Combinations of KRAS G12D inhibitors and EGFR inhibitors used to treat cancer

Abstract

This article describes a method for treating cancer by administering a combination therapy containing a KRAS G12D inhibitor and an EGFR inhibitor.

Description

[0001] Cross-references to related applications

[0002] This application relates to priority of U.S. Provisional Application No. 63 / 588,922, filed October 9, 2023, and U.S. Provisional Application No. 63 / 678,693, filed August 2, 2024, the contents of each of the aforementioned U.S. Provisional Applications are hereby incorporated herein in their entirety. Background Technology

[0003] KRAS mutations are among the most common genetic alterations in cancer (DA Erlanson et al., Curr. Opin. Chem. Biol., 2021, 62, 101-108). KRAS is a membrane-bound GTPase that promotes cell survival and proliferation upon activation by its upstream receptor tyrosine kinase (D. Uprety et al., Cancer Treat. Rev., 2020, 89, 102070). The KRAS protein exists in an "on" state for binding GTP and an "off" state for binding GDP. When binding GTP, the signal is transduced through activation of the mitogen-activated protein kinase pathway, the PI3K pathway, and other pathways. KRAS mutations are present in approximately 23% of solid tumors. The G12D subtype is the most common, accounting for approximately 29% of KRAS mutations in cancer (JK Lee et al., NPJ Precis. Oncol., 2022, 6, 91). KRAS G12D mutations are present in approximately 40% of pancreatic cancers (pancreatic ductal adenocarcinoma), 15% of colorectal cancers, and 5% of non-small cell lung adenocarcinomas, representing a major unmet medical need. KRASG12D mutations can impair GTP hydrolysis, resulting in hyperactivated KRAS subtypes, which drive high levels of oncogenic ERK and PI3K signaling (M. Malumbres, et al., Nat. Rev. Cancer., 2003, 3, 459-65).

[0004] Inhibition of KRAS G12D by binding to the KRAS G12D switch-II pocket (which leads to conformational changes unfavorable to GTP binding and RAF association) is presumed to eliminate KRAS signaling and prevent tumor growth in KRAS G12D-mutant tumors. It is hypothesized that inhibition of KRAS G12D in this manner would eliminate KRAS signaling and prevent tumor growth in KRAS G12D-mutant tumors. EGFR activity in colorectal cancer has been shown to induce KRAS inhibitor resistance in KRAS G12C-mutant tumors (V. Amodio, et al., Cancer Discov 2020;10:1129-1139). Summary of the Invention

[0005] This article provides a method for treating cancer in subjects with this need, comprising administering to the subject a KRAS G12D inhibitor or a pharmaceutically acceptable salt thereof and an EGFR inhibitor or a pharmaceutically acceptable salt thereof. The combination of a KRAS G12D inhibitor and an EGFR inhibitor produces superior antitumor activity against KRAS G12D-mutant colorectal cancer compared to treatment with either agent alone. Attached Figure Description

[0006] Figure 1 The antitumor activity of compound 1 ± cetuximab in the LS513 model is shown.

[0007] Figure 2 The changes in body weight of LS513 tumor-bearing mice treated with compound 1 ± cetuximab are shown.

[0008] Figure 3 This study demonstrates the inhibition of pERK in LS513 tumors by compound 1 ± cetuximab after a single dose of treatment.

[0009] Figure 4 The antitumor activity of compound 2 ± cetuximab in the LS513 model is shown.

[0010] Figure 5 The antitumor activity of compound 1 ± cetuximab in the HPAFII model is shown. Detailed Implementation

[0011] Ras proteins belong to the small GTPase family and can be activated by growth factors and various extracellular stimuli. The Ras family regulates intracellular signaling pathways responsible for cell growth, migration, survival, and differentiation. Activation of Ras proteins on the cell membrane leads to the binding of key effector factors and initiates a series of intracellular signaling pathways, including the RAF and PI3K kinase pathways. Somatic mutations in RAS can lead to uncontrolled cell growth and malignant transformation, while the activation of RAS proteins is tightly regulated in normal cells (D. Simanshu et al., Cell, 2017, 170(1), 17-33). The Ras family consists of three members: KRAS, NRAS, and HRAS. RAS-mutant cancers account for approximately 25% of human cancers. KRAS is the most common mutation subtype, accounting for 85% of all RAS mutations, while NRAS and HRAS mutations account for 12% and 3% of all Ras-mutant cancers, respectively (D. Simanshu et al., Cell, 2017, 170(1), 17-33). KRAS mutations are prevalent in the three deadliest cancer types: pancreatic cancer (97%), colorectal cancer (44%), and lung cancer (30%) (AD Cox, et al., Nat. Rev. Drug. Discov., 2014, 13(11), 828-51). Most RAS mutations occur at amino acid residues 12, 13, and 61. The frequency of specific mutations varies by RAS genotype, and while G12 and Q61 mutations are dominant in KRAS and NRAS, respectively, G12, G13, and Q61 mutations are most common in HRAS. Furthermore, the mutation spectrum of RAS subtypes varies by cancer type. For example, KRAS G12D mutations are dominant in pancreatic cancer (40%), followed by colorectal adenocarcinoma (15%) and lung cancer (5%) (Lee JK, et al., NPJ Precis. Oncol., 2022, 6, 459-465). Genomic studies across hundreds of cancer cell lines have shown that cell growth and survival of cancer cells carrying KRAS mutations are highly dependent on KRAS function (R. McDonald, et al., Cell, 2017, 170(3), 577-92). Extensive in vivo experimental evidence further supports the role of mutant KRAS as a carcinogenic driver, demonstrating that mutant KRAS is essential for early tumorigenesis and maintenance in animal models (AD Cox, et al., Nat. Rev. Drug. Discov., 2014, 13(11), 828-51).

[0012] Epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that acts as a receptor for members of the epidermal growth factor family (EGF family) that target extracellular protein ligands. Mutations leading to EGFR overexpression are associated with a variety of cancers, including lung adenocarcinoma, anal cancer, glioblastoma, and epithelial tumors of the head and neck. These somatic mutations involving EGFR result in its persistent activation, which causes uncontrolled cell division.

[0013] This disclosure relates to a method of treating cancer in a subject who requires such treatment, the method comprising administering to the subject a KRASG12D inhibitor or a pharmaceutically acceptable salt thereof and an EGFR inhibitor or a pharmaceutically acceptable salt thereof.

[0014] Certain terms used herein are described as follows. The compounds disclosed herein are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0015] definition

[0016] The following lists the definitions of various terms used herein. These definitions apply to the terminology used throughout this specification and claims, unless otherwise limited, either individually or as part of a larger group, in specific instances.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein, as well as laboratory procedures for cell culture, molecular genetics, organic chemistry, and peptide chemistry, are well-known and commonly used nomenclature and laboratory procedures in the art.

[0018] As used herein, the articles “a” and “an” refer to one or more grammatical objects of the article (i.e., at least one). For example, “element” means one or more elements. Furthermore, the use of the term “including” and other forms such as “include,” “includes,” and “included” is not restrictive.

[0019] The term "about" when used in conjunction with a numerical value means to include a set or range of values. For example, "about X" includes a range of values ​​such as ±10%, ±5%, ±2%, ±1%, ±0.5%, ±0.2%, or ±0.1% of X, where X is a numerical value. In one embodiment, the term "about" refers to a range of values ​​that are 10% more or less than a specified value. In another embodiment, the term "about" refers to a range of values ​​that are 5% more or less than a specified value. In yet another embodiment, the term "about" refers to a range of values ​​that are 1% more or less than a specified value.

[0020] As used herein, “drug combination” or “combination” means a formulation of individual compounds with or without instructions for combined use, or a combination product. Thus, combination compounds may be completely independent drug dosage forms or drug compositions that are also sold independently of each other, and in which instructions for combined use for simultaneous or sequential action are provided in the packaging accessories (e.g., instructions for use, etc.) or in other information provided to physicians and medical personnel (e.g., verbal instructions, written instructions, etc.).

[0021] The terms “treat,” “treated,” “treating,” or “treatment” include reducing or alleviating at least one symptom associated with or caused by the treated state, condition, or disease. In some embodiments, treatment includes contacting an effective amount of the compound disclosed herein with KRAS or EGFR for cancer-related symptoms.

[0022] As used herein, the terms “prevent” or “prevention” mean that if a symptom or disease does not occur, there is no development of a symptom or disease, or if a symptom or disease has already developed, there is no further development of a symptom or disease. The ability to prevent some or all of the symptoms associated with a symptom or disease is also considered.

[0023] As used herein, the terms “patient,” “individual,” or “subject” refer to a human or a non-human mammal. Non-human mammals include, for example, livestock and pets, such as sheep, cattle, pigs, dogs, cats, and rodents. Preferably, the patient, subject, or individual is a human.

[0024] As used herein, the term "free base equivalent" refers to the amount of active agent or a pharmaceutically acceptable salt of active agent (e.g., compound 1) equivalent to a dose of free base of the active agent. In other words, the term "free base equivalent" means the amount of free base of compound 1, or the equivalent of free base of compound 1 provided by a salt of said compound.

[0025] As used herein, the terms “effective amount,” “pharmaceutical effective amount,” and “therapeutic effective amount” refer to a non-toxic but sufficient amount of a drug to provide the desired biological outcome. This outcome can be a reduction or relief of signs, symptoms, or causes of disease, or any other desired alteration of a biological system. In any individual case, the appropriate therapeutic amount can be determined by a person skilled in the art using routine laboratory methods.

[0026] As used herein, the term “pharmaceutically acceptable” means a material, such as a carrier or diluent, that does not eliminate the biological activity or properties of a compound and is relatively non-toxic, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting with any component of a composition containing the material in a harmful manner.

[0027] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral salts or organic acid salts of basic residues such as amines; alkali metal salts or organic salts of acidic residues such as carboxylic acids; and so on. Pharmaceutically acceptable salts disclosed herein include, for example, conventional non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts disclosed herein can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods. Typically, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water, in an organic solvent, or in a mixture of both; typically, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is used. The phrase "pharmaceutically acceptable salt" is not limited to a single salt or a 1:1 salt. For example, "pharmaceutically acceptable salt" also includes disalts, such as dihydrochlorides. A list of suitable salts can be found in: AR Gennaro (ed.), Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, 1985), p. 1418; SM Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19; S. Gaisford et al., Remington, The Science and Practice of Pharmacy, 23rd ed. (Elsevier, 2020), Chapter 17, pp. 307-14; SM Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19; TS Wiedmann et al., Asian J. Pharm. Sci., 2016; 11, 722–34. D. Gupta et al., Molecules, 2018, 23(7), 1719; PH Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002) and PH Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use. 2nd edition (Wiley, 2011).

[0028] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound with a pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate the administration of the compound to a patient or subject. Various techniques for administering compounds available in the art include, but are not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0029] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or carrier (such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material) that involves carrying or transporting a useful compound to a patient so that it can perform its intended function. Typically, such constructs carry or deliver from one organ or part of the body to another. Each carrier must be "acceptable" in the sense that it is compatible with other components of a formulation containing the compounds disclosed herein and is harmless to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; astragalus powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer; and other non-toxic and compatible substances used in pharmaceutical formulations.

[0030] As used herein, "pharmaceuticalally acceptable carrier" also includes any and all coating agents, antibacterial and antifungal agents, and absorption delay agents that are compatible with the activity of the compounds disclosed herein and are physiologically acceptable to a patient. Additional active compounds may also be incorporated into the composition. "Pharmaceuticalally acceptable carrier" may further include pharmaceutically acceptable salts of the compounds disclosed herein. Other additional ingredients that may be included in the pharmaceutical composition are known in the art and are described, for example, in: P. Beringer, et al., (ed.), Remington: The Science and Practice of Pharmacy, 21st edition; (Lippincott Williams & Wilkins: Philadelphia, Pa., 2005); A. Adejare (ed.), Remington, The Science and Practice of Pharmacy, 23rd edition, (Elsevier, 2020); RC Rowe et al., eds., Handbook of Pharmaceutical Excipients, 6th edition; (Pharmaceutical Press, 2009); PJ Shesky et al., eds., Handbook of Pharmaceutical Excipients, 9th edition; (The Pharmaceutical Press, 2020); M. Ash et al. (eds.), Handbook of Pharmaceutical Additives, 3rd edition; (Gower Publishing Company: 2007); and M. Gibson (ed.), Pharmaceutical Preformulation and Formulation. 2nd edition (CRC Press LLC, 2009).

[0031] As used herein, the term "single formulation" refers to a single carrier or mediator formulated to deliver an effective amount of two therapeutic agents to a patient. A single mediator is designed to deliver an effective amount of each of these pharmaceutical agents, along with any pharmaceutically acceptable carrier or excipient. In some embodiments, the mediator is a tablet, capsule, pill, or patch. In other embodiments, the mediator is a solution or suspension.

[0032] The term "combination therapy" refers to the administration of two or more therapeutic compounds to treat the therapeutic symptoms or conditions described in this disclosure. Such administration encompasses the combined administration of these therapeutic compounds in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple or separate containers (e.g., capsules) for each active ingredient. Furthermore, such administration also encompasses the sequential use of each type of therapeutic compound at approximately simultaneous or at different times. In either case, the treatment regimen will provide the beneficial effect of the combination of drugs in treating the symptoms or conditions described herein.

[0033] The combination of drugs described herein can exhibit synergistic effects. As used herein, the term "synergistic effect" refers to the action of two drugs (such as, for example, a KRAS inhibitor (e.g., a KRAS inhibitor of formula I) and an EGFR inhibitor) that produces an effect (e.g., slowing the symptom progression of cancer or its symptoms) greater than the simple sum of the effects of each drug when administered alone. Synergistic effects can be calculated, for example, using appropriate methods such as the Sigmoid-Emax equation (NHGHolford, et al., Clin. Pharmacokinet., 1981, 6: 429-53), the Loewe additivity equation (S.Loewe, et al., Arch. Exp. Pathol Pharmacol., 1926, 114, 313-26), the median action equation (TC Chou, et al., Adv. Enzyme Regul., 1984, 22: 27-55), or based on the Bliss definition of drug independence (E. Demidenko, et al., PloS ONE, 2019, 14(11): e0224137). Each of the equations mentioned above can be applied to experimental data to generate corresponding graphs to assist in evaluating the effects of drug combinations. The corresponding graphs associated with the equations mentioned above are concentration-response curves, equivalence curves, and combination exponent curves.

[0034] As used herein, the term "synergistic effect" refers to the effect achieved when the active ingredients (i.e., KRAS inhibitors and EGFR inhibitors) are used together, which is greater than the sum of the effects of using the compounds alone.

[0035] In one embodiment, this article provides a combination therapy comprising an effective amount of a KRAS inhibitor and an EGFR inhibitor. An “effective amount” of the combination of agents (i.e., a KRAS inhibitor and an EGFR inhibitor) is an amount sufficient to provide an observable improvement relative to baseline clinically observable signs and symptoms of the condition treated with the combination.

[0036] This article provides combinations of therapeutic agents and combinations of agents for the treatment of cancer and related indications. As used herein, the term "cancer" includes related indications such as anemia. As used herein, "combination of agents" and similar terms refer to combinations of two types of agents: KRAS inhibitors or pharmaceutically acceptable salts thereof, and EGFR inhibitors or pharmaceutically acceptable salts thereof. Uses of racemic mixtures of individual agents are also provided. Pharmacologically active metabolites include those that are inactive but are converted into their pharmacologically active forms in vivo after administration.

[0037] As used herein, the term "alkyl" itself, or as part of another substituent, unless otherwise specified, means a straight-chain or branched hydrocarbon having a specified number of carbon atoms (i.e., C1-C6-alkyl means alkyl having one to six carbon atoms) and includes both straight-chain and branched chains. In one embodiment, C1-C3, C1-C4, and C1-C6 alkyl groups are provided herein. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl.

[0038] The term "alkylene" used alone or in combination with other terms refers to a divalent alkyl linking group. Alkylene groups formally correspond to alkane groups, where the two CH bonds are replaced by the alkylene group at the connection point with the rest of the compound. The term "C..." n-m "alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethane-1,2-diyl, ethane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propane-1,3-diyl, etc.

[0039] As used herein, the term "alkoxy" refers to a –O-alkyl group, wherein the alkyl group is as defined herein. Alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, etc. In one embodiment, C1-C3, C1-C4, and C1-C6 alkoxy groups are provided herein.

[0040] The term "amino" as used alone or in combination with other terms refers to a group of the formula –NH2, in which the hydrogen atom may be replaced by a substituent as described herein. For example, "alkylamino" can refer to –NH (alkyl) and –N (alkyl)2.

[0041] As used herein, unless otherwise stated, the term “halogenated” or “halogen”, alone or as part of another substituent, refers to a fluorine, chlorine, bromine, or iodine atom.

[0042] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by halogen atoms. The term "C" n-m "Haloalkyl" refers to a C14-alkyl group having n to m carbon atoms and at least one to up to {2(n to m) + 1} halogen atoms. n-mAlkyl groups, wherein the halogen atoms may be the same or different. In some embodiments, the halogen atom is a fluorine atom. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, etc. In some embodiments, the haloalkyl group is a fluoroalkyl group.

[0043] The term "haloalkoxy" used alone or in combination with other terms refers to a group of the formula -O-haloalkyl, wherein the haloalkyl group is as defined above. The term "C" n-m "Haloalkoxy" refers to a haloalkoxy group whose haloalkyl group has n to m carbon atoms. Examples of haloalkoxy groups include trifluoromethoxy groups. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0044] As used herein, the term "cycloalkyl" means a partially or fully saturated non-aromatic carbocyclic system having one, two, or three rings, wherein such rings may be fused. The term "fused" means that the second ring exists (i.e., is connected or formed) by sharing (i.e., co-occurring) two adjacent atoms with the first ring. Cycloalkyl also includes bicyclic structures that may be inherently bridged or spirocyclic, wherein each individual ring within the bicyclic has from 3 to 10, 3 to 8, 3 to 7, 3 to 6, and 5 to 10 atoms. The term "cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptyl, bicyclo[2.2.2]octyl, and bicyclo[1.1.1]pentyl. In one embodiment, 3- to 10-membered cycloalkyl groups are provided herein.

[0045] As used herein, the term "heterocyclic alkyl" means a non-aromatic carbocyclic system containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having 1, 2, or 3 rings, wherein such rings may be fused, as defined above. Heterocyclic alkyl also includes bicyclic structures that may be essentially bridged or spirocyclic, wherein each individual ring within the bicyclic has 3 to 8, 5 to 10, 4 to 6, or 3 to 10 atoms and contains 0, 1, or 2 N, O, or S atoms. The term "heterocyclic alkyl" includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams) and also specifically includes, but is not limited to, epoxy groups, oxacyclobutane, tetrahydrofuranyl, tetrahydropyranyl (i.e., epoxyhexyl), pyranyl, dioxane, aziridinyl, aziridine, pyrrolidinyl, 2,5-dihydro-1H-pyrrolidinyl, oxazolyl, thiazolyl, piperidinyl, morpholinyl, piperazine, thiomorpholinyl, 1,3-oxazinyl, 1,3-thiazolyl, 2-azabicyclo[2.1.1]hexane, 5-azabicyclo[2.1.1]hexane, 6-azabicyclo[3.1.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 2-azabicyclo[3.1.1]heptyl Alkyl, 3-azabicyclo-[3.1.0]hexyl, 2-azabicyclo-[3.1.0]hexyl, 3-azabicyclo-[3.2.1]octyl, 8-azabicyclo-[3.2.1]octyl, 3-oxa-7-azabicyclo-[3.3.1]nonyl, 3-oxa-9-azabicyclo-[3.3.1]nonyl, 2-oxa-5-azabicyclo-[2.2.1]heptyl, 6-oxa-3-azabicyclo-[3.1.1]heptyl, 2-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, 2-oxaspiro[3.5]nonyl, 3-oxaspiro[5.3]nonyl and 8-oxabicyclo-[3.2.1]octyl. In one embodiment, this document provides 3- to 10-membered heterocyclic alkyl groups. In another embodiment, this document provides 5- to 10-membered heterocyclic alkyl groups. In yet another embodiment, this document provides 4- to 6-membered heterocyclic alkyl groups.

