b Each of the following is independently H, F, and C (either substituted or unsubstituted). 1-2 alkyl.

[0305] 16. The compound as described in embodiment 15, wherein R 3a It is H, methyl, methyl-d3, fluoromethyl, difluoromethyl, or trifluoromethyl; and R 3b It is H.

[0306] 17. The compound as described in any of embodiments 15 to 16, wherein R 3a and R 3b Both are H.

[0307] 18. The compound as described in any of embodiments 15 to 16, wherein R 3a It is methyl; R 3b It is H.

[0308] 19. The compound as described in any of embodiments 15, 16 and 18, wherein R 3a and R 3b The bonded carbon atom has an R configuration.

[0309] 20. The compound as described in any of embodiments 15, 16 and 18, wherein R 3a and R 3b The bonded carbon atoms have an S configuration.

[0310] 21. The compound as described in embodiment 15, wherein the compound of formula (IIb) is the compound of formula (IIIa): (IIIa).

[0311] 22. The compound as described in embodiment 15, wherein the compound of formula (IIIa) is a compound of formula (IVa), wherein: (IVa).

[0312] 23. The compound as described in any of embodiments 14 to 22, wherein a portion of B is substituted or unsubstituted C. 3-6 Cycloalkyl, or a substituted or unsubstituted 4- to 6-membered heterocyclic group containing one or more heteroatoms; preferably cyclopropyl, or a substituted or unsubstituted heterocyclic group containing one or more heteroatoms selected from N or O, wherein the cyclopropyl is optionally substituted by one or more substituents selected from halogens, or substituted or unsubstituted alkyl groups.

[0313] 24. The compound as described in any of embodiments 14 to 23, wherein part B is , in R 21a Each is independently either H or halogen; R 22a and R 22b Each is independently H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted heterocyclic group, or R. 22a and R22b With R 22a and R 22b The atoms that are attached together form substituted or unsubstituted heterocyclic groups; and v can be 0, 1, 2, 3, or 4.

[0314] 25. The compound as described in any of embodiments 14 to 23, wherein part B is , in R 23a and R 23b Each is independently either H or halogen; R 22a and R 22b Each is independently H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted heterocyclic group, or R. 22a and R 22b With R 22a and R 22b The atoms that are attached together form a heterocyclic group that is either substituted or unsubstituted.

[0315] 26. The compound as described in embodiment 25, wherein it contains R 22a and R 22b The carbon atom of the cyclopropyl group connected by the branch has an R configuration.

[0316] 27. The compound as described in embodiment 25, wherein it contains R 22a and R 22b The carbon atom of the cyclopropyl group connected by the branch has an S configuration.

[0317] 28. The compound as described in any of embodiments 25 to 27, wherein R 22a and R 22b Each is independently H, a substituted or unsubstituted amino group, or a substituted or unsubstituted C group. 1-3 Alkyl; preferably, R 22a and R 22b Each can be H, methyl, or dimethylamino independently.

[0318] 29. The compound as described in any of embodiments 25 to 28, wherein part B is , , , , , , , , , or .

[0319] 30. The compound as described in any of embodiments 24 to 27, wherein R 22b It is H or methyl, and R 22a It is a substituted or unsubstituted heterocyclic group; preferably, R 22b It is H or methyl, and R 22a It is a substituted or unsubstituted azacyclic butyl group, a substituted or unsubstituted pyrrolidinyl group, a substituted or unsubstituted piperidinyl group, a substituted or unsubstituted 3-azabicyclo[3.1.0]hexyl group, a substituted or unsubstituted 2,5-dihydro-1H-pyrrolidinyl group, a substituted or unsubstituted 6-azaspiro[2.5]octyl group, a substituted or unsubstituted 1,2,3,6-tetrahydropyridyl group, a substituted or unsubstituted morpholinyl group, a substituted or unsubstituted 2-oxa-6-azaspiro[3.3]heptyl group, a substituted or unsubstituted (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptyl group, a substituted or unsubstituted (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptyl group; more preferably, R 22b It is H or methyl, and R 22a It is substituted or unsubstituted azacyclobutane-1-yl, substituted or unsubstituted pyrrolidine-1-yl, substituted or unsubstituted piperidin-1-yl, substituted or unsubstituted 2,5-dihydro-1H-pyrrolo-1-yl, substituted or unsubstituted 6-azaspiro[2.5]oct-6-yl, substituted or unsubstituted 1,2,3,6-tetrahydropyridin-1-yl, substituted or unsubstituted morpholino-4-yl, substituted or unsubstituted 2-oxa-6-azaspiro[3.3]hept-6-yl, substituted or unsubstituted (1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl, substituted or unsubstituted ( 1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl, substituted or unsubstituted 2-azaspiro[3.3]hept-2-yl, substituted or unsubstituted 2-azabicyclo[2.2.1]hept-2-yl, substituted or unsubstituted 3-azabicyclo[3.1.1]hept-3-yl, substituted or unsubstituted 2-oxa-6-azaspiro[3.4]oct-6-yl, substituted or unsubstituted 2-oxa-7-azaspiro[4.4]non-7-yl, substituted or unsubstituted 7-oxa-1-azaspiro[4.4]non-1-yl, or substituted or unsubstituted 7-azaspiro[3.5]non-7-yl.

[0320] 31. The compound as described in any of embodiments 24 to 27 or 30, wherein part B is The ring C is a substituted or unsubstituted 4- to 10-membered heterocyclic group optionally containing one or more additional heteroatoms selected from N, O or S; preferably it is a substituted or unsubstituted 4- to 7-membered heterocyclic group optionally containing one or more additional heteroatoms selected from N, O or S.

[0321] 32. The compound as described in embodiment 31, wherein part B is , , , , , , , , , , , , or , where R 24a and R 24b Each independently is H, methyl, ethyl, methyl-d3, F, or Cl; R 24c It is H, F, methoxy, methyl, methyl-d3, ethyl, difluoromethyl or trifluoromethyl; and z is 0, 1 or 2.

[0322] 33. The compound as described in embodiment 31, wherein part B is , , , or .

[0323] 34. The compound as described in embodiment 31, wherein part B is , , , , , , , , , , , , or , where R 24a and R 24b Each independently is H, methyl, ethyl, methyl-d3, F, or Cl; R 24c It is H, F, methoxy, methyl, methyl-d3, ethyl, difluoromethyl or trifluoromethyl; and z is 0, 1 or 2.

[0324] 35. The compound as described in embodiment 31, wherein part B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , where R 24a and R 24b Each is independently H, methyl, ethyl, methyl-d3, F, or Cl; and R 24c It is H, F, hydroxyl, cyano, methoxy, methyl, methyl-d3, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, difluoromethoxy, cyclopropyl, or oxetane.

[0325] 36. The compound as described in embodiment 31, wherein part B is, , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , or .

[0326] 37. The compound as described in any of embodiments 24 to 27, wherein R 22a and R 22b With R 22a and R 22b The atoms connected together form a substituted or unsubstituted 5- or 6-membered heterocyclic group; preferably substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, or substituted or unsubstituted morpholinyl; more preferably pyrrolidinyl, piperidinyl, and morpholinyl, wherein each of the pyrrolidinyl, piperidinyl, and morpholinyl is optionally substituted with H, a halogen, a substituted or unsubstituted alkoxy, or a substituted or unsubstituted alkyl.

[0327] 38. The compound as described in any of embodiments 24 to 27 and 37, wherein part B is , Where R 25a C is a C that is optionally substituted with one or more substituents. 1-3 Alkyl group, wherein the substituent is selected from methyl, methyl-d3, F or alkenyl; R 25b It is H, F, methoxy, methyl, difluoromethyl, or trifluoromethyl; X 1 It is O or C; and r is 0, 1, or 2.

[0328] 39. The compound as described in embodiment 38, wherein part B is , , , , , , , or .

[0329] 40. The compound as described in any of embodiments 14 to 23, wherein part B is a substituted or unsubstituted 4- to 6-membered heterocyclic group containing one or two heteroatoms selected from N or O.

[0330] 41. The compound as described in any of embodiments 14 to 23 and 40, wherein part B is a substituted or unsubstituted 4- to 6-membered heterocyclic group containing one oxygen atom; preferably substituted or unsubstituted oxetane, substituted or unsubstituted tetrahydrofuranyl, or substituted or unsubstituted tetrahydro-2H-pyranyl; more preferably substituted or unsubstituted oxetane-2-yl, substituted or unsubstituted tetrahydrofuran-3-yl, substituted or unsubstituted tetrahydrofuran-2-yl, substituted or unsubstituted tetrahydro-2H-pyran-4-yl, or substituted or unsubstituted tetrahydro-2H-pyran-3-yl.

[0331] 42. The compound as described in any of embodiments 14 to 23 and 40 to 41, wherein part B is 3-dimethylamino-oxetane-2-yl, 4-dimethylamino-tetrahydrofuran-3-yl, 3-dimethylamino-tetrahydrofuran-2-yl, 3-dimethylamino-tetrahydro-2H-pyran-4-yl or 4-dimethylamino-tetrahydro-2H-pyran-3-yl, wherein each of the 3-dimethylamino-oxetane-2-yl, 4-dimethylamino-tetrahydrofuran-3-yl, 3-dimethylamino-tetrahydrofuran-2-yl, 3-dimethylamino-tetrahydro-2H-pyran-4-yl and 4-dimethylamino-tetrahydro-2H-pyran-3-yl is optionally substituted with methyl, F, hydroxyl, methoxy or difluoromethyl.

[0332] 43. The compound as described in any of embodiments 14 to 23 and 40 to 42, wherein part B is , , , , , , , , , , , , , , , , , , , , , , or .

[0333] 44. The compound as described in any of embodiments 14 to 23, wherein part B is a substituted or unsubstituted pyrrolidinyl; preferably a substituted or unsubstituted pyrrolidin-2-yl, optionally substituted with one or more substituents selected from H, F, methyl, difluoromethyl, ethyl, 2-fluoroethyl, 2-(methoxy-d3)ethyl, 1-allyl-2-methyl or methoxy.

[0334] 45. The compound as described in any of embodiments 14 to 23 and 44, wherein part B is , in R 26a It is H, methyl, or difluoromethyl; R 26b It is methyl, methyl-d3, ethyl, 2-fluoroethyl, 2-(methoxy-d3)ethyl, 1-allyl-2-methylcyclopropylmethyl, oxetyl, tetrahydrofuranyl or tetrahydro-2H-pyranyl; Each R 26c It is independently H, F, or methoxy, or a pair of R 26c Together with the atoms they are attached to, they form substituted or unsubstituted cyclopropyl groups; and c is 0, 1, or 2.

[0335] 46. ​​The compound as described in any of embodiments 14 to 23 and 45, wherein R 26a The bonded carbon atoms have an S configuration.

[0336] 47. The compound as described in any of embodiments 14 to 23 and 45, wherein R 26a The bonded carbon atom has an R configuration.

[0337] 48. The compound as described in any of embodiments 14 to 23 and 45 to 47, wherein part B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , where R 26a It is H, methyl, or difluoromethyl; each R 26b It is independently methoxy, methoxy-d3, fluorine, methyl, fluoromethyl or difluoromethyl.

[0338] 49. The compound as described in any of embodiments 14 to 23 and 45 to 48, wherein part B is , , , , , , , , , , , , , , , , , or .

[0339] 50. The compound as described in any of embodiments 14 to 23, wherein part B is a substituted or unsubstituted 6-membered heterocyclic group containing one or two heteroatoms selected from O or N, provided that at least one heteroatom is N; preferably, part B is a substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazineyl.

[0340] 51. The compound as described in any of embodiments 14 to 23 and 50, wherein part B is , in X 2 It is -CHF-, -CF2-, -CH(CH3)-, N(CH3)-, CH(OCH3)-, -CH(CHF2)-, -C(=CHF)- or -O-; R 27a It is methyl, ethyl, difluoromethyl, or trifluoromethyl; R 27b It is H, F, methyl, or methoxy; R 27c It is C 1-3 Alkyl, oxetane butyl, tetrahydrofuranyl, or tetrahydropyranyl, wherein the C 1-3 The alkyl group may optionally be substituted with one or more substituents selected from methyl, methyl-d3, F, or alkenyl; and n is an integer from 0 to 4.

[0341] 52. The compound as described in any of embodiments 14 to 23 and 50 to 51, wherein part B is , , , , , , , , , , , , , , , , or , where R 27c It is C 1-3 Alkyl, oxetane butyl, tetrahydrofuranyl, or tetrahydropyranyl, wherein the C 1-3 The alkyl group may optionally be substituted with one or more substituents selected from deuterium, methyl, methyl-d3, F, cyclopropylmethyl or alkenyl.

[0342] 53. The compound as described in any of embodiments 14 to 23 and 50 to 52, wherein part B is , , , , , , , , , , or .

[0343] 54. The compound as described in any of embodiments 14 to 23, wherein part B is a substituted or unsubstituted bicyclic heterocyclic group.

[0344] 55. The compound as described in any of embodiments 14 to 23, wherein part B is a substituted or unsubstituted bicyclic heterocyclic group containing one or two heteroatoms selected from N or O, provided that at least one fused atom is N; preferably a substituted or unsubstituted hexahydro-1H-pyrrolazinyl, a substituted or unsubstituted octahydroindazinyl, a substituted or unsubstituted hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, or a substituted or unsubstituted octahydropyrido[2,1-c][1,4]oxazinyl.

[0345] 56. The compound as described in any of embodiments 14 to 23 and 54 to 55, wherein part B is , , , , , or , in R 28a It is H, methyl, methyl-d3, fluoromethyl, difluoromethyl, or trifluoromethyl; R 28b and R 28c Each is H, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a pair of R groups. 28b Or R 28c Together with the atoms they are attached to, they form unsubstituted or substituted alkenyl groups, or unsubstituted or substituted cycloalkyl groups; and s and p are each independently 0, 1, 2, 3 or 4; The premise is that, no .

[0346] 57. The compound as described in any of embodiments 14 to 23 and 54 to 56, wherein part B is , , , , , , , or .

[0347] 58. The compound as described in any of embodiments 14 to 23 and 54 to 56, wherein part B is , , , , , , , , , or .

[0348] 59. The compound as described in any of embodiments 14 to 23, wherein part B is a substituted or unsubstituted bicyclic heterocyclic group containing one or two heteroatoms selected from N or O, provided that both fused atoms are C; preferably substituted or unsubstituted octahydro-1H-cyclopentano[b]pyridyl, substituted or unsubstituted octahydrocyclopentano[b][1,4]oxazinyl, or substituted or unsubstituted octahydrofurano[3,2-b]pyridyl.

[0349] 60. The compound as described in any of embodiments 14 to 23 and 59, wherein part B is , or , in R 29c It is methyl, methyl-d3, difluoromethyl, or trifluoromethyl; R 29a and R 29b Each is H, a halogen, or a substituted or unsubstituted alkyl group; and t and g are each independently 0, 1, 2, 3 or 4.

[0350] 61. The compound as described in any of embodiments 14 to 23, wherein part B is a substituted or unsubstituted cyclobutyl, a substituted or unsubstituted cyclopentyl, or a substituted or unsubstituted cycloheptyl; preferably a substituted or unsubstituted 2-dimethylaminocyclobutyl, a substituted or unsubstituted 2-dimethylaminocyclopentyl, or a substituted or unsubstituted 2-dimethylaminocycloheptyl; more preferably 2-dimethylaminocyclobutyl, 2-dimethylaminocyclopentyl, or 2-dimethylaminocycloheptyl, wherein each of the 2-dimethylaminocyclobutyl, 2-dimethylaminocyclopentyl, and 2-dimethylaminocycloheptyl is optionally substituted with H, a halogen, a methoxy group, or a methoxy-d3 group.

[0351] 62. The compound as described in any of embodiments 14 to 23 and 61, wherein part B is , in R 20 It is H, halogen, methyl, methyl-d3, methoxy, or methoxy-d3; and h can be 1, 2, or 3.

[0352] 63. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0353] 64. The compound as described in any one of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0354] 65. The compound as described in any one of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0355] 66. The compound as described in any one of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0356] 67. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0357] 68. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0358] 69. The compound as described in any one of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0359] 70. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0360] 71. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0361] 72. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0362] 73. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0363] 74. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1aR 1b R 2a and R 2b Both are H.

[0364] 75. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0365] 76. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0366] 77. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0367] 78. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0368] 79. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0369] 80. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0370] 81. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0371] 82. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0372] 83. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0373] 84. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0374] 85. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0375] 86. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0376] 87. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0377] 88. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0378] 89. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0379] 90. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0380] 91. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R1a R 1b R 2a and R 2b Both are H.

[0381] 92. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0382] 93. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0383] 94. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0384] 95. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0385] 96. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0386] 97. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0387] 98. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0388] 99. The compound as described in any one of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0389] 100. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0390] 101. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0391] 102. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2bBoth are H.

[0392] 103. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0393] 104. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0394] 105. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0395] 106. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0396] 107. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0397] 108. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0398] 109. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0399] 110. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0400] 111. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0401] 112. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0402] 113. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0403] 114. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0404] 115. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0405] 116. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0406] 117. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0407] 118. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0408] 119. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R1b R 2a and R 2b Both are H.

[0409] 120. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0410] 121. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0411] 122. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0412] 123. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0413] 124. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0414] 125. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0415] 126. The compound as described in any of embodiments 14 to 23, wherein yes ; yes ;R 1a R 1b R 2a and R 2b Both are H; and R 3a and R 3b Both are H, where H refers to deuterium.

[0416] 127. The compound as described in any of embodiments 14 to 23, wherein yes ; yes ;R 1a R 1b R 2a and R 2b Both are H; and R 3a and R 3b Both are H, where H refers to deuterium.

[0417] 128. The compound as described in any of embodiments 14 to 23, wherein yes ; yes And R 1a R 1b R 2a and R 2b Both are H.

[0418] 129. The compound as described in any of embodiments 14 to 23, wherein yes ; yes ;R 1a R 1b R 2a and R 2b Both are H; and R 3a and R 3b Both are H, where H refers to deuterium.

[0419] 130. The compound as described in any of embodiments 14 to 23, wherein yes ; yes ;R 1a It is methyl; and R 1b R 2a and R 2b Both are H.

[0420] 131. The compound as described in embodiment 1, wherein L 1 It is a direct key.

[0421] 132. The compound as described in either embodiment 1 or 131, wherein part B is a substituted or unsubstituted azacyclobutyl, a substituted or unsubstituted diazaspiro[3.3]heptyl, a substituted or unsubstituted diazaspiro[3.4]octyl, or a substituted or unsubstituted diazaspiro[3.5]nonyl; preferably a substituted or unsubstituted 1,6-diazaspiro[3.3]hept-6-yl, a substituted or unsubstituted 2,5-diazaspiro[3.4]oct-2-yl, or a substituted or unsubstituted 2,5-diazaspiro[3.5]non-2-yl.

[0422] 133. The compound as described in embodiments 1 and 131 to 132, wherein part B is , or , where R 31 It is H, substituted or unsubstituted C 1-4 alkyl.

[0423] 134. The compound as described in embodiment 133, wherein R 31 It is H, methyl, methyl-d3, or ethyl.

[0424] 135. The compound as described in embodiment 1 or 131, wherein the compound of formula (I) is a compound of formula (IIc): (IIc) in R 32a and R 32b Each is independently H, or C that has been substituted or has been substituted. 1-4 Alkyl, unsubstituted or substituted amino, or unsubstituted or substituted heterocyclic group.

[0425] 136. The compound as described in embodiment 135, wherein R 32aIt is dimethylamino, ethyl(methyl)amino, diethylamino, aziridine-1-yl, 3-fluoroaziridine-1-yl, 3-methoxyaziridine-1-yl, pyrrolidine-1-yl, 2-fluoropyrrolidine-1-yl, 2-methoxypyrrolidine-1-yl, piperidin-1-yl, 2-fluoropiperidin-1-yl, 3-fluoropiperidin-1-yl, 2-methoxypiperidin-1-yl, 3-methoxypiperidin-1-yl, morpholino, 3-oxa-6-azabicyclo[3.1.1]hept-6-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3 -yl, (1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl, 3-oxa-8-azabicyclo[3.2.1]oct-8-yl, 8-azabicyclo[3.2.1]oct-8-yl, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, 3-azabicyclo[3.1.1]hept-3-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl or 6-azabicyclo[3.1.1]hept-6-yl.