[0046] The term "aromatic" refers to a carbon ring or heterocycle having one or more polyunsaturated rings with aromatic characteristics (i.e., having (4n + 2) delocalized π (pi) electrons, where n is an integer).

[0047] The term "aryl," used alone or in combination with other terms, refers to an aromatic hydrocarbon group, which can be monocyclic or polycyclic (e.g., having two fused rings). The term "C..." n-m"Aryl" refers to an aryl group having n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, etc. In some embodiments, the aryl group has 6 to about 10 carbon atoms. In some embodiments, the aryl group has 6 carbon atoms. In some embodiments, the aryl group has 10 carbon atoms. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group is naphthyl.

[0048] As used herein, the term "heteroaryl" refers to an aromatic carbocyclic system containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having 1, 2, or 3 rings, wherein such rings may be fused, where fusion is as defined above. The term "heteroaryl" includes, but is not limited to, furanyl, phenylthio, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrazinyl, imidazo[1,2-a]pyridinyl, pyrazol[1,5-a]pyridinyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopentano[b]pyridinyl, 6,7-dihydro-5H-cyclopentano[c]pyridinyl, 1,4, 5,6-Tetrahydrocyclopentano[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopentano[c]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-b]-[1,2,4]triazolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridyl, 4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridyl, 4,5,6,7-tetrahydro-1H-indazoleyl, and 4,5,6,7-tetrahydro-2H-indazoleyl. In one embodiment, 5- to 10-membered heteroaryl groups are provided herein.

[0049] It should be understood that if a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl moiety can be bonded to a specified moiety by different ring atoms (i.e., the specific connection point shown or described but not specified), it means all possible points, whether by a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridinyl" means 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl, and the term "thiophenyl" means 2-thiophenyl or 3-thiophenyl, and so on.

[0050] As used herein, the term “substituted” means that an atom or group of atoms replaces hydrogen as a substituent attached to another group.

[0051] As used herein, the term "optionally substituted" means that the mentioned group may be substituted or unsubstituted. In one embodiment, the mentioned group is optionally substituted with zero substituents, i.e., the mentioned group is unsubstituted. In another embodiment, the mentioned group is optionally substituted with one or more additional groups, individually and independently selected from the groups described herein.

[0052] KRAS G12D inhibitors

[0053] This disclosure relates to a combination therapy comprising a KRAS G12D inhibitor and an EGFR inhibitor. This combination therapy can be used to treat a variety of conditions associated with abnormal activity of KRAS or EGFR.

[0054] In one embodiment, the KRAS G12D inhibitor is a compound of formula I:

[0055]

[0056] I

[0057] Or its pharmaceutically acceptable salt, wherein:

[0058] Y is N or CR 6 ;

[0059] R 1 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, cyclopropyl, halogenated, D, CN and OR a1 ; wherein C 1-3 The alkyl and cyclopropyl groups are each optionally selected independently from R by one or two. g Substituents of the substituents;

[0060] R 2 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, 4- to 6-membered heterocyclic alkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5- to 6-membered heteroaryl-C 1-3 Alkylene, Halogenated, D, CN, and OR a2 ; wherein C 1-3 Alkyl, 4- to 6-membered heterocyclic alkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5- to 6-membered heteroaryl-C 1-3 Each alkylene group is optionally selected independently from one or two of R. g Substituents of the substituents;

[0061] Cy 1 Selected from C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl and 6- to 10-membered heteroaryl; wherein the 4- to 10-membered heterocyclic alkyl and the 6- to 10-membered heteroaryl each have at least one cyclic carbon atom and 1, 2, 3 or 4 cyclic heteroatoms independently selected from N, O and S; wherein the cyclic carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocyclic alkyl are optionally substituted with oxy to form a carbonyl group; and wherein C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 The aryl group and the 6- to 10-membered heteroaryl group are each optionally selected independently by 1, 2, 3, or 4 groups from R. 10 Substituents of the substituents;

[0062] R 3 Selected from H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4- to 6-membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5- to 6-membered heteroaryl-C 1-3 Alkylene, Halogenated, D, CN, OR f3 C(O)NR c3 R d3 NR c3 R j3 and NR c3 C(O)R b3 ; wherein C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4- to 6-membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- to 6-membered heteroaryl-C 1-3 Each alkylene group is optionally selected independently from R by one, two, or three independent groups. 30 Substituents of the substituents;

[0063] R 5 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, cyclopropyl, halogenated, D, CN and OR a5 ; wherein C 1-3The alkyl and cyclopropyl groups are each optionally selected independently from R by one or two. g Substituents of the substituents;

[0064] R 6 Selected from H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 9-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4- to 6-membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5- to 6-membered heteroaryl-C 1-3 Alkylene, Halogenated, D, CN, OR a6 and C(O)NR c6 R d6 ; wherein C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 9-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4- to 6-membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- to 6-membered heteroaryl-C 1-3 Each alkylene group is optionally selected independently from one or two of R. 60 Substituents of the substituents;

[0065] R 7 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, cyclopropyl, halogenated, D, CN and OR a7 ; wherein C 1-3 The alkyl and cyclopropyl groups are each optionally selected independently from R by one or two. g Substituents of the substituents;

[0066] Cy 2 Selected from

[0067]

[0068] Where n is 0, 1, or 2;

[0069] Each R 10 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN, OR a10 C(O)R b10 C(O)NR c10 R d10 C(O)ORa10 NR c10 R d10 and S(O)2R b10 ;

[0070] Each R 20 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN and OR a20 ;

[0071] Each R 30 Selected independently from C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogenated, D, CN, OR a30 C(O)R b30 C(O)NR c30 R d30 C(O)OR a30 NR c30 R d30 and S(O)2R b30 ; wherein C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R 31 Substituents of the substituents;

[0072] Each R 31 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN, OR a31 C(O)R b31 C(O)NR c31 R d31 C(O)OR a31 NR c31 R d31 and S(O)2R b31 ;

[0073] Each R 33 Selected independently from C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogenated, D, CN, OR a30 C(O)NR c30 R d30 and NR c30 R d30 ; wherein C 1-3Alkyl, C 3-6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected independently by one or two of R. 31 Substituents of the substituents;

[0074] Each R 60 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, 4- to 6-membered heterocyclic alkyl, 5- to 6-membered heteroaryl, halogenated, D, CN, OR a60 C(O)R b60 C(O)NR c60 R d60 NR c60 C(O)R b60 C(O)OR a60 NR c60 C(O)OR a60 NR c60 R d60 NR c60 S(O)2R b60 and S(O)2R b60 ; wherein C 1-3 Alkyl, 4- to 6-membered heterocyclic alkyl and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R 61 Substituents of the substituents;

[0075] Each R 61 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN, OR a61 and NR c61 R d61 ;

[0076] R a1 Selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0077] Each R a2 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0078] Each R b3 R c3 and R d3 Independently selected from H and C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, C3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by 1, 2, or 3 independently from R 30 Substituents of the substituents;

[0079] Or R connected to the same N atom c3 and R d3 Together with the N atom to which they are attached, they form 4-, 5-, or 6-membered heterocyclic alkyl groups, optionally substituted with 1, 2, or 3 substituents, which are independently selected from R. 30 ;

[0080] R j3 Selected from C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by 1, 2, or 3 independently from R 30 Substituents of the substituents;

[0081] Or R connected to the same N atom c3 and R j3 Together with the N atom to which they are attached, they form 4-, 5-, or 6-membered heterocyclic alkyl groups, optionally substituted with 1, 2, or 3 substituents, which are independently selected from R. 30 ;

[0082] R f3 Selected from C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; wherein the C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by 1, 2, or 3 independently from R 30 Substituents; or

[0083] R f3 Selected from

[0084]

[0085] Where R x For H or C 1-2 Alkyl, and R y C 1-2 alkyl;

[0086] Or R x and R yTogether with the C atoms they are attached to, they form 3- or 4-membered cycloalkyl groups;

[0087] R a5 Selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0088] Each R a6 R c6 and R d6 Independently selected from H and C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R 60 Substituents of the substituents;

[0089] R a7 Selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0090] Each R a10 R b10 R c10 and R d10 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0091] Each R a20 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0092] R b20 Selected from NH2, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0093] Each R a30 R b30 R c30 and R d30 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0094] Each R a31 R b31 R c31 and R d31 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0095] Each R a60 R b60 R c60 and R d60 Independently selected from H and C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 The cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R. 61 Substituents of the substituents;

[0096] Or any R connected to the same N atom c60 and R d60 Together with the N atom to which they are attached, they form 4-, 5-, or 6-membered heterocyclic alkyl groups, optionally substituted with one or two substituents, which are independently selected from R. 61 ;

[0097] Each R a61 R c61 and R d61 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; and

[0098] Each R g Independently selected from D, OH, CN, halogenated, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, amino, C 1-3 Alkylamino and di(C) 1-3 Alkyl)amino.

[0099] In one embodiment of Formula I or a pharmaceutically acceptable salt thereof

[0100] Y is CR 6 ;

[0101] R 1 Selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0102] R 2 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN and OR a2 ; wherein C 1-3 The alkyl group is optionally selected by one or two independently from R.g Substituents of the substituents;

[0103] Cy 1 Selected from C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl and 6- to 10-membered heteroaryl; wherein the 4- to 10-membered heterocyclic alkyl and the 6- to 10-membered heteroaryl each have at least one cyclic carbon atom and 1, 2, 3 or 4 cyclic heteroatoms independently selected from N, O and S; wherein the cyclic carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocyclic alkyl are optionally substituted with oxy to form a carbonyl group; and wherein C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 The aryl group and the 6- to 10-membered heteroaryl group are each optionally selected independently by 1, 2, 3, or 4 groups from R. 10 Substituents of the substituents;

[0104] R 3 Selected from H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogenated, D, CN, C(O)NR c3 R d3 and NR c3 C(O)R b3 ; wherein C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by 1, 2, or 3 independently from R 30 Substituents of the substituents;

[0105] R 5 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and halogenated groups;

[0106] R 6 Selected from H, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogenated, D, CN, OR a6 and C(O)NR c6 R d6 ; wherein C 3-6 Cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R 60 Substituents of the substituents;

[0107] R 7 Selected from H, C 1-3Alkyl, C 1-3 Halogenated alkyl groups, halogenated groups, and CN groups;

[0108] Cy 2 Selected from

[0109]

[0110] Where n is 0, 1, or 2;

[0111] Each R 10 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN, OR a10 C(O)R b10 C(O)NR c10 R d10 C(O)OR a10 NR c10 R d10 and S(O)2R b10 ;

[0112] Each R 20 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN and OR a20 ;

[0113] Each R 30 Selected independently from C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogenated, D, CN, OR a30 C(O)R b30 C(O)NR c30 R d30 C(O)OR a30 NR c30 R d30 and S(O)2R b30 ; wherein C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R 31 Substituents of the substituents;

[0114] Each R 31 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN, OR a31 C(O)R b31 C(O)NR c31 Rd31 C(O)OR a31 NR c31 R d31 and S(O)2R b31 ;

[0115] Each R 60 Selected independently from C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, 4- to 6-membered heterocyclic alkyl, 5- to 6-membered heteroaryl, halogenated, D, CN, OR a60 C(O)R b60 C(O)NR c60 R d60 NR c60 C(O)R b60 C(O)OR a60 NR c60 C(O)OR a60 NR c60 R d60 NR c60 S(O)2R b60 and S(O)2R b60 ; wherein C 1-3 Alkyl, 4- to 6-membered heterocyclic alkyl and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R 61 Substituents of the substituents;

[0116] Each R 61 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN, OR a61 and NR c61 R d61 ;

[0117] Each R a2 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0118] Each R b3 R c3 and R d3 Independently selected from H and C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by 1, 2, or 3 independently from R 30Substituents of the substituents;

[0119] Or R connected to the same N atom c3 and R d3 Together with the N atom to which they are attached, they form 4-, 5-, or 6-membered heterocyclic alkyl groups, optionally substituted with 1, 2, or 3 substituents, which are independently selected from R. 30 ;

[0120] Each R a6 R c6 and R d6 Independently selected from H and C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R 60 Substituents of the substituents;

[0121] Each R a10 R b10 R c10 and R d10 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0122] Each R a20 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0123] R b20 Selected from NH2, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0124] Each R a30 R b30 R c30 and R d30 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0125] Each R a31 R b31 R c31 and R d31 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0126] Each R a60 Rb60 R c60 and R d60 Independently selected from H and C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 The cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R. 61 Substituents of the substituents;

[0127] Or any R connected to the same N atom c60 and R d60 Together with the N atom to which they are attached, they form 4-, 5-, or 6-membered heterocyclic alkyl groups, optionally substituted with one or two substituents, which are independently selected from R. 61 ;as well as

[0128] Each R a61 R c61 and R d61 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; and

[0129] Each R g Independently selected from D, CN, halogenated, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0130] In another embodiment of Formula I or a pharmaceutically acceptable salt thereof

[0131] Y is CR 6 ;

[0132] R 1 For H;

[0133] R 2 Selected from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, CN and -CH2CH2CN;

[0134] Cy 1 Selected from C 3-10 cycloalkyl, C 6-10 Aryl and 6- to 10-membered heteroaryl; wherein the 6- to 10-membered heteroaryl has at least one cyclic carbon atom and one cyclic heteroatom independently selected from N and S; and wherein C 3-10 cycloalkyl, C 6-10 The aryl group and the 6- to 10-membered heteroaryl group are each optionally selected independently by one or two of the R groups. 10Substituents of the substituents;

[0135] R 3 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, 4- to 6-membered heterocyclic alkyl groups, phenyl groups, and 5- to 6-membered heteroaryl groups; wherein the C 1-3 Alkyl, 4- to 6-membered heterocyclic alkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally represented by 1, 2, or 3 independently selected from R 30 Substituents of the substituents;

[0136] R 5 Selected from H and halogenated;

[0137] R 6 Selected from H, C 1-3 Halogenated alkyl, 4- to 8-membered heterocyclic alkyl, and 5- to 6-membered heteroaryl; wherein the 4- to 8-membered heterocyclic alkyl and the 5- to 6-membered heteroaryl are each optionally selected independently by one or two from R 60 Substituents; or

[0138] R 7 Halogenated;

[0139] Cy 2 for

[0140]

[0141] Each R 10 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN and OR a10 ;

[0142] Each R 30 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, 4- to 6-membered heterocyclic alkyl, halogenated, D, CN, OR a30 C(O)NR c30 R d30 and NR c30 R d30 ; where C 1-3 The alkyl group and the 4- to 6-membered heterocyclic alkyl group are each optionally selected independently by one or two of R. 31 Substituents of the substituents;

[0143] Each R 31 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, CN, OR a31 and NR c31 R d31 ;

[0144] Each R 60 Selected independently from C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, 4- to 6-membered heterocyclic alkyl, 5- to 6-membered heteroaryl, halogenated, D, CN, OR a60 C(O)R b60 C(O)NR c60 R d60 NR c60 C(O)R b60 C(O)OR a60 NR c60 C(O)OR a60 NR c60 R d60 NR c60 S(O)2R b60 and S(O)2R b60 ; wherein C 1-3 Alkyl, 4- to 6-membered heterocyclic alkyl and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R 61 Substituents of the substituents;

[0145] Each R 61 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, halogenated groups, and CN groups;

[0146] Each R a10 Independently selected from H and C 1-3 alkyl;

[0147] Each R a30 R c30 and R d30 Independently selected from H and C 1-3 alkyl;

[0148] Each R a31 R c31 and R d31 Independently selected from H and C 1-3 alkyl;

[0149] Each R a60 R b60 R c60 and R d60 Independently selected from H and C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6The cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R. 61 Substituents of the substituents;

[0150] Or any R connected to the same N atom c60 and R d60 Together with the N atom to which they are attached, they form 4-, 5-, or 6-membered heterocyclic alkyl groups, optionally substituted with one or two substituents, which are independently selected from R. 61 .

[0151] In another embodiment of Formula I or a pharmaceutically acceptable salt thereof,

[0152] Y is CR 6 ;

[0153] R 1 For H;

[0154] R 2 -CH2CH2CN;

[0155] Cy 1 It is a phenyl group; wherein the phenyl group is optionally selected by one or two independently selected from R. 10 Substituents of the substituents;

[0156] R 3 Selected from H, C 1-3 Alkyl, phenyl, and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally represented by 1, 2, or 3 independently selected from R 30 Substituents of the substituents;

[0157] R 5 Selected from H and halogenated;

[0158] R 6 Selected from 4- to 8-membered heterocyclic alkyl groups; wherein the 4- to 8-membered heterocyclic alkyl group is optionally selected by one or two independently from R 60 Substituents; or

[0159] R 6 Selected from C 1-3 Alkyl; wherein the C 1-3 The alkyl group is selected independently by one or two of R. 60 Substituents of the substituents;

[0160] R 7 Halogenated;

[0161] Cy 2 for

[0162]

[0163] Each R 10 Selected independently from C 1-3 Alkyl and halogenated;

[0164] Each R 30 Selected independently from C 1-3 Alkyl, halogenated, D, OH and C(O)NR c30 R d30 ; wherein C 1-3 Alkyl groups are optionally selected independently from R 31 One substituent is substituted;

[0165] Each R 31 OR a31 ;

[0166] Each R 60 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkoxy, 4- to 6-membered heterocyclic alkyl, 5- to 6-membered heteroaryl, halogenated, C(O)R b60 C(O)NR c60 R d60 NR c60 C(O)R b60 C(O)OR a60 NR c60 C(O)OR a60 and NR c60 S(O)2R b60 ; wherein C 1-3 Alkyl, 4- to 6-membered heterocyclic alkyl and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R 61 Substituents of the substituents;

[0167] Each R 61 Selected independently from C 1-3 Alkyl and halogenated;

[0168] Each R c30 and R d30 Independently selected from H and C 1-3 alkyl;

[0169] Each R a31 Independently selected from H and C 1-3 Alkyl groups; and

[0170] Each R a60 R b60 R c60 and R d60 Independently selected from H and C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6Cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 The cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R. 61 Substituents of the substituents;

[0171] Or any R connected to the same N atom c60 and R d60 Together with the N atom to which they are attached, they form 4-, 5-, or 6-membered heterocyclic alkyl groups, optionally substituted with one or two substituents, which are independently selected from R. 61 .

[0172] In another embodiment of Formula I or a pharmaceutically acceptable salt thereof,

[0173] Y is CR 6 ;

[0174] R 1 For H;

[0175] R 2 -CH2CH2CN;

[0176] Cy 1 It is a phenyl group; wherein the phenyl group is optionally selected by one or two independently selected from R. 10 Substituents of the substituents;

[0177] R 3 Selected from H, methyl, ethyl, phenyl, 1,2,4-triazolyl, pyrazinyl, and pyridinyl; wherein the methyl, phenyl, 1,2,4-triazolyl, pyrazinyl, and pyridinyl groups are each optionally selected independently by one, two, or three groups selected from R. 30 Substituents of the substituents;

[0178] R 5 Selected from H and chlorine;

[0179] R 6 The molecule is selected from pyrrolidinyl, 2-azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.1]heptyl, and 5-oxo-1,2,3,5-tetrahydroindoleazin-3-yl; wherein the pyrrolidinyl, 2-azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.1]heptyl, and 5-oxo-1,2,3,5-tetrahydroindoleazin-3-yl are optionally selected by one or two independently from R 60 Substituents of the substituents;

[0180] R 7 It is fluorine;

[0181] Cy 2 for

[0182]

[0183] Each R 10 Independently selected from methyl, fluorine, and chlorine;

[0184] Each R 30 Independently selected from methyl, fluorine, OH, D and C(O)NR c30 R d30 The methyl group is optionally replaced by one substituent, namely R. 31 replace;

[0185] Each R 31 OR a31 ;

[0186] Each R 60 Independently selected from methyl, fluorine, C 1-2 Haloalkoxy, 3-oxomorpholino, 2-oxopyrazin-1(2H)-yl), C(O)R b60 C(O)NR c60 R d60 NR c60 C(O)R b60 C(O)OR a60 NR c60 C(O)OR a60 and NR c60 S(O)2R b60 ; wherein the 3-oxomorpholino group and the 2-oxopyrazin-1(2H)- group are each optionally selected independently by one or both from R 61 Substituents of the substituents;

[0187] Each R 61 Independently selected from methyl and fluorine;

[0188] Each R c30 and R d30 Independently selected from H and methyl;

[0189] Each R a31 Independently selected from H and methyl; and

[0190] Each R a60 R b60 R c60 and R d60 Independently selected from H and C 1-2 Alkyl, C1 haloalkyl, cyclopropyl, tetrahydrofuranyl, and thiazolyl; wherein the C 1-2 Alkyl, cyclopropyl, tetrahydrofuranyl, and thiazolyl groups are each optionally selected independently by one or two of the groups R. 61 Substituents of the substituents;

[0191] Or any R connected to the same N atom c60 and R d60 Together with the N atom to which they are attached, they form an azircyclic butyl group, optionally substituted with one or two substituents, which are independently selected from R. 61 .