[0426] 137. The compound as described in any of embodiments 135 to 136, wherein R 32b It is H, methyl, methyl-d3, fluoromethyl, methoxymethyl or ethyl; preferably H, methyl or methyl-d3.

[0427] 138. The compound as described in any of embodiments 135 to 137, wherein... yes , , , , , , , , , , , , , , , , , , , , , , , , , , , or , Where R32b It is H, methyl, methyl-d3, fluoromethyl, methoxymethyl, or ethyl; and R 33b It is H, methyl, methyl-d3, or ethyl.

[0428] 139. The compound as described in any of the embodiments 1 to 12, 14 to 58 and 131 to 138, wherein R 1a R 1b R 2a and R 2b Each is independently H or methyl, or R 1a and R 1b Together they form oxo, substituted, or unsubstituted cyclopropyl groups.

[0429] 140. The compound as described in any of the embodiments 1 to 12, 14 to 58 and 131 to 139, wherein R 1a R 1b R 2a and R 2b Both are H.

[0430] 141. The compound as described in any of the embodiments 1 to 12, 14 to 58 and 131 to 140, wherein ring A is a substituted or unsubstituted phenyl or a substituted or unsubstituted naphthyl; preferably, ring A is phenyl or naphthyl, wherein the phenyl and naphthyl are optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of: amino, -Cl, -F, vinyl, ethyl, methyl, trifluoromethyl, cyclopropyl, hydroxy or 1,1-difluoroethyl.

[0431] 142. The compound as described in any of embodiments 1 to 12, 14 to 58 and 131 to 141, wherein ring A is a phenyl group optionally substituted with 1, 2, 3 or 4 substituents, said substituents being independently selected from amino, hydroxy, -Cl, -F, ethyl, methyl, methyl-d3, trifluoromethyl or cyclopropyl; preferably an aminophenyl group optionally substituted with 1, 2, 3 or 4 substituents, said substituents being independently selected from -Cl, -F, ethyl, methyl, methyl-d3, trifluoromethyl or cyclopropyl.

[0432] 143. The compound as described in any of embodiments 1 to 12, 14 to 58, and 131 to 142, wherein yes , , , , , , , , or .

[0433] 144. The compound as described in any of embodiments 1 to 12, 14 to 58 and 131 to 141, wherein ring A is a naphthyl group optionally substituted with 1, 2, 3 or 4 substituents, said substituents being independently selected from -Cl, -F, vinyl, ethyl, cyclopropyl or hydroxy; preferably a hydroxynaphthyl group optionally substituted with 1, 2, 3 or 4 substituents, said substituents being independently selected from -Cl, -F, vinyl, ethyl or cyclopropyl.

[0434] 145. The compound as described in any of embodiments 1 to 12, 14 to 58, 131 to 141 and 144, wherein yes , , , , , or .

[0435] 146. The compound as described in any of embodiments 1 to 12, 14 to 58, and 131 to 141, wherein yes , , , , , , , , , , , , , , , , , or .

[0436] 147. The compound as described in Embodiment 1, wherein the compound is a compound of formula (IVb): (IVb) in The ring C is a substituted or unsubstituted 4- to 7-membered heterocyclic group that optionally contains one or more additional heteroatoms selected from N or O; R c Each of these can be independently H, halogen, amino, -OH, -CN, or unsubstituted or substituted C. 1-4 Alkyl, or unsubstituted or substituted C 1-4 alkoxy, or a pair of said Rc The groups together with the atoms they are attached to form unsubstituted or substituted bridges, unsubstituted or substituted cycloalkyl groups, or unsubstituted or substituted heterocyclic groups; u is an integer ranging from 0 to the maximum allowed number of substituents on ring C; and Other variables are as defined above.

[0437] 148. The compound as described in embodiment 1, wherein the compound is a compound of formula (Vb): (Vb) in R a It is methyl, methyl-d3, or Cl; The ring C is a substituted or unsubstituted 4- to 7-membered heterocyclic group that optionally contains one or more additional heteroatoms selected from N or O; R c Each of these can be independently H, halogen, amino, -OH, -CN, or unsubstituted or substituted C. 1-4 Alkyl, or unsubstituted or substituted C 1-4 alkoxy, or a pair of said R c The groups together with the atoms they are attached to form unsubstituted or substituted bridges, unsubstituted or substituted cycloalkyl groups, or unsubstituted or substituted heterocyclic groups; u is an integer ranging from 0 to the maximum allowed number of substituents on ring C; and Other variables are as defined above.

[0438] 149. The compound as described in Embodiment 1, wherein the compound is a compound of formula (IVc): (IVc) in R 28b and R 28c Each is H, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a pair of R groups. 28b Or R 28c Together with the atoms they are attached to, they form unsubstituted or substituted alkenyl groups, or unsubstituted or substituted cycloalkyl groups; and s and p are each independently 0, 1, 2, 3 or 4; The premise is no ;and Other variables are as defined above.

[0439] 150. The compound as described in embodiment 1, wherein the compound is a compound of formula (Vc): (Vc) in R a It is methyl, methyl-d3, or Cl; R 28b and R 28c Each is H, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a pair of R groups. 28b Or R 28c Together with the atoms they are attached to, they form unsubstituted or substituted alkenyl groups, or unsubstituted or substituted cycloalkyl groups; and s and p are each independently 0, 1, 2, 3 or 4; The premise is no ;and Other variables are as defined above.

[0440] 151. The compound as described in any one of embodiments 1 to 150, wherein the compound is one of the compounds in Table 2.

[0441] 152. A pharmaceutical composition comprising a compound as described in any one of embodiments 1 to 151, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or transisomer thereof, and a pharmaceutically acceptable carrier, excipient, or mediator.

[0442] 153. A method for inhibiting the activity of a KRAS mutant protein in cells, the method comprising contacting the cells with a compound as described in any of embodiments 1 to 151, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, enantiomer, or transisomer thereof, optionally wherein the KRAS mutant protein is a KRASG12D mutant protein.

[0443] 154. A method for treating or preventing cancer, the method comprising administering to a subject in need a compound as described in any of embodiments 1 to 151, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or transisomer thereof, optionally wherein the cancer is caused by a KRAS mutation; preferably mediated by a KRAS G12D mutation.

[0444] The embodiments of the present invention can be more fully understood by referring to the detailed description and examples, which are intended to illustrate non-limiting embodiments.

[0445] Methods for preparing compounds The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials. By way of example and not limitation, compounds of formula (I) can be prepared as outlined in schemes 1-3 below and in the examples described herein. It should be noted that those skilled in the art will know how to modify the procedures described in the illustrative schemes and examples to obtain the desired product. Common protecting groups can be used to prevent certain functional groups from undergoing undesirable reactions. Illustrative protecting groups are described in “Protective Groups in Organic Synthesis”, 4th edition, PGM Wuts; TW Greene, John Wiley, 2007 and the references cited therein.

[0446] Option 1: As shown in Scheme 1, in some embodiments, this document provides methods for preparing compounds as defined in formula (I). Compound 1-1 is converted to compound 1-2 under substitution conditions (e.g., NaH, THF); then, compound 1-2 is converted to compound 1-3 under substitution conditions (e.g., BOPCI, DIEA); then, compound 1-3 is converted to compound 1-4 under oxidation conditions (e.g., NaIO4, RuCl3); then, compound 1-4 is converted to compound 1-5, which is subsequently subjected to substitution or coupling reactions (e.g., LIHMDS); compound 1-5 further undergoes metal-catalyzed cross-coupling reactions, such as Suzuki coupling, Negishi coupling, or Stille coupling (e.g., for Suzuki coupling, Pd(dtbpf)Cl2, K3PO4, 1,4-dioxane, water) to obtain compound 1-6, where M can be boric acid, borate ester, metal (e.g., Zn), tributyltin, etc.; finally, compound 1-6 containing the protecting group is then deprotected (e.g., using HCl / dioxane to remove the Boc group) to obtain the compound defined by formula (I).

[0447] Option 2: As shown in Scheme 2, in some embodiments, methods for preparing compounds defined in formula (IIa) are provided herein. Compounds 1-4 are converted to compound 2-1, followed by a substitution or coupling reaction (e.g., LIHMDS); compound 2-1 further undergoes a metal-catalyzed cross-coupling reaction, such as Suzuki coupling, Negishi coupling, or Stilt coupling (e.g., for Suzuki coupling, Pd(dtbpf)Cl2, K3PO4, 1,4-dioxane, water) to obtain compound 2-2, wherein M can be boric acid, borate ester, metal (e.g., Zn), tributyltin, etc.; finally, compound 2-2 containing the protecting group is deprotected (e.g., using HCl / dioxane to remove the Boc group) to obtain the compound defined in formula (IIa).

[0448] Option 3: As shown in Scheme 3, in some embodiments, methods for preparing compounds defined in formula (IIb) are provided herein. Compounds 1-4 are converted to compound 3-1, followed by a substitution or coupling reaction (e.g., LIHMDS); compound 3-1 further undergoes a metal-catalyzed cross-coupling reaction, such as Suzuki coupling, Negishi coupling, or Stilt coupling (e.g., for Suzuki coupling, Pd(dtbpf)Cl2, K3PO4, 1,4-dioxane, water) to obtain compound 3-2, wherein M can be boric acid, borate ester, metal (e.g., Zn), tributyltin, etc.; finally, compound 3-2 containing the protecting group is deprotected (e.g., using HCl / dioxane to remove the Boc group) to obtain the compound defined in formula (IIb).

[0449] Option 4: As shown in Scheme 4, in some embodiments, methods for preparing compounds defined by formula (IIc) are provided herein. Compounds 1-4 are converted to compound 4-1, followed by a substitution or coupling reaction (e.g., LIHMDS); compound 4-1 further undergoes a metal-catalyzed cross-coupling reaction, such as Suzuki coupling, Negishi coupling, or Stilwell coupling (e.g., for Suzuki coupling, Pd(dtbpf)Cl2, K3PO4, 1,4-dioxane, water) to obtain compound 4-2, wherein M can be boric acid, borate ester, metal (e.g., Zn), tributyltin, etc.; finally, compound 4-2 containing the protecting group is deprotected (e.g., using HCl / dioxane to remove the Boc group) to obtain the compound defined by formula (IIc).

[0450] Option 5: As shown in Scheme 5, in some embodiments, methods for preparing compounds defined by formula (Vb) are provided herein. Compounds 1-4 are converted to compound 5-1, followed by a substitution or coupling reaction (e.g., LIHMDS); compound 5-1 further undergoes a metal-catalyzed cross-coupling reaction, such as Suzuki coupling, Negishi coupling, or Stihl coupling (e.g., for Suzuki coupling, Pd(dtbpf)Cl2, K3PO4, 1,4-dioxane, water) to obtain compound 5-2, wherein M can be boric acid, borate ester, metal (e.g., Zn), tributyltin, etc.; then, compound 5-2 is converted to compound 5-3, followed by a substitution reaction (e.g., DIEA); then, compound 5-3 is converted to compound 5-4, followed by a substitution or coupling reaction (e.g., ACN, TEA); finally, compound 5-4 containing a protecting group is then deprotected (e.g., using HCl / dioxane to remove the Boc group) to obtain the compound defined by formula (Vb).

[0451] Option 6: As shown in Scheme 6, in some embodiments, this document provides another method for preparing the compound defined by formula (Vb). Compounds 1-4 are converted to compound 6-1, followed by a substitution or coupling reaction (e.g., LIHMDS); then, compound 6-1 is converted to compound 6-2, followed by an oxidation reaction (e.g., DMP); then, compound 6-2 is converted to compound 6-3, followed by a substitution or coupling reaction (e.g., STAB, DCE); compound 6-3 further undergoes a metal-catalyzed cross-coupling reaction, such as Suzuki coupling, Negishi coupling, or Stihl coupling (e.g., for Suzuki coupling, Pd(dtbpf)Cl2, K3PO4, 1,4-dioxane, water) to obtain compound 6-4, wherein M can be boric acid, borate ester, metal (e.g., Zn), tributyltin, etc.; finally, compound 6-4 containing the protecting group is then deprotected (e.g., using HCl / dioxane to remove the Boc group) to obtain the compound defined by formula (Vb).

[0452] The embodiments of the present invention can be more fully understood by referring to the detailed description and examples, which are intended to illustrate non-limiting embodiments.

[0453] Example The following examples are intended to be entirely exemplary and should not be considered as limiting in any way. Unless otherwise stated, the experimental methods described in the examples below are conventional methods. Unless otherwise stated, reagents and materials are commercially available. All solvents and chemicals used are analytical grade or chemically pure. Solvents were redistilled before use. Anhydrous solvents were prepared according to standard or reference methods. Silica gel (100-200 mesh) for column chromatography and silica gel (GF254) for thin-layer chromatography (TLC) were available from Tsingdao Haiyang Chemical Co., Ltd. or Yantai Chemical Co., Ltd. in China; unless otherwise stated, elution was performed with petroleum ether (60-90°C) / ethyl acetate (v / v) and color development was achieved by a solution of iodine or molybdenum phosphate in ethanol. Unless otherwise stated, all extraction solvents were dried over anhydrous Na2SO4.

[0454] Unless otherwise stated, all reactions are carried out under positive pressure of nitrogen or argon or in anhydrous solvent using a drying tube; reaction flasks are equipped with rubber septa for introducing substrates and reagents via syringe; glassware is oven-dried and / or heat-dried.

[0455] Unless otherwise specified, column chromatography purification is performed on a Biotage system (manufacturer: Dyax Corporation) with silica columns, on silica SepPak columns (Waters), or on a Teledyne Isco Combiflash purification system using pre-packed silica columns.

[0456] Recording on Varian instruments operating at 400MHz or 500MHz 1 ¹H NMR spectra were obtained, with TMS (tetramethylsilane) as an internal standard. CDCl₃, CD₂Cl₂, CD₃OD, D₂O, and other reagents were used. d 6-DMSO, d 6-Acetone or (CD3)2CO was used as a solvent, and tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm); d 6-DMSO: 2.50 ppm; d 6-Propane: 2.05; (CD3)2CO: 2.05) were used as reference standards to obtain 1H-NMR spectra. When reporting peak multiplicity, the following abbreviations are used: s (single), d (double), t (triple), q (quartet), qn (quintet), sx (sextet), m (multiple), br (broad peak), dd (double doublet), dt (double triplet). The coupling constant is reported in Hertz (Hz).

[0457] LC / MS data were recorded using an Agilent 1100 or 1200 high-performance liquid chromatography-ion trap mass spectrometry (LC-MSD trap) system equipped with a diode array detector (DAD) for detection at 214 nm and 254 nm and an ion trap (ESI source). All compound names, except for reagents, were provided by ChemDraw. ® 19.1 generated.

[0458] In the following embodiments, the following abbreviations are used:

[0459] Compound Synthesis Preparation of intermediate 1: (1S,2R,5R)-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester Synthetic route: Step 1: (1S,2S,5R)-3-benzyl-2-formyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester To a 250 mL round-bottom flask, add (1S,2S,5R)-3-benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.55 g, 4.65 mmol), DMP (2.37 g, 5.58 mmol), and DCM (50 mL). Stir the reaction mixture at room temperature for 2 hours, then concentrate under vacuum. Purify the crude product by column chromatography (PE / EA = 0-12%) to give the title product (1.02 g, 68% yield) as a colorless oil.

[0460] Step 2: (1S,2R,5R)-3-benzyl-2-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester To a 50 mL round-bottom flask, add PPh3MeBr (748 mg, 2.11 mmol), THF (6 mL), and KHMDS (1 M, 1.76 mL, 1.76 mmol). Stir the reaction mixture at room temperature for 30 minutes, then add dropwise THF (6 mL) containing (1S,2S,5R)-3-benzyl-2-formyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (580 mg, 1.76 mmol) at room temperature. Stir the resulting mixture at room temperature for 2 hours. Then, quench the reaction by adding saturated NH4Cl (50 mL). Extract the mixture three times with EtOAc (20 mL). Combine the organic phases, dry with Na2SO4, and filter through diatomaceous earth. Concentrate the mixture under vacuum. The crude product was purified by column chromatography (PE / EA = 0-12%) to obtain the title compound (400 mg, yield 69%) as a white solid.

[0461] Step 3: (1S,2R,5R)-3-benzyl-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester To a 100 mL round-bottom flask, add (1S,2R,5R)-3-benzyl-2-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1 g, 0.0030 mol), 9-BBN (0.5 M, 36.5 mL, 0.018 mol), and THF (10 mL). Stir the reaction mixture at 50 °C for 2 hours under a nitrogen atmosphere. After LCMS indicated completion, add dropwise NaOH aqueous solution (3 M, 7 mL) and H2O2 (7 mL) at 0 °C. Stir the resulting mixture at room temperature for 2 hours. Dilute the mixture with H2O (50 mL) and extract three times with EtOAc (30 mL). Combine the organic layers, dry over Na2SO4, and concentrate under vacuum. Purify the crude product by column chromatography (PE / EA = 0-23%) to give the title compound (900 mg, 85% yield) as a colorless oil.

[0462] Step 4: (1S,2R,5R)-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester To a 100 mL round-bottom flask, (1S,2R,5R)-3-benzyl-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.7 g, 4.91 mmol), Pd / C (10 wt%, 1.7 g), and MeOH (15 mL) were added. The reaction mixture was stirred at room temperature for 3 hours under a H2 atmosphere. The reaction mixture was then filtered through diatomaceous earth and concentrated under vacuum to give the title compound (1.1 g, 91% yield) as a colorless oil. MS (ESI, m / e) [M+H] + =257.10. 1 HNMR (300 MHz, DMSO-d6) δ4.45 (d, J = 4.8 Hz, 1H), 4.06 –3.80 (m, 1H), 3.73 (d, J = 6.6 Hz, 1H), 3.42 (q, J = 11.1, 8.8 Hz, 2H), 3.06 –2.63 (m, 2H), 2.09 (t, J = 33.2 Hz, 1H), 1.87 –1.48 (m, 4H), 1.39 (s, 9H).

[0463] Preparation of intermediate 2: (6aR,7S,10R)-2-chloro-1-fluoro-13-(methanesulfonyl)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester Synthetic pathway Step 1: (1S,2R,5R)-2-(2-((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 To a mixture of (1S,2R,5R)-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.53 g, 6 mmol) and 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.68 g, 6 mmol) in THF (150 mL), NaH (1.2 g, 30 mmol) was added. The mixture was stirred at room temperature for 20 hours. The reaction was then quenched by adding saturated ammonium chloride aqueous solution (50 mL) and water (50 mL). The resulting mixture was extracted three times with EtOAc (50 mL). The organic layers were combined, dried over Na2SO4, and concentrated under vacuum to give the crude title product (4 g). MS (ESI, m / e) [M+H] + 499.8.

[0464] Step 2: (6aR,7S,10R)-2-chloro-1-fluoro-13-(methylthio)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester To a solution of (1S,2R,5R)-2-(2-((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 (4 g, 8 mmol) in MeCN (220 mL), BOP-Cl (4.1 g, 5.1 mmol) and DIPEA (980 mg, 7.6 mmol) were added. The resulting mixture was stirred at 70 °C for 1 hour. The mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified by column chromatography (DCM / EtOAc = 5 / 1) to give the title product (1.6 g). MS (ESI, m / e) [M+H] + 481.9.

[0465] Step 3: (6aR,7S,10R)-2-chloro-1-fluoro-13-(methanesulfonyl)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester To a solution of (6aR,7S,10R)-2-chloro-1-fluoro-13-(methylthio)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentazaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (378 mg, 0.8 mmol) in THF (28 mL) and water (7 mL), NaIO4 (505 mg, 2.4 mmol) and RuCl3 (16 mg, 0.08 mmol) were added. The resulting mixture was stirred at 0 °C for 1 hour. The mixture was diluted with water (20 mL) and extracted three times with EtOAc (20 mL). The organic phases were combined and concentrated under vacuum to give the crude title compound (335 mg), which was used as is in the next step. MS (ESI, m / e) [M+H) + 514.2.

[0466] Example 01: 3-((6a) R 7 S 10 R )-13-((2,2-difluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline Synthetic pathway Step 1: (6a) R 7 S 10 R )-2-chloro-13-((2,2-difluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester At room temperature, LiHMDS (1N, 0.1 mL, 0.1 mmol) was added to a solution of (1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methanol (17.7 mg, 0.1 mmol) in THF (5 mL). The resulting mixture was stirred at room temperature for 1 hour. Then, (6a) R 7 S 10 R2-Chloro-1-fluoro-13-(methanesulfonyl)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentazaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (25.7 mg, 0.05 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 1 hour. After the reaction was indicated by TLC, the reaction mixture was diluted with EtOAc (15 mL) and washed with brine (5 mL × 3). The organic layer was dried over anhydrous Na2SO4 and filtered through diatomaceous earth. The filtrate was concentrated to give a crude residue. The residue was purified by silica gel column chromatography and eluted with 0 to 100% EtOAc in petroleum ether to give the title product (20 mg, 0.03 mmol). MS (ESI, m / e) [M+1] + 611.2.

[0467] Step 2: (6a) R 7 S, 10 R 2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-13-((2,2-difluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester At room temperature, to (6a) R 7 S 10 R2-chloro-13-((2,2-difluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (20 mg, 0.03 mmol), Pd(dtbpf)Cl2 (6.51 mg, 0.01 mmol) and K3PO4 (21.2 mg, 0.1 mmol) were added to a mixture of dioxane (5 mL) and water (1 mL) with (5-amino-3-methyl-2-(trifluoromethyl)phenyl)boronic acid (21.9 mg, 0.01 mmol). The resulting mixture was stirred at 100 °C for 4 hours under a nitrogen atmosphere. After TLC indicated completion of the reaction, the reaction mixture was diluted with DCM (20 mL) and washed with brine (10 mL × 3). The organic layer was dried over anhydrous Na₂SO₄ and filtered through diatomaceous earth. The filtrate was concentrated to give a crude residue. The residue was purified by silica gel column chromatography, eluting with 0–10% MeOH in DCM to give the title product (22.5 mg, 0.03 mmol). MS (ESI, m / e) [M+1] + 750.3.

[0468] Step 3: 3-((6a) R 7 S 10 R )-13-((2,2-difluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline At room temperature, to (6a) R 7 S, 10 R2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-13-((2,2-difluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (22.5 mg, 0.03 mmol) in DCM (3 mL) was added to a solution of 4 N HCl in dioxane (1 mL). The resulting mixture was stirred at room temperature for 1 hour. After the reaction was indicated by TLC to be complete, the reaction mixture was concentrated to give a crude residue. The residue was subjected to preparative HPLC (column: Waters SunFire C18, 19). 150 mm, 5 µm; Mobile phase A: H2O (0.1% FA), Mobile phase B: MeCN (0.1% FA); Flow rate: 17 mL / min; Temperature: 25 °C; Detector: UV 254 and 280 nm; Gradient: 0% to 10% B in 1 min, 10% to 25% B in 1 to 11 min, and 25% to 100% B in 11 to 13 min) to obtain the title product (10.0 mg). 1 H NMR (500 MHz, CD3OD) δ6.69 (s, 1H), 6.44 (s, 1H), 4.30 –3.76(m, 9H), 3.44-3.42 (m, 1H), 3.15-3.10 (m, 2H), 2.84-2.54 (m, 2H), 2.42 (s,3H), 2.38 –1.88 (m, 11H). MS (ESI, m / e) [M+1] + 650.5.

[0469] Examples 02-06 below were prepared in a manner similar to that of Example 01, by replacing (2,2-difluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol with the corresponding alkyl alcohol.

[0470] Example 07: (3) R 4 R) -4-(((6a R 7 S 10 R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphth-13-yl)oxy)-N,N-dimethyltetrahydro-2H-pyran-3-amine Synthetic pathway Step 1: (3R,4R)-3-(dimethylamino)tetrahydro-2H-pyran-4-ol At room temperature, paraformaldehyde (909 mg, 30.0 mmol) and NaBH3CN (366.0 mg, 6.0 mmol) were added to a mixture of (3R,4R)-3-aminotetrahydro-2H-pyran-4-ol (351.3 g, 3.0 mmol) in MeOH (30 mL). The resulting mixture was stirred at room temperature for 16 hours. After LCMS indicated the reaction was complete, the reaction mixture was concentrated under vacuum to give a crude residue. The residue was purified by silica gel column chromatography, eluting with 0 to 10% MeOH in DCM to give the title product (200 mg, 1.38 mmol). MS (ESI, m / e) [M+1] + 146.1.

[0471] Steps 2-4: Example 07 was prepared in a similar manner to Example 01 by replacing (2,2-difluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol with (3R,4R)-3-(dimethylamino)tetrahydro-2H-pyran-4-ol. 1 H NMR(500 MHz, CD3OD) δ6.69 (s, 1H), 6.46-6.44 (m, 1H), 5.44-5.40 (m, 1H), 4.30-3.72 (m,10H), 3.55 –3.51 (m, 1H), 3.17 –3.16 (m, 1H), 2.49 (s, 6H), 2.42 (s,3H), 2.18 –1.80 (m, 8H). MS (ESI, m / e) [M+1] + 618.5.

[0472] Examples 08 to 12: The following examples were prepared in a manner similar to that of Example 07, by replacing (3R,4R)-3-aminotetrahydro-2H-pyran-4-ol with the corresponding amino alcohol.

[0473] Examples 16 and 17: 3-((6a) R 7 S, 10 R )-13-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline Synthetic pathway Step 1: (1-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluorocyclopropyl)methanol At room temperature, TBDPSCl (8.22 g, 30.0 mmol) and imidazole (4.08 g, 60.0 mmol) were added to a solution of (2,2-difluorocyclopropane-1,1-diyl)diethanol (4.14 g, 30.0 mmol) in DCM (300 mL). The resulting mixture was stirred at room temperature for 16 hours. After the reaction was indicated by TLC, the reaction mixture was diluted with saturated NaHCO3 (200 mL) and extracted with DCM (150 mL × 3). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum to give a crude residue. The residue was purified by silica gel column chromatography, eluting with 0 to 30% EtOAc in petroleum ether to give the title product (3.0 g, 7.97 mmol). MS (ESI, m / e) [M+23] + 399.2.

[0474] Step 2: Methanesulfonate (1-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluorocyclopropyl)methyl ester At room temperature, triethylamine (1.61 g, 15.9 mmol) and methanesulfonyl chloride (1.36 g, 12.0 mmol) were added to a mixture of (1-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluorocyclopropyl)methanol (3.0 g, 7.97 mmol) in THF. The resulting mixture was stirred at 25 °C for 1 hour. After the reaction was indicated by TLC to be complete, the reaction mixture was concentrated under vacuum to give a crude product, which was used directly in the next step without further purification. MS (ESI, m / e) [M+23] + 477.1.

[0475] Step 3: 1-(1-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluorocyclopropyl)-N,N-dimethylmethylamine At room temperature, K₂CO₃ (2.76 g, 20 mmol) and dimethylamine (2N in THF, 100 mL) were added to a mixture of crude methyl methanesulfonic acid (1-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluorocyclopropyl)methyl ester in THF (50 mL). The resulting mixture was stirred at 65 °C for 16 hours in a sealed tube. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated under vacuum to give a crude residue. The residue was purified by silica gel column chromatography, eluting with 0 to 70% EtOAc in petroleum ether to give the title product (2.4 g, 5.95 mmol). MS (ESI, m / e) [M+1] + 404.2.

[0476] Step 4: (1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methanol At room temperature, 3HF•Et3N (1.61 g, 10 mmol) was added to a solution of 1-(1-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluorocyclopropyl)-N,N-dimethylmethylamine (2.4 g, 5.95 mmol) in THF (50 mL). The resulting mixture was stirred at room temperature for 1 hour. After TLC indicated the reaction was complete, the reaction mixture was concentrated under vacuum to give a crude residue. The residue was purified by silica gel column chromatography, eluting with 0 to 10% MeOH in DCM to give the title product (800 mg, 4.8 mmol). MS (ESI, m / e) [M+1] + 166.1.

[0477] Steps 5-7: 3-((6a) in the form of a mixture of two isomers R 7 S, 10 R )-13-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline was prepared in a manner similar to that of Example 01, by replacing (2,2-difluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol with (1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methanol.

[0478] Step 8: The two isomers (120 mg) were subjected to chiral preparative HPLC (column: i-Cellulose-5, 21.2 mm × 250 mm, 5 μm; mobile phase A: n - hexane The mobile phase B was EtOH (MeOH containing 0.2% 2M NH3); the flow rate was 18 mL / min; the temperature was 25°C; the gradient was 50% B over 18 minutes; the retention time-isomer 1 was 9.0 minutes; and the retention time-isomer 2 was 12.0 minutes. The first eluted isomer (35 mg) was obtained as Example 16, and the second eluted isomer (42 mg) was obtained as Example 17.

[0479] Example 16: 1 H NMR (500 MHz, CD3OD) δ6.68 (s, 1H), 6.46-6.41 (m, 1H), 4.62-4.54 (m, 2H), 4.36-4.00 (m, 5H), 3.69 –3.44 (m, 2H), 2.82 –2.81 (m, 1H),2.45-2.42 (m, 4H), 2.28 (s, 6H), 2.09 –1.80 (m, 6H), 1.68 –1.65 (m, 1H),1.42-1.37 (m, 1H). MS (ESI, m / e) [M+1] + 638.5.

[0480] Example 17: 1 H NMR (500 MHz, CD3OD) δ6.68 (s, 1H), 6.45-6.44 (m, 1H), 4.58 (s, 2H), 4.36-4.00 (m, 5H), 3.38 –3.44 (m, 2H), 2.86 –2.83 (m, 1H),2.45-2.42 (m, 4H), 2.27 (s, 6H), 2.16 –1.80 (m, 6H), 1.68 –1.65 (m, 1H),1.42-1.37 (m, 1H). MS (ESI, m / e) [M+1] + 638.5.

[0481] Example 18: The following example is based on 3-((6a) R 7 S, 10 R)-13-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentazaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline was prepared by replacing (5-amino-3-methyl-2-(trifluoromethyl)phenyl)boronic acid with the corresponding chlorophenyl analogue.

[0482] Example 19: 3-((6aR,7S,10R)-13-((1-(azacyclobutane-1-ylmethyl)-2,2-difluorocyclopropyl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cycloheptano[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline Synthetic pathway Step 1: 1-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluorocyclopropane-1-carboxaldehyde At -78 °C, (COCl)₂ (7.3 mL, 14.28 mmol, 2M in DCM) was added to a solution of DMSO (1.86 g, 23.8 mmol) in DCM (20 mL). The resulting mixture was stirred at -78 °C for 0.5 h, followed by the addition of (1-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluorocyclopropyl)methanol (3.8 g, 9.52 mmol). The mixture was stirred at -78 °C for another 0.5 h, followed by the addition of TEA (6.6 mL, 47.6 mmol). After the reaction was indicated by TLC completion, the reaction was quenched by the addition of NH₄Cl aqueous solution (10 mL). The mixture was extracted with DCM (50 mL × 2). The organic layers were combined, washed with H₂O and brine, and then concentrated under vacuum. The crude product was used for the next step without further purification. MS (ESI, m / e) was performed without MS.

[0483] Step 2: 1-((1-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)azacyclobutane At room temperature, NaBH(OAc)3 (462 mg, 31.82 mmol) was added to a mixture of 1-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluorocyclopropane-1-carboxaldehyde (500 mg, 1.82 mmol, crude) and azacyclobutane (104 mg, 1.82 mmol) in DCM (20 mL). The resulting mixture was stirred for 1 hour. The reaction was then quenched by adding H2O (50 mL). The mixture was extracted with DCM (30 mL × 2). The organic layers were combined, washed with H2O and brine, and then concentrated under vacuum. The crude product was purified by column chromatography (eluting with DCM / MeOH = 20 / 1) to give the title compound (210 mg, 79% yield after 2 steps) as a colorless oil. MS (ESI, m / e) [M+1] + 416.5.

[0484] Step 3: (1-(azacyclobutane-1-ylmethyl)-2,2-difluorocyclopropyl)methanol At room temperature, TBAF (0.58 mL, 0.58 mmol, 1 M in THF) was added to a solution of 1-((1-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)azacyclobutane (200 mg, 0.48 mmol) in THF (5 mL). The resulting mixture was stirred for 1 hour and then concentrated under vacuum. The crude product was purified by column chromatography (eluting with DCM / MeOH = 15 / 1) to give the title compound (75 mg, 88% yield) as a colorless oil. MS (ESI, m / e) [M+1] + 178.5.

[0485] Steps 4-6: Example 19, in the form of a mixture of two isomers, was prepared in a similar manner to Example 01, by replacing (2,2-difluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol with (1-(azacyclobutane-1-ylmethyl)-2,2-difluorocyclopropyl)methanol. ¹H NMR (500 MHz, CD3OD) δ 6.70 (s, 1H), 6.45–6.43 (m, 1H), 4.69–4.61 (m, 1H), 4.56–4.46 (m, 1H), 4.42–4.25 (m, 2H), 4.20–4.06 (m, 2H), 3.96–3.76 (m, 6H), 3.30–3.18 (m, 3H), 2.44 (d, J= 2.5 Hz, 3H), 2.36 –2.28 (m, 2H), 2.24 –1.80 (m, 6H), 1.76 –1.61 (m, 2H). MS (ESI, m / e) [M+1] + 650.5.

[0486] Examples 20-27: The following examples are prepared in a manner similar to that of Example 19, by replacing the aziridine with the corresponding amine, and then further separating the isomers by chiral preparative HPLC (column: i-Cellulose-5, 21.2 mm × 250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: EtOH (MeOH containing 0.2% 2M NH3); flow rate: 18 mL / min; temperature: 25 °C; gradient: 50% B over 18 minutes).

[0487] Example 30: 1-((6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cycloheptano[4,5]cyclooctano[1,2,3-de]naphth-13-yl)-N,N,3-trimethylazacyclobutane-3-amine Synthetic pathway Step 1: (6aR,7S,10R)-2-chloro-13-(3-(dimethylamino)-3-methylazacyclobutane-1-yl)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester At room temperature, tert-butyl phthalate (120 mg, 0.233 mmol) of (6aR,7S,10R)-2-chloro-1-fluoro-13-(methanesulfonyl)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentazaza-7,10-methylbridged cyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylic acid in a solution of (6aR,7S,10R)-2-chloro-1-fluoro-13-(methanesulfonyl)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylic acid in 10 mL of DCM was added to...N,N,3 -Trimethylazacyclobutane-3-amine hydrochloride (140 mg, 0.934 mmol) and DIPEA (163 µL, 0.934 mmol). The resulting mixture was stirred at room temperature for 6 hours. After LCMS indicated the completion of the reaction, silica gel was added to the reaction mixture. The resulting mixture was concentrated under vacuum. The residue was purified by rapid chromatography (dry loading, eluting with 0 to 100% EtOAc in petroleum ether) to give the title product (117 mg).

[0488] Step 2: (6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-13-(3-(dimethylamino)-3-methylazacyclobutane-1-yl)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester At room temperature, tert-butyl 5-amino-3-chloro-13-(3-(dimethylamino)-3-methylazacyclobutane-1-yl)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentazaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid (62 mg, 0.113 mmol) in dioxane / H2O (15 mL / 3 mL) was added to a solution of (6aR,7S,10R)-2-chloro-13-(3-(dimethylamino)-3-methylazacyclobutane-1-yl)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid (tert-butyl ester) (76 mg, 0.35 mmol), Pd(dppf)Cl2 (43 mg, 0.059 mmol), and NaHCO3 (61 mg, 0.73 mmol). The mixture was degassed by purging with nitrogen for 5 minutes, and then stirred at 90°C for 4 hours. After LCMS indicated completion, silica gel was added to the reaction mixture. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (dry loading, eluting with 0–10% MeOH in DCM) to give the title product (100 mg). MS (ESI, m / e) [M+H] + 687.5.

[0489] Step 3: 1-((6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphth-13-yl)-N,N,3-trimethylazacyclobutane-3-amine At room temperature, trifluoroacetic acid (4 mL) was added to a solution of (6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-13-(3-(dimethylamino)-3-methylazacyclobutane-1-yl)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (100 mg, 0.15 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 4 hours. After the reaction was indicated by LCMS, the mixture was concentrated under vacuum. The residue was redissolved in MeCN / DCM, followed by dropwise addition of a methanol solution of 7 N ammonia to adjust the pH to greater than 7. The mixture was concentrated again under vacuum, and the residue was purified by preparative HPLC to give the title product (28 mg). 1 H NMR (500 MHz, CD3OD) δ6.67 (s, 1H), 6.44-6.42 (m, 1H), 4.59 (s, 1H), 4.24 (s, 2H), 4.07-4.06 (m, 2H), 3.90-3.88 (m,3H), 3.75-3.45 (m, 3H), 2.42-2.41 (m, 3H), 2.24 (s, 7H), 2.18-1.80 (m, 5H), 1.38 (s, 3H). MS (ESI, m / e) [M+H] + 587.55.

[0490] Example 31: The following examples were prepared in a similar manner to those in Example 30.

[0491] Examples 33-36: The following examples were prepared in a manner similar to Examples 01 and 06, by replacing the corresponding alkyl alcohols in the form of isomer mixtures with alkyl alcohols in the form of separate single enantiomers.

[0492] Examples 37-38 below were prepared in a manner similar to that of Example 01, by replacing (2,2-difluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol with the corresponding alkyl alcohol.

[0493] Examples 39-41: The following examples were prepared in a manner similar to that of Example 07, by replacing (3R,4R)-3-aminotetrahydro-2H-pyran-4-ol with the corresponding amino alcohol.

[0494] Examples 42-43: The following examples were performed using a chiral preparative HPLC (column: i-Cellulose-5, 21.2 mm × 250 mm, 5 μm; mobile phase A: n - hexane Mobile phase B: EtOH (MeOH containing 0.2% 2M NH3); flow rate: 18 mL / min; temperature: 25℃; gradient: 50% within 18 minutes. Example 15 was prepared by further separating the two isomers into a mixture.

[0495] Examples 44-45: The following examples were prepared in a manner similar to that in Example 18, by replacing the corresponding alkyl alcohols in the form of a mixture of isomers with alkyl alcohols in the form of a single enantiomer.

[0496] Examples 46-56: The following examples were prepared in a similar manner to those in Examples 16 and 17, by replacing the corresponding substitutes or coupling agents.

[0497] Examples 57-58: The following examples were prepared by further separation of Example 19 using a chiral preparative HPLC (column: i-Cellulose-5, 21.2 mm × 250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: EtOH (MeOH containing 0.2% 2M NH3); flow rate: 18 mL / min; temperature: 25 °C; gradient: 50% B over 18 minutes).

[0498] Examples 59-62: 3-((6aR,7S,10R)-13-((1-(1-(dimethylamino)ethyl)-2,2-difluorocyclopropyl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cycloheptano[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline Synthetic pathway Step 1: 1-(1-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluorocyclopropyl)ethanol-1-ol To a 100-mL round-bottom flask, add 1-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluorocyclopropane-1-carboxaldehyde (374 mg, 1.0 mmol), MeMgBr (3M, 0.5 mL, 1.5 mmol), and THF (10 mL). Stir the reaction mixture at room temperature for 2 hours, then concentrate under vacuum. Purify the crude product by column chromatography (EA / PE = 0-20%) to give a colorless oily product (350 mg, 90% yield).