[0192] In one embodiment, the compound of formula I is a compound of formula II:

[0193]

[0194] II

[0195] Or its pharmaceutically acceptable salt.

[0196] In another embodiment, the compound of formula I is the compound of formula III:

[0197]

[0198] III

[0199] Or its pharmaceutically acceptable salt.

[0200] In one embodiment of Formula I or a pharmaceutically acceptable salt thereof, Y is CR 6 In another embodiment of Formula I or a pharmaceutically acceptable salt thereof, R 1 For H. In another embodiment of Formula I or a pharmaceutically acceptable salt thereof, Cy 1 The phenyl group is optionally substituted with one or two independently selected halogenated substituents. In another embodiment of Formula I or a pharmaceutically acceptable salt thereof, R 3 R is methyl. In one embodiment of Formula I or a pharmaceutically acceptable salt thereof, R 5 For H. In one embodiment of Formula I or a pharmaceutically acceptable salt thereof, R 6 For R 60 Substituted 2-azabicyclo[3.1.0]hexyl. In another embodiment of formula I or a pharmaceutically acceptable salt thereof, R 7 It is fluorine. In another embodiment of Formula I or a pharmaceutically acceptable salt thereof, Cy 2 For Cy 2 -b. In another embodiment, R 60 It is C(O)cyclopropyl.

[0201] In one embodiment, the KRAS G12D inhibitor is selected from...

[0202] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(7-chloro-3-hydroxynaphth-1-yl)-6-fluoro-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0203] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(5,7-difluoro-1H-indol-3-yl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0204] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(6-fluoro-5-methyl-1H-indol-3-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0205] 3-(2-(3-(azacyclobutan-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0206] 3-((1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(3-hydroxynaphth-1-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-2-yl)methyl)oxazolidin-2-one;

[0207] 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-2,8-dimethyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile;

[0208] 1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-7-(8-cyanonaphthal-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidone-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-8-carboxynitrile;

[0209] 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-2-((3-oxomorpholino)methyl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile;

[0210] 3-(7-(benzo[b]thiophene-3-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-2-((2-oxopyrrolidine-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0211] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-4-(((S)-1-(dimethylamino)propane-2-yl)oxy)-6-fluoro-7-(7-fluoronaphthyl-1-yl)-2-((2-oxopyrrolidine-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0212] 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile;

[0213] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0214] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-6-fluoro-4-((3-fluoro-1-methylazacyclobutane-3-yl)methoxy)-7-(3-hydroxynaphthyl-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropionamide;

[0215] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(3-hydroxynaphth-1-yl)-2-methyl-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0216] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphth-1-yl)-4-methyl-2-((4-methyl-2-oxoperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0217] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-4-ethoxy-6-fluoro-2-((4-isopropyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0218] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-4-(3-(dimethylamino)-3-methylazacyclobutane-1-yl)-6-fluoro-7-(7-fluoronaphthyl)-2-((3-oxomorpholino)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0219] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphth-1-yl)-2-(1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0220] 3-(1-((endo)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(3-hydroxynaphth-1-yl)-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-2-(pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0221] 3-(2-(3-(azacyclobutan-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7,8-difluoronaphthyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0222] 3-(2-(3-(azacyclobutan-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(6,7-difluoronaphthyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0223] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphth-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0224] 1-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-7-yl)isoquinoline-8-carboxynitrile;

[0225] 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinoline-7-yl)-1-naphthonitrile;

[0226] 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-7-yl)-1-naphthonitrile;

[0227] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphth-1-yl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0228] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphthyl-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0229] (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)-N,N-dimethylpyrrolidine-1-carboxamide;

[0230] (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2-chloro-3-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidin-1-carboxylic acid methyl ester;

[0231] (1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester;

[0232] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-(5-oxo-1,2,3,5-tetrahydroindoleazine-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0233] (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-1-carboxylic acid methyl ester;

[0234] (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-1-carboxylic acid methyl ester;

[0235] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2-chloro-3-fluorophenyl)-2-((R)-1-(cyclopropanecarbonyl)pyrrolidine-2-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0236] 8-(2-((R)-1-acetylpyrrolidine-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-8-methyl-4-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxynitrile;

[0237] 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(3-chloro-2-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinoline-4-yl)-N-methylpyridineamide;

[0238] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphth-1-yl)-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0239] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0240] (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(5-fluoro-6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-1-carboxylic acid methyl ester;

[0241] (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-1-carboxylic acid methyl ester;

[0242] (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-1-carboxylic acid ethyl ester;

[0243] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazabicyclobutane-1-carbonyl)pyrrolidine-2-yl)-6-fluoro-4-(methyl-d3)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0244] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazabicyclobutane-1-carbonyl)pyrrolidine-2-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0245] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0246] 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphth-1-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinoline-4-yl)-N-methylpyridineamide;

[0247] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphth-1-yl)-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0248] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphth-1-yl)-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0249] (1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester;

[0250] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0251] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0252] (2R,4S)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)-4-fluoropyrrolidine-1-carboxylic acid methyl ester;

[0253] (2R,5R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)-5-methylpyrrolidin-1-carboxylic acid methyl ester;

[0254] (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-3-chloro-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidin-1-carboxylic acid methyl ester;

[0255] 4-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinoline-4-yl)-2-fluoro-N-methylbenzamide;

[0256] ((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)carbamate;

[0257] N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-2,2-difluoroacetamide;

[0258] N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-2,2-difluoroacetamide;

[0259] (2S)-N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)tetrahydrofuran-2-carboxamide;

[0260] N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)cyclopropanesulfonamide;

[0261] N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)thiazolyl-4-carboxamide;

[0262] N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-N-methylcyclopropaneformamide;

[0263] N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-1-methylcyclopropane-1-carboxamide;

[0264] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0265] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0266] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0267] N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-1-fluorocyclopropane-1-carboxamide;

[0268] N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-1-fluorocyclobutane-1-carboxamide;

[0269] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(3-chloro-2-methylphenyl)-2-(1-(2,6-dimethyl-3-oxo-2,3-dihydropyridazin-4-yl)ethyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0270] N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)pyrimidin-4-carboxamide;

[0271] N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)pyridazine-3-carboxamide;

[0272] N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-3,3-difluoroazabicyclobutane-1-carboxamide;

[0273] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-((R)-1-((1-methyl-1H-pyrazol-4-yl)amino)ethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0274] 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-fluorocyclopropane-1-carbonyl)pyrrolidine-2-yl)-1H-pyrrolo[3,2-c]quinoline-4-yl)-N,N-dimethylpyridineamide; and

[0275] (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(4-((dimethylamino)methyl)-2,3-difluorophenyl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidin-1-carboxylic acid methyl ester;

[0276] And its pharmaceutically acceptable salts.

[0277] In another embodiment, the KRAS G12D inhibitor is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile or a pharmaceutically acceptable salt thereof.

[0278] In another embodiment, the KRAS G12D inhibitor is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate (“Compound 1*”).

[0279] In yet another embodiment, the KRAS G12D inhibitor is 3-((R aCompound 1)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate:

[0280] .

[0281] In one embodiment, the KRAS G12D inhibitor is 3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate (“Compound 1a”):

[0282] .

[0283] On the other hand, KRAS G12D inhibitors are compounds of formula IV:

[0284] (IV)

[0285] Or its pharmaceutically acceptable salt, wherein:

[0286] Cy 1 A phenyl group optionally substituted with 1, 2, 3, or 4 substituents, each selected from D, C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 Alkyne, Halogen, OH, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups;

[0287] R 1 It is a halogen;

[0288] R 2 Selected from H, D, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 3-5 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4- to 6-membered heterocyclic alkyl-C1-3 Alkylene, phenyl-C 1-3 Alkylene, 5- to 6-membered heteroaryl-C 1-3 Alkylene, Halogenated, CN, OR a2 C(O)R b2 C(O)NR c2 R d2 NR c2 R e2 and NR c2 C(O)R b2 ; where R is formed 2 C 3-5 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4- to 6-membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- to 6-membered heteroaryl-C 1-3 Each alkylene group is optionally selected independently from R by one, two, or three independent groups. 2A Substituents are substituted; wherein R is formed 2 4- to 6-membered heterocyclic alkyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene and 4- to 6-membered heterocyclic alkyl-C 1-3 The cyclic atoms of the alkylene group consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S; wherein R forms 2 4- to 6-membered heterocyclic alkyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene and 4- to 6-membered heterocyclic alkyl-C 1-3 The cyclic carbon atom of the alkylene group is optionally substituted with an oxo group to form a carbonyl group; and R is formed therein. 2 C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. 2B Substituents of the substituents;

[0289] Each R a2 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- to 6-membered heteroaryl; wherein R is formed a2 C 3-6Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by 1, 2, or 3 independently from R 2A Substituents are substituted; wherein R is formed a2 The cyclic atoms of the 4- to 6-membered heterocyclic alkyl groups and the 5- to 6-membered heteroaryl groups consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S; wherein R forms a2 The cyclic carbon atoms of the 4- to 6-membered heterocyclic alkyl groups and the 5- to 6-membered heteroaryl groups are optionally substituted with oxygen to form a carbonyl group; and wherein R is formed. a2 C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each alkynyl group is optionally composed of one, two, or three independently selected from R. 2B Substituents of the substituents;

[0290] Each R b2 R c2 and R d2 Independently selected from H and C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- to 6-membered heteroaryl; wherein R is formed b2 R c2 and R d2 C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by 1, 2, or 3 independently from R 2A Substituents are substituted; forming R b2 R c2 and R d2 The cyclic atoms of the 4- to 6-membered heterocyclic alkyl groups and the 5- to 6-membered heteroaryl groups consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S; wherein R forms b2 R c2 and R d2 The cyclic carbon atoms of the 4- to 6-membered heterocyclic alkyl groups and the 5- to 6-membered heteroaryl groups are optionally substituted with oxygen to form a carbonyl group; and wherein R is formed. b2 R c2 and R d2 C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. 2B Substituents; or

[0291] Any R connected to the same N atom c2and R d2 Together with the N atoms to which they are attached, they form 4-, 5-, or 6-membered heterocyclic alkyl groups optionally substituted with 1, 2, or 3 substituents, said substituents being independently selected from R. 2B ;

[0292] Each R e2 Selected independently from C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- to 6-membered heteroaryl; wherein R is formed e2 C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by 1, 2, or 3 independently from R 2A Substituents are substituted; wherein R is formed e2 The cyclic atoms of the 4- to 6-membered heterocyclic alkyl groups and the 5- to 6-membered heteroaryl groups consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S; wherein R forms e2 The cyclic carbon atoms of the 4- to 6-membered heterocyclic alkyl groups and the 5- to 6-membered heteroaryl groups are optionally substituted with oxygen to form a carbonyl group; and wherein R is formed. e2 C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. 2B Substituents; or

[0293] R connected to the same N atom c2 and R e2 Together with the N atoms to which they are attached, they form 4-, 5-, or 6-membered heterocyclic alkyl groups optionally substituted with 1, 2, or 3 substituents, said substituents being independently selected from R. 2B ;

[0294] Each R 2A Selected independently from C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Halogenated alkyl groups and R 2B R is formed 2A C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. 2B Substituents of the substituents;

[0295] Each R 2BSelected independently from C 3-6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogenated, D, CN, OR a2B C(O)R b2B C(O)NR c2B R d2B C(O)OR a2B NR c2B R d2B and S(O)2R b2B ; where C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by 1, 2, or 3 independently from R 2C Substituents of the substituents;

[0296] Each R 2C Selected independently from C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogenated, D, CN, OR a2C C(O)R b2C C(O)NR c2C R d2C C(O)OR a2C NR c2C R d2C and S(O)2R b2C ;

[0297] Each R a2B R b2B R c2B and R d2B Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0298] Each R a2C R b2C R c2C and R d2C Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0299] R 3 Selected from C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10Aryl, 5- to 10-member heteroaryl, OR 3A and NR 3B R 3C ; where R is formed 3 C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl C 1-3 Each alkyl group is optionally selected independently from R by one, two, or three alkyl groups. 3D Substituents are substituted; wherein R is formed 3 The cyclic atoms of the 4- to 10-membered heterocyclic alkyl groups and the 5- to 10-membered heteroaryl groups consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S; wherein R forms 3 The cyclic carbon atom of the 4- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl group is optionally substituted with an oxo group to form a carbonyl group; and wherein R is formed. 3 C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. 3E Substituents of the substituents;

[0300] R 3A Selected from C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; wherein R is formed 3A C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl C 1-3 Each alkyl group is optionally selected independently from R by one, two, or three alkyl groups. 3D Substituents are substituted; wherein R is formed 3A The cyclic atoms of the 4- to 10-membered heterocyclic alkyl groups and the 5- to 10-membered heteroaryl groups consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S; wherein R forms 3A The cyclic carbon atom of the 4- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl group is optionally substituted with an oxo group to form a carbonyl group; and wherein R is formed. 3A C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. 3E Substituents of the substituents;

[0301] R 3B Selected from H, C1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; wherein R is formed 3B C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group are each optionally selected by one, two, or three independently chosen from R 3D Substituents are substituted; wherein R is formed 3B The cyclic atoms of the 4- to 10-membered heterocyclic alkyl groups and the 5- to 10-membered heteroaryl groups consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S; wherein R forms 3B The cyclic carbon atoms of the 4- to 10-membered heterocyclic alkyl groups and the 5- to 10-membered heteroaryl groups are optionally substituted with oxygen to form a carbonyl group; and wherein R is formed. 3B C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. 3E Substituents of the substituents;

[0302] R 3B and R 3C Together with the N atom attached to both of them, they optionally form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl group, optionally substituted with 1, 2, or 3 substituents, said substituents being independently selected from R. 3D ;

[0303] R 3C Selected from H, C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Alkyne group; wherein R is formed 3C C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. 3E Substituents of the substituents;

[0304] Each R 3D Selected independently from C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl and R 3E ; where R is formed 3D C 1-3 Alkyl, C 2-3 alkenyl and C 2-3Each of the ynyl groups is optionally selected from 1, 2, or 3 independently from R. 3E Substituents of the substituents;

[0305] Each R 3E Independently selected from D, halogenated, CN, OR a3 SR a3 C(O)R b3 C(O)NR c3 R d3 C(O)OR a3 OC(O)R b3 OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 C(=NR) e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 S(O)R b3 S(O)NR c3 R d3 S(O)2R b3 NR c3 S(O)2R b3 and S(O)2NR c3 R d3 ;

[0306] R a3 R b3 R c3 and R d3 Each is independently selected from H and C. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 Alkyl groups; wherein R is formeda3 R b3 R c3 and R d3 C 6-10 Aryl-C 1-3 Alkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 Each alkyl group is optionally substituted with 1, 2, 3, 4, or 5 substituents, which are independently selected from C10. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 Alkyne, Halogenated, CN, OR a3A SR a3A C(O)R b3A C(O)NR c3A R d3A C(O)OR a3A OC(O)R b3A OC(O)NR c3A R d3A NR c3A R d3A NR c3A C(O)R b3A NR c3A C(O)NR c3A R d3A NR c3A C(O)OR a3A C(=NR) e3A )NR c3A R d3A NR c3A C(=NR e3A )NR c3A R d3A S(O)R b3A S(O)NR c3A R d3A S(O)2R b3A NR c3A S(O)2R b3A and S(O)2NR c3A R d3A ; where R is formed a3 R b3 R c3 and R d3 4- to 10-membered heterocyclic alkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3The cyclizing atom of the alkyl group consists of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S; wherein R forms a3 R b3 R c3 and R d3 4- to 10-membered heterocyclic alkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 The cyclic carbon atom of the alkyl group is optionally substituted with an oxygen to form a carbonyl group; or

[0307] R connected to the same N atom c3 and R d3 Together with the N atom attached to both of them, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl group or a 5-membered heteroaryl group, each optionally substituted with 1, 2, or 3 substituents, these substituents being independently selected from C. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 Alkyne, Halogenated, CN, OR a3A SR a3A C(O)R b3A C(O)NR c3A R d3A C(O)OR a3A OC(O)R b3A OC(O)NR c3A R d3A NR c3A R d3A NR c3A C(O)R b3A NR c3A C(O)NR c3A R d3A NR c3A C(O)OR a3A C(=NR) e3A )NR c3A R d3A NR c3A C(=NR e3A )NR c3A R d3A S(O)R b3A S(O)NR c3A R d3A S(O)2R b3A NR c3A S(O)2R b3A and S(O)2NR c3A R d3A ;

[0308] R a3A R b3A R c3A and R d3A Each is independently selected from H and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, aryl, C 6-10 Aryl-C 1-3 Alkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 Alkyl groups; wherein R is formed a3A R b3A R c3A and R d3A C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl-C 1-3 Alkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 Each alkyl group is optionally substituted by one, two, or three substituents, which are independently selected from OH, CN, amino, NH(C) 1-6 alkyl), N(C) 1-6 Alkyl)2, Halogenated, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy groups; wherein R is formed a3A R b3A R c3A and R d3A 4- to 10-membered heterocyclic alkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 The cyclizing atom of the alkyl group consists of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S; and R is formed therein. a3A R b3A R c3A and R d3A 4- to 10-membered heterocyclic alkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3The cyclic carbon atom of the alkyl group is optionally substituted with an oxygen to form a carbonyl group; or

[0309] R connected to the same N atom c3A and R d3A Together with the N atom attached to both of them, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl group or a 5-membered heteroaryl group, each optionally substituted with 1, 2, or 3 substituents, which are independently selected from OH, CN, amino, NH(C) 1-6 alkyl), N(C) 1-6 Alkyl)2, Halogenated, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy; R e3 and R e3A Each can be independently H, CN, or NO2;

[0310] Each R 4 Independently selected from H, D, and C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 Alkyne, halogenated and OR a4 ;

[0311] Each R a4 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0312] An R 5 For R 5A ; and each other R 5 Independently selected from H, D, halogenated, C 1-3 Alkyl, OR a5 C 1-3 Haloalkyl, C 2-3 alkenyl and C 2-3 Alkyne group; or, optionally, two other R groups attached to the same carbon atom. 5 Together with the carbon atoms attached to both, they form spirocarbons that are optionally substituted with 1, 2, 3, or 4 substituents. 3-6 Cycloalkyl ring, wherein the substituents are each selected from D, C 1-3 Alkyl and halogenated; or, optionally, two other R atoms attached to adjacent carbon atoms. 5 Together with the carbon atoms to which they are attached, they form fused C atoms that are optionally substituted with 1, 2, 3, or 4 substituents. 3-6 Cycloalkyl ring, wherein the substituents are each selected from D, C 1-3 Alkyl and halogenated;

[0313] R5A For H, D, C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 Alkyne, Halogen, OR a5A ,CN or Cy 2 ; where R is formed 5A C 1-3 The alkyl group is optionally composed of 1, 2, 3, or 4 each selected from R 5B Substituents are substituted, and optionally Cy is also used. 2 Substitute, or, optionally, attach R to the same carbon atom 5A and R 5 Together with the carbon atoms attached to both, they form spirocarbons that are optionally substituted with 1, 2, 3, or 4 substituents. 3-6 Cycloalkyl ring, wherein the substituents are each selected from D, C 1-3 Alkyl and halogenated; or, optionally, R attached to an adjacent carbon atom. 5A and R 5 Together with the carbon atoms to which they are attached, they form fused C atoms that are optionally substituted with 1, 2, 3, or 4 substituents. 3-6 Cycloalkyl ring, wherein the substituents are each selected from D, C 1-3 Alkyl and halogenated;

[0314] Each R 5B Independently selected from D and halogenated;

[0315] Each R a5 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0316] R a5A Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and Cy 2 R is formed a5A C 1-3 The alkyl group is optionally composed of 1, 2, 3, or 4 each selected from R 5B Substituents are substituted, and optionally Cy is also used. 2 replace;

[0317] Cy 2 Selected from C 3-7 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; wherein Cy is formed 2 C 3-7 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 6-10Aryl and 5- to 10-membered heteroaryl groups are optionally selected by 1, 2, 3, or 4 independently selected from R Cy2 Substituents are substituted; wherein Cy is formed 2 The cyclic atoms of the 4- to 10-membered heterocyclic alkyl groups and the 5- to 10-membered heteroaryl groups consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and Cy forms therein. 2 The cyclic carbon atoms of the 4- to 10-membered heterocyclic alkyl groups and the 5- to 10-membered heteroaryl groups are optionally substituted with oxygen to form carbonyl groups.

[0318] Each R Cy2 Independently selected from D and C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 3-6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, halogenated, CN, OR aCy21 SR aCy21 C(O)R bCy21 C(O)NR cCy21 R dCy21 C(O)OR aCy21 OC(O)R bCy21 OC(O)NR cCy21 R dCy21 NR cCy21 R dCy21 NR cCy21 C(O)R bCy21 NR cCy21 C(O)NR cCy21 R dCy21 NR cCy21 C(O)OR aCy21 C(=NR) eCy21 )NR cCy21 R dCy21 NR cCy21 C(=NR eCy21 )NR cCy21 R dCy21 S(O)R bCy21 S(O)NR cCy21 R dCy21 S(O)2R bCy21 NR cCy21 S(O)2R bCy21 and S(O)2NR cCy21 R dCy21 ; where R is formed Cy2 C 3-6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10The aryl group and the 5- to 10-membered heteroaryl group are each optionally selected independently by 1, 2, 3, or 4 groups from R. Cy2A Substituents are substituted; wherein R is formed Cy2 The cyclic atoms of the 4- to 10-membered heterocyclic alkyl groups and the 5- to 10-membered heteroaryl groups consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; wherein R forms Cy2 The cyclic carbon atoms of the 4- to 10-membered heterocyclic alkyl groups and the 5- to 10-membered heteroaryl groups are optionally substituted with oxygen to form a carbonyl group; and wherein R is formed. Cy2 C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. Cy2B Substituents of the substituents;

[0319] Each R Cy2A Selected independently from C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl and R Cy2B ; where R is formed Cy2A C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. Cy2B Substituents of the substituents

[0320] Each R Cy2B Independently selected from D, halogenated, CN, OR aCy21 SR aCy21 C(O)R bCy21 C(O)NR cCy21 R dCy21 C(O)OR aCy21 OC(O)R bCy21 OC(O)NR cCy21 R dCy21 NR cCy21 R dCy21 NR cCy21 C(O)R bCy21 NR cCy21 C(O)NR cCy21 R dCy21 NR cCy21 C(O)OR aCy21 C(=NR) eCy21 )NR cCy21 R dCy21 NR cCy21 C(=NR eCy21 )NR cCy21R dCy21 S(O)R bCy21 S(O)NR cCy21 R dCy21 S(O)2R bCy21 NR cCy21 S(O)2R bCy21 and S(O)2NR cCy21 R dCy21 ,

[0321] R aCy21 R bCy21 R cCy21 and R dCy21 Each is independently selected from H and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 Alkyl groups; wherein R is formed aCy21 R bCy21 R cCy21 and R dCy21 C 6-10 Aryl-C 1-3 Alkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 Each alkyl group is optionally substituted with one, two, or three substituents, which are independently selected from C10. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 Alkyne, Halogenated, CN, OR aCy22 SR aCy22 C(O)R bCy22 C(O)NR cCy22 R dCy22 C(O)OR aCy22 OC(O)R bCy22 OC(O)NR cCy22 R dCy22 NR cCy22 R dCy22 NR cCy22C(O)R bCy22 NR cCy22 C(O)NR cCy22 R dCy22 NR cCy22 C(O)OR aCy22 C(=NR) eCy22 )NR cCy22 R dCy22 NR cCy22 C(=NR eCy22 )NR cCy22 R dCy22 S(O)R bCy22 S(O)NR cCy22 R dCy22 S(O)2R bCy22 NR cCy22 S(O)2R bCy22 and S(O)2NR cCy22 R dCy22 ; where R is formed aCy21 R bCy21 R cCy21 and R dCy21 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 Each of the alkyl groups consists of at least one carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and wherein R is formed. aCy21 R bCy21 R cCy21 and R dCy21 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 The cyclic carbon atom of the alkyl group may be optionally substituted with an oxygen to form a carbonyl group;

[0322] Or R connected to the same N atom cCy21 and R dCy21 Together with the N atom attached to both of them, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl group or a 5-membered heteroaryl group, each optionally substituted with 1, 2, or 3 substituents, these substituents being independently selected from C. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 Alkyne, Halogenated, CN, OR aCy22 SR aCy22 C(O)R bCy22 C(O)NR cCy22 R dCy22C(O)OR aCy22 OC(O)R bCy22 OC(O)NR cCy22 R dCy22 NR cCy22 R dCy22 NR cCy22 C(O)R bCy22 NR cCy22 C(O)NR cCy22 R dCy22 NR cCy22 C(O)OR aCy22 C(=NR) eCy22 )NR cCy22 R dCy22 NR cCy22 C(=NR eCy22 )NR cCy22 R dCy22 S(O)R bCy22 S(O)NR cCy22 R dCy22 S(O)2R bCy22 NR cCy22 S(O)2R bCy22 and S(O)2NR cCy22 R dCy22 ;

[0323] R aCy22 R bCy22 R cCy22 and R dCy22 Each is independently selected from H and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, aryl, C 6-10 Aryl-C 1-3 Alkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 Alkyl groups; wherein R is formed aCy22 R bCy22 R cCy22 and R dCy22 C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 6-10 Aryl-C 1-3 Alkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C1-3 Each alkyl group is optionally substituted by one, two, or three substituents, which are independently selected from OH, CN, amino, NH(C) 1-3 alkyl), N(C) 1-3 Alkyl)2, Halogenated, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 Haloalkoxy groups; wherein R is formed aCy22 R bCy22 R cCy22 and R dCy22 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 Each of the alkyl groups consists of at least one carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and wherein R is formed. aCy22 R bCy22 R cCy22 and R dCy22 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 The cyclic carbon atom of the alkyl group is optionally substituted with an oxygen to form a carbonyl group; or

[0324] R connected to the same N atom cCy22 and R dCy22 Together with the N atom attached to both of them, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl group or a 5-membered heteroaryl group, each optionally substituted with 1, 2, or 3 substituents, which are independently selected from OH, CN, amino, NH(C) 1-6 alkyl), N(C) 1-6 Alkyl)2, Halogenated, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 Halogenated alkoxy groups; and

[0325] R eCy21 and R eCy22 Each can be independently H, CN, or NO2.

[0326] In one embodiment of formula IV,

[0327] Cy 1 A phenyl group optionally substituted with one or two substituents, each selected from D, C 1-3 Alkyl, C 1-3Halogenated alkyl, halogenated, OH and C 1-3 Alkoxy;

[0328] R 1 Halogenated;

[0329] R 2 C that is optionally substituted with OH 1-3 alkyl;

[0330] R 3 C that is optionally halogenated 3-10 cycloalkyl;

[0331] Each R 4 For H;

[0332] An R 5 For R 5A ; and each other R 5 Independently selected from H, D, halogenated, C 1-3 Alkyl, OC 1-3 Alkyl, C 1-3 Haloalkyl; or, optionally, two other R atoms attached to adjacent carbon atoms. 5 Together with the carbon atoms to which they are attached, they form fused C atoms that are optionally substituted with one or two substituents. 3-6 Cycloalkyl ring, wherein the substituents are each selected from D, C 1-3 Alkyl and halogenated; and

[0333] R 5A H, halogenated or OR a5A ;

[0334] R a5A Selected from C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and Cy 2 R is formed a5A C 1-3 The alkyl group is optionally substituted with 1, 2, or 3 D atoms, and is also optionally substituted with Cy atoms. 2 Replace; and

[0335] Cy 2 Selected from C 6-10 Aryl and 5- to 10-membered heteroaryl groups.

[0336] In another embodiment of formula IV,

[0337] Cy 1 A phenyl group optionally substituted with one or two substituents, each selected from D, C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, OH and C 1-3 Alkoxy;

[0338] R 1 Halogenated;

[0339] R 2 C that is optionally substituted with OH 1-3 alkyl;

[0340] R 3 OR that is optionally replaced by halogenation 3A Or C 3-10 cycloalkyl;

[0341] R 3A C 1-3 alkyl;

[0342] Each R 4 For H;

[0343] An R 5 For R 5A ; and each other R 5 Independently selected from H, D, halogenated, C 1-3 Alkyl, OC 1-3 Alkyl, C 1-3 Haloalkyl; or, optionally, two other R atoms attached to adjacent carbon atoms. 5 Together with the carbon atoms to which they are attached, they form fused C atoms that are optionally substituted with one or two substituents. 3-6 Cycloalkyl ring, wherein the substituents are each selected from D, C 1-3 Alkyl and halogenated;

[0344] R 5A H, halogenated or OR a5A ;

[0345] R a5A Selected from C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and Cy 2 R is formed a5A C 1-3 The alkyl group is optionally substituted with 1, 2, or 3 D atoms, and is also optionally substituted with Cy atoms. 2 Replace; and

[0346] Cy 2 Selected from C 6-10 Aryl and 5- to 10-membered heteroaryl groups.

[0347] In another embodiment of formula IV,

[0348] Cy 1 A phenyl group optionally substituted with one or two substituents, each of which is selected from C10. 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, OH and C1-3 Alkoxy;

[0349] R 1 Halogenated;

[0350] R 2 C that is optionally substituted with OH 1-3 alkyl;

[0351] R 3 OR that is optionally replaced by halogenation 3A Or C 3-10 cycloalkyl;

[0352] R 3A C 1-3 alkyl;

[0353] Each R 4 For H;

[0354] An R 5 For R 5A ; and each other R 5 Independently selected from H, halogen, C 1-3 Alkyl, OC 1-3 Alkyl, C 1-3 Halogenated alkyl groups;

[0355] R 5A H, halogenated or OR a5A ;as well as

[0356] R a5A Selected from C 1-3 Alkyl and C 1-3 Halogenated alkyl groups, wherein R is formed a5A C 1-3 The alkyl group may optionally be substituted with 1, 2 or 3 D atoms.

[0357] In one embodiment, the compound of formula IV is a compound of formula IV-A or formula IV-B:

[0358]

[0359] Or its pharmaceutically acceptable salt.

[0360] In another embodiment, the compound of formula IV is selected from:

[0361] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-methoxy-2-azabicyclo[2.2.1]heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0362] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-fluoro-2-azabicyclo[2.2.1]heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0363] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-2-(6-(cyclopropanecarbonyl)-6-azatricyclo[3.2.1.02,4]octane-7-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0364] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-(methoxy-d3)-2-azabicyclo[2.2.1]heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0365] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-(pyridin-3-yloxy)-2-azabicyclo[2.2.1]heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0366] 3-(2-(5-(benzyloxy)-2-(cyclopropanecarbonyl)-2-azabicyclo[2.2.1]heptane-3-yl)-1-(2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0367] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0368] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-(5-fluoro-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptane-3-yl)-4-((R)-1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0369] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-(difluoromethyl)-2-azabicyclo[2.2.1]heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0370] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-2-azabicyclo[2.2.1]heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0371] 5-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-2-(2-(cyclopropanecarbonyl)-2-azabicyclo[2.2.1]heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-4-yl)-N,N-dimethylpyridineamide;

[0372] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-2-azabicyclo[2.2.1]heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0373] 4-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-2-(2-(cyclopropanecarbonyl)-2-azabicyclo[2.2.1]heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-4-yl)-2-fluoro-N-methylbenzamide;

[0374] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-methyl-2-azabicyclo[2.2.1]heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0375] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0376] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-(pyridin-2-yloxy)-2-azabicyclo[2.2.1]heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0377] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-(pyridin-4-yloxy)-2-azabicyclo[2.2.1]heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0378] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-2-(5-(difluoromethoxy)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptane-3-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0379] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-(5-fluoro-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptane-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0380] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-2-(5-chloro-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0381] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-(trifluoromethoxy)-2-azabicyclo[2.2.1]heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0382] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-2-(5-(difluoromethoxy)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptane-3-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0383] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-cyclopropoxy-2-azabicyclo[2.2.1]heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0384] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-2-(5-(difluoromethoxy)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptane-3-yl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0385] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-2-(5-cyclopropoxy-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0386] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)-5-(trifluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid methyl ester;

[0387] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-(2-(1-fluorocyclopropane-1-carbonyl)-5-(trifluoromethoxy)-2-azabicyclo[2.2.1]heptane-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0388] 3-(1-(2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)-5-(difluoromethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid methyl ester; and

[0389] 3-(1-(2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-2-(5-(difluoromethyl)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptane-3-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0390] And its pharmaceutically acceptable salts.

[0391] In another embodiment, the KRAS G12D inhibitor is (1R,3R,4R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate (“Compound 2”) or a pharmaceutically acceptable salt thereof.

[0392] In yet another embodiment, the KRAS G12D inhibitor is (1R,3R,4R,5S)-3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid methyl ester:

[0393] .

[0394] In one embodiment, the KRAS G12D inhibitor is (1R,3R,4R,5S)-3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid methyl ester:

[0395] .

[0396] In another embodiment, the KRAS G12D inhibitor is selected from MRTX1133, RMC-9805, HRS-4642, ASP-3082, BI-2852, MRTX-EX185, 3144, QTX3046, VRTX153, JAB-22000, TH-Z827, TH-Z801, TH-Z814, TH-Z816, TH-Z835, TH-Z827, TH-Z837, KD-8, NS-1 and CAS No.: 2765254-39-3.

[0397] In some embodiments, the inhibitor of the KRAS G12D inhibitor is selected from compounds disclosed in WO2018 / 145020, WO2022 / 015375, WO2021 / 091967, WO2022 / 060836, US2023 / 0293464A1, US2023 / 0219951A1 or US2023 / 0285498A1, the contents of which are incorporated herein by reference in their entirety.

[0398] In some embodiments, the inhibitor of the KRAS G12D inhibitor is selected from compounds disclosed below: WO2016161361; WO2020212895; WO2021041671; WO2021081212; WO2021106231; WO2021107160; WO2021126799; WO2021215544; WO2021248079; WO2021248082; WO2021248095; WO2022002102; WO2022015375; WO2022031678; WO2022042630; WO2022066646; WO2022098625; WO2022105855; WO2022105857; WO2022105859; WO2022173033; WO2022177917; WO2022184178; WO2022188729; WO2022192794; WO2022194066; WO2022 194191; WO2022194192; WO2022198905; WO2022199170; WO2022199586; WO2022206723; WO2022206724; WO2022212947; WO2022214102; WO2022217042; WO2022221739; WO2022223020; WO2022227987; WO2022228543; WO2022232331; WO2022232332; WO2022234639; WO2022234851; WO2022240971; WO2022 261154; WO2022262686; WO2022262838; WO2022266069; WO2022268051; WO2023001123; WO2023001141; WO2023018810; WO2023018812; WO2023020347; WO2023025116; WO2023030495; WO2023051586; WO2023056951; WO2023059594; WO2023059596; WO2023059597; WO2023059598; WO2023059600; WO2023 061294; WO2023061463; WO2023072188; WO2023085657; WO2023098425; WO2023098426; WO2023098832; WO2023101928; WO2023103523; WO2023103906;WO2023104018; WO2023113739; WO2023122662; WO2023125627; WO2023125989; WO2023133183; WO2023134465; WO2023143312; W The contents of the patents O2023280280; WO2023283933; WO2023284537; WO2023284881; US11453683; US20180086752; US20180201610; US20220323614; US20220402971; US20230077225; US20230083431; US20230174518; US20230242544; and US20230279025 are incorporated herein by reference in their entirety.

[0399] In another embodiment, the KRAS G12D inhibitor is a proteolytic targeting chimera (PROTAC). PROTAC is a heterobifunctional compound containing a ligand for a target protein (e.g., KRAS with a G12D mutation) and a ligand for an E3 ligase that binds via a linker.

[0400] In some embodiments, the inhibitor of the KRAS G12D proteolytic targeting chimera (PROTAC) is selected from compounds disclosed as follows: WO2022148421; WO2022148422; WO2022173032; WO2023077441; WO2023081476; WO2023119677; WO2023120742; WO2023138524; and WO2023171781; the contents of these patents are incorporated herein by reference in their entirety.

[0401] In one embodiment, the disclosed compound may exist as a tautomer. All tautomers are included within the scope of the compounds described herein.

[0402] The compounds presented herein can exist as transisomeric forms (i.e., conformational diastereomers), which are stable at room temperature and can be separated by, for example, chromatography. For instance, compounds of formula I can exist as transisomeric forms, which can be separated by, for example, the formation of a Cy group around a Cy group. 1(or any embodiment thereof) interchanges with the bonds of the rest of the molecule through rotation. References to the compounds described herein or any embodiments should be understood to include all such transisomer forms of the compound. Without being limited by any theory, it should be understood that for a given compound, one transisomer may be more potent as a KRAS (including the G12D mutant form of KRAS) inhibitor than another transisomer. For example, compounds of formula I as described herein, wherein Cy 1 It is a 2,3-dichlorophenyl, which can exist as a trans-restricted isomer, wherein the conformation of the dichlorophenyl relative to the rest of the molecule is shown in the following partial formula (IV-A or IV-B). The asymmetry of the trans-restricted isomer is assigned as R. a or S a As determined by conventional methods for characterizing asymmetric points. Without being bound by any theory, it should be understood that, for a given compound, the transisomer represented by formula IV-A is generally more potent as a KRAS (including the G12D mutant form of KRAS) inhibitor than the transisomer represented by formula IV-B.

[0403]

[0404] The compounds described herein also include isotopically labeled compounds, wherein one or more atoms are replaced by atoms having the same number of atoms but with an atomic mass or mass number different from those normally found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include, but are not limited to, those that are suitable for inclusion in the compounds described herein. 2 H, 3 H, 11 C 13 C 14 C 36 Cl、 18 F, 123 I, 125 I, 13 N、 15 N、 15 O、 17 O、 18 O、 32 P and 35 S. In another embodiment, the isotope-labeled compound can be used for drug or substrate tissue distribution studies. In another embodiment, substitution with a heavier isotope, such as deuterium, can produce greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement). In yet another embodiment, the compound described herein comprises 2 H (i.e., deuterium) isotope.

[0405] In another embodiment, isotopes that emit positrons (such as...) are used. 11 C 18 F,15 O and 13 Substitution with N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds are prepared by any suitable method or by a process that uses an appropriate isotopically labeled reagent instead of an unlabeled reagent.