[0499] Step 2: 1-(1-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluorocyclopropyl)-N,N-dimethylethyl-1-amine To a 50-mL round-bottom flask, add 1-(1-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluorocyclopropyl)ethanol-1-ol (350 mg, 0.90 mmol), THF (6 mL), Et3N (181.8 mg, 1.8 mmol), and MsCl (205 mg, 1.8 mmol). Stir the reaction mixture at room temperature for 30 minutes, then add 6 mL of THF containing dimethylamine (2 M in THF, 20 mL, 40 mmol) at room temperature. In a sealed tube, stir the resulting mixture at 65°C for 32 hours. After completion, quench the reaction by adding saturated NH4Cl (20 mL). Extract the mixture three times with EtOAc (20 mL). Combine the organic phases, dry with Na2SO4, and filter through diatomaceous earth. Concentrate the mixture under vacuum. The crude product was purified by column chromatography (EA / PE = 0-30%) to obtain the title compound (300 mg, 80% yield) as a colorless oil.

[0500] Step 3: (1-(1-(dimethylamino)ethyl)-2,2-difluorocyclopropyl)methanol To a 100 mL round-bottom flask, add 1-(1-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluorocyclopropyl)-N,N-dimethylethyl-1-amine (300 mg, 0.72 mmol), Et3N•3HF (116 mg, 0.72 mol), and THF (10 mL). Stir the reaction mixture at room temperature for 2 hours. The reaction is complete as indicated by LCMS. Concentrate the resulting mixture under vacuum. Purify the crude product by column chromatography (MeOH / DCM = 0-10%) to give the title compound (50 mg, 39% yield) as a colorless oil.

[0501] Steps 4-6: 3-((6aR,7S,10R)-13-((1-(1-(dimethylamino)ethyl)-2,2-difluorocyclopropyl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline, in the form of a mixture of four isomers, was prepared in a manner similar to that in Example 01, by replacing (2,2-difluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol with (1-(1-(dimethylamino)ethyl)-2,2-difluorocyclopropyl)methanol.

[0502] Step 7: The mixture of the above four isomers (30 mg) was separated by chiral preparative HPLC (column: i-Cellulose-5, 21.2 mm × 250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: EtOH (MeOH containing 0.2% 2MNH3); flow rate: 18 mL / min; temperature: 25℃; gradient: 50% B within 18 minutes; retention time-isomer 1: 9.0 min; retention time-isomer 2: 12.0 min) to obtain the four eluents used in Examples 59-62: Example 59 (Isomer 1): 1.2 mg was isolated. 1 H NMR (500 MHz, DMSO-d8) δ 6.59 (s,1H), 6.35 (s, 1H), 5.87 (s, 2H), 4.71-3.43 (m, 9H), 2.36 (s, 3H), 2.17 (s6H), 1.99- 1.40 (m, 9H), 1.20-1.19 (m, 3H). MS (ESI, m / e) [M+H] + 652.5.

[0503] Example 60 (Isomer 2): 2.0 mg was isolated. 1 H NMR (500 MHz, DMSO-d8) δ 6.59 (s,1H), 6.36 (s, 1H), 5.87 (s, 2H), 4.72-3.43 (m, 9H), 2.36 (s, 3H), 2.17 (s6H), 1.99- 1.50 (m, 9H), 1.21-1.19 (m, 3H). MS (ESI, m / e) [M+H] + 652.5.

[0504] Example 61 (Isomer 3): 6.1 mg was isolated. 1 H NMR (500 MHz, DMSO-d8) δ 6.59 (s,1H), 6.36 (s, 1H), 5.87 (s, 2H), 4.72-3.45(m, 9H), 2.36 (s,3H), 2.17 (s 6H),1.99- 1.45(m,9H), 1.21-1.19 (m, 3H). MS (ESI, m / e) [M+H] + 652.5.

[0505] Example 62 (Isomer 4): 1.2 mg was isolated. 1 H NMR (500 MHz, DMSO-d8) δ 6.59 (s,1H), 6.36 (s, 1H), 5.87 (s, 2H), 4.72-3.43 (m, 9H), 2.36 (m, 3H), 2.17 (s,6H), 1.99- 1.5 (m, 9H), 1.21-1.19 (m, 3H). MS (ESI, m / e) [M+H] + 652.5.

[0506] Example 63: 3-((6aR,7S,10R)-1-fluoro-13-((1-(1-methylpyrrolidone-2-yl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cycloheptano[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline Synthetic pathway Step 1: 2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester Diazomethyl(trimethyl)silane (2 M, 18 mL, 36 mmol) was added to a mixture of 2-(1-(tert-butoxycarbonyl)pyrrolidine-2-yl)acetic acid (4.6 g, 20 mmol) and DIPEA (3.56 mL, 21.4 mmol) in MeOH (2.64 mL) and MeCN (80 mL). The mixture was stirred at room temperature for 20 hours. The reaction was then quenched by adding saturated NaHCO3 (50 mL). The resulting mixture was extracted three times with EtOAc (50 mL). The organic layers were combined, dried over Na2SO4, and concentrated under vacuum to give the crude title product (4 g).

[0507] Step 2: tert-butyl 2-(2-hydroxyethyl)pyrrolidine-1-carboxylate LiAlH4 (912 mg, 24 mmol) was added to a solution of 4 g of 2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in THF (50 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction was then quenched with Na2SO4•10H2O, filtered through diatomaceous earth, and concentrated under vacuum to give a crude product (4.0 g).

[0508] Step 3: tert-butyl 2-(2-oxoethyl)pyrrolidine-1-carboxylate At room temperature, 4.0 g of 2-(2-hydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester, 17.0 g of DMP, and 100 mL of DCM were added to a 250 mL round-bottom flask. The reaction mixture was stirred at room temperature for 2 hours, and then concentrated under vacuum. The crude product was purified by column chromatography (EtOAc / PE = 0 to 40%) to give the title product (3.2 g) as a colorless oil.

[0509] Step 4: 2-(3-oxopropyl-1-en-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester To a 100-mL round-bottom flask, add tert-butyl 2-(2-oxoethyl)pyrrolidine-1-carboxylate (1.9 g, 8.9 mmol), pyrrolidine (63 mg, 0.89 mmol), 37% HCHO solution (0.8 mL, 10.7 mmol), propionic acid (65.9 mg, 0.89 mmol), and MeOH (40 mL). Stir the reaction mixture at 55 °C for 16 hours. After TLC indicated completion, concentrate the reaction mixture under vacuum. Purify the crude product by column chromatography (EtOAc / PE = 0 to 20%) to give the title product (1.4 g, 70% yield) as a colorless oil.

[0510] Step 5: 2-(1-Formylcyclopropyl)pyrrolidine-1-carboxylic acid tert-butyl ester Trimethyl sulfoxide (1.76 g, 8.0 mmol), potassium tert-butoxide (896 mg, 8.0 mmol), and DMSO (20 mL) were added to a 50 mL round-bottom flask. The reaction mixture was stirred at 55 °C for 10 min, followed by the addition of DMSO (10 mL) containing tert-butyl 2-(3-oxopropyl-1-en-2-yl)pyrrolidine-1-carboxylate (1.2 g, 5.3 mmol) at room temperature. The resulting mixture was stirred at 55 °C for 0.5 h. After the reaction was indicated by TLC, it was quenched by the addition of saturated NaHCO3 (30 mL). The mixture was extracted three times with EtOAc (20 mL). The organic phases were combined, dried over Na2SO4, and filtered through diatomaceous earth. The filtrate was concentrated under vacuum. The crude product was purified by column chromatography (EA / PE = 0–30%) to give the title compound (750 mg, 59% yield) as a colorless oil.

[0511] Step 6: (1-(1-methylpyrrolidone-2-yl)cyclopropyl)methanol LiAlH4 (114 mg, 3 mmol) was added to a solution of 2-(1-formylcyclopropyl)pyrrolidine-1-carboxylic acid tert-butyl ester (239 mg, 1.0 mmol) in THF (15 mL). The resulting mixture was stirred at 65 °C for 16 hours. After the reaction was indicated by TLC to be complete, the reaction was quenched with Na2SO4•10 H2O and filtered through diatomaceous earth. The filtrate was concentrated under vacuum to give the crude product (80 mg).

[0512] Steps 7-9: Example 63, which is a mixture of two isomers, was prepared in a similar manner to Example 01 by replacing (2,2-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol with (1-(1-methylpyrrolidine-2-yl)cyclopropyl)methanol. 1H NMR (500 MHz, CD3OD) δ 6.68(s, 1H), 6.46-6.40 (m, 1H), 4.54-3.44(m, 12H), 2.49 – 2.35 (m, 6H), 1.98 – 1.60 (m, 10H), 0.90 – 0.52 (m, 4H). MS(ESI, m / e) [M+H] + 628.5.

[0513] Examples 64-71: The following examples were prepared in a manner similar to that of Example 19, by replacing (2,2-difluorocyclopropane-1,1-diyl)diethanol with cyclopropane-1,1-diyldiethanol and replacing aziridine with the corresponding amine.

[0514] Examples 72-73: The following examples were prepared in a manner similar to that of Example 36, by replacing the corresponding boric acid in the Suzuki coupling reaction.

[0515] Example 74: The following example is in a similar manner to Example 37, by ( S )-1-(( S It is prepared by replacing (S)-1-methylpyrrolidone-2-yl)ethanol-1-ol with (S)-1-((2S,4R)-4-fluoro-1-methylpyrrolidone-2-yl)ethanol-1-ol.

[0516] Examples 75-76: The following examples are in a similar manner to Example 37, by ( S )-1-(( S The 1-methylpyrrolidone-2-yl)ethanol-1-ol was replaced with the corresponding alcohol in the form of a mixture of two isomers, and then further separated by chiral preparative HPLC (column: i-Cellulose-5, 21.2 mm × 250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: EtOH (MeOH containing 0.2% 2M NH3); flow rate: 18 mL / min; temperature: 25 °C; gradient: 50% B over 18 minutes).

[0517] Example 77: 3-((6aR,7S,10R)-1-fluoro-13-((1-(pyrrolidone-1-ylmethyl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cycloheptano[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline Synthetic pathway Step 1: (6aR,7S,10R)-2-chloro-1-fluoro-13-((1-(hydroxymethyl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester LHMDS (1N, 5.5 mL, 5.5 mmol) was added to a solution of cyclopropane-1,1-dimethyldiethanol (567 mg, 5.56 mmol) in THF (30 mL). The resulting mixture was stirred at 0 °C for 10 minutes, followed by the addition of (6a) R 7 S 10 R 2-Chloro-1-fluoro-13-(methanesulfonyl)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentazaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (1.9 g, 3.7 mmol) in THF (20 mL). The resulting mixture was stirred at room temperature for 1 hour. After the reaction was indicated by TLC, the reaction mixture was concentrated to give a crude residue. The residue was purified by silica gel column chromatography, eluting with 0 to 10% MeOH in DCM to give the title product (1.9 g, 96%). MS (ESI, m / e) [M+1] + 536.4.

[0518] Step 2: (6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-13-((1-(hydroxymethyl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester At room temperature, 1,4-dioxane (50 mL) and water (10 mL) were added to a mixture of (6aR,7S,10R)-2-chloro-1-fluoro-13-((1-(hydroxymethyl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentazaza-7,10-methylbridged cyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (1.9 g, 3.55 mmol), (5-amino-3-methyl-2-(trifluoromethyl)phenyl)boronic acid (1.56 g, 7.12 mmol), cataCXium A Pd G3 (260 mg, 0.36 mmol), and K3PO4 (2.26 g, 10.7 mmol). The resulting mixture was degassed by purging with nitrogen for 10 minutes, and then stirred at 95°C for 3 hours under N2 atmosphere. After TLC indicated completion, the reaction mixture was concentrated, dissolved in DCM (20 mL), and filtered through diatomaceous earth. The filtrate was concentrated to obtain a crude residue. The residue was purified by column chromatography, eluting with 0–10% MeOH in DCM to give the title product (1.83 g, 76%). MS (ESI, m / e) [M+1] + 675.4.

[0519] Step 3: (6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-13-((1-((((ethanesulfonyl)oxy)methyl)cyclopropyl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester At 0 °C, a solution of ethanesulfonyl chloride (228 mg, 1.78 mmol) in DCM (5 mL) was added to a solution of (6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-13-((1-(hydroxymethyl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentazaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (1 g, 1.48 mmol) and DIPEA (574 mg, 4.45 mmol) in DCM (30 mL). The reaction mixture was stirred at 0 °C for 0.5 h and then washed with a saturated aqueous solution of NaHCO3. The organic phase was dried over Na₂SO₄ and filtered through diatomaceous earth. The filtrate was concentrated to give the crude product (1.13 g, 100%). MS (ESI, m / e) [M+1] + 767.5.

[0520] Step 4: (6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-13-((1-(pyrrolidone-1-ylmethyl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester TEA (10.1 mg, 0.1 mmol) was added to a solution of crude (6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-13-((1-((((ethylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentazaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (37.6 mg, 0.05 mmol) and pyrrolidine (35.5 mg, 0.5 mmol) in CH3CN (2 mL). The solution was stirred at 80 °C for 4 hours, then concentrated after cooling and washed with an aqueous solution of NaHCO3. The solution was dried over Na2SO4 and concentrated to give the title product (30 mg). MS (ESI, m / e) [M+1] + 728.5.

[0521] Step 5: 3-((6aR,7S,10R)-1-fluoro-13-((1-(pyrrolidine-1-ylmethyl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cycloheptano[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline At room temperature, a solution of dioxane in 4 N HCl (2 mL) was added to a solution of (6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-13-((1-(pyrrolidone-1-ylmethyl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (30 mg, crude) in DCM (2 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting solution was concentrated, diluted with an aqueous solution of NaHCO3, and extracted twice with DCM (10 mL). The combined DCM phases were dried and concentrated with Na2SO4 to obtain a crude residue, which was then subjected to preparative HPLC (column: Waters X-Select C18, 19). 150 mm, 5 µm; Mobile phase A: H2O (0.1% FA), Mobile phase B: MeCN (0.1% FA); Flow rate: 17 mL / min; Temperature: 25 °C; Detector: UV 254 nm and 214 nm; Gradient: 12% to 35% over 1 min to 11 min. B) Further purification yielded the title product (1.26 mg). 1 H NMR (500 MHz, CD3OD) δ 6.69 (s, 1H), 6.46-6.39(m,1H), 4.41-4.10 (m, 7H), 3.45-3.37 (m, 4H), 3.16-2.93(m, 4H), 2.42 (s, 3H), 2.15-1.62 (m, 10H), 0.90- 0.73 (m, 4H). MS (ESI, m / e) [M+1] + 628.5.

[0522] Examples 78-109: The following examples were prepared in a manner similar to that of Example 77, by replacing pyrrolidine with the corresponding alkylamine.

[0523] Example 110: 3-((6aR,7S,10R)-1-fluoro-13-((1-((4-methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cycloheptano[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline Synthetic pathway Step 1: (6aR,7S,10R)-2-chloro-1-fluoro-13-((1-formylcyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester At 0 °C, 0.70 g (1.3 mmol) of tert-butyl (D&M)-2-chloro-1-fluoro-13-((1-(hydroxymethyl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentazaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid in DCM (60 mL) was added to a solution of D&M (6aR,7S,10R)-2-chloro-1-fluoro-13-((1-(hydroxymethyl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid in DCM (60 mL) was stirred at room temperature for 30 min. The reaction was then quenched by adding saturated sodium thiosulfate solution (30 mL). The mixture was extracted three times with DCM (20 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, and filtered through diatomaceous earth. The filtrate was concentrated under vacuum and purified by silica gel column chromatography (PE / EtOAc = 3 / 1) to give the title product (0.57 g). MS (ESI, m / e) [M+H] + 534.3.

[0524] Step 2: (6aR,7S,10R)-2-chloro-1-fluoro-13-((1-((4-methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester To a solution of (6aR,7S,10R)-2-chloro-1-fluoro-13-((1-formylcyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentazaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (38 mg, 0.07 mmol) in a DCE (5 mL), 4-methoxypiperidine (18 mg, 0.14 mmol) and acetic acid (2 drops) were added. The resulting mixture was stirred at 50 °C for 6 hours, followed by the addition of sodium triacetoxyborohydride (45 mg, 0.21 mmol). The mixture was stirred at 50 °C for another 16 hours. The reaction was quenched by adding saturated aqueous NaHCO3 solution (10 mL) after TLC indicated completion. The mixture was extracted three times with EtOAc (20 mL). The combined organic phases were washed with brine (10 mL), dried over sodium sulfate, and filtered through diatomaceous earth. The filtrate was concentrated under vacuum and purified by silica gel column chromatography (eluting with EtOAc) to give the title product (20 mg). MS (ESI, m / e) [M+H] + 633.5.

[0525] Step 3: (6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-13-((1-((4-methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester A mixture of (6aR,7S,10R)-2-chloro-1-fluoro-13-((1-((4-methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentazaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (20 mg, 0.03 mmol), (5-amino-3-methyl-2-(trifluoromethyl)phenyl)boronic acid (25 mg, 0.11 mmol), potassium phosphate (33 mg, 0.16 mmol), dioxane / H2O (5:1 ratio, 10 mL) and Pd(dtbpf)Cl2 (6 mg, 0.009 mmol) was degassed by purging with nitrogen for 10 minutes. The resulting mixture was stirred at 85°C for 2 hours. The mixture was then diluted with EtOAc and filtered through diatomaceous earth. The filtrate was concentrated under vacuum and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give the title product (18 mg). MS (ESI, m / e) [M+H] + 772.5.

[0526] Step 4: ((6aR,7S,10R)-1-fluoro-13-((1-((4-methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cycloheptano[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline TFA (2 mL) was added to a solution of (6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-13-((1-((4-methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (18 mg, 0.02 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. The residue was diluted with saturated aqueous NaHCO3 solution and extracted twice with DCM (10 mL). The combined DCM phases were dried and concentrated with Na2SO4 to obtain a crude residue. The crude residue was then subjected to preparative HPLC (column: Waters X-Select C18, 19). 150 mm, 5 µm; Mobile phase A: H2O (0.1% FA), Mobile phase B: MeCN (0.1% FA); Flow rate: 17 mL / min; Temperature: 25 °C; Detector: UV 254 nm and 214 nm; Gradient: 12% to 35% B over 1 min to 11 min. Further purification yielded the title product (2.6 mg). 1 H NMR (500 MHz, CD3OD) δ 6.70 (s, 1H), 6.44(d, J = 18.7 Hz, 1H), 4.67 – 3.68 (m, 9H), 3.46 (d, J = 19.0 Hz, 1H), 3.35 (s,3H), 3.05 (s, 3H), 2.42 (d, J = 1.6 Hz, 3H), 2.28 – 1.57 (m, 10H), 0.90 (s, 2H), 0.76 (s, 2H). MS (ESI, m / e) [M+H] + 672.6.

[0527] Examples 111-121: The following examples were prepared in a manner similar to that of Example 110, by replacing 4-methoxypiperidine with the corresponding alkylamine.

[0528] Examples 124 and 125: (1-((1-((((6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphth-13-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine-2-yl)methanol Synthetic pathway Step 1: (6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-13-((1-formylcyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester IBX (183 mg, 0.65 mmol) was added to a solution of (6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-13-((1-(hydroxymethyl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (220 mg, 0.33 mmol) in DMSO (9 mL). After stirring at 100 °C for 3 hours, the reaction mixture was cooled to room temperature, diluted with brine, and extracted three times with EtOAc. The combined organic phases were concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to give the title product (88 mg). MS (ESI, m / e) [M+1] + 673.4.

[0529] Step 2: (6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-13-((1-((2-(hydroxymethyl)pyrrolidone-1-yl)methyl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester Ti(OiPr)4 (56 mg, 0.2 mmol) was added to a mixture of (6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-13-((1-formylcyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (67 mg, 0.1 mmol) and pyrrolidine-2-ylmethanol (20 mg, 0.2 mmol) in THF (2 mL). The mixture was stirred at room temperature for 30 minutes, followed by the addition of NaBH3CN (15 mg, 0.23 mmol). The resulting mixture was stirred at room temperature for 16 hours, then quenched with MeOH (5 mL). The mixture was concentrated under vacuum and purified by silica gel column chromatography to give the title product (36 mg). MS (ESI, m / e) [M+1] + 758.6.