[0406] The compounds described herein, as well as other compounds covered by one or more of the formulas described herein with different substituents, were synthesized using the techniques and materials described herein and are described, for example, in the following: Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1–17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1–5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1–40 (John Wiley and Sons, 1991); Carey and Sundberg, Advanced Organic Chemistry, 4th Edition, Volumes A and B (Plenum 2000, 2001); Advances in Heterocyclic Chemistry, Volumes 1–114 (Elsevier, 1963–2023); Journal of Heterocyclic Chemistry, Volumes 1–60 (Journal of Heterocyclic Chemistry, 1964–2023); EM Carreira, et al. (eds.) Science of Synthesis, Volumes 1–48 (2001–2010) and Knowledge Updates KU 2010 / 1–4; 2011 / 1–4; 2012 / 1–4, 2013 / 1–4; 2014 / 1–4, 2015 / 1–2; 2016 / 1–3, 2017 / 1–3; 2018 / 1–4, 2019 / 1–3; 2020 / 1–3, 2021 / 1–3, 2022 / 1–3, 2023 / 1 (Thieme, 2001–2023); Houben-Weyl, Method of Organischen Chemie, 4th edition, Volumes 1-67 (Thieme, 1952-1987); Houben-Weyl, Methoden der Organischen Chemie, E series, Volumes 1-23 (Thieme, 1982-2003); AR Katritzky et al. (eds.), Comprehensive Organic Functional Group Transformations, Volumes 1-6 (Pergamon Press, 1995); AR Katritzky et al. (eds.), Comprehensive Organic Functional Group Transformations II, Volumes 1-6 (Elsevier, 2nd edition, 2005); AR Katritzky et al. (eds.); Comprehensive Heterocyclic Chemistry, Volumes 1-8 (Pergamon Press, 1984); AR Katritzky et al. (eds.); Comprehensive Heterocyclic Chemistry II, Volumes 1-10 (Pergamon Press, 1996); AR Katritzky et al. (eds.); Comprehensive Heterocyclic Chemistry III, Volumes 1-14 (Elsevier Science, 2008); D. St.C. Black, et al. (editors); Comprehensive Heterocyclic Chemistry IV, Volumes 1-14 (Elsevier Science, 2022); MB Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. 6th edition (Wiley, 2007); MB Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8th edition (Wiley, 2020); BM Trost et al. (eds.), Comprehensive Organic Synthesis, Volumes 1–9 (Pergamon Press, 1991); and Patai's Chemistry of Functional Groups, Volumes 100 (Wiley 1964–2022) (all of these references are incorporated herein by reference to such publications). The general methods for preparing the compounds described herein are modified by using appropriate reagents and conditions to incorporate the various parts found in the formulas provided herein.

[0407] The compounds described herein can be synthesized from commercially available compounds using any suitable procedure, or prepared using the procedure described herein.

[0408] EGFR inhibitors

[0409] The combination therapy presented in this article may include a KRAS G12D inhibitor as well as any of a variety of EGFR inhibitors.

[0410] EGFR is a member of the ErbB family of receptor tyrosine kinases, present in both normal and tumor cells; it is responsible for regulating epithelial tissue development and homeostasis. EGFR is associated with various types of cancer because it is frequently overexpressed in malignant cells, and EGFR overexpression is linked to later-stage disease and poor prognosis. EGFR is commonly mutated in certain types of cancer and acts as a driver of tumorigenesis. In vitro, cetuximab has been shown to mediate antitumor effects in various cancer cell lines and human tumor xenografts.

[0411] In some embodiments, the EGFR inhibitor is a small molecule inhibitor. In one embodiment, the EGFR inhibitor is selected from afatinib, brigatinib, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, mobocertinib, neratinib, osimertinib, and vandetanib.

[0412] In some embodiments, the EGFR inhibitor is an anti-EGFR antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the EGFR inhibitor is selected from cetuximab, mateuzumab, nexituzumab, nimotuzumab, panitumumab, and zarumumab.

[0413] In some embodiments, the EGFR inhibitor is cetuximab.

[0414] Cetuximab is a recombinant chimeric human / mouse IgG1 monoclonal antibody that competitively binds to the epidermal growth factor receptor (EGFR) and competitively inhibits the binding of epidermal growth factor (EGF). Antibodies composed of the heavy and light chains listed below are called cetuximab.

[0415] Cetuximab heavy chain (HC)

[0416] QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQG TLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0417] Cetuximab light chain (LC)

[0418] DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECT

[0419] Treatment

[0420] In one aspect, this article provides a method for treating cancer in a subject with this need, the method comprising administering to the subject a KRAS G12D inhibitor or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor.

[0421] On the other hand, this article provides a method for treating cancer in subjects who require this treatment, the method comprising administering to the subject:

[0422] A pharmaceutical composition comprising a KRAS G12D inhibitor or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient; and

[0423] A pharmaceutical composition comprising an EGFR inhibitor or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

[0424] In one embodiment, the KRAS G12D inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof. In another embodiment, the KRAS G12D inhibitor is selected from the compounds listed above. In yet another embodiment, the KRAS G12D inhibitor is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile or a pharmaceutically acceptable salt thereof.

[0425] In another embodiment, the KRAS G12D inhibitor is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate (“Compound 1*”).

[0426] In yet another embodiment, the KRAS G12D inhibitor is 3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate (“Compound 1”).

[0427] In one embodiment, the KRAS G12D inhibitor is 3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate (“Compound 1a”).

[0428] In one embodiment, the KRAS G12D inhibitor is a compound of formula IV or a pharmaceutically acceptable salt thereof. In another embodiment, the KRAS G12D inhibitor is selected from the compounds of formula IV listed above. In yet another embodiment, the KRAS G12D inhibitor is (1R,3R,4R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate (“Compound 2”) or a pharmaceutically acceptable salt thereof.

[0429] In another embodiment, the KRAS G12D inhibitor is (1R,3R,4R,5S)-3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0430] In another embodiment, the KRAS G12D inhibitor is (1R,3R,4R,5S)-3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0431] In some embodiments, the EGFR inhibitor is an anti-EGFR antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the EGFR inhibitor is selected from cetuximab, mateuzumab, nexituzumab, nimotuzumab, panitumumab, and zarumumab. In some embodiments, the EGFR inhibitor is cetuximab.

[0432] In one embodiment, the EGFR inhibitor is a small molecule inhibitor. In one embodiment, the EGFR inhibitor is selected from afatinib, brigatinib, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, mobocetinib, neratinib, osimertinib, and vandetanib.

[0433] In another embodiment, a KRAS G12D inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with an EGFR inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is a small molecule inhibitor. In one embodiment, the EGFR inhibitor is selected from afatinib, brigatinib, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, mobocetinib, neratinib, osimertinib, and vandetanib.

[0434] In some embodiments, the EGFR inhibitor is an anti-EGFR antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the EGFR inhibitor is selected from cetuximab, mateuzumab, nexituzumab, nimotuzumab, panitumumab, and zarumumab. In some embodiments, the EGFR inhibitor is cetuximab.

[0435] On another front, this article provides a method for treating cancer in subjects who require this treatment, the method comprising administering to the subject:

[0436] A pharmaceutical composition comprising compound 1 and at least one pharmaceutically acceptable carrier or excipient; and

[0437] A pharmaceutical composition comprising cetuximab and at least one pharmaceutically acceptable carrier or excipient.

[0438] On another front, this article provides a method for treating cancer in subjects who require this treatment, the method comprising administering to the subject:

[0439] A pharmaceutical composition comprising compound 1* and at least one pharmaceutically acceptable carrier or excipient; and

[0440] A pharmaceutical composition comprising cetuximab and at least one pharmaceutically acceptable carrier or excipient.

[0441] In yet another embodiment, the KRAS G12D inhibitor has an IC50 of approximately 100 nM or lower. 50 In yet another embodiment, the KRAS G12D inhibitor is selective for inhibiting G12D relative to wild-type KRAS.

[0442] In another embodiment, the KRAS G12D inhibitor is administered to a subject as a pharmaceutical composition comprising a KRAS G12D inhibitor or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

[0443] In yet another embodiment, the EGFR inhibitor is administered to a subject as a pharmaceutical composition comprising an EGFR inhibitor or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

[0444] In another aspect, this article provides a method for treating cancer in a subject with this need, the method comprising administering to the subject: a KRAS G12D inhibitor, which is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile or a pharmaceutically acceptable salt thereof; and an EGFR inhibitor, which is cetuximab.

[0445] In one embodiment, the KRAS G12D inhibitor is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile hydrochloride dihydrate (“Compound 1*”).

[0446] In another embodiment, the KRAS G12D inhibitor is 3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate (“Compound 1”).

[0447] In yet another embodiment, the KRAS G12D inhibitor is 3-((S a)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate (“Compound 1a”).

[0448] On the other hand, this article provides a method for treating cancer in a subject with this need, the method comprising administering to the subject: a KRAS G12D inhibitor, which is (1R,3R,4R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate (“Compound 2”) or a pharmaceutically acceptable salt thereof; and an EGFR inhibitor, which is cetuximab.

[0449] In another embodiment of the method, the KRAS G12D inhibitor is administered twice daily (BID). In another embodiment, the KRAS G12D inhibitor is administered once daily (QD). In yet another embodiment, the KRAS G12D inhibitor is administered orally (PO).

[0450] In one embodiment, the EGFR inhibitor is administered twice weekly (BIW). In another embodiment, the EGFR inhibitor is administered intravenously (IV).

[0451] In another embodiment, the cancer is selected from carcinoma, hematologic malignancies, sarcomas, and glioblastoma. In yet another embodiment, the cancer is a cancer comprising abnormally proliferating cells with a KRAS G12D mutation.

[0452] In one embodiment, the method further includes identifying the presence of abnormally proliferating cells with a KRAS G12D mutation.

[0453] In another embodiment, the cancer is selected from the following blood cancers: myeloproliferative neoplasms, myelodysplastic syndromes, chronic and juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and multiple myeloma.

[0454] In another embodiment, the cancer is selected from the following: pancreatic cancer, colorectal cancer, lung cancer, bladder cancer, stomach cancer, esophageal cancer, breast cancer, head and neck cancer, cervical cancer, skin cancer, and thyroid cancer. In yet another embodiment, the cancer is colorectal cancer. In still another embodiment, the cancer is lung cancer. In one embodiment, the cancer is pancreatic cancer.

[0455] In another embodiment, the cancer is colorectal cancer.

[0456] In yet another embodiment, the cancer is non-small cell lung cancer (NSCLC).

[0457] In yet another embodiment, the cancer is pancreatic ductal adenocarcinoma.

[0458] On the other hand, this article provides a method for treating colorectal cancer in subjects with this need, the method comprising administering to the subject: a KRAS G12D inhibitor, which is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile or a pharmaceutically acceptable salt thereof; and an EGFR inhibitor, which is cetuximab.

[0459] In one embodiment, the KRAS G12D inhibitor is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile hydrochloride dihydrate (“Compound 1*”).

[0460] In another embodiment, the KRAS G12D inhibitor is 3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate (“Compound 1”).

[0461] In yet another embodiment, the KRAS G12D inhibitor is 3-((S a)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate (“Compound 1a”).

[0462] On the other hand, this article provides a method for treating colorectal cancer in subjects with this need, the method comprising administering to the subject: a KRAS G12D inhibitor, which is (1R,3R,4R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate (“Compound 2”) or a pharmaceutically acceptable salt thereof; and an EGFR inhibitor, which is cetuximab.

[0463] In one embodiment, the cancer is metastatic.

[0464] In one embodiment of the method, the KRAS inhibitor and the EGFR inhibitor are administered separately.

[0465] In another embodiment of the method, the cancer is a myeloproliferative tumor.

[0466] In another embodiment of the method, the cancer is myelodysplastic syndrome (MDS). MDS can include hematopoietic stem cell disorders characterized by one or more of the following: ineffective hematopoiesis, progressive cytopenia, risk of progression to acute leukemia, or morphologically and maturingly impaired bone marrow cells (myelogenesis disorder). MDS can also include refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excessive blasts, refractory anemia with excessive blasts in transformation, and chronic myelomonocytic leukemia.

[0467] In another embodiment of the method, the cancer is selected from the group consisting of: chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, eosinophilic syndrome, systemic mastocytosis, atypical chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). In yet another embodiment, the cancer is myelofibrosis (MF).

[0468] In one embodiment of the method, the cancer is selected from the group consisting of: primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis.

[0469] In another embodiment of the method, the subject is a human.

[0470] In another embodiment of the method, the treatment includes essentially simultaneous administration of a KRAS inhibitor and an EGFR inhibitor.

[0471] In another embodiment of the method, the treatment includes administering a KRAS inhibitor and an EGFR inhibitor at different times.

[0472] In one embodiment of the method, a KRAS inhibitor is administered to the subject, followed by an EGFR inhibitor. In yet another embodiment, an EGFR inhibitor is administered to the subject, followed by a KRAS inhibitor.

[0473] In another embodiment of the method, the KRAS inhibitor and / or EGFR inhibitor are administered at doses that would be ineffective if one or both of the KRAS inhibitor and EGFR inhibitor were administered alone, but these doses would be effective when combined.

[0474] In one embodiment of the method, the method involves administering a therapeutically effective amount of a combination or composition comprising the compounds provided herein or pharmaceutically acceptable salts thereof to a subject (including, but not limited to, a human or animal) (including a subject identified as having a need for treatment).

[0475] In another embodiment of the method, the treatment comprises co-administering the amount of the KRAS inhibitor and the amount of the EGFR inhibitor. In one embodiment, the amount of the KRAS inhibitor and the amount of the EGFR inhibitor are in a single formulation or unit dosage form. In other embodiments, the amount of the KRAS inhibitor and the amount of the EGFR inhibitor are in separate formulations or unit dosage forms.

[0476] In the aforementioned methods, treatment may include administering the amount of the KRAS inhibitor and the amount of the EGFR inhibitor substantially simultaneously, or administering the amount of the KRAS inhibitor and the amount of the EGFR inhibitor at different times. In some embodiments of the aforementioned methods, the amount of the KRAS inhibitor and / or the amount of the EGFR inhibitor is administered at a dose that would be ineffective if either or both of the KRAS inhibitor and EGFR inhibitor were administered alone, but these amounts are effective when combined.

[0477] Drug combination

[0478] In one aspect, this document provides a pharmaceutical combination comprising a KRAS G12D inhibitor or a pharmaceutically acceptable salt thereof and an EGFR inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical combination may comprise separate pharmaceutical dosage forms or pharmaceutical compositions that are also sold independently of each other. In another embodiment, the pharmaceutical combination is intended for simultaneous or sequential use to achieve a combined effect. In yet another embodiment, the pharmaceutical combination may comprise separate components or components together in a single unit dose.

[0479] In one embodiment, the KRAS G12D inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof. In another embodiment, the KRAS G12D inhibitor is selected from the compounds listed above. In yet another embodiment, the KRAS G12D inhibitor is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile or a pharmaceutically acceptable salt thereof.

[0480] In another embodiment, the KRAS G12D inhibitor is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate (“Compound 1*”).

[0481] In yet another embodiment, the KRAS G12D inhibitor is 3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate (“Compound 1”).

[0482] In one embodiment, the KRAS G12D inhibitor is 3-((S a)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate (“Compound 1a”).

[0483] In one embodiment, the KRAS G12D inhibitor is a compound of formula IV or a pharmaceutically acceptable salt thereof. In another embodiment, the KRAS G12D inhibitor is selected from the compounds of formula IV listed above. In yet another embodiment, the KRAS G12D inhibitor is (1R,3R,4R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate (“Compound 2”) or a pharmaceutically acceptable salt thereof.

[0484] In another embodiment, the KRAS G12D inhibitor is (1R,3R,4R,5S)-3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0485] In another embodiment, the KRAS G12D inhibitor is (1R,3R,4R,5S)-3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0486] In some embodiments, the EGFR inhibitor is an anti-EGFR antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the EGFR inhibitor is selected from cetuximab, mateuzumab, nexituzumab, nimotuzumab, panitumumab, and zarumumab. In some embodiments, the EGFR inhibitor is cetuximab.

[0487] In one embodiment, the EGFR inhibitor is a small molecule inhibitor. In one embodiment, the EGFR inhibitor is selected from afatinib, brigatinib, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, mobocetinib, neratinib, osimertinib, and vandetanib.

[0488] In another embodiment of the drug combination, the KRAS G12D inhibitor is administered twice daily (BID). In another embodiment, the KRAS G12D inhibitor is administered once daily (QD). In yet another embodiment, the KRAS G12D inhibitor is administered orally (PO).

[0489] In one embodiment, the EGFR inhibitor is administered twice weekly (BIW). In another embodiment, the EGFR inhibitor is administered intravenously (IV). In yet another embodiment, the EGFR inhibitor is administered intraperitoneally (IP).

[0490] Applying the drug combinations provided herein can produce beneficial effects, such as synergistic therapeutic effects, for example, in terms of relieving symptoms, delaying the progression of symptoms, or inhibiting symptoms, and can also produce further surprising beneficial effects, such as fewer side effects, improved quality of life, or reduced morbidity compared to monotherapy using only one of the pharmaceutical active ingredients used in the combinations of the present invention.

[0491] Pharmaceutical Composition

[0492] In one aspect, this document provides a pharmaceutical composition comprising...

[0493] a) KRAS G12D inhibitors or pharmaceutically acceptable salts thereof;

[0494] b) EGFR inhibitors or their pharmaceutically acceptable salts; and

[0495] c) At least one pharmaceutically acceptable carrier or excipient.

[0496] In one embodiment, the KRAS G12D inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof. In another embodiment, the KRAS G12D inhibitor is selected from the compounds listed above. In yet another embodiment, the KRAS G12D inhibitor is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile or a pharmaceutically acceptable salt thereof.

[0497] In another embodiment, the KRAS G12D inhibitor is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate (“Compound 1*”).

[0498] In yet another embodiment, the KRAS G12D inhibitor is 3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate (“Compound 1”).

[0499] In one embodiment, the KRAS G12D inhibitor is 3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate (“Compound 1a”).

[0500] In one embodiment, the KRAS G12D inhibitor is a compound of formula IV or a pharmaceutically acceptable salt thereof. In another embodiment, the KRAS G12D inhibitor is selected from the compounds of formula IV listed above. In yet another embodiment, the KRAS G12D inhibitor is (1R,3R,4R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate (“Compound 2”) or a pharmaceutically acceptable salt thereof.

[0501] In another embodiment, the KRAS G12D inhibitor is (1R,3R,4R,5S)-3-((R a)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0502] In another embodiment, the KRAS G12D inhibitor is (1R,3R,4R,5S)-3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0503] In some embodiments, the EGFR inhibitor is an anti-EGFR antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the EGFR inhibitor is selected from cetuximab, mateuzumab, nexituzumab, nimotuzumab, panitumumab, and zarumumab. In some embodiments, the EGFR inhibitor is cetuximab.

[0504] In one embodiment, the EGFR inhibitor is a small molecule inhibitor. In one embodiment, the EGFR inhibitor is selected from afatinib, brigatinib, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, mobocetinib, neratinib, osimertinib, and vandetanib.

[0505] Packaged blends

[0506] This article includes packaged pharmaceutical formulations or pharmaceutical products. Such packaged formulations include one or more pharmaceutical formulations containing a combination of a KRAS inhibitor and an EGFR inhibitor. The combination of compounds in formulation form is contained in a container. The packaging typically includes instructions for using the formulation to treat animals (usually human patients) with cancer.

[0507] In some embodiments, the packaged pharmaceutical formulation or pharmaceutical product contains a combination of compounds described herein in a container along with instructions for administration in a fixed schedule. In some of these embodiments, the combination of compounds is provided in separate unit dosage forms.

[0508] In certain embodiments, the compounds in the combination can be administered according to the same schedule, either by administering a single formulation or unit dosage form containing all the compounds in the combination, or by administering separate formulations or unit dosage forms of the compounds in the combination. However, some of the compounds used in the combination may be administered at a higher frequency than once daily, or at a different frequency than the other compounds in the combination. Therefore, in one embodiment, the packaged pharmaceutical formulation contains formulations or unit dosage forms of all the compounds in the combination containing the compounds in a container, as well as an additional formulation or unit dosage form of one of these compounds in the combination containing the pharmaceutical agent, without additional active compounds, and has instructions for administration according to a fixed schedule.

[0509] The packaged formulations described herein include, for example, prescribing information for patients or healthcare providers, or as labeled in packaged pharmaceutical formulations. Prescribing information may include, for example, information regarding the efficacy, dosage and administration, contraindications, and adverse reactions of the pharmaceutical formulation.

[0510] In all the foregoing, the combination of compounds of the present invention can be applied alone, as a mixture, or with an additional activator.

[0511] Application / Dosage / Formulation

[0512] On the other hand, this document provides a pharmaceutical composition or combination of pharmaceuticals comprising the compounds disclosed herein and a pharmaceutically acceptable carrier.

[0513] Administration of this combination includes administering the combination as a single formulation or unit dosage form, administering each agent in the combination simultaneously but separately, or administering the individual agents in the combination sequentially via any suitable route. The dosage of each agent in the combination may require more frequent administration than the other agents in the combination. Therefore, to allow for proper dosing, packaged pharmaceutical products may contain dosage forms of one or more combinations containing agents, and dosage forms of one or more combinations containing one agent but not the other agents in the combination.

[0514] The actual dose level of the active ingredient in a pharmaceutical composition can be altered to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response for a specific subject, composition, and administration mode, while being non-toxic to the patient.

[0515] Specifically, the chosen dose level will depend on a variety of factors, including the activity of the particular compound used, the timing of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds or materials used in combination with the compound, the patient’s age, sex, weight, condition, general health and prior medical history, and similar factors well known in the medical field.

[0516] A physician or veterinarian with ordinary skills in the art can readily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian may begin administration of the pharmaceutical composition at a level lower than required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[0517] In one embodiment, the free base equivalent of compound 1 is administered at a dose of about 50 mg to about 2000 mg. In one embodiment, the free base equivalent of compound 1 is administered at a dose of about 200 mg to about 1600 mg. In one embodiment, the free base equivalent of compound 1 is administered at a dose of about 200 mg to about 1200 mg.

[0518] In some embodiments, the free base equivalent of compound 1 is administered at doses of about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg.

[0519] In one embodiment, compound 1 is administered once, twice, three times, or four times daily.

[0520] In one embodiment, the free base equivalent of compound 1 is administered at a dose of about 50 mg to about 2000 mg. In one embodiment, the free base equivalent of compound 1 is administered at a dose of about 200 mg to about 1600 mg. In one embodiment, the free base equivalent of compound 1 is administered at a dose of about 200 mg to about 1200 mg.

[0521] In some embodiments, the free base equivalent of compound 1 is administered at doses of about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg.

[0522] In one embodiment, cetuximab is administered at approximately 100 mg / m². 2 Approximately 1000 mg / m 2 The dosage is as follows. In one embodiment, cetuximab is administered at approximately 300 mg / m². 2 Approximately 800 mg / m 2 The dosage is as follows. In one embodiment, cetuximab is administered at approximately 400 mg / m². 2 Approximately 600 mg / m 2 Dosage administration.

[0523] In one embodiment, cetuximab is administered at approximately 100 mg / m². 2 Approximately 200 mg / m 2 Approximately 250 mg / m 2 Approximately 300 mg / m 2 Approximately 350 mg / m 2 Approximately 400 mg / m 2 Approximately 450 mg / m 2 Approximately 500 mg / m 2 Approximately 550 mg / m 2 Approximately 600 mg / m 2 Approximately 700 mg / m 2 Approximately 800 mg / m 2 Approximately 900 mg / m 2 Approximately 1000 mg / m 2 Approximately 1100 mg / m 2 Approximately 1200 mg / m 2 Approximately 1300 mg / m 2 Approximately 1400 mg / m 2 Approximately 1500 mg / m 2 Approximately 1600 mg / m 2 Approximately 1700 mg / m 2 Approximately 1800 mg / m 2Approximately 1900 mg / m 2 Or approximately 2000 mg / m 2 Dosage administration.

[0524] In one embodiment, cetuximab is administered intravenously (IV). In another embodiment, cetuximab is administered every two weeks (q2wk).

[0525] In certain embodiments, it is particularly advantageous to formulate compounds in unit dosage form to facilitate dosage administration and uniformity. As used herein, unit dosage form refers to a physically discrete unit suitable as a single dose to a patient to be treated; each unit contains a predetermined amount of the disclosed compound calculated to bind with a desired pharmaceutical medium to produce the desired therapeutic effect. The unit dosage form is defined by and directly depends on (a) the unique properties of the disclosed compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations of mixing / formulating such disclosed compounds for the treatment of a patient's pain, depression, or drug addiction.

[0526] In one embodiment, the compounds provided herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical composition provided herein comprises a therapeutically effective amount of the disclosed compound and a pharmaceutically acceptable carrier.

[0527] The pharmaceutical compounds (e.g., KRAS inhibitors and EGFR inhibitors) described herein are present in ratios ranging from 100:1 to 1:100 in the combinations, dosage forms, pharmaceutical compositions, and pharmaceutical formulations disclosed herein. For example, the ratio of PD EGFR inhibitor to KRAS inhibitor may range from 1:100 to 1:1 (e.g., 1:100, 1:90, 1:80, 1:70, 1:60, 1:50, 1:40, 1:30, 1:20, 1:10, 1:5, 1:2, or 1:1 EGFR inhibitor:KRAS inhibitor). In another example, the KRAS inhibitor:EGFR inhibitor ratio can range from 1:100 to 1:1 (e.g., 1:100, 1:90, 1:80, 1:70, 1:60, 1:50, 1:40, 1:30, 1:20, 1:10, 1:5, 1:2 or 1:1 KRAS inhibitor:EGFR inhibitor).

[0528] The optimal ratio, individual and combined doses and concentrations of pharmaceutical compounds that produce efficacy without toxicity are determined based on the kinetics of the availability of the active ingredient to the target site and using methods known to those skilled in the art.

[0529] Routes of administration for any of the compositions discussed herein include oral, intranasal, rectal, intravaginal, parenteral, oral, sublingual, or topical application. The compounds may be formulated for administration via any suitable route, such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lateral lingual, buccal, urethral, ​​vaginal (e.g., vaginal and perivallary), intranasal, intrarectal, intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, intrasheathal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical application. In one embodiment, oral administration is preferred.

[0530] Suitable compositions and dosage forms include, for example, tablets, capsules, pouches, pills, capsule tablets, lozenges, dispersants, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, emulsions, sugar tablets, creams, pastes, plasters, lotions, round tablets, suppositories, liquid sprays for nasal or oral administration, dry powders or nebulized formulations for inhalation, and compositions and formulations for intravesical administration. It should be understood that formulations and compositions are not limited to the specific formulations and compositions described herein.

[0531] For oral applications, tablets, sugar-coated pills, liquids, drops, suppositories or capsules, pouches, and soft capsules are particularly suitable. Compositions intended for oral use can be prepared according to any method known in the art, and such compositions may contain one or more pharmaceutical agents selected from the group consisting of inert, non-toxic pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example: inert diluents, such as lactose; granulating and disintegrants, such as corn starch; binding agents, such as starch; and lubricants, such as magnesium stearate. For aesthetic purposes or to delay the release of the active ingredient, tablets may be uncoated or may be coated using known techniques. Formulations for oral use may also be hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0532] For parenteral administration, the disclosed compounds may be formulated for injection or infusion, such as intravenous, intramuscular, or subcutaneous injection or infusion, or for bolus administration and / or continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous media may be used, optionally containing other formulation agents such as suspending agents, stabilizers, or dispersants.

[0533] Those skilled in the art will recognize or be able to determine many equivalents of the specific procedures, embodiments, claims, and examples described herein using only conventional experiments. Such equivalents are considered to be within the scope of this disclosure and covered by the appended claims. For example, it should be understood that the use of art-recognized alternatives to the reaction conditions and modifications to conventional experiments (including, but not limited to, reaction time; reaction size / volume; and experimental reagents, such as solvents, catalysts, pressure, atmospheric conditions (e.g., nitrogen atmosphere), and reducing / oxidizing agents) are within the scope of this application.

[0534] It should be understood that whatever values ​​and ranges are provided herein, all values ​​and ranges encompassed by these values ​​and ranges are included within the scope of this disclosure. Furthermore, all values ​​falling within these ranges, as well as the upper or lower limits of the value ranges, are also contemplated in this application.

[0535] The following examples further illustrate aspects of this disclosure. However, they are by no means intended to limit the teachings set forth in this disclosure.

[0536] Example

[0537] The compounds and methods disclosed herein are further illustrated by the following examples, which should not be construed as limiting. Unless otherwise stated, the practice of this disclosure will employ conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, which are within the scope of the art.

[0538] The KRAS inhibitors, their synthesis, and their bioactivity against KRAS described herein can be found in WO 2023 / 064857, which is incorporated herein by reference in its entirety. The KRAS inhibitors, their synthesis, and their bioactivity against KRAS described herein can be found in PCT / US2024 / 025160, which is incorporated herein by reference in its entirety. The EGFR inhibitors, their synthesis, and their bioactivity against EGFR described herein can be found in US 6,217,866, which is incorporated herein by reference in its entirety.

[0539] The following abbreviations may be used in this article: AcOH (acetic acid); Ac2O (acetic anhydride); aq. (aqueous solution); atm. (atmosphere); Boc (tert-butyloxycarbonyl); BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate); br (broad); Cbz (carboxybenzyl); calc. (calculated value); d (doublet); dd (double doublet); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); DCM (dichloromethane); DIAD (N,N'-diisopropylazidodicarboxylate); DIEA (N,N-diisopropylethylamine); DIPEA (N,N-diisopropylethylamine); DIBAL (diisobutylaluminum hydride); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); E t (ethyl); EtOAc (ethyl acetate); FCC (fast column chromatography); g (gram); h (hour); HATU (N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)ureonium hexafluorophosphate); HCl (hydrochloric acid); HPLC (high performance liquid chromatography); Hz (hertz); J (coupling constant); L (liter); LCMS (liquid chromatography-mass spectrometry); LDA (lithium diisopropylaminodimethylamine); m (multiplexes); M ( Moles); mCPBA (3-chloroperoxybenzoic acid); MS (mass spectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg (milligram); min. (minute); mL (milliliter); mmol (millimole); MTBE (methyl tert-butyl ether); N (normal); NCS (N-chlorosuccinimide); NET3 (triethylamine); nM (nanomoles); NMP (N-methylpyrrolidone); NMR (nuclear magnetic resonance spectroscopy); OTf (trifluoromethanesulfonate); Ph (phenyl); pM (picomoles); PPT (precipitate); RP-HPLC (reversed-phase high-performance liquid chromatography); room temperature (room temperature); s (single peak); t (triple peak or triplet); TBS (tert-butyldimethylsilyl); tert (tert-); tt (triple triplet); TFA (trifluoroacetic acid); THF (tetrahydrofuran); µg (microgram); µL (microliter); µM (micromoles); wt% (weight percentage). The brine is a saturated aqueous solution of sodium chloride. In a vacuum is under a vacuum.

[0540] Example 1: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile

[0541]

[0542] Step 1. Methyl 2-amino-4-bromo-3-fluorobenzoate:

[0543]

[0544] Dimethyl sulfate (823 g, 6.53 mol) was added to a mixture of 2-amino-4-bromo-3-fluorobenzoic acid (1500 g, 6.22 mol) and potassium carbonate (945 g, 6.84 mol) in N,N-dicarboxamide or 1,4-dioxane (6 L) at 5 °C to 50 °C. After addition, the mixture was stirred at room temperature for 2 hours to complete the reaction. Water (7.5 L) was gradually added to the reaction mixture to precipitate the product. After water addition, the mixture was stirred at room temperature for 1 hour. The solid was separated by filtration, and the wet filter cake was washed with water (3 x 1.5 L). The solid was dried under vacuum overnight at about 50 °C to give the desired product (1530 g, 99% yield). LCMS calculated value of C8H7BrFNO2: 246.96; Found value: 248 (M + H + ). 1 H NMR (400MHz, DMSO-d6) δ 7.49 (dd, J = 8.8, 1.7 Hz, 1H), 6.87 – 6.77 (m, 3H), 3.82 (s,3H). 19 F NMR (376 MHz, DMSO-d6) δ -127.24

[0545] Step 2. Methyl 3-amino-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylate:

[0546]

[0547] Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (Pd-132) (8.12 g, 0.011 mol) was added to a mixture of methyl 2-amino-4-bromo-3-fluorobenzoate (1420 g, 5.72 mol), 2,3-dichlorophenylboronic acid (1226 g, 6.3 mol), and potassium fluoride (732 g, 12.6 mol) in acetonitrile (6 L) and water (1.5 L). The mixture was degassed and refilled with nitrogen, and heated to 70 °C for 1 hour to complete the reaction. Water (6 L) was added to the reaction mixture at 50 °C. The mixture was cooled to room temperature and stirred for 1 hour. The solids were separated by filtration, and the wet filter cake was washed with water (2 x 2 L) containing 50% acetonitrile and water (2 x 2 L). The solid was dried under vacuum overnight at approximately 50°C to obtain the desired product (1700 g, yield 94%). LCMS, C14 Calculated value of H9Cl2FNO2: 313.01; Measured value: 314 (M + H + ). 1 H NMR(400 MHz, DMSO-d6) δ 7.74 (dd, J = 8.0, 1.6 Hz, 1H), 7.64 (dd, J = 8.4, 1.4Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.40 (dd, J = 7.9, 1.6 Hz, 1H), 6.70 (s(b), 2H), 6.51 (dd, J = 8.3, 6.6 Hz, 1H), 3.86 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -134.70

[0548] Step 3. 3-Amino-6-bromo-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid:

[0549]

[0550] N-bromosuccinimide (684 g, 3.84 mol) was added to a solution of methyl 3-amino-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylate (1150 g, 3.66 mol) in acetonitrile (5.75 L) at 50 °C to 66 °C. After the reaction was complete, the acetonitrile (3 L) was removed by rotary evaporation. Water (5.75 L) was added to the concentrated mixture and stirred at room temperature for 2 to 3 hours. The solid was separated by filtration, and the wet filter cake was washed with water to give methyl 3-amino-6-bromo-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylate. LCMS, C 14 Calculated value of H9BrFCl2NO2: 390.92; Measured value: 391 (M+H). 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 1.7 Hz, 1H), 7.79 (dd, J = 8.1, 1.5Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.40 (dd, J = 7.7, 1.5 Hz, 1H), 6.83 (s(b), 2H), 3.87 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -128.19.

[0551] Step 4. 3-Amino-6-bromo-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid:

[0552]

[0553] The wet filter cake of 3-amino-6-bromo-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid was dissolved in THF (3 L) and methanol (1.5 L). A 1.5 M aqueous solution of sodium hydroxide (5 L) was added to the solution, and the mixture was stirred at approximately 50 °C for 2 hours to complete the saponification reaction. A 1.5 M aqueous solution of hydrochloric acid was gradually added to the mixture to adjust the pH to 3 to 4, and the mixture was stirred at room temperature for 1 hour. The solid was separated by filtration, and the wet filter cake was washed with water (3 x 1.2 L). The solid was dried under vacuum overnight at approximately 50 °C to give the desired product (1354 g, 97.5% yield over two steps). LCMS, C 13 Calculated value of H7BrCl2FNO2: 376.90; Measured value: 378 (M + H + ). 1 H NMR (400 MHz, DMSO-d6) δ7.85 (d, J = 1.7 Hz, 1H), 7.78 (dd, J = 8.1, 1.5 Hz, 1H), 7.52 (t, J = 7.9Hz, 1H), 7.39 (dd, J = 7.9, 1.5 Hz, 1H), 6.88. 19 F NMR (376 MHz, DMSO-d6) δ -128.95.

[0554] Step 5. 6-Bromo-7-(2,3-dichlorophenyl)-8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione:

[0555]

[0556] A solution of 3-amino-6-bromo-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid (1254 g, 3.31 mol) in THF (4 L) was added to tetrahydrofuran (THF) (500 g, 1.65 mol) at 60 °C and stirred for 1 hour to complete the reaction. The mixture was cooled to 35 °C and n-heptane (10 L) was slowly added to precipitate the product. The mixture was cooled to room temperature and stirred for 1 hour. The solid was separated by filtration and washed with n-heptane (2 x 1 L). The wet filter cake was dried under vacuum overnight at about 50 °C to give the desired product (1385 g, quantitative yield). LCMS, C 14 Calculated value of H5BrCl2FNO3: 402.88; Measured value: 404 (M + H + ). 1 H NMR (400 MHz, DMSO-d6) δ12.24 (s, 1H), 8.10 (d, J = 1.5 Hz, 1H), 7.85 (dd, J = 8.1, 1.5 Hz, 1H), 7.58(t, J = 7.9 Hz, 1H), 7.43 (dd, J = 7.7, 1.5 Hz, 1H). 19 F NMR (376 MHz, DMSO-d6)δ -123.98.

[0557] Step 6. Ethyl 6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate:

[0558]

[0559] A mixture of 6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (1078 g, 2.66 mol), ethyl acetoacetate (693 g, 5.32 mol), sodium acetate (393 g, 4.79 mol), and sodium chloride (933 g, 16 mol) in dimethyl sulfoxide (5 L) was heated to 50-60 °C for 5 hours. The temperature was increased to 100 °C and stirred for 1 hour to complete the reaction. The mixture was cooled to 60 °C and water (10 L) was gradually added to precipitate the product. The mixture was cooled to room temperature and stirred for 1 hour. The solid was separated by filtration, and the wet filter cake was washed with water (2 x 2 L). The wet solid was dried overnight under vacuum at about 50 °C to give the desired product (1145 g, 91% yield). LCMS, C 19 H 13Calculated value of BrCl2FNO2: 470.94; Measured value: 472 (M + H) + ). 1 H NMR (400 MHz, DMSO-d6) δ12.05 (s, 1H), 8.18 (d, J = 1.5 Hz, 1H), 7.84 (dd, J = 8.0, 1.6 Hz, 1H), 7.58(t, J = 7.9 Hz, 1H), 7.50 (dd, J = 7.7, 1.6 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 2.46 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -124.80.

[0560] Step 6b. Ethyl 6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate:

[0561] The title compound can be prepared alternatively by the following method. A solution of methyl 3-amino-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylate (100 g, 0.254 mol), ethyl acetoacetate (33.1 g, 0.51 mol), and p-toluenesulfonic acid (2.2 g, 0.013 mol) in xylene (1 L) was refluxed for 5 hours to remove water azeotropically. Sodium ethoxide (26 g, 0.381 mol) was added to the mixture, and the mixture was refluxed again for 5 hours. The mixture was cooled to room temperature and poured into dilute hydrochloric acid at pH = 6 to 7. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were concentrated, and the product was purified by silica gel column chromatography, eluting with ethyl acetate and heptane (0% to 30%) to give the desired product (65 g, 54%). LCMS, C 19 H 13 Calculated value of BrCl2FNO3: 470.91; Measured value: 472 (M + H) + ). 1H NMR (400 MHz, DMSO-d6) δ12.05 (s, 1H), 8.18 (d, J = 1.5 Hz, 1H), 7.84 (dd, J = 8.0, 1.6 Hz, 1H), 7.58(t, J = 7.9 Hz, 1H), 7.50 (dd, J = 7.7, 1.6 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 2.46 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -124.80.