[0530] Step 3: (1-((1-((((6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphth-13-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine-2-yl)methanol At room temperature, TFA (1 mL) was added to a solution of (6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-13-((1-((2-(hydroxymethyl)pyrrolidone-1-yl)methyl)cyclopropyl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (35 mg, 0.046 mmol) in DCM (2 mL). After stirring at room temperature for 2 hours, the mixture was concentrated under vacuum and alkalized with NH3 / MeOH (7 M) to approximately pH 9. The resulting mixture was purified by preparative TLC (DCM / MeOH (containing NH3) = 8:1) to obtain Example 124 (3 mg) as the first eluting isomer and Example 125 (6 mg) as the second eluting isomer.

[0531] Example 124: 1H NMR (400 MHz, CD3OD) δ 6.70 (s, 1H), 6.50 – 6.35 (m, 1H), 4.50 – 4.27 (m, 5H), 3.93 – 3.83 (m, 4H), 3.70 – 3.61 (m, 2H), 3.59 – 3.51(m, 1H), 3.07 – 2.93 (m, 1H), 2.42 (s, 3H), 2.19 – 2.03 (m, 7H), 1.97 – 1.85(m, 4H), 1.33 – 1.26 (m, 3H), 0.93 – 0.88 (m, 3H). MS (ESI, m / e) [M+1] + 658.5.

[0532] Example 125: 1 H NMR (400 MHz, CD3OD) δ 6.68 (s, 1H), 6.43 (d, J = 23.6 Hz,1H), 4.80 – 4.63 (m, 1H), 4.49 – 4.18 (m, 3H), 4.17 – 3.81 (m, 3H), 3.68 (s,1H), 3.63 – 3.39 (m, 5H), 2.84 – 2.60 (m, 1H), 2.42 (s, 3H), 2.13 – 1.62 (m, 11H), 1.28 (s, 1H), 0.81 – 0.58 (m, 3H), 0.53 (s, 1H). MS (ESI, m / e) [M+1] + 658.5.

[0533] Examples 126 to 129: 3-((6aR,7S,10R)-1-fluoro-13-((5-methoxy-1,3-dimethylpiperidin-3-yl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cycloheptano[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline Synthetic pathway Step 1: 3-methyl 1-(tert-butyl) 5-methoxypiperidine-1,3-dicarboxylic acid ester DIPEA (2.95 g, 22.7 mmol) and di-tert-butyl dicarbonate (1.49 g, 6.8 mmol) were added to a solution of methyl 5-methoxypiperidine-3-carboxylate hydrochloride (0.95 g, 4.6 mmol) in DCM (100 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was then diluted with brine (30 mL) and extracted three times with DCM (20 mL). The combined organic phases were dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by column chromatography (EtOAc in PE, 30% to 100%) to give the title product (1.10 g). MS (ESI, m / e) [M+Na] + 296.3.

[0534] Step 2: 3-methyl 1-(tert-butyl) 5-methoxy-3-methylpiperidine-1,3-dicarboxylic acid ester LiHMDS was added dropwise to a solution of 1-(tert-butyl)-3-methyl 5-methoxypiperidine-1,3-dicarboxylic acid (1.0 g, 3.6 mmol) in THF (50 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 20 min, followed by the slow addition of MeI (1.0 g, 7.3 mmol). After 2 hours, the reaction was quenched with saturated ammonium chloride solution (20 mL). The mixture was extracted three times with EtOAc (20 mL), washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by column chromatography (pure EtOAc) to give the title product (474 ​​mg). MS (ESI, m / e) [M+Na] + 310.2.

[0535] Step 3: (5-methoxy-1,3-dimethylpiperidin-3-yl)methanol LiAlH4 (0.21 g, 5.2 mmol) was added to a solution of 3-methyl 1-(tert-butyl) 5-methoxy-3-methylpiperidin-1,3-dicarboxylic acid (0.37 g, 1.3 mmol) in THF (30 mL). The resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was then cooled to 0 °C, diluted with ether (20 mL), and H2O (0.2 mL), 15% sodium hydroxide aqueous solution (0.2 mL), and H2O (0.6 mL) were added slowly in sequence. The slurry was heated to room temperature and stirred for 15 min, followed by the addition of anhydrous magnesium sulfate. The mixture was stirred for another 15 min and then filtered to remove salts. The filtrate was concentrated under vacuum to give the title product (260 mg), which was used directly in the next step without further purification. MS (ESI, m / e) [M+H]+ 174.1.

[0536] Steps 4-6: Examples 126-129 were prepared in a manner similar to Example 01 by replacing (2,2-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol with the above-mentioned (5-methoxy-1,3-dimethylpiperidin-3-yl)methanol. The compound was further separated by chiral preparative HPLC (column: CHIRALPAK® IE, 20 mm × 250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: EtOH (MeOH containing 0.2% 2M NH3); flow rate: 18 mL / min; room temperature; gradient: 70% B within 18 minutes), and then separated by chiral preparative HPLC (column: i-Cellulose-5, 21.2 mm × 250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: EtOH (MeOH containing 0.2% 2M NH3); flow rate: 18 mL / min; room temperature; gradient: 50% B within 18 minutes) to obtain four isomers as Examples 126-129: Example 126: 1 H NMR (500 MHz, CD3OD) δ 6.68 (s, 1H), 6.44 (d, J = 26.8 Hz,1H), 4.33 – 4.08 (m, 7H), 3.69 (s, 1H), 3.61 – 3.48 (m, 2H), 3.34 (s, 3H), 3.02 (d, J = 7.9 Hz, 1H), 2.80 (d, J = 11.5 Hz, 1H), 2.42 (s, 3H), 2.27 (s, 3H), 2.18 – 1.68 (m, 9H), 1.11 (s, 3H), 1.08 – 0.99 (m, 1H). [M+H] + 646.55.

[0537] Example 127: 1 H NMR (500 MHz, CD3OD) δ 6.68 (s, 1H), 6.44 (d, J = 31.2 Hz,1H), 4.56 – 3.89 (m, 7H), 3.69 (s, 1H), 3.59 (s, 2H), 3.01 (d, J = 7.5 Hz, 1H), 2.78 (d, J= 11.3 Hz, 1H), 2.42 (s, 3H), 2.27 (s, 3H), 2.20 – 1.67 (m, 9H), 1.29 (s, 2H), 1.11 (s, 3H), 1.09 – 0.99 (m, 1H). [M+H] + 646.55.

[0538] Example 128: 1 H NMR (500 MHz, CD3OD) δ 6.68 (s, 1H), 6.44 (d, J = 23.8 Hz,1H), 4.61 – 3.90 (m, 7H), 3.70 (s, 1H), 3.56 – 2.54 (m, 2H), 3.34 (s, 3H), 2.72 (s, 1H), 2.55 – 2.34 (m, 5H), 2.29 (s, 3H), 2.21 – 1.76 (m, 7H), 1.67(d, J = 9.7 Hz, 1H), 1.56 (s, 1H), 1.29 (s, 2H), 1.16 (s, 3H). [M+H] + 646.55.

[0539] Example 129: 1 H NMR (500 MHz, CD3OD) δ 6.69 (s, 1H), 6.45 (s, 1H), 4.54 –3.97 (m, 7H), 3.74 (s, 1H), 3.56 (s, 2H), 3.35 (s, 4H), 2.42 (s, 4H), 2.32 (s, 3H), 1.79 – 1.59 (m, 9H), 1.16 (s, 3H), 1.14 – 1.03 (m, 1H). [M+H] + 646.55.

[0540] Examples 130-132: The following examples were prepared in a manner similar to that of Example 07, by replacing (3R,4R)-3-aminotetrahydro-2H-pyran-4-ol with the corresponding alkyl alcohol.

[0541] Examples 133-134: The following examples were prepared by further separation of Example 63 by chiral preparative HPLC (column: i-Cellulose-5, 21.2 mm × 250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: EtOH (MeOH containing 0.2% 2M NH3); flow rate: 18 mL / min; temperature: 25 °C; gradient: 50% B over 18 minutes).

[0542] Example 135: The following examples were prepared in a manner similar to that in Examples 59-62, by replacing (2,2-difluorocyclopropane-1,1-diyl)diethanol with cyclopropane-1,1-diyldiethanol.

[0543] Examples 136-137: The following examples were prepared by further separation of a mixture of two isomers by chiral preparative HPLC (column: CHIRAL ART Amylose-SA, 2 × 25 cm, 5 μm; mobile phase A: n-hexane, mobile phase B: EtOH (MeOH containing 1% 2M NH3); flow rate: 20 mL / min; temperature: 25 °C; gradient: 40% isocratic) as in Example 49.

[0544] Examples 138-139: The following examples were prepared by further separation of a mixture of two isomers in the form of Example 90 by chiral preparative HPLC (column: i-Cellulose-5, 21.2 mm × 250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: EtOH (MeOH containing 0.2% 2M NH3); flow rate: 18 mL / min; temperature: 25 °C; gradient: 50% B over 18 minutes).

[0545] Examples 140-143: The following examples were prepared in a similar manner to those in Example 37, by replacing the corresponding substitutes or coupling agents.

[0546] Examples 144-145: The following examples were prepared in a similar manner to those in Examples 75-76.

[0547] Examples 146-153: The following examples were prepared in a similar manner to those in Example 77, by replacing the corresponding substitutes or coupling complexes. The products were purified by preparative TLC (DCM / MeOH (containing NH3) = 8:1).

[0548] Examples 154-156: The following examples were prepared in a manner similar to that of Example 110, by replacing the corresponding substitutes or coupling complexes. The products were purified by preparative TLC (DCM / MeOH (containing NH3) = 8:1).

[0549] Examples 157-194: The following examples were prepared in a similar manner to Example 77, by replacing the corresponding substitutes or coupling complexes. The products were subjected to preparative HPLC (column: Waters Xselect C18, 19). 150 mm, 5 µm; Mobile phase A: H2O (0.1% NH3·H2O + 10 mM NH4HCO3), Mobile phase B: MeCN; Flow rate: 17 mL / min; Detector: UV 214 and 254 nm; Gradient: 45 to 70% B from 0 to 11.0 min, 70 to 90% B from 11.0 to 11.2 min) purification.

[0550] Examples 195-201 below were prepared in a manner similar to that of Example 01, by replacing (2,2-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol with the corresponding alkyl alcohol.

[0551] Examples 202-203: The following examples were prepared in a manner similar to Example 01, by replacing (2,2-difluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol with the corresponding alkyl alcohol in the form of a mixture of isomers, and then further separating them by chiral preparative HPLC (column: CHIRALPAK IG, 2 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M NH3-MeOH), mobile phase B: EtOH: DCM = 1:1; flow rate: 20 mL / min; temperature: 25 °C; gradient: 20% isocratic B).

[0552] Examples 204 and 205: 3-((6aR,7S,10R)-1-fluoro-13-(((2R)-2-fluoro-2,3-dihydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cycloheptano[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline Synthetic pathway Step 1: (8S)-8-(chloromethyl)-6-oxo-7-oxa-1-azaspiro[4.4]non-3-ene-1-carboxylic acid tert-butyl ester At -78 °C, 2-methyl 1-(tert-butyl) 2,5-dihydro-1H-pyrrole-1,2-dicarboxylic acid (1 g, 4.4 mmol) was added dropwise to a solution of 1-(tert-butyl) 2-methyl ester in THF (0.8 L) with LiHMDS solution (7 mL, 1 M, 7 mmol). The reaction was stirred at -78 °C for 1 h, followed by the addition of (S)-2-(chloromethyl)ethylene oxide (1.2 g, 13.2 mmol). The reaction was stirred at -78 °C for another 1 h, then heated to room temperature and stirred for another 15 h. The reaction was quenched by the addition of a saturated aqueous solution of NH4Cl. The resulting mixture was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (dry loading, eluting with 0 to 20% EtOAc in PE) to give the title product (0.6 g). MS (ESI, m / e) [M+Na] + 310.1.

[0553] Step 2: Methyl 2-((S)-3-chloro-2-hydroxypropyl)-2,5-dihydro-1H-pyrrole-2-carboxylate At room temperature, 0.1 mL of SOCl2 was added to a solution of (8S)-8-(chloromethyl)-6-oxo-7-oxa-1-azaspiro[4.4]non-3-ene-1-carboxylic acid tert-butyl ester (0.6 g, 2.1 mmol) in MeOH (10 mL). The resulting mixture was degassed by purging with nitrogen and stirred at 60 °C for 15 hours. The mixture was then concentrated under vacuum to give the title product (0.56 g), which was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 220.2.

[0554] Step 3: (2S)-2-hydroxy-2,3-dihydro-1H-pyrrolizine-7a(5H)-formate methyl ester At room temperature, methyl 2-((R)-3-chloro-2-hydroxypropyl)-2,5-dihydro-1H-pyrrole-2-carboxylate (0.56 g) in CH3CN (10 mL) was added to NaHCO3 (0.53 g, 6.3 mmol). The mixture was degassed by purging with nitrogen and stirred at 70 °C for 30 min. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (dry loading, eluting with 0 to 100% EtOAc in PE) to give the title product (0.23 g, 28% yield in 3 steps). MS (ESI, m / e) [M+H] + 184.2.

[0555] Step 4: Methyl (2R)-2-fluoro-2,3-dihydro-1H-pyrrolizine-7a(5H)-formate DAST (0.06 g, 0.37 mmol) was added to a solution of (2S)-2-hydroxy-2,3-dihydro-1H-pyrrolazine-7a(5H)-carboxylate (0.23 g, 1.25 mmol) in DCM (5 mL) at 0 °C. The mixture was degassed by purging with nitrogen and stirred at 0 °C for 1 hour. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (dry loading, eluting with 0 to 100% EA in PE) to give the title product (0.11 g, 47%). MS (ESI, m / e) [M+H] + 186.3.

[0556] Step 5: ((2R)-2-fluoro-2,3-dihydro-1H-pyrrolizin-7a(5H)-yl)methanol At 0 °C, LiAlH4 (2.5 M, 0.23 mL, 0.6 mmol) was added to a solution of methyl (2R)-2-fluoro-2,3-dihydro-1H-pyrrolizin-7a(5H)-carboxylate (0.11 g, 0.6 mmol) in THF (5 mL). The mixture was degassed by purging with nitrogen and stirred at 0 °C for 20 min. The reaction was quenched by adding Na2SO4·10H2O after TLC indicated completion. The resulting mixture was concentrated under vacuum to give the title product (90 mg), which was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 158.1.

[0557] Steps 6-8: Examples 204-205 were prepared in a manner similar to Example 01, by replacing (2,2-difluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol with the aforementioned ((2R)-2-fluoro-2,3-dihydro-1H-pyrrolazin-7a(5H)-yl)methanol. The compound was further separated by preparative HPLC to obtain two isomers (column: Waters Xselect C18, 19). 150 mm, 5 µm; Mobile phase A: H2O (containing 0.03% NH3-H2O), Mobile phase B: MeCN; Flow rate: 17 mL / min; Detector: UV 214 and 254 nm; Gradient: 32 to 57% B in 0–11.0 min, 57 to 90% B in 11.0–11.2 min.

[0558] Example 204 (First Elution): 1 H NMR (400 MHz, CD3OD) δ 6.66 (s, 1H), 6.48 –3.29 (m, 1H), 5.94 (d, J = 5.8 Hz, 1H), 5.82 (d, J = 5.8 Hz, 1H), 5.24 (d, J= 52.9 Hz, 1H), 4.84 – 4.79 (m, 1H), 4.46 (d, J = 10.3 Hz, 1H), 4.38 – 4.19(m, 3H), 4.07 (s, 1H), 3.92 (d, J = 16.1 Hz, 1H), 3.76 – 3.56 (m, 2H), 3.55 –3.36 (m, 2H), 2.84 – 2.66 (m, 1H), 2.46 – 2.32 (m, 4H), 2.21 – 1.72 (m, 8H). MS (ESI, m / e) [M+1] +630.5.

[0559] Example 205 (Second Elution): 1 H NMR (400 MHz, CD3OD) δ 6.66 (s, 1H), 6.49 –6.31 (m, 1H), 5.85 – 5.75 (m, 2H), 5.27 (d, J = 54.0 Hz, 1H), 4.81 – 4.78 (m,1H), 4.39 – 4.22 (m, 4H), 4.09 – 3.95 (m, 2H), 3.74 (d, J = 15.3 Hz, 1H), 3.66 – 3.45 (m, 2H), 3.22 – 3.19 (m, 2H), 2.40 (s, 3H), 2.30 – 2.17 (m, 2H),2.11 – 1.71 (m, 7H). MS (ESI, m / e) [M+1] + 630.5.

[0560] The following Examples 206-217 were prepared in a similar manner to Examples 200-201 and 204-205.

[0561] Examples 218-222: The following examples were prepared in a similar manner to those in Example 142, by replacing the corresponding substitutes or coupling agents.

[0562] Example 223: 3-((6aR,7S,10R)-1-fluoro-13-((S)-1-((1S,2S,5R)-3-methyl-3-azabicyclo[3.1.0]hex-2-yl)ethoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cycloheptano[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline Synthetic pathway Step 1: (1S,2S,5R)-2-(methoxy(methyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester At room temperature, HATU (4.4 g, 11.5 mmol) was added to a solution of (1S,2S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2.0 g, 8.81 mmol), N,O-dimethylhydroxylamine hydrochloride (1.1 g, 11.4 mmol), and DIPEA (2.8 g, 22.0 mmol) in DCM (20 mL). The resulting mixture was stirred for 2 hours and then concentrated under vacuum. The residue was purified by column chromatography (eluting with PE / EA = 3 / 1) to give the title product (1.8 g, 76% yield) as a pale yellow solid. MS (ESI, m / e) [M+23] + 293.5.

[0563] Step 2: (1S,2S,5R)-2-acetyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester At 0 °C, CH3MgBr (6.7 mL, 20.0 mmol) was added to a solution of (1S,2S,5R)-2-(methoxy(methyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.8 g, 6.67 mmol) in THF and stirred for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (eluting with PE / EA = 5 / 1) to give the title product (1.2 g, 79% yield) as a colorless oil. MS (ESI, m / e) [M+23] + 248.5.

[0564] Step 3: (1S,2S,5R)-2-((R)-1-hydroxyethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester At -10 °C, B₂H₆ (3.43 mL, 3.43 mmol, 1 M THF solution) was added to a solution of (R)-methyloxazolarane (170 mg, 0.53 mmol) in THF (10 mL). The resulting mixture was stirred for 1 hour, followed by the addition of (1S,2S,5R)-2-acetyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (600 mg, 2.64 mmol). The resulting mixture was stirred at -10 °C for 1 hour. The reaction was then quenched by the addition of MeOH. The crude product was concentrated under vacuum and purified by column chromatography (eluting with DCM / MeOH = 20 / 1) to give the title compound (600 mg, 99% yield) as a colorless oil. MS (ESI, m / e) [M+23] + 250.5.

[0565] Step 4: (R)-1-((1S,2S,5R)-3-methyl-3-azabicyclo[3.1.0]hex-2-yl)ethanol-1-ol At room temperature, LiAlH4 (200 mg, 5.28 mmol) was added to a solution of (1S,2S,5R)-2-((R)-1-hydroxyethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (600 mg, 2.64 mmol) in THF (10 mL). The resulting mixture was heated to reflux and stirred for 5 hours. The reaction mixture was cooled to room temperature, and then Na2SO4·10H2O was added. The resulting mixture was filtered. The filtrate was concentrated under vacuum to give the title compound (280 mg, 75% yield) as a colorless oil, which was used directly in the next step without further purification. MS (ESI, m / e) [M+1]+ 142.5.

[0566] Steps 5-7: Example 223 was prepared in a manner similar to Example 01, by replacing (2,2-difluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol with (R)-1-((1S,2S,5R)-3-methyl-3-azabicyclo[3.1.0]hex-2-yl)ethanol-1-ol. The title product was subjected to preparative HPLC (column: Xselect C18, 19). 150 mm, 5 µm; Mobile phase A: H2O (0.1% FA), Mobile phase B: MeCN (0.1% FA); Flow rate: 17 mL / min; Room temperature; Detector: UV 214 and 254 nm; Gradient: 13% to 23% B in 11 min, 23% to 90% B in 0.2 min, 90% B held for 2 min, 90% to 13% B in 0.3 min, 13% B held for 1.5 min) purification.1 H NMR (500 MHz, CD3OD) 6.68 (s, 1H), 6.44-6.40 (m, 1H), 5.40-5.37 (m, 1H), 4.35-4.08 (m, 4H), 3.72-3.63 (m, 2H), 3.09-3.08 (m, 1H), 2.64-2.62 (m, 1H), 2.49-2.42 (m, 6H), 2.10-1.86 (m, 5H), 1.61-1.29 (m, 7H), 0.90-0.77 (m,2H), 0.31-0.27 (m, 1H). MS (ESI, m / e) [M+H] + 614.5.

[0567] Examples 224-225: The following examples were prepared in a manner similar to that in Example 223.

[0568] Example 226: 3-((6aR,7S,10R)-1-fluoro-13-((S)-1-((S)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidine-2-yl)ethoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cycloheptano[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline Synthetic pathway Step 1: (S)-1-((S)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidine-2-yl)ethanol-1-ol At room temperature, tetrahydro-4H-pyran-4-one (199 mg, 1.99 mmol) was added to a solution of (S)-1-((S)-pyrrolidone-2-yl)ethanol-1-ol hydrochloride (100 mg, 0.662 mmol) in DCE (3 mL). The resulting mixture was stirred at room temperature for 30 min. STAB (421 mg, 1.99 mmol) was added to the mixture at room temperature. The resulting mixture was stirred at room temperature for 16 h. The mixture was quenched with saturated Na2CO3 solution (3 mL) at 0 °C and extracted with DCM (5 mL × 3). The combined extracts were dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM / MeOH = 10:1) to give the title product (86 mg, 65%). MS (ESI, m / e) [M+1] + 200.2.

[0569] Steps 2-4: Example 226 was prepared in a similar manner to Example 01 by replacing (2,2-difluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol with the above-mentioned (S)-1-((S)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidine-2-yl)ethanol-1-ol. 1 H NMR (500 MHz, CD3OD) δ 6.68 (s, 1H), 6.43 (d, J = 29.5 Hz, 1H),5.32-5.26 (m, 1H), 4.44 – 4.17 (m, 3H), 4.13-3.85 (m, 4H), 3.68 (s, 1H),3.63-3.51 (m, 1H), 3.44-3.30 (m, 3H), 2.95 (s, 2H), 2.65 (s, 1H), 2.42 (d, J =1.9 Hz, 3H), 2.15-1.95 (m, 3H), 1.92-1.70 (m, 9H), 1.68-1.52 (m, 2H), 1.38(d, J = 6.1 Hz, 3H). MS (ESI, m / e) [M+1] + 672.5.

[0570] Examples 227-230: The following examples were prepared in a similar manner to those in Example 226, by replacing the corresponding substitutes or coupling agents.

[0571] Example 231: 3-((6aR,7S,10R)-13-((S)-1-((S)-1-allylpyrrolidine-2-yl)ethoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cycloheptano[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline Synthetic pathway Step 1: (S)-1-((S)-1-allylpyrrolidone-2-yl)ethanol K₂CO₃ (274 mg, 1.99 mmol) was added to a solution of (S)-1-((S)-pyrrolidone-2-yl)ethylene-1-ol hydrochloride (100 mg, 0.66 mmol) and 3-bromoprop-1-ene (79 mg, 0.66 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with ethyl acetate (20 mL) and washed with H₂O (3 × 20 mL) and brine (20 mL). The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by silica gel column chromatography (CH₂Cl₂ / MeOH = 9:1) to give the title product (70 mg, 68% yield) as a white oil. MS (ESI, m / e) [M+1] + 156.

[0572] Step 2: (6aR,7S,10R)-2-(5-((tert-butoxycarbonyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-13-(methylthio)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, at 25°C, Pd(dtbpf)Cl2 (16 mg, 0.025 mmol) and K3PO4 (159 mg, 0.75 mmol) were added to a solution of (6aR,7S,10R)-2-chloro-1-fluoro-13-(methylthio)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentazaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (120 mg, 0.25 mmol) and (5-((tert-butoxycarbonyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)boronic acid (159 mg, 0.5 mmol) in dioxane (2 mL) and H2O (0.4 mL). The resulting mixture was stirred at 90 °C for 2 hours. Then, the mixture was diluted with ethyl acetate (20 mL) and washed with H₂O (20 mL) and brine (20 mL). The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by silica gel column chromatography (DCM / MeOH = 9:1) to give the title product (90 mg, 50% yield) as a yellow solid. MS (ESI, m / e) [M+1] + 721.

[0573] Step 3: (6aR,7S,10R)-2-(5-((tert-butoxycarbonyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-13-(methanesulfonyl)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, at room temperature, RuCl3 (2.58 mg, 0.0125 mmol) and NaIO4 (81 mg, 0.375 mmol) were added to a solution of (6aR,7S,10R)-2-(5-((tert-butyloxycarbonyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-13-(methylthio)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (90 mg, 0.125 mmol) in THF (2 mL) and H2O (0.5 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (20 mL) and washed with H₂O (20 mL) and brine (20 mL). The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by preparative TLC (DCM / MeOH = 10:1) to give the title product (65 mg, 69% yield) as a pale yellow solid. MS (ESI, m / e) [M+1]+ 753.

[0574] Step 4: (6aR,7S,10R)-13-((S)-1-((S)-1-allylpyrrolidine-2-yl)ethoxy)-2-(5-((tert-butoxycarbonyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, at room temperature, a THF solution of LiHMDS (0.09 mL, 1 M, 0.09 mmol) was added dropwise to a solution of (S)-1-((S)-1-allylpyrrolidone-2-yl)ethanol-1-ol (14.4 mg, 0.09 mmol) and 4A molecular sieve (50 mg) in THF (2 mL). The resulting mixture was stirred at room temperature for 0.5 hours, and then (6aR,7S,10R)-2-(5-((tert-butoxycarbonyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-13-(methanesulfonyl)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (35 mg, 0.047 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (10 mL) and washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative TLC (DCM / MeOH = 10:1) to obtain the title product (5 mg, 13% yield) as a pale yellow solid. MS (ESI, m / e) [M+1]+ 828.

[0575] Step 4: 3-((6aR,7S,10R)-13-((S)-1-((S)-1-allylpyrrolidine-2-yl)ethoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cycloheptano[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline At room temperature, TFA (0.2 mL) was added to a solution of (6aR,7S,10R)-13-((S)-1-((S)-1-allylpyrrolidone-2-yl)ethoxy)-2-(5-((tert-butoxycarbonyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester (5 mg, 0.006 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The crude product was passed through a preparative HPLC (column: Waters SunFire C18, 19). 150 mm, 5 µm; Mobile phase A: H2O (0.1% FA), Mobile phase B: MeCN (0.1% FA); Flow rate: 17 mL / min; Room temperature; Detector: UV 214 and 254 nm; Gradient: 12% to 28% B over 11 min, 28% to 90% B over 0.2 min, 90% B for 2 min, 90% to 12% B over 0.3 min, 12% B for 1.5 min) purification, yielding the title product (0.42 mg, 11% yield) as a white solid. MS (ESI, m / e) [M+1] + 628. 1H NMR (500 MHz, MeOD) δ6.69 (s, 1H), 6.44 (d, J = 24.4 Hz, 1H), 5.95-5.88 (m, 1H), 5.42 – 5.22 (m,3H), 4.58 (s, 1H), 3.6-4.4 (m, 8H), 3.34 (s, 2H), 3.24 – 3.18 (m, 1H), 2.42(d, J = 1.9 Hz, 3H), 2.25-1.75 (m, 10H), 1.44 (d, J = 6.2 Hz, 3H).

[0576] Examples 232-235 below were prepared in a manner similar to Examples 126-129 by replacing (5-methoxy-1,3-dimethylpiperidin-3-yl)methanol with the corresponding alkyl alcohols in the form of a mixture of isomers, followed by further separation by chiral preparative HPLC (column: i-Cellulose-5, 21.2 mm × 250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: EtOH (MeOH containing 0.2% 2M NH3); flow rate: 18 mL / min; temperature: 25 °C; gradient: 50% B over 18 minutes).

[0577] Examples 236 and 237: 3-((6aR,7S,10R)-1-fluoro-13-(((E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cycloheptano[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline Synthetic pathway Step 1: 3-Methyl-4-oxopiperidin-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-methyl ester Iodomethane (56.7 g, 400.0 mmol) was added to a mixture of 3-methyl-4-oxopiperidinium-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-methyl ester (25.7 g, 100.0 mmol), K₂CO₃ (41.37 g, 300 mmol) in acetonitrile (500 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated NH₄Cl (200 mL) and extracted with DCM (150 mL × 3). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography, eluting with 0–30% EA in PE, to give the title product (24.4 g, 90 mmol). MS (ESI, m / e) [M+1] + 272.1.

[0578] Step 2: (E)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-methyl ester At -78 °C, t-BuOK (1 M, 27.64 mL) was added to a solution of tetrafluoroborate (fluoromethyl)triphenylphosphine (10.56 g, 27.64 mmol) in THF (100 mL). The resulting mixture was stirred at -78 °C for 1 hour, followed by the addition of 3-methyl-4-oxopiperidinium-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-methyl ester (5.0 g, 18.4 mmol). The reaction mixture was stirred at room temperature for 16 hours, then quenched with saturated NH4Cl (200 mL) and extracted with DCM (150 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography, eluting with 0–30% EA in PE to give the title product (3.2 g). MS (ESI, m / e) [M+1] + 288.1.

[0579] Step 3: (E)-(4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol At room temperature, LiAlH4 (304 mg, 8 mmol) was added to a mixture of (E)-4-(fluoromethylene)-3-methylpiperidin-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-methyl ester (1.15 g, 4 mmol) in THF (50 mL). The resulting mixture was stirred at 65 °C for 16 hours. The reaction was then quenched with sodium sulfate decahydrate, filtered, and concentrated to give a crude product (1.0 g), which was used directly in the next step without further purification. MS (ESI, m / e) [M+1] + 174.1.

[0580] Steps 4-6: Examples 236 and 237 were prepared in a manner similar to Example 01, by replacing (2,2-difluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol with the aforementioned (E)-(4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol. The compounds were further separated by chiral preparative HPLC (column: i-Cellulose-5, 21.2 mm × 250 mm, 5 μm; mobile phase A: n-hexane; mobile phase B: EtOH (MeOH containing 0.2% 2M NH3); flow rate: 18 mL / min; room temperature; gradient: 40% B over 18 minutes) to obtain two isomers: Example 236 (First Elution): 1 H NMR (500 MHz, CD3OD) δ 6.75-6.58 (m, 2H), 6.47-6.41 (m, 1H), 4.60-4.10 (m, 7H), 3.71-3.57 (m, 2H), 2.88-2.67 (m, 3H), 2.42(s, 3H), 2.27-2.23 (m, 4H), 2.10-1.75 (m, 8H), 1.21(s, 3H). [M+H] + 646.5.

[0581] Example 237 (Second Elution): 1 H NMR (500 MHz, CD3OD) δ 6.74-6.57 (m, 2H), 6.47-6.41 (m, 1H), 4.54-4.10 (m, 7H), 3.71-3.58 (m, 2H), 2.90-2.67 (m, 3H), 2.42(s, 3H), 2.27-2.23 (m, 4H), 2.09-1.75 (m, 8H), 1.21(s, 3H). [M+H] + 646.5.

[0582] Examples 238 and 239: 3-((6aR,7S,10R)-13-(((E)-1-(cyclopropylmethyl)-4-(fluoromethylene)-3-methylpiperidin-3-yl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cycloheptano[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline Synthetic pathway Step 1: (E)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylic acid methyl ester At room temperature, a solution of dioxane in HCl (4 M, 2 mL) was added to a solution of (E)-4-(fluoromethylene)-3-methylpiperidin-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-methyl ester (287 mg, 1.0 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under vacuum to give a crude product (250 mg), which was used directly in the next step without further purification. MS (ESI, m / e) [M+1] + 188.1.

[0583] Step 2: (E)-1-(cyclopropylmethyl)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylic acid methyl ester At room temperature, cyclopropaneformaldehyde (140 mg, 2 mmol) and sodium triacetoxyborohydride (423.9 mg, 2 mmol) were added to a mixture of (E)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylate (250 mg crude) in DCM (5 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then quenched with saturated Na₂HCO₃ (20 mL) and extracted with DCM (15 mL × 3). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude residue. The crude product was purified by silica gel column chromatography, eluting with 0–40% EA in PE to give the title product (200 mg, 0.83 mmol). MS (ESI, m / e) [M+1] + 242.1.

[0584] Step 3: (E)-(1-(cyclopropylmethyl)-4-(fluoromethylene)-3-methylpiperidin-3-yl)methanol At room temperature, LiAlH4 (38 mg, 1 mmol) was added to a solution of (E)-1-(cyclopropylmethyl)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylate (200 mg, 0.83 mmol) in THF (5 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then quenched with sodium sulfate decahydrate, filtered, and concentrated to give a crude product (120 mg), which was used directly in the next step without further purification. MS (ESI, m / e) [M+1] + 214.2.

[0585] Steps 4-6: Examples 238 and 239 were prepared in a manner similar to Example 01, by replacing (2,2-difluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol with the aforementioned (E)-(1-(cyclopropylmethyl)-4-(fluoromethylene)-3-methylpiperidin-3-yl)methanol. The compounds were further separated by chiral preparative HPLC (column: i-Cellulose-5, 21.2 mm × 250 mm, 5 μm; mobile phase A: n-hexane; mobile phase B: EtOH (MeOH containing 0.2% 2M NH3); flow rate: 18 mL / min; room temperature; gradient: 40% B over 18 minutes) to obtain two isomers: Example 238 (First Elution): 1 H NMR (500 MHz, CD3OD) δ 6.74-6.57 (m, 2H), 6.42-6.41 (m, 1H), 4.56-4.08 (m, 7H), 3.73-3.59 (m, 2H), 3.11-2.68 (m, 2H), 2.42(s, 3H), 2.27-1.81 (m, 12H), 1.22-1.15 (m,4H), 0.90-0.47 (m, 4H). [M+H] + 686.5.

[0586] Example 239 (Second Elution): 1 H NMR (500 MHz, CD3OD) δ 6.72-6.55 (m, 2H), 6.42-6.41 (m, 1H), 4.56-4.08 (m, 7H), 3.70-3.59 (m, 2H), 3.09-2.67 (m, 2H), 2.42(s, 3H), 2.24-1.81 (m, 12H), 1.22-1.15 (m,4H), 0.90-0.45 (m, 4H). [M+H] + 686.5.

[0587] Examples 240 and 241: 3-((6aR,7S,10R)-13-((4-(difluoromethyl)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cycloheptano[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline Synthetic pathway Step 1: 3-methyl 1-(tert-butyl) 4-(difluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid ester At -78 °C, t-BuOK (1 M, 33.17 mL) was added to a mixture of 2-((difluoromethyl)sulfonyl)pyridine (5.34 g, 27.65 mmol) and 3-methyl-4-oxopiperidinium-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-methyl ester (5.0 g, 18.43 mmol) in DMF (50 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated NH4Cl (200 mL) and extracted with DCM (150 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give a crude residue. The crude product was purified by silica gel column chromatography, eluting with 0–30% EA in PE to give the title product (1.2 g, 3.9 mmol). MS (ESI, m / e) [M+1] + 306.1.

[0588] Step 2: 3-methyl 1-(tert-butyl) 4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylic acid ester Pd / C (200 mg, 10% w / w) was added to a mixture of 1-(tert-butyl)-3-methyl 4-(difluoromethylene)-3-methylpiperidin-1,3-dicarboxylic acid ester (1.2 g, 3.9 mmol) in MeOH (5 mL). The resulting mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction mixture was then filtered and concentrated to give a crude residue. The residue was purified by silica gel column chromatography, eluting with 0–40% EA in PE, to give the title product (1.0 g, 3.3 mmol). MS (ESI, m / e) [M+1] + 308.2.

[0589] Step 3: (4-(difluoromethyl)-3-methyl-1-(methyl-d3)piperidin-3-yl)methyl-d2-ol At room temperature, LiAlD4 (76 mg, 2 mmol) was added to a solution of 3-methyl 1-(tert-butyl) 4-(difluoromethyl)-3-methylpiperidin-1,3-dicarboxylic acid (300 mg, X mmol) in THF (15 mL). The resulting mixture was stirred at 60 °C for 1 hour. The reaction mixture was cooled to room temperature, quenched with sodium sulfate decahydrate, filtered, and concentrated to give a crude product (200 mg), which was used directly in the next step without further purification. MS (ESI, m / e) [M+1] + 199.2.

[0590] Steps 4-6: Examples 240 and 241 were prepared in a manner similar to Example 01, by replacing (2,2-difluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol with the aforementioned (4-(difluoromethyl)-3-methyl-1-(methyl-d3)piperidin-3-yl)methanol-d2-ol. The compounds were further separated by chiral preparative HPLC (column: i-Cellulose-5, 21.2 mm × 250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: EtOH (MeOH containing 0.2% 2M NH3); flow rate: 18 mL / min; temperature: room temperature; gradient: 40% B over 12 minutes) to obtain two 3,4-trans isomers: Example 240 (First Elution): 1 H NMR (500 MHz, CD3OD) δ 6.69 (s, 1H), 6.43-6.41(m, 1H), 6.33-6.11 (m, 1H), 4.27-4.10 (m, 5H), 3.77-3.63 (m, 2H), 3.16-3.05(m, 2H), 2.42 (s, 3H), 2.20-1.81 (m, 11H), 1.23 (s, 3H). [M+H] + 671.5.

[0591] Example 241 (Second Elution): 1H NMR (500 MHz, CD3OD) δ 6.69 (s, 1H), 6.46-6.43(m, 1H), 6.34-6.11 (m, 1H), 4.38-4.10 (m, 5H), 3.71-3.59 (m, 2H), 3.16-3.05(m, 2H), 2.42 (s, 3H), 2.20-1.85 (m, 11H), 1.22 (s, 3H). [M+H] + 671.5.

[0592] Examples 242-247: The following examples were prepared in a manner similar to that in Examples 236-241.

[0593] Examples 248 and 249: 3-((6aR,7S,10R)-13-(((R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-1-fluoro-5-methyl-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline Synthetic pathway Step 1: (1R,2R,5S)-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylic acid 3-benzyl ester 8-(tert-butyl) ester At room temperature, methyl chloroformate (1.87 g, 11 mmol) was added to a mixture of (1R,2R,5S)-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.56 g, 10 mmol) and NaHCO3 (2.52 g, 30 mmol) in a mixed solvent of THF / H2O (8:2, 30 mL), and the mixture was stirred for 16 hours. The mixture was diluted with EA (100 mL), washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by rapid column chromatography to give the title product (3.59 g, 92%), which was used directly in the next step without further purification. MS (ESI, m / e) [M+23] + 413.2.

[0594] Step 2: (1R,2R,5S)-2-(2-oxoethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylic acid 3-benzyl ester 8-(tert-butyl) ester At room temperature, DMP (5.10 g, 12.0 mmol) was added to a solution of (1R,2R,5S)-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylic acid 3-benzyl ester 8-(tert-butyl) ester (3.59 g, 9.2 mmol) in CH2Cl2 (40 mL). The resulting mixture was stirred for 16 hours. The mixture was diluted with CH2Cl2 (100 mL), washed with NaHCO3 (50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by rapid column chromatography to give the title product (2.64 g, 74%). MS (ESI, m / e) [M+1] + 389.3.