[0562] Step 7. Ethyl 6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate:

[0563]

[0564] A mixture of ethyl 6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate (246 g, 0.52 mol), acrylonitrile (69 g, 1.3 mol), trimethylamine (156 g, 1.56 mol), and bis(di-tert-butyl)-dimethylaminophenylphosphine palladium(II) dichloride (Pd-132) (14.7 g, 0.02 mol) in N,N-dimethylamide (1.5 L) was heated to 85 °C for approximately 5 hours to complete the reaction. The mixture was cooled to 50 °C, and water (1 L) was gradually added. The mixture was cooled to room temperature, and 1 M hydrochloric acid aqueous solution was added to adjust the pH to pH 5 to 6. The solids were separated by filtration, and the wet filter cake was washed with water (2 x 500 mL). The wet solids were dissolved in methanol (1 L) and dichloromethane (9 L). Sodium bisulfite (186 g, 1.8 mol) and water (4 L) were added to the solution. The mixture was stirred at room temperature for 1 hour, and the aqueous phase was separated and discarded. The organic phase was washed with water (2 × 2 L). Activated carbon (150 g) was added to the organic solution, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered through a diatomaceous earth bed, and the bed was washed with dichloromethane (2 L). The organic solution was concentrated to about 1 L, and heptane (3.5 L) was gradually added to precipitate the product. The solid was separated by filtration and washed with heptane (2 × 2 L). The wet solid was dried under vacuum at about 50 °C overnight to give the desired product (210 g). g, yield 90%). LCMS, C 22 H 15Calculated value of Cl2FNO3: 444.04; Measured value: 445 (M + H) + ). 1 ¹H-NMR (400 MHz, DMSO-d6) (cis and trans mixture): δ 12.05 (s, 1H), 8.64 (s, 0H), 8.39 (s, 1H), 7.86 (td, J = 7.7, 1.5 Hz, 1H), 7.63 – 7.53 (m, 1H), 7.47 (td, J = 7.5, 1.6 Hz, 1H), 7.04 (d, J = 16.5 Hz, 1H), 6.88 (d, J = 11.9 Hz, 0H), 6.55 (d, J = 16.6 Hz, 1H), 5.91 (d, J = 12.0 Hz, 0H), 4.29 (q, J = 7.1 Hz, 2H). 2.47 (d, J = 5.0 Hz, 4H), 1.30 (td, J = 7.1, 3.2 Hz, 4H).

[0565] Step 8. Ethyl 6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate:

[0566]

[0567] A mixture of ethyl 6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate (155 g, 348 mmol), pyridine (450 mL), and 1,4-dioxane (450 mL) was heated to 50°C to 60°C to obtain a homogeneous solution. Sodium borohydride (65.8 g, 1741 mmol) was added partically to this solution at 50°C to 60°C. The resulting mixture was stirred at 50°C to 60°C for 22 hours to complete the reduction. After cooling to approximately 15°C, ethyl acetate (950 mL) was added to the reaction mixture. Concentrated hydrochloric acid was gradually added to the mixture to adjust the pH of the aqueous phase to 1 to 2. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (500 mL). The combined ethyl acetate phases were washed with 1N hydrochloric acid aqueous solution (500 mL), water (2 × 500 mL), and 10% brine (300 mL), and dried over sodium sulfate (75 g). The solution was concentrated, and the residue was purified by silica gel column chromatography (0% to 20% MeOH in DCM) to give the desired product (117.8 g, 76%). LCMS, C 22 H 17Calculated value of Cl2FN2O3: 446.06; Measured value: 447 (M + H) + ). 1 H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.00 (s, 1H), 7.84 (dd, J = 7.9, 1.7 Hz, 1H), 7.71 – 7.48 (m, 2H), 4.28 (q, J =7.1 Hz, 2H), 2.79 (ddd, J = 11.7, 7.4, 3.7 Hz, 1H), 2.73 – 2.59 (m, 3H), 2.46(s, 3H), 1.30 (t, J = 7.1 Hz, 3H).

[0568] Step 9. Ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate:

[0569]

[0570] Phosphorus oxychloride (62 g, 405 mmol) was added to a mixture of ethyl 6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate (60 g, 134 mmol), benzyltriethylammonium chloride (31 g, 135 mmol), and N,N-dimethylaniline (49.1 g, 405 mmol) in acetonitrile (300 mL) at below 20 °C. The mixture was heated to 60 °C for 1 hour to complete the reaction. The mixture was cooled to room temperature and collected in ice water (900 mL) at below 20 °C. The product precipitated during water quenching. The mixture was stirred at room temperature for more than 5 hours. The solids were separated by filtration, and the wet filter cake was washed with water containing 10% acetonitrile (2 x 150 mL). The wet solids were dried overnight under vacuum at about 50 °C to give the desired product (57 g, 90% yield). LCMS, C 22 H 16 Calculated value of Cl3FN2O2: 464.03; Measured value: 465 (M + H) + ). 1 H-NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.86 (dd, J = 7.5, 2.1 Hz,1H), 7.64 – 7.53 (m, 2H), 4.52 (q, J = 7.1 Hz, 2H), 2.97 – 2.86 (m, 1H), 2.85– 2.72 (m, 3H), 2.69 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).

[0571] Step 10. Ethyl 4-chloro-6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate:

[0572]

[0573] Phosphorus oxychloride (389.7 g, 4.04 mol) was added to a mixture of ethyl 6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate (600 g, 1.35 mol), benzyltriethylammonium chloride (307 g, 1.35 mol), and N,N-dimethylaniline (603 g, 4.04 mol) in acetonitrile (3 L). The mixture was heated to 60 °C for 1 hour to complete the reaction. The mixture was cooled to room temperature and collected in ice water (9 L) at a temperature below 20 °C. The product precipitated during water quenching. The mixture was stirred at room temperature for more than 5 hours. The solids were separated by filtration, and the wet filter cake was washed with water containing 10% acetonitrile (2 x 1.5 L). The wet solids were dried overnight under vacuum at about 50 °C to give the desired product (563 g, 90% yield). LCMS, C 22 H 14 Calculated value of Cl3FN2O2: 462.01; Measured value: 463 (M + H) + ). 1 H-NMR (400 MHz, DMSO-d6) (mixture of cis and trans isomers) δ 8.72 (s,0.3H), 8.51 (s, 1H), 7.87 (ddd, J = 7.3, 5.6, 1.5 Hz, 1.3H), 7.64 – 7.46 (m,3H), 7.21 (d, J = 16.5 Hz, 1H), 7.05 (d, J = 11.9 Hz, 0.3H), 6.73 (d, J =16.5 Hz, 1H), 6.08 (d, J = 11.9 Hz, 0.3H), 4.53 (qd, J = 7.1, 2.0 Hz, 2H), 2.72 (d, J = 7.4 Hz, 4H), 1.41 (t, J = 7.1 Hz, 4H).

[0574] Step 11. Ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate:

[0575]

[0576] A mixture of ethyl 4-chloro-6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate (528 g, 1.14 mol) and PMHS (411 g, 6.83 mol) in toluene (1.8 L) was stirred at about 50 °C. In another 2 L flask, copper diacetoxyhydrate (4.1 g, 0.02 mol), (9,9-dimethyl-9H-xanthon-4,5-diyl)bis(diphenylphosphine) (13.58 g, 0.023 mol) in toluene (300 ml) and tert-butanol (483 g, 6.52 mol) was stirred for 1 to 2 hours to form a solution. A copper acetate solution was slowly added to a solution of ethyl 4-chloro-6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate and PMHS in toluene at 50-60°C to complete the reduction. The reaction mixture was concentrated to approximately 2 L under vacuum distillation. Heptane (8 L) was added to the 2 L residue at approximately 50°C for 1 hour. The mixture was cooled to room temperature and stirred overnight. The solids were separated by filtration, and the wet filter cake was washed with heptane (2 x 1.2 L). The wet filter cake and silica gel (260 g) were stirred in dichloromethane (2.7 L) for 1 hour. The mixture was filtered through a silica gel bed (260 g), and the silica gel bed was washed with DCM (4 L) until the eluent was almost colorless. The dichloromethane was removed. Dichloromethane (140 mL) and methyl tert-butyl ether (260 mL) were added to the residue. The solids were separated by filtration, and the wet filter cake was washed with MTBE (2 x 1.2 L). The wet solids were dried under vacuum overnight at approximately 50 °C to give the desired product (476 g, 90% yield). LCMS, C 22 H 16 Calculated value of Cl3FN2O2: 464.03; Measured value: 465 (M + H) + ). 1 H-NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.86 (dd, J = 7.5, 2.1 Hz, 1H), 7.64 – 7.53 (m, 2H), 4.52 (q, J = 7.1 Hz, 2H), 2.97 – 2.86 (m, 1H), 2.85 – 2.72 (m, 3H), 2.69 (s,3H), 1.40 (t, J = 7.1 Hz, 3H).

[0577] Step 12. (R) a 4-Chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid ethyl ester:

[0578]

[0579] Racemic 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate was subjected to chiral separation (Chiralpak IB N, MTBE as eluent) to yield both (R)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate and (S)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate. LCMS, C 22 H 16 Calculated value of Cl3FN2O2: 464.03; Measured value: 465 (M + H) + ). 1 H-NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.86 (dd, J = 7.5,2.1 Hz, 1H), 7.64 – 7.53 (m, 2H), 4.52 (q, J = 7.1 Hz, 2H), 2.97 – 2.86 (m,1H), 2.85 – 2.72 (m, 3H), 2.69 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H)

[0580] Step 13. Racemization yields ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate:

[0581]

[0582] A mixture of (S)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate (100 g) in sulfolane (200 mL) was heated to 185 °C for 2 hours to give racemic 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate. The mixture was cooled to 50 °C and acetonitrile (200 mL) was added. Water (700 mL) was added to the solution at 50 °C. The mixture was cooled to room temperature and stirred for 4 hours. The solid was separated by filtration, and the wet filter cake was washed with water (2 x 200 mL). The wet solid was dried under vacuum at about 50 °C overnight to give the desired product (97 g, 97% yield). LCMS, C 22 H16 Calculated value of Cl3FN2O2: 464.03; Measured value: 465 (M + H) + ). 1 H-NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.86 (dd, J = 7.5, 2.1Hz, 1H), 7.64 – 7.53 (m, 2H), 4.52 (q, J = 7.1 Hz, 2H), 2.97 – 2.86 (m, 1H), 2.85 – 2.72 (m, 3H), 2.69 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H)

[0583] Step 14. (1R,4R,5S)-5-(((R) a 6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1] tert-butyl hexane-2-carboxylate:

[0584]

[0585] (R) a A mixture of ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate (106.3 g, 228 mmol), (1R,4R,5S)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl ester (58.8 g, 297 mmol), lithium chloride (19 g, 446 mmol), and diisopropylethylamine (99.5 g, 670 mmol) in dimethyl sulfoxide (400 mL) was heated to 80 °C overnight. The reaction mixture was cooled to room temperature, and subsequently tert-butyl methyl ether (TBME) (1 L) and water (500 mL) were added. The organic phase was separated. The organic phase was washed with 0.1 N hydrochloric acid aqueous solution (500 mL), saturated sodium bicarbonate (500 mL), and water (500 mL). The solvent was removed under reduced pressure to obtain the desired product, which could be used in the next step without further purification. The analytical sample was purified by silica gel column chromatography (0% to 10% MeOH in DCM). LCMS, C 32 H 33 Calculated value of Cl2FN4O4: 626.19; Measured value: 627 (M + H) + ). 1 H-NMR (400 MHz, DMSO-d6) δ8.09 (s, 1H), 7.82 (dd, J = 8.1, 1.5 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.38 (dd, J = 7.7, 1.5 Hz, 1H), 7.14 (s, 1H), 4.49 – 4.37 (m, 2H), 4.31 (s, 1H), 3.71 (d, J = 4.1 Hz, 1H), 3.65 – 3.43 (m, 1H), 3.18 (d, J = 9.3 Hz, 1H), 3.02(s, 1H), 2.91 – 2.74 (m, 2H), 2.70 (dd, J = 13.6, 5.9 Hz, 2H), 2.55 (s, 3H), 1.81 – 1.60 (m, 1H), 1.38 (t, J = 7.1 Hz, 3H), 1.34 – 1.06 (m, 4H), 0.92 (s, 9H).

[0586] Step 14a. (1R,4R,5S)-5-(((R) a 6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1] tert-butyl hexane-2-carboxylate:

[0587] The title compound can be prepared alternatively by the following method. A mixture of (R)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate (40 g, 85 mmol), lithium carbonate (19 g, 258 mmol), and (1R,4R,5S)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl oxalate (29.4 g, 98 mmol) in DMSO (120 mL) was heated to 80 °C overnight. The reaction mixture was cooled to room temperature and MTBE (300 mL) and filtered. The solids were washed with MTBE (100 mL). The combined filtrates were washed with water (2 × 320 mL). The organic phases were separated. The solvent was removed under reduced pressure to give the product, which could be used in the next step without further purification. The analytical sample was purified by silica gel column chromatography (0% to 10% MeOH in DCM). LCMS, C 32 H 33 Calculated value of Cl2FN4O4: 626.19; Measured value: 627 (M+ H) + ). 1 H-NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.82 (dd, J=8.1, 1.5 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.38 (dd, J=7.7, 1.5 Hz, 1H), 7.14 (s, 1H), 4.49–4.37(m, 2H), 4.31 (s, 1H), 3.71 (d, J==4.1 Hz, 1H), 3.65–3.43 (m, 1H), 3.18 (d, J==9.3 Hz, 1H), 3.02 (s, 1H), 2.91–2.74 (m, 2H), 2.70 (dd, J==13.6, 5.9 Hz,2H), 2.55 (s, 3H), 1.81–1.60 (m, 1H), 1.38 (t, J=7.1 Hz, 3H), 1.34–1.06 (m,4H), 0.92 (s, 6H).

[0588] Substitute transisomers (1R,4R,5S)-5-(((R) a 6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester is prepared via a similar route by the following: from (S a Ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate is substituted for (R a Starting with ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate, a similar method is followed.

[0589] Step 15. (R) a )-4-(((1R,4R,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-yl)amino)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid:

[0590]

[0591] A 2 M aqueous solution of sodium hydroxide (134 mL, 268 mmol) was added to a solution of (1R,4R,5S)-5-((6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (140.0 g, 223 mmol) in acetonitrile (560 mL) and methanol (210 mL) at room temperature. The mixture was heated to 50 °C for 1 to 1.5 hours. The mixture was cooled to room temperature and acidified with 1 M aqueous hydrochloric acid to approximately pH 5. Acetonitrile and methanol were removed under vacuum. The product was extracted with ethyl acetate (1.7 L). The aqueous phase was separated and extracted with ethyl acetate (420 mL). The combined ethyl acetate phases were concentrated under vacuum to give the residue. 300 mL of tert-butyl methyl ether was added to the residue, and the mixture was stirred at room temperature for 2 hours. The solid was separated by filtration, and the wet filter cake was washed with TBME (2 x 100 mL). The solid was dried under vacuum at about 50 °C to give the desired product (135 g, quantitative), which could be used in the next step without further purification.

[0592] Step 15b. (R) a )-4-(((1R,4R,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-yl)amino)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid:

[0593] The title compound can be prepared alternatively by the following method. Sodium trimethylsilanolate (338 g, 95%) was added to a solution of (1R,4R,5S)-5-((6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (1400 g, 2.231 mol) in tetrahydrofuran (14 L) and water (80 mL) at room temperature. The mixture was heated to 50 °C for 1 to 3 hours to complete the reaction. The mixture was cooled to room temperature and acidified with 1M hydrochloric acid aqueous solution to approximately pH 5. The tetrahydrofuran was removed under vacuum. The product was extracted with dichloromethane (6 L). The aqueous phase was separated and extracted with dichloromethane (6 L). The combined organic phases were concentrated under vacuum to give a DCM solution (6 L) containing the product. A concentrated dichloromethane solution was added to tert-butyl methyl ether (7 L) and then to the residue, and the mixture was stirred at room temperature for 2 hours. Then, n-heptane (7 L) was added to the mixture. The dichloromethane was removed under vacuum. The solid was separated by filtration, and the wet filter cake was washed with n-heptane (2 x 3 L). The solid was dried under vacuum at approximately 50 °C to obtain the desired product, which could be used in the next step without further purification.

[0594] Step 16. (1R,4R,5S)-5-(((R) a 6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester:

[0595]

[0596] N-iodosuccinimide (94 g, 396 mmol) was added to a solution of 4-(((1R,4R,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-yl)amino)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid (132 g, 220 mmol) and sodium phosphate (74.4 g, 440 mmol) in anhydrous acetonitrile (1614 ml), and the mixture was stirred for 1 hour. Water (1.6 L) was added to the mixture, and the resulting slurry was stirred at room temperature for 5 hours. The solids were separated by filtration, and the wet filter cake was re-slurryed in water (2.6 L) at room temperature for 5 hours. The solids were separated by filtration, and the wet filter cake was washed with water (2 x 250 mL). The solid was dried under vacuum at approximately 50°C to obtain the desired product (120 g, 80% yield). LCMS, C 39 H28 Calculated value of Cl2FIN4O2: 680.06; Measured value: 681 (M + H) + ). 1 H-NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.82 (dd, J = 8.0, 1.6 Hz, 1H), 7.56(t, J = 7.8 Hz, 1H), 7.50 (dd, J = 7.7, 1.6 Hz, 1H), 5.49 (s, 1H), 4.28 (s,2H), 3.09 (s, 1H), 2.96 – 2.58 (m, 8H), 1.71 (s, 1H), 1.59 – 0.96 (m, 11H).

[0597] Step 17. (1R,4R,5S)-5-(((R) a 6-(2-cyanoethyl)-3-(((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)ethynyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]tert-butyl hexane-2-carboxylate:

[0598]

[0599] A mixture of cyclopropyl((1R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexan-2-yl) methyl ketone (47.5 g, 260 mmol), (1R,4R,5S)-5-((6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexan-2-carboxylic acid tert-butyl ester (136.5 g, 200 mmol) and tetrabutylammonium acetate (242 g, 801 mmol) in DMF (1100 ml) was purged under nitrogen for 10 min. Tris(dibenzylideneacetone)dipalladium(0) (2.75 g, 3 mmol) was added to the mixture. The mixture was purged under nitrogen for an additional 15 min, then heated to 70 °C for 1 hour. The reaction mixture was cooled to room temperature and added to a semi-saturated aqueous solution of sodium bicarbonate (2200 mL). The solid was separated by filtration, and the wet filter cake was washed with water (600 mL). The solid was dried under vacuum at about 50 °C and purified by silica gel column chromatography, eluting with 0% to 2% methanol in ethyl acetate to give the desired product (142 g, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 12.4 Hz, 1H), 7.81 (dd, J =8.1, 1.6 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 7.3 Hz, 1H), 6.70 –6.44 (m, 1H), 5.68 – 5.13 (m, 1H), 4.54 – 4.18 (m, 2H), 4.00 – 3.80 (m, 1H), 3.51 (s, 1H), 3.19 (t, J = 9.0 Hz, 1H), 3.07 – 2.91 (m, 1H), 2.78 (d, J =10.7 Hz, 3H), 2.66 (d, J = 9.0 Hz, 3H), 2.57 (d, J = 11.7 Hz, 4H), 2.36 –2.08 (m, 2H), 1.88 (dd, J = 17.9, 10.5 Hz, 2H), 1.35 (d, J = 9.7 Hz, 2H),1.15 – 0.59 (m, 16H).