[0595] Step 3: (1R,2R,5S)-2-(2-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylic acid 3-benzyl ester 8-(tert-butyl) ester Under a nitrogen atmosphere, at 0 °C, MeMgBr (3.0 M, 4.2 mL, 12.6 mmol) was added dropwise to a solution of (1R,2R,5S)-2-(2-oxoethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylic acid 3-benzyl ester 8-(tert-butyl) ester (2.5 g, 6.44 mmol) in THF (50 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (50 mL × 3). The combined extracts were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography to give the title product (720 mg, 28%). MS (ESI, m / e) [M+23] + 427.3.

[0596] Step 4: (1R,2R,5S)-2-(2-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, a mixture of (1R,2R,5S)-2-(2-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylic acid 3-benzyl ester 8-(tert-butyl) ester (700 mg, 1.73 mmol) and Pd / C (200 mg, 5% wet) in isopropanol (20 mL) was stirred for 16 hours at room temperature. The mixture was then filtered and concentrated under vacuum to give the title product (480 mg, 100%), which was used directly in the next step without further purification. MS (ESI, m / e) [M+1] + 271.2.

[0597] Step 5: (1S,2R,5R)-2-(2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyridino[4,3-d]pyrimidin-5-yl)oxy)propyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester To a mixture of (1R,2R,5S)-2-(2-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (450 mg, 1.67 mmol) and 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (470 mg, 1.67 mmol) in THF (20 mL), NaH (333 mg, 8.33 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was then quenched by adding a saturated aqueous solution of ammonium chloride (20 mL). The resulting mixture was extracted with EtOAc (20 mL × 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude title product (851 g), which was used directly in the next step without further purification. MS (ESI, m / e) [M+1] + 514.2.

[0598] Step 6: (6aR,7S,10R)-2-chloro-1-fluoro-5-methyl-13-(methylthio)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester To a solution of (1S,2R,5R)-2-(2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)propyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (800 mg, 1.56 mmol) in MeCN (220 mL), DIPEA (402 mg, 3.12 mmol) and BOP-Cl (515 mg, 2.03 mmol) were added. The resulting mixture was stirred at 70 °C for 1 hour. The mixture was diluted with EA (30 mL), washed with brine (15 mL × 2), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give the title product (720 mg, 93%). MS (ESI, m / e) [M+1] + 496.3.

[0599] Step 7: (6aR,7S,10R)-2-chloro-1-fluoro-5-methyl-13-(methanesulfonyl)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylic acid tert-butyl ester At 0 °C, tert-butyl (720 mg, 1.45 mmol) of (6aR,7S,10R)-2-chloro-1-fluoro-5-methyl-13-(methylthio)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentazaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid was added to a solution of (6aR,7S,10R)-2-chloro-1-fluoro-5-methyl-13-(methylthio)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylic acid in a mixed solvent THF / H2O (4:1, 40 mL). The resulting mixture was stirred at 0 °C for 1 hour. The mixture was then diluted with water (20 mL) and extracted with EA (20 mL × 2). The combined organic phases were dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography to obtain the title product (620 mg, 81%). MS (ESI, m / e) [M+1] + 528.2.

[0600] Steps 8-10: Examples 248 and 249 were prepared in a similar manner to Example 45, by replacing the corresponding coupling complexes. The mixture of methyl isomers was further separated by preparative TLC (CH2Cl2 / MeOH (containing NH3) = 8:1) to obtain the first eluting isomer (8 mg, 28%) as Example 248 and the second eluting isomer (3 mg, 10%) as Example 249. Example 248: 1 H NMR (400 MHz, CD3OD) δ 6.68 (s, 1H), 6.42 (d, J = 59.6 Hz,1H), 4.67 – 4.51 (m, 2H), 4.50 – 4.37 (m, 1H), 4.35 – 4.16 (m, 1H), 3.99 –3.39 (m, 3H), 3.29 – 3.16 (m, 1H), 2.96 – 2.79 (m, 1H), 2.54 – 2.45 (m, 1H), 2.44 – 2.16 (m, 9H), 2.11 – 1.57 (m, 6H), 1.54 – 1.24 (m, 5H). MS (ESI, m / e)[M+1] + 652.5.

[0601] Example 249: 1 H NMR (400 MHz, CD3OD) δ 6.69 (s, 1H), 6.42 (d, J = 51.6 Hz,1H), 4.84 – 4.49 (m, 3H), 4.28 – 3.76 (m, 2H), 3.74 – 3.61 (m, 1H), 3.29 –3.19 (m, 2H), 3.07 – 2.88 (m, 1H), 2.71 – 2.50 (m, 1H), 2.52 – 2.26 (m, 6H), 2.25 – 1.96 (m, 2H), 1.94 – 1.64 (m, 3H), 1.64 – 1.20 (m, 8H), 0.96 – 0.81(m, 1H). MS (ESI, m / e) [M+1] + 652.5.

[0602] Example 250: 3-((6aR,7S,10R)-1-fluoro-13-((S)-1-((S)-1-(2-fluoroethyl)pyrrolidine-2-yl)ethoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methylbridged cycloheptano[4,5]cyclooctano[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline Synthetic pathway Step 1: (S)-1-((S)-1-(2-fluoroethyl)pyrrolidine-2-yl)ethanol-1-ol At room temperature, 1-bromo-2-fluoroethane (70 mg, 0.56 mmol) and K₂CO₃ (190 mg, 1.38 mmol) were added to a solution of (S)-1-((S)-pyrrolidone-2-yl)ethanol-1-ol hydrochloride (70 mg, 0.46 mmol) in DMF (2 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (20 mL) and washed with H₂O (20 mL × 3) and brine (20 mL). The organic phase was dried over Na₂SO₄ and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10:1) to give the title product (20 mg). MS (ESI, m / e) [M+1] + 162.3.

[0603] Steps 2-4: Example 250 was prepared in a similar manner to Example 01 by replacing (2,2-difluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol with the above-mentioned (S)-1-((S)-1-(2-fluoroethyl)pyrrolidine-2-yl)ethanol-1-ol. 1 H NMR (500 MHz, CD3OD) δ 6.69 (s, 1H), 6.46-6.41 (m, 1H), 5.31-5.27 (m, 1H), 4.58-4.50 (m, 6H), 4.50-4.41 (m, 1H), 4.38-4.21 (m, 2H), 4.19-3.98 (m, 2H), 3.92-3.66 (m, 3H), 3.10-2.75 (m, 1H), 2.42-2.38 (m, 3H), 2.30 – 2.06 (m, 2H), 2.04 – 1.73 (m, 7H), 1.39 (d, J= 6.3 Hz, 3H). MS (ESI, m / e) [M+1] + 634.5.

[0604] Measurement KRAS WT and KRAS G12D probe displacement assay This assay was used to identify compounds that bind to GDP-loaded KRAS protein and are capable of displacing biotinylated probes occupying the KRAS binding site. GST-labeled GDP-loaded WT KRAS (amino acids 1-188) and GST-labeled GDP-loaded KRAS G12D (amino acids 1-188) were expressed in *E. coli* and purified in vitro. All proteins and reaction solutions were prepared in assay buffer containing 50 mM HEPES (pH 7.5), 50 mM NaCl, 1 mM MgCl2, 1 mM TCEP, 0.01% BSA, and 0.008% Brij-35. The purified WT KRAS (3 nM final concentration) or KRAS G12D protein (0.5 nM final concentration) was incubated with 3-fold serial dilutions of the compound in assay plates (384-well microplates, black, Corning). The plates were incubated at 24°C for 1 hour. After incubation, biotinylated probe 1 (60 nM final assay concentration) for WT KRAS and biotinylated probe 2 (4 nM final assay concentration) for KRAS G12D were added to the assay plate, respectively. After incubation at 24°C for 1 hour, Mab anti-GST-Tb cavitation compound (Cisbio) and streptavidin-XL665 (Cisbio) were added, and incubation was continued at 24°C for another hour. TR-FRET signals (ex 337 nm, em 665 nm / 620 nm) were read on a BMG PHERAstar FSX instrument. The percentage of KRAS protein inhibition by biotinylated probe binding in the presence of increasing concentrations of the compounds was calculated based on the ratio of fluorescence at 665 nm to fluorescence at 620 nm. The IC50 of each compound was calculated by fitting the data to a four-parameter logistic model using Dotmatics. 50 value.

[0605] The synthetic routes for probes 1 and 2 disclosed in PCT / CN2022 / 070676 are hereby incorporated herein.

[0606] Probe 1: N-(2-(2-(3-(3-((S)-2-(((7-(8-chloronaphthyl-1-yl)-4-((S)-3-(cyanomethyl)-4-(methanesulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidine-1-yl)propoxy)propamido)ethoxy)ethyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thienro[3,4-d]imidazol-4-yl)pentanamide Synthetic pathway Step 1: (2-(2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thiopheno[3,4-d]imidazol-4-yl)pentamido)ethoxy)ethyl)tert-butyl carbamate To a solution of 5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)valeric acid (244 mg, 1 mmol) in DMF (20 mL), HATU (380 mg, 1.2 mmol), DIPEA (380 mg, 3 mmol), and tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (204 mg, 1 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The resulting solution was concentrated and purified by combi-flash (DCM / MeOH / NH3H2O ​​= 10 / 1 / 0.1) to give the title product (430 mg, 100%). MS (ESI, m / e) [M+H]+ 431.3.

[0607] Step 2: N-(2-(2-aminoethoxy)ethyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thiopheno[3,4-d]imidazol-4-yl)pentanamide To a solution of (2-(2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentamido)ethoxy)ethyl)carbamate (100 mg, 0.23 mmol) in DCM (5 mL), 4 M HCl / dioxane (2.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. The resulting solution was concentrated to give the title product (100 mg, 30%, HCl salt) as a white solid. MS (ESI, m / e) [M+H]+ 331.2.

[0608] Step 3: 3-(3-((S)-2-(((7-(8-chloronaphthyl-1-yl)-4-((S)-3-(cyanomethyl)-4-(methanesulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidine-1-yl)propoxy)methyl propionate To a solution of methyl 3-(3-((S)-2-(((7-(8-chloronaphthyl-1-yl)-4-((S)-3-(cyanomethyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidine-1-yl)propoxy)propionate (290 mg, 0.44 mmol) in DCM, DIPEA (375 mg, 2.91 mmol) and MsCl (200 mg, 1.75 mmol) were added, and the mixture was stirred at 0 °C for 1.5 hours. The resulting solution was then rinsed with saline (30 mL). 2) The solution was washed, dried over Na2SO4, concentrated, and purified by preparative TLC (DCM / MeOH / NH3H2O ​​= 10 / 1 / 0.1) to obtain the title product (130 mg, 40%). MS (ESI, m / e) [M / 2+H]+ 740.4.

[0609] Step 4: 3-(3-((S)-2-(((7-(8-chloronaphthyl-1-yl)-4-((S)-3-(cyanomethyl)-4-(methanesulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidine-1-yl)propoxy)propionic acid To a solution of methyl 3-(3-((S)-2-(((7-(8-chloronaphthyl-1-yl)-4-((S)-3-(cyanomethyl)-4-(methanesulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidine-1-yl)propoxy)propionate (130 mg, 0.18 mmol) in methanol (5 mL), THF (5 mL) and LiOH / H2O (1 M, 2.5 mL) were added, and the mixture was stirred at room temperature for 0.5 h. The solution was then neutralized to pH 5–6 with HCl / H2O (1 M), the solution was evaporated, dissolved in DCM (10 mL), the solid was filtered off, and the filtrate was concentrated to give the title product (127 mg, 99%). MS (ESI, m / e) [M+H]+ 726.4.

[0610] Step 5: N-(2-(2-(3-(3-((S)-2-(((7-(8-chloronaphthyl-1-yl)-4-((S)-3-(cyanomethyl)-4-(methanesulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidine-1-yl)propoxy)propamido)ethoxy)ethyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thiopheno[3,4-d]imidazol-4-yl)pentanamide Add DCM (10 mL) and DMF (5 mL) to a mixture of 3-(3-((S)-2-(((7-(8-chloronaphthyl-1-yl)-4-((S)-3-(cyanomethyl)-4-(methanesulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidine-1-yl)propoxy)propionic acid (100 mg, 0.14 mmol), N-(2-(2-aminoethoxy)ethyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide hydrochloride (46 mg, 0.14 mmol) and HATU (79 mg, 0.21 mmol), followed by DPEA (225 mg, 1.74 mmol). The solution was stirred at room temperature for 1.5 hours (mmol). The resulting solution was washed with water (20 mL each time, 3 times) and dried over Na2SO4. The solution was concentrated and purified by preparative HPLC to give the title product (5.92 mg, 4%) in the form of FA salt. 1 H NMR (500 MHz, CD3OD) δ8.35 (bs, 2H), 7.84-7.83 (m, 1H), 7.70-7.68 (m, 1H), 7.554-7.48 (m,2H), 7.40-7.31 (m, 2H), 4.74-4.70 (m, 2H), 4.50-4.39 (m, 2H), 4.37-4.31 (m,1H), 4.28-4.16 (m, 2H), 4.06-4.04 (m, 1H), 3.96-3.90 (m, 1H), 3.82-3.56 (m,10H), 3.52- 3.42 (m, 5H), 3.38-23.33 (m, 2H), 3.28-3.11 (m, 7H), 3.10-3.04(m, 4H), 2.96-2.95 (m, 1H), 2.91-2.88 (m, 1H), 2.76-2.65 (m, 2H), 2.49-2.29(m, 3H), 2.25-2.09 (m, 4H), 2.09-1.92 (m, 4H), 1.77-1.49 (m, 4H), 1.44-1.38 (m, 2H). MS (ESI, m / e) [M / 2+H] + 520.0.

[0611] Probe 2: N-(2-(2-(3-(3-(4-(3-((7-(2-amino-7-fluorobenzo[d]thiazolyl-4-yl)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)oxy)propyl)piperazin-1-yl)propoxy)propamido)ethoxy)ethyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thienro[3,4-d]imidazol-4-yl)pentanamide Synthetic pathway Step 1: 4-(7-(2-amino-7-fluorobenzo[d]thiazolyl-4-yl)-2-(3-(4-(3-(3-(tert-butoxy)-3-oxopropoxy)propyl)piperazin-1-yl)propoxy)-6-chloro-8-fluoroquinazoline-4-yl)piperazin-1-carboxylic acid methyl ester To a mixture of 4-(7-(2-amino-7-fluorobenzo[d]thiazolyl-4-yl)-6-chloro-8-fluoro-2-(3-(piperazin-1-yl)propoxy)quinazolin-4-yl)piperazin-1-carboxylic acid methyl ester (1 g, 1.4 mmol) in CH3CN (100 mL), DIPEA (300 mg, 2.3 mmol) and NaHB(AcO)3 (600 mg, 2.8 mmol) were added, and the mixture was stirred at room temperature for 17 hours. The resulting mixture was filtered through diatomaceous earth, the filtrate was concentrated, and purified by combi-flash (DCM / MeOH / NH3H2O ​​= 10 / 1 / 0.1) to give the title product (800 mg, 64%). MS (ESI, m / e) [M+H] + 895.7 Step 2: 3-(3-(4-(3-((7-(2-amino-7-fluorobenzo[d]thiazolyl-4-yl)-4-(4-(((benzoxy)carbonyl)piperazin-1-yl)-6-chloro-8-fluoroquinazolin-2-yl)oxy)propyl)piperazin-1-yl)propoxy)propionic acid TFA (10 mL) was added to a solution of methyl 4-(7-(2-amino-7-fluorobenzo[d]thiazo-4-yl)-2-(3-(4-(3-(3-(tert-butoxy)-3-oxopropoxy)propyl)piperazin-1-yl)propoxy)-6-chloro-8-fluoroquinazoline-4-yl)piperazin-1-carboxylic acid (800 mg, 0.9 mmol) in DCM (50 mL), and the mixture was stirred at room temperature for 2 hours. The resulting solution was concentrated to give the title product (1 g, crude) as a thick, brown oil, which was used directly in the next step. MS (ESI, m / e) [M+H] + 839.6 Step 3: 4-(7-(2-amino-7-fluorobenzo[d]thiazolyl-4-yl)-6-chloro-2-(3-(4-(7,15-dioxo-19-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazolyl-4-yl)-4,11-dioxa-8,14-diazanonadecanyl)piperazin-1-yl)propoxy)-8-fluoroquinazolin-4-yl)piperazin-1-carboxylic acid methyl ester Add DIPEA (92 mg, 0.72 mmol) to a solution of 3-(3-(4-(3-((7-(2-amino-7-fluorobenzo[d]thiazolyl-4-yl)-4-(4-(((benzoxy)carbonyl)piperazin-1-yl)-6-chloro-8-fluoroquinazolin-2-yl)oxy)propyl)piperazin-1-yl)propoxy)propionic acid (200 mg, 0.24 mmol), N-(2-(2-aminoethoxy)ethyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide (80 mg, 0.24 mmol) and HATU (136 mg, 0.36 mmol) in DMF (15 mL) and stir for 2 hours at room temperature. The resulting solution was concentrated and purified by preparative TLC (DCM / MeOH / NH3H2O ​​= 10 / 1 / 0.1) to give the title product (100 mg, 36%) as a brown solid. MS (ESI, m / e) [M / 2+H] + 576.5 Step 4: N-(2-(2-(3-(3-(4-(3-((7-(2-amino-7-fluorobenzo[d]thiazolyl-4-yl)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)oxy)propyl)piperazin-1-yl)propoxy)propamido)ethoxy)ethyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thienro[3,4-d]imidazol-4-yl)pentanamide To a solution of 4-(7-(2-amino-7-fluorobenzo[d]thiazolyl-4-yl)-6-chloro-2-(3-(4-(7,15-dioxo-19-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazolyl-4-yl)-4,11-dioxa-8,14-diazanonadecanyl)piperazin-1-yl)propoxy)-8-fluoroquinazolin-4-yl)piperazin-1-carboxylic acid methyl ester (90 mg, 0.08 mmol) in DCM (20 mL), TMSI (200 mg, 1 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. The resulting solution was concentrated and purified by preparative HPLC to give the title product (44 mg, 54%, FA salt) as a white solid. 1 H NMR (500 MHz, CD3OD) δ8.36 (s, 1H), 7.93 (s, 1H), 7.24-7.21 (m, 1H), 7.02-6.99 (m,1H), 4.59-4.51 (m, 2H), 4.49-4.46 (m, 1H), 4.30-4.27 (m, 1H), 4.07-4.05 (m,4H), 3.69-3.67 (m, 2H), 3.59-3.56 (m, 2H), 3.53-3.50 (m, 4H), 3.47-3.45 (m,4H), 3.38-3.33 (m, 4H), 3.20-3.06 (m, 7H), 2.93-2.78 (m, 7H), 2.70-2.66 (m,1H), 2.48-2.45 (m, 2H), 2.22-2.19 (m, 2H), 2.12-2.07 (m, 2H), 1.96-1.91 (m,2H), 1.75-1.53 ​​(m, 4H), 1.45-1.39 (m, 2H). MS (ESI, m / e) [M+H] + 1017.7.

[0612] Metabolic stability of liver microsomes in different species First, liver microsomes were mixed with NADPH to achieve final concentrations of 0.5 mg / mL and 1 mM, respectively. The test compound was added to the incubation system at a final concentration of 1 μM and incubated at 37 °C. Incubation was initiated by adding NADPH to the system. At 0, 15, 30, 45, and 60 minutes after incubation, 20 µL aliquots were removed from the incubation system. The reaction solution was stopped by adding cold acetonitrile containing the analytical standard (IS). The samples were centrifuged at 4000 rpm for 5 minutes and then analyzed on LC-MS / MS.

[0613] Peak areas at different time points were determined from extracted ion chromatograms; then, graphs were plotted to calculate metabolic stability. The slope value k was determined by linear regression of the natural logarithm of the parent drug residue percentage against incubation time. The in vitro half-life (in vitro t) was determined from the slope value. 1 / 2 ): Use the following formula to measure in vitro t 1 / 2 (in minutes) converted to in vitro intrinsic clearance rate (in vitro CL) int (Unit: µL / min / mg protein) (Average of repeated measurements): A control compound (verapamil) was included in the assay to ensure data consistency. A negative control (same experimental setup, but without NADPH in the incubation system) was used to eliminate misleading factors caused by the instability of the chemical itself.

[0614] Assay for CYP (cytochrome P450) enzyme inhibition in human liver microsomes Incubation was performed in 96-well plates. 1 μL of the working solution or mediator of the test compound was added to 179 μL of human liver microsomes containing the substrates CYP1A2 (40 μM phenacetin), 2C9 (6 μM diclofenac), 2C19 (50 μM (S)-mephenytoin), 2D6 (10 μM dextromethorphan), and 3A4 (1 μM midazolam or 50 μM testosterone). The plate was preheated in a 37°C water bath for 5 minutes, and then the reaction was initiated by adding 20 μL of 10 mM NADPH solution. The reaction was carried out in a 37°C water bath.

[0615] At the predetermined time point, the reaction was stopped by adding 300 μL of quenching solution (acetonitrile containing the internal standard) to each well. The sample plate was vortexed for 1 minute and centrifuged at 3000 g for 10 minutes. 100 μL of the supernatant was transferred to a new 96-well plate and mixed with 100 μL of water. The mixture was analyzed by LC-MS / MS, followed by data processing (i.e., determination of the percentage of inhibition at 10 μM or IC50).

[0616] Time-dependent inhibition assay (TDI) of cytochrome P450 (CYP) enzymes in human liver microsomes The TDI assay involves pre-incubating 0.1 mg·mL⁻¹ human liver microsomes with 10 uM of the test compound and a positive control at 37°C for 30 minutes in the presence or absence of 1 mM NADPH (“inactivation incubation”). After the pre-incubation period, the remaining CYP activity was determined by subsequently adding substrates (1A2, 40 μM phenacetin; CYP2B6, 50 μM bupropion; CYP2C8, 5 μM paclitaxel; CYP2C9, 6 μM diclofenac; CYP2C19, 50 μM (S)-methionine; CYP2D6, 10 μM dextromethorphan; CYP3A, 1 μM midazolam or 50 μM testosterone) and NADPH to the pre-incubation mixture. CYP1A2, 2B6, 2C19 and 2D6 were then subjected to a 20-minute "activity incubation", CYP2C8 and CYP3A (testosterone) were subjected to a 10-minute "activity incubation", CYP2C9 was subjected to a 6-minute "activity incubation", and CYP3A (midazolam) was subjected to a 5-minute "activity incubation". The reaction was terminated by adding ice-cold acetonitrile and an internal standard, followed by centrifugation for LC-MS / MS analysis.

[0617] Assay for bidirectional permeability of MDCKII-MDR1 cell monolayers First, MDCKII-MDR1 cells were prepared in cell seeding medium. 50 μL of the cultured cell suspension was added to each well of a pre-prepared Transwell plate. The plates were incubated for 4–8 days. The medium was changed every other day. The integrity of the cell monolayer was assessed by electrical impedance method before measuring permeability.

[0618] To determine the drug transport rate in the top-to-substrate direction, 125 μL of the working solution of the test compound was added to the Transwell chamber (top chamber), and 50 μL of the sample (D0 sample) was immediately transferred from the top chamber to a new 96-well plate. To determine the drug transport rate in the substrate-to-top direction, 285 μL of the working solution of the compound was added to each well of the receiving plate (substrate-side chamber), and 50 μL of the sample (D0 sample) was immediately transferred from the substrate-side chamber to a new 96-well plate. The plate was incubated at 37°C for 2 hours. At the end of the transport period, 50 μL was transferred directly from the top and substrate-side wells to a new plate. Then, 200 μL of cold acetonitrile containing internal standards (IS: 2 µM ketoprofen, 200 nM labetalol, 200 nM caffeine, and 100 nM alprazolam) was added to the plate. The plate was vortexed for 5 minutes. The sample was centrifuged at 3,220 g for 20 minutes. Take an aliquot of 100 µL of supernatant, dilute with 100 µL of ultrapure H2O, and use the mixture for LC / MS / MS analysis. All incubations were performed in duplicate. The apparent permeability (Papp, in cm / s) of the MDCKII-MDR1 drug transport assay can be calculated using the following formula: Where VA is the volume of the acceptor pore (in mL) (Ap→Bl flux is 0.235 mL and Bl→Ap flux is 0.075 mL), and Area is the surface area of ​​the membrane (0.143 cm² for Transwell-96 pore permeability support). 2 ), and time is the total transit time, in seconds.

[0619] The outflow rate can be determined using the following formula: in P app (B-A) This represents the apparent permeability coefficient in the direction from the outer edge of the substrate to the top, and P app (A-B) It represents the apparent permeability coefficient in the direction from the top to the outer side of the substrate.

[0620] The recovery rate can be determined using the following formula: Where V A V is the volume of the acceptor pore (in mL) (Ap→Bl flux is 0.235 mL and Bl→Ap flux is 0.075 mL). DThis is the volume of the donor well (in mL) (Ap→Bl flux is 0.075 mL and Bl→Ap flux is 0.235 mL).

[0621] Inherent clearance rate of hepatocytes in different species Prepare stock solutions of the 10 mM test compound and positive control using a suitable solvent (DMSO). Incubate the medium (Williams's E medium supplemented with GlutaMAX) in a 37°C water bath and heat for at least 15 minutes before use. Dilute the 10 mM test compound and positive control to 100 μM in separate conical tubes by combining 198 μL of 50% acetonitrile / 50% water with 2 μL of the 10 mM stock solution. Pipette 198 μL of cryopreserved hepatocytes (0.5 × 10⁻⁶ cells) into the solution. 6 Transfer live cells / mL to each well of a 96-well uncoated plate. Add 2 μL of 100 μM test compound or positive control to the corresponding well of the uncoated plate to initiate the reaction. The final concentration of the test or control compound is 1 μM. Return the plate to the incubator and place it on a vortex mixer. At time points of 0, 15, 30, 60, 90, and 120 minutes, remove 25 μL aliquots of the contents from each well. Then, terminate the reaction by mixing the aliquots with 6 volumes (150 μL) of cold acetonitrile containing 150 nmol (2 μM ketoprofen, 200 nM labetalol, 200 nM caffeine, and 100 nM alprazolam). Centrifuge at 3,220 g for 30 minutes. Perform LC / MS / MS analysis on 100 μL aliquots of the supernatant. Dilute the supernatant with ultrapure water according to the LC-MS signal response and peak shape. All incubations were performed in duplicate.

[0622] All calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The in vitro half-life (t) of the parent compound was determined by regression analysis of the percentage disappearance of the parent compound versus time curves. 1 / 2 ).

[0623] Determining the in vitro half-life (in vitro t) by the slope value 1 / 2 ): In vitro t 1 / 2 = 0.693 / k In vitro t 1 / 2 (minutes) converted to in vitro intrinsic clearance rate (in vitro CL) int μL / min / 10 6 (Cells) use the following formula: In vitro CL int = kV / N V = incubation volume (0.2 mL); N = number of hepatocytes per well (0.1 × 10⁻⁶). 6 (cells).

[0624] PK studies in mice and rats The pharmacokinetics of the compound administered intravenously and orally were evaluated in male CD1 mice or SD-JVC rats. For intravenous administration studies, the test compound was dissolved in DMA:30% Solutol HS 15 (w / v): physiological saline (20:20:60, v / v) and administered via tail vein at a dose of 1 mg / kg. For oral administration studies, the test compound was dissolved in 0.5% MC or 0.5% MC + 0.1% Tween-80 or 30% PEG400 / 60% Phosal 50 PG / 10% EtOH and administered to mice via tube feeding at doses of 10 mg / kg, 30 mg / kg, or 100 mg / kg. Animals were grouped and treated according to body weight. Blood samples were collected from rats at post-administration time points (5 minutes (IV only), 15 minutes, and 30 minutes, and 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration). Mice were anesthetized with isoflurane, and blood samples were collected via orbital sampling. Blood samples were collected into 1.5 mL EP tubes coated with EDTA.K2. Approximately 50 µL of blood (mice) and 150 µL of blood (rats) were collected at each time point and placed on ice, then centrifuged at 5600 rpm for 7 minutes at 4°C to obtain plasma. The plasma was transferred to new tubes and temporarily stored at -20°C or dry ice. Samples were stored at -80°C until in vitro PK assays were performed.

[0625] Plasma concentration was determined using the following sample preparation method and measurement conditions. A 10 µL aliquot of the sample was added to 200 µL of ACN solution containing terfenadine (5 ng / mL). The mixture was vortexed for 1 minute and centrifuged at 4000 rpm for 10 minutes at 4°C. An 80 µL aliquot of the supernatant was taken, diluted with 80 µL of water, and the mixed sample was injected into a liquid chromatography-tandem mass spectrometry (LC-MS / MS, Triple Quad 5500) for analysis. Injection volume: 2 μL. Monitor: MRM; Column: Advanced Materials Technology, HALO AQ-C18 2.7 µm 90Å, 50 2.1 mm; Column temperature: 40℃; Mobile phase A: H2O-0.1% FA, Mobile phase B: ACN-0.1% FA, Gradient program: 15% B-15% B (0 min-0.3 min), 15% B-90% B (0.3 min-1.0 min), 90% B-90% B (1.0 min-1.8 min), 90% B-30% B (1.8 min-2.0 min), 30% B-30% B (2.0 min-2.5 min).

[0626] SW1990 PD Study: 5 × 10 6 SW1990 cells / 200 μL PBS / Matrix gel were subcutaneously implanted into the right abdomen of female BALB / c nude mice. After inoculation, when the average tumor volume reached approximately 350-450 mm², [the tumors were observed to develop]. 3 At the time of administration, mice were randomly assigned to treatment groups. Randomized mice received a single oral dose of a mediator consisting of 0.5% MC or various doses of the test compound (e.g., 30, 50, or 100 mg / kg). Plasma was collected at 0.5, 2, 4, and 7 hours post-administration, and tumor fragments were collected at 7 hours post-administration to determine exposure levels. Tumor fragments were placed in homogenization tubes, rapidly frozen in liquid nitrogen, and homogenized with T-PER tissue protein extraction buffer freshly supplemented with protease and phosphatase inhibitors before use. ERK1 / 2 phosphorylation in the tumor lysis products was then analyzed.

[0627] SW1990 Efficacy Study: 5 × 10 6 SW1990 cells / 200 μL PBS / Matrix gel were subcutaneously implanted into the right abdomen of female BALB / c nude mice. After inoculation, when the average tumor volume reached approximately 150-250 mm², [the tumors were observed to develop]. 3 At the time of birth, mice were randomly assigned to treatment groups. Randomized mice received a mediator consisting of 0.5% MC or various doses of the test compound (e.g., 25, 50, or 100 mg / kg BID) administered orally. Animals were monitored daily, and tumor volume was determined twice weekly using calipers in two dimensions and expressed as follows (in mm). 3 (in units): V = 0.5(a × b) 2 (a) and (b) represent the long and short diameters of the tumor, respectively. Partial regression (PR) is defined as tumor volume being less than 50% of the initial tumor volume on day 1 of drug administration in three consecutive measurements, and complete regression (CR) is defined as tumor volume being less than 14 mm in three consecutive measurements. 3Data are presented as mean tumor volume ± standard error of the mean (SEM). Tumor growth inhibition (TGI) is calculated using the following formula: Treatment time t = tumor volume treated at time t The tumor volume treated at time t0 = time 0. Placebo t = Placebo tumor volume at time t Placebo t0 = Placebo tumor volume at time 0 AsPC-1 PD Study: 3 × 10 6 AsPC-1 cells / 200 μL PBS / matrix were subcutaneously implanted into the right abdomen of female BALB / c nude mice. After inoculation, when the average tumor volume reached approximately 350-450 mm², [the tumors were observed to develop]. 3 At the time of administration, mice were randomly assigned to treatment groups. Randomized mice received a single oral dose of a mediator consisting of 0.5% MC or various doses of the test compound (e.g., 30, 50, or 100 mg / kg). Plasma was collected at 0.5, 2, 4, and 8 hours post-administration, and tumor fragments were collected at 4 and 8 hours post-administration to determine exposure levels. Tumor fragments were placed in homogenization tubes, rapidly frozen in liquid nitrogen, and homogenized with T-PER tissue protein extraction buffer freshly supplemented with protease and phosphatase inhibitors before use. ERK1 / 2 phosphorylation in the tumor lysis products was then analyzed.

[0628] AsPC-1 efficacy study: 3 × 10 6 AsPC-1 cells / 200 μL PBS / Matrix gel were subcutaneously implanted into the right abdomen of female BALB / c nude mice. After inoculation, when the average tumor volume reached approximately 150-250 mm... 3 At the time of birth, mice were randomly assigned to treatment groups. Randomized mice received a mediator consisting of 0.5% MC or various doses of the test compound (e.g., 25, 50, or 100 mg / kg BID) administered orally. Animals were monitored daily, and tumor volume was determined twice weekly using calipers in two dimensions and expressed as follows (in mm). 3 (in units): V = 0.5(a × b) 2 (a) and (b) represent the long and short diameters of the tumor, respectively. Partial regression (PR) is defined as tumor volume being less than 50% of the initial tumor volume on day 1 of drug administration in three consecutive measurements, and complete regression (CR) is defined as tumor volume being less than 14 mm in three consecutive measurements. 3Data are presented as mean tumor volume ± standard error of the mean (SEM). Tumor growth inhibition (TGI) is calculated using the following formula: Treatment time t = tumor volume treated at time t The tumor volume treated at time t0 = time 0. Placebo t = Placebo tumor volume at time t Placebo t0 = Placebo tumor volume at time 0 Active Tablet Each compound in Table 2 was tested in one or more of the biochemical assays provided herein and was found to be active.

[0629] Table 2

[0630] Based on the following rules, the activities in Table 2 are divided into categories “A”, “B” and “C” according to the corresponding values.

[0631] As shown in Table 2, the inventors of this case were surprised and unexpected to find that the exemplary compounds in Table 2 modulate or inhibit the activity of KRAS G12D.

[0632] Many references have been cited, and their published content is incorporated into this paper in its entirety through citation.

Claims

1. A compound having formula (I): (I) Or its pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or transisomer. in Ring A is an unsubstituted or substituted aryl group, or an unsubstituted or substituted heteroaryl group; Part of B is an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclic group; L 1 is a direct bond, or -O-R a -; wherein said R a is absent or unsubstituted or substituted C 1-4 alkylene; R 0 each independently is H, halogen, -CN, -OH, unsubstituted or substituted C 1-4 alkyl, unsubstituted or substituted C 1-4 alkoxy, unsubstituted or substituted C 1-4 alkenyl, unsubstituted or substituted C 3-5 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocyclyl, or unsubstituted or substituted amino; or one or more pairs of said R 0 groups together with the atoms to which they are attached form unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; R 1a , R 1b , R 2a and R 2b are each independently H, halogen, unsubstituted or substituted C 1-3 alkyl, or R 1a and R 1b together form oxo, or substituted or unsubstituted cyclopropyl; m and q are each independent integers ranging from 0 to the maximum number of substituents allowed on ring A and ring B, respectively; The premise is that the compound is not one of the compounds in Table 1.

2. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (IIa): (IIa)。 3. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (IIb): (IIb) in R 3a and R 3b each independently is H, F, unsubstituted or substituted C 1-2 alkyl.

4. The compound of claim 3, wherein part B is , in R 21a each independently H or halogen; R 22a and R 22b each independently is H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, or substituted or unsubstituted heterocyclyl, or R 22a and R 22b together with the atom to which they are attached form a substituted or unsubstituted heterocyclyl; and 22a and R 22b together with the atom to which they are attached form a substituted or unsubstituted heterocyclyl; and v can be 0, 1, 2, 3, or 4.

5. The compound of claim 4, wherein part B is , in R 23a and R 23b each independently is H or halogen; R 22a and R 22b each independently is H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, or substituted or unsubstituted heterocyclyl, or R 22a and R 22b together with the atom to which they are attached form a substituted or unsubstituted heterocyclyl. 22a and R 22b together with the atom to which they are attached form a substituted or unsubstituted heterocyclyl.

6. The compound of claim 5, wherein part B is The ring C is a substituted or unsubstituted 4- to 10-membered heterocyclic group, optionally containing one or more additional heteroatoms selected from N, O, or S.

7. The compound of claim 3, wherein part B is , in X 2 is -CHF-, -CF2-, -CH(CH3)-, N(CH3)-, -CH(OCH3)-, -CH(CHF2)-, -C(=CHF)- or -O-; R 27a It is methyl, ethyl, difluoromethyl, or trifluoromethyl; R 27b It is H, F, methyl, or methoxy; R 27c It is C 1-3 Alkyl, oxetane butyl, tetrahydrofuranyl, or tetrahydropyranyl, wherein the C 1-3 The alkyl group may optionally be substituted with one or more substituents selected from methyl, methyl-d3, F, or alkenyl; and n is an integer from 0 to 4.

8. The compound of any one of claims 3, wherein part B is , , , , , or , in R 28a It is methyl, methyl-d3, fluoromethyl, difluoromethyl, or trifluoromethyl; R 28b and R 28c Each is H, halogen, substituted or unsubstituted alkyl group, or a pair of R groups. 28b Or R 28c Together with the atoms they are attached to, they form substituted or unsubstituted alkenyl groups, or unsubstituted or substituted cycloalkyl groups; and s and p are each independently 0, 1, 2, 3 or 4; The premise is that, no .

9. The compound of claim 3, wherein part B is , in R 26a It is H, methyl, or difluoromethyl; R 26b It is methyl, methyl-d3, ethyl, 2-fluoroethyl, 2-(methoxy-d3)ethyl, 1-allyl-2-methyl, 2-methoxyethyl, 1-allyl-2-methyl, cyclopropylmethyl, oxetane, tetrahydrofuranyl or tetrahydro-2H-pyranyl; Each R 26c It is independently H, F, or methoxy, or a pair of R 26c Together with the atoms they are attached to, they form substituted or unsubstituted cyclopropyl groups; and c is 0, 1, or 2.

10. The compound of claim 6, wherein the compound is a compound of formula (IVb): (IVb) in The ring C is a substituted or unsubstituted 4- to 7-membered heterocyclic group that optionally contains one or more additional heteroatoms selected from N or O; R c Each of these can be independently H, halogen, amino, -OH, -CN, or unsubstituted or substituted C. 1-4 Alkyl, or unsubstituted or substituted C 1-4 alkoxy, or a pair of said R c The groups together with the atoms they are attached to form unsubstituted or substituted bridges, unsubstituted or substituted cycloalkyl groups, or unsubstituted or substituted heterocyclic groups; u is an integer ranging from 0 to the maximum number of substituents allowed on ring C.

11. The compound of claim 8, wherein the compound is a compound of formula (IVb): (IVc), in R 28b and R 28c Each is H, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a pair of R groups. 28b Or R 28c Together with the atoms they are attached to, they form unsubstituted or substituted alkenyl groups, or unsubstituted or substituted cycloalkyl groups; and s and p are each independently 0, 1, 2, 3, or 4; and The premise is that, no .

12. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (IIc): (IIc) in R 32a and R 32b Each is independently H, or C that has been substituted or has been substituted. 1-4 Alkyl, unsubstituted or substituted amino, or unsubstituted or substituted heterocyclic group.

13. A compound, wherein the compound is selected from the compounds in Table 2.

14. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 13 or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or transisomer thereof, and a pharmaceutically acceptable carrier, excipient, or mediator.

15. A method for inhibiting the activity of a KRAS mutant protein in cells, the method comprising contacting the cells with a compound as described in any one of claims 1 to 13 or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or transisomer thereof, optionally wherein the KRAS mutant protein is a KRAS G12D mutant protein.

16. A method for treating or preventing cancer, the method comprising administering to a subject in need a compound as described in any one of claims 1 to 13, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or transisomer thereof, optionally wherein the cancer is caused by a KRAS mutation; preferably mediated by a KRAS G12D mutation.

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