[0600] Step 17a. (1R,4R,5S)-5-(((R) a 6-(2-cyanoethyl)-3-(((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)ethynyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]tert-butyl hexane-2-carboxylate:

[0601] The title compound can be prepared alternatively by the following method: A mixture of cyclopropyl((1R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-yl) ketone (17.7 kg, 101 mol), (1R,4R,5S)-5-((6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (64.7 kg, 95 mol), copper(I) iodide (0.42 kg, 2 mol), tris(4-fluorophenyl)phosphine (0.39 kg, 1 mol), and K2CO3 (36.4 kg, 191 mol) in DMSO (488.4 L) was purged under nitrogen for 30 min. Palladium(II) acetate (60 g, 30 mmol) was added to the mixture. The mixture was purged with nitrogen under the liquid surface for an additional 30 min, then heated to 50 °C for more than 10 h. The reaction mixture was cooled to room temperature and EtOAc (906 L) was added, followed by the slow addition of water (1267 L). The mixture was stirred at room temperature for 30 min and filtered through a diatomaceous earth bed. The diatomaceous earth bed was washed with EtOAc (33 L). The organic phase was separated from the aqueous phase, and the aqueous phase was back-extracted with EtOAc (195 L). The combined organic phases were washed with water (195 L). Water (130 L) and ammonium pyrrolidine dithiocarbamate (3.1 kg, 19 mol) were added to the EtOAc phase. The mixture was stirred at 50 °C for at least 4 h. The mixture was cooled to room temperature and filtered. The aqueous phase was separated and discarded. The organic phase was washed with water (325 L). The organic phase was heated to 50°C and passed through an activated carbon filter. The solution was concentrated under vacuum, and the solvent was exchanged for toluene to remove residual water, yielding the desired product in 98% solution yield. The toluene solution was then solvent-exchanged for NMP for the next step of indole cyclization without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.03(d, J=12.4 Hz, 1H), 7.81 (dd, J=8.1, 1.6 Hz, 1H), 7.55 (t, J=7.9 Hz, 1H), 7.36 (d, J=7.3 Hz, 1H), 6.70–6.44 (m, 1H), 5.68–5.13 (m, 1H), 4.54–4.18 (m,2H), 4.00–3.80 (m, 1H), 3.51 (s, 1H), 3.19 (t, J=9.0 Hz, 1H), 3.07–2.91 (m,1H), 2.78 (d, J=10.7 Hz, 3H), 2.66 (d, J=9.0 Hz, 3H), 2.57 (d, J=11.7 Hz,4H), 2.36–2.08 (m, 2H), 1.88 (dd, J=17.9, 10.5 Hz, 2H), 1.35 (d, J=9.7 Hz,2H), 1.15–0.59 (m, 16H).

[0602] Substitute transisomers (1R, 4R, 5S)-5-(((S) a )-6-(2-cyanoethyl)-3-(((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)ethynyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester is prepared via a similar route by replacing (R)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid ethyl ester with (R) a Beginning with ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate, the method is performed similarly to steps 14 to 17.

[0603] Step 18. (1R,4R,5S)-5-((R) a 8-(2-cyanoethyl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester:

[0604]

[0605] A mixture of (1R,4R,5S)-5-((6-(2-cyanoethyl)-3-(((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)ethynyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (141.0 g, 159 mmol) and cesium carbonate (78 g, 238 mmol) in dimethyl sulfoxide (1 L) or N-methyl-2-pyrrolidone was heated to 80-85 °C for 1.5 h. The reaction was cooled to room temperature and water (2 L) was gradually added. The product gradually precipitated from the solution. The resulting slurry was stirred at room temperature for 1 h. The solid was separated by filtration, and the wet filter cake was washed with water (2 x 300 mL). The wet solid was dried under vacuum. The solid was purified by rapid chromatography using 60% to 100% ethyl acetate in dichloromethane. The solvent was removed, and the solid was crystallized from ethyl acetate (420 mL) and tert-butyl methyl ether (420 mL) and heptane (9840 mL) in heptane (840 mL) to give the desired product (122 g, 87% yield). LCMS, C 40 H 40 Calculated value of Cl2FN5O3: 727.25; Measured value: 728 (M + H) + ). 1H NMR (500 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.81 (dt, J = 8.0, 2.1 Hz, 1H), 7.55 (td, J = 7.8, 5.0 Hz, 1H), 7.45 – 7.29 (m, 1H), 6.26 (s, 1H), 5.81 –5.49 (m, 1H), 5.34 – 5.13 (m, 1H), 5.00 (dd, J = 14.3, 6.8 Hz, 1H), 4.19 –3.97 (m, 1H), 3.63 (dt, J = 6.8, 3.1 Hz, 1H), 3.40 (d, J = 9.4 Hz, 1H), 3.27– 3.09 (m, 1H), 2.95 (dt, J = 14.2, 7.6 Hz, 1H), 2.89 – 2.73 (m, 3H), 2.70 (d, J = 2.7 Hz, 4H), 2.34 – 2.20 (m, 1H), 2.21 – 1.97 (m, 2H), 1.73 (dp, J =15.0, 4.8 Hz, 1H), 1.66 – 1.34 (m, 2H), 1.21 – 1.03 (m, 1H), 1.02 – 0.79 (m,4H), 0.78 – 0.22 (m, 11H).

[0606] Step 19. 3-((R) a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile:

[0607]

[0608] At room temperature, (1R,4R,5S)-5-((R) aA solution of tert-butyl hexane-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (167.7 g, 230.1 mmol) in dichloromethane (1.35 L) was mixed with trimethyliodosilane (69 g, 345 mmol) and stirred for 1 h. Sodium bicarbonate aqueous solution (500 mL) was added to quench the reaction. The organic phase was separated and washed with water. The solvent was evaporated by rotary evaporation, and the residue was passed through a silica gel bed (1% to 20% methanol in dichloromethane). The solvent was exchanged for ethyl acetate and tert-butyl methyl ether to give the crystalline product (136 g, 94% yield). LCMS, C 35 H 32 Calculated value of Cl2FN5O: 627.20; Measured value: 628 (M + H) + ). 1 H-NMR (400 MHz, DMSO-d6) δ 1 H NMR (500 MHz, DMSO-d6) δ 8.15 (d, J = 13.6 Hz, 1H), 7.89 – 7.73 (m, 1H), 7.64 – 7.33 (m, 2H), 6.69 – 6.14 (m, 1H), 5.76 – 5.43(m, 1H), 4.97 (d, J = 4.9 Hz, 1H), 4.31 (dd, J = 17.0, 6.0 Hz, 1H), 4.18 –3.94 (m, 1H), 3.58 – 3.45 (m, 1H), 2.94 (dt, 2H, J = 12.4, 6.1 Hz), 2.89 –2.56 (m, 8H), 2.44 – 2.19 (m, 2H), 2.07 (d, J = 12.9 Hz, 1H), 1.96 – 1.54 (m,3H), 1.30 – 1.13 (m, 1H), 1.06 – 0.20 (m, 6H).

[0609] Substitute for the transisomer 3-((S) a)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile was prepared via a similar route by replacing (R)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate with (R) a Begin with ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate, and perform a method similar to steps 14 to 19.

[0610] Step 20: 3-((R) a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile monohydrochloride dihydrate (compound 1):

[0611]

[0612] At 30℃ to 50℃, towards 3-((R) a A solution of 53.8 g (85 mmol) of free base of propionitrile (53.8 g, 85 mmol) dissolved in methanol (110 mL), ethyl acetate (50 mL), water (11 mL), and tert-butyl methyl ether (TBME) (110 mL) was added to the solution. 6N hydrochloric acid aqueous solution (14.5 mL) was added. The mixture was inoculated, and the solution gradually became turbid. TBME (440 mL) was slowly added to the mixture over 1 hour at approximately 40 °C. The mixture was cooled to approximately 15 °C and stirred for 2 hours. The solid was separated by filtration, and the wet filter cake was washed with TBME (2 x 110 mL) containing 5% methanol and 20% ethyl acetate. The wet solid was slurried in ethyl acetate (270 mL) and dried under vacuum at about 50 °C to give the desired product (53.7 g, 90% yield). LCMS, C 35 H 32Calculated value of Cl2FN5O: 627.20; Measured value: 628 (M + H) + ). 1 H NMR (500 MHz, DMSO-d6) δ8.15 (s, 1H), 7.83 (dd, J = 8.1, 1.6 Hz, 1H); 7.57 (dd, J = 7.9, 7.9,1H); 7.45 (dd, J = 7.7, 1.6 Hz, 1H); 6.44 (s, 1H); 5.65 (s, 1H); 5.51 (d, J = 10.6Hz, 1H); 4.14 (td, J = 6.4, 2.6 Hz, 1H); 3.84-3.90 (m, 1H); 3.30-3.37 (m, 1H); 3.43-3.50 (m, 1H); 2.86-2.95 (m, 1H); 2.83-2.92 (m.1H); 2.79 (s, 3H); 2.70-2.79 (m, 1H); 2.29-2.35 (m, 1H); 2.25-2.32 (m, 1H); 1.97 (dd, J = 13.0, 2.6Hz, 1H); 1.69 -1.83 (m, 1H); 1.65 (d, J = 9.1Hz, 1H); 0.91-1.00 (m, 2H); 0.82-0.88 (m, 2H); 0.72-0.80 (m, 1H); 0.63-0.69 (m, 1H). 13C NMR (125 MHz, DMSO-d6) δ 171.6; 145.8;132.8;135.1;132.8;131.9;131.5;131.4;129.2;101.6;120.7;57.9;5 6.5;44.5;42.5;30.5;38.3;32.8;22.1;17.5;17.1;13.2;13.0;7.70;7.80.19F NMR (376 MHz, DMSO-d6) δ -122.1 (s).

[0613] Substitute for the transisomer 3-((S) a)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile monohydrochloride dihydrate is prepared via a similar route by the following: from 3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile instead of 3-((R a Beginning with 1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile, the method is performed similarly to steps 15 to 21.

[0614] Example 1A: (1R,3R,4R,5S)-3-((R a Synthesis of methyl heptan-2-carboxylate (compound 2) -1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0615]

[0616] Step 1. Methyl (1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0617]

[0618] HCl (4 N dissolved in dioxane, 10 mL) was added to a solution of intermediate 5 (1.85 g, 3.89 mmol) dissolved in dioxane (10 mL). The reaction was stirred at room temperature for 0.5 h. Upon completion, volatiles were removed under reduced pressure. The residue was dissolved in DCM (20 mL). While stirring, N,N-diisopropylethylamine (2.0 mL, 11.7 mmol) was added, followed by methyl chloroformate (0.6 mL, 7.78 mmol). The mixture was stirred for 0.5 h. Once complete, the reaction mixture was diluted with DCM, washed with water, dried over Na2SO4, filtered, and concentrated. The crude product was purified by rapid chromatography (0%–50% ethyl acetate / hexane) to give the title compound. LC-MS, C 26 H 32 NO3Si (M+H) + Calculated value: m / z = 434.2; Measured value: 434.2.

[0619] Step 2. Methyl (1R,3R,4R,5S)-3-ethynyl-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0620]

[0621] TBAF (1N dissolved in THF, 4.0 mL, 3.96 mmol) was added to a solution of (1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.43 g, 3.30 mmol) dissolved in THF (11 mL). The reaction was stirred at room temperature for 16 h. Upon completion, volatiles were removed. The crude product was purified by rapid chromatography (0%–10% methanol / DCM) to give the title compound. LC-MS, C 10 H 14 NO3 (M+H) + Calculated value: m / z = 196.1; Measured value: 196.1.

[0622] Step 3. Methyl (1R,3R,4R,5S)-5-(difluoromethoxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0623]

[0624] Acetonitrile (13 mL) was added to a flask containing methyl (1R,3R,4R,5S)-3-ethynyl-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (0.514 g, 2.63 mmol) and copper iodide (I) (0.100 g, 0.527 mmol). The mixture was stirred at 50 °C before the slow addition of 2 mL of acetonitrile solution containing 2-(fluorosulfonyl)difluoroacetic acid (0.703 g, 3.95 mmol). The reaction mixture was stirred at 50 °C for 1 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was dissolved in DCM and washed with saturated NaHCO3 solution and water. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (0%–50% ethyl acetate / hexane) to give the title compound (0.467 g, 72% yield). LC-MS, C 11 H 14 F2NO3 (M+H) + Calculated value: m / z = 246.1; Measured value: 246.1.

[0625] Step 4. (1R,4R,5S)-5-((R) a )-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-2-((1R,3R,4R,5S)-5-(difluoromethoxy)-2-(methoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]tert-butyl hexane-2-carboxylate

[0626]

[0627] A mixture of intermediate 2 (0.500 g, 0.734 mmol), (1R,3R,4R,5S)-5-(difluoromethoxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (0.270 g, 1.10 mmol), copper iodide (I) (0.056 g, 0.294 mmol), tetrakis(triphenylphosphine)palladium (0) (0.170 g, 0.147 mmol), and N,N-diisopropylethylamine (1.3 mL, 7.34 mmol) in DMF (4.6 mL) was bubbled with N2 and heated at 70 °C for 1 h. Then, cesium carbonate (0.717 g, 2.20 mmol) was added to the reaction mixture. The resulting slurry was stirred at 90 °C for an additional 18 h. Upon completion, the mixture was cooled to room temperature and poured into water. The solution was extracted twice with ethyl acetate. The combined organic layers were then washed five times with brine, dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by rapid chromatography (0%-100% EtOAc / hexane) to obtain the title compound. LC-MS, C₂ 40 H 41 Cl2F3N5O5 (M+H) + Calculated value: m / z = 798.2; measured value: 798.3.

[0628] Step 4. (1R,3R,4R,5S)-3-((R) a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid methyl ester

[0629] To (1R,4R,5S)-5-((R) a A solution of tert-butyl hexane-2-carboxylate (0.350 g, 0.439 mmol) in DCM (7 mL) was prepared by adding acetonitrile (0.7 mL) and TFA (7 mL). The reaction mixture was stirred at room temperature for 0.5 hours. After completion, the volatiles were removed under reduced pressure, and the residue was dissolved in acetonitrile (4 mL) and water (1 mL) and analyzed by preparative LC-MS (XBridge). ®Purification was performed using a C18 column with a gradient elution of acetonitrile / water (containing 0.1% TFA at a flow rate of 60 mL / min) to obtain the title compound. LC-MS, C18... 35 H 33 Cl2F3N5O3 (M+H) + Calculated value: m / z = 698.2; measured value: 698.2. TFA salt collection. 1 HNMR. 1 H NMR (500 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 7.86 (dd, J=8.1, 1.5 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.47 (td, , 3.92 (m, 1H), 3.74 (s, 3H), 3.53 (m,1H), 3.44 (m, 1H), 3.12–2.99 (m, 1H), 2.97–2.78 (m, 5H), 2.76–2.62 (m, 2H), 2.39–2.32 (m, 1H), 2.32–2.19 (m, 1H), 1.76–1.59 (m, 3H), 1.57–1.47 (m, 1H).

[0630] Alternative transisomers (1R, 3R, 4R, 5S)-3-((S a Methyl heptane-2-carboxylate (1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate can be prepared via a similar route by the following: from (1R,4R,5S)-5-((S a)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-2-((1R,3R,4R,5S)-5-(difluoromethoxy)-2-(methoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester instead of (1R,4R,5S)-5-((R a Starting with tert-butyl hexane-2-carboxylate ((1R,3R,4R,5S)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-2-((1R,3R,4R,5S)-5-(difluoromethoxy)-2-(methoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate, a method similar to the steps described above is performed.

[0631] Intermediate 1.(R)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid ethyl ester

[0632]

[0633] Step 1. 3-Amino-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid

[0634]

[0635] A mixture of 2-amino-4-bromo-3-fluorobenzoic acid (28.0 g, 120 mmol), (2,3-dichlorophenyl)boronic acid (25.1 g, 132 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (2.12 g, 3.00 mmol), and potassium phosphate (50.8 g, 239 mmol) in 1,4-dioxane (170 mL) and water (30 mL) was bubbled with N2 and heated at 70 °C for 1 hour. After completion, the reaction mixture was cooled to room temperature and poured into 1 N HCl (200 mL). The mixture was stirred for another 10 minutes, and a precipitate formed. The solid was collected on a sintered filter, washed with water followed by hexane, and dried under reduced pressure to give the subtitle compound in near-quantitative yield. The crude product was used in the next step without further purification. LC-MS, C 13 H9Cl2FNO2 (M+H) + Calculated value: m / z = 300.0; Measured value: 300.0.

[0636] Step 2. 3-Amino-6-bromo-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid

[0637]

[0638] N-bromosuccinimide (22.3 g, 125 mmol) was added to a solution of 3-amino-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid (35.8 g, 119 mmol) in DMSO (100 mL). The resulting mixture was heated at 50 °C for 1 hour. After completion, the reaction mixture was cooled to room temperature and poured into ice water (400 mL). 20 mL of saturated Na₂S₂O₃ solution was added to the suspension. After stirring for 15 minutes, the solid was collected on a sintering filter, washed with water followed by hexane, and dried under reduced pressure to give the subtitle compound (43.0 g, 95% yield). The crude product was used in the next step without further purification. LC-MS, C₂ 13 H8BrCl2FNO2 (M+H) + Calculated values: m / z = 377.9, 379.9; measured values: 378.0, 380.0.

[0639] Step 3. 6-Bromo-7-(2,3-dichlorophenyl)-8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione

[0640]

[0641] Triphosgene (10.6 g, 35.6 mmol) was added fractionally to a solution of 3-amino-6-bromo-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid (38.6 g, 102 mmol) dissolved in THF (300 mL). After addition, the mixture was heated at 60 °C for 0.5 h. After completion, the reaction mixture was cooled to room temperature and poured into heptane (1000 mL). After stirring for 1 h, the solid was collected on a sintered filter, washed with hexane, and dried under reduced pressure to give the subtitle compound in near-quantitative yield. The crude product was used in the next step without further purification.

[0642] Step 4. Ethyl 6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylic acid

[0643]

[0644] Sodium (18.7 g, 123 mmol) was added fractionally to a solution of 6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (41.5 g, 102 mmol) in DMSO (200 mL). After addition, the mixture was heated at 80 °C for 1 hour. Upon completion, the reaction mixture was cooled to room temperature and poured into 1 N HCl (400 mL). After stirring for 1 hour, the solid was collected on a sintered filter, washed with water followed by hexane, and dried under reduced pressure to give the subtitle compound (40.0 g, 83% yield). The crude product was used in the next step without further purification. LC-MS, C 19 H 14 BrCl2FNO3 (M+H) + Calculated values: m / z = 471.9, 473.9; measured values: 471.9, 474.0.

[0645] Step 5. Ethyl (E)-6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylic acid ester

[0646]

[0647] Acrylonitrile (12.3 mL, 185 mmol) and NEt3 (30.9 mL, 222 mmol) were added to a solution of ethyl 6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate (35.0 g, 74.0 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (2.62 g, 3.70 mmol) in DMF (100 mL). The mixture was sprayed with N2 and heated to 85 °C for 1 h. Once complete, the reaction mixture was cooled to room temperature and poured into 1 N HCl (500 mL). After stirring for 1 hour, the solid was collected on a sintered filter, washed with water followed by hexane, and dried under reduced pressure to give the subtitle compound (19.2 g, 58% yield). The crude product was used in the next step without further purification. LC-MS, C 22 H 16 Cl2FN2O3 (M+H) + Calculated value: m / z = 445.0; Measured value: 445.0.

[0648] Step 6. Ethyl (E)-4-chloro-6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid ester

[0649]

[0650] DIPEA (23.5 mL, 135 mmol) was added to a slurry of (E)-6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylic acid ethyl ester (30.0 g, 67.4 mmol) and benzyltriethylammonium chloride (15.4 g, 67.4 mmol) dissolved in MeCN (150 mL) at 0 °C. After stirring at 0 °C, phosphoryl chloride (12.6 mL, 135 mmol) was added dropwise to the mixture. The mixture was then heated at 60 °C for 1 hour. After completion, the reaction mixture was cooled to room temperature and slowly poured into ice water (1000 mL). The mixture was extracted three times with DCM, dried over Na2SO4, filtered, and concentrated. The crude product was further purified by FCC (0%–50% EtOAc / hexane) to give the subtitle compound (4.5 g, 14% yield). LC-MS, C 22 H 15 Cl3FN2O2 (M+H) + Calculated value: m / z = 463.0; Measured value: 463.0.

[0651] Step 7. (R)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid ethyl ester

[0652] A mixture of copper(II) acetate monohydrate (0.19 g, 0.97 mmol) and Xantphos (0.56 g, 0.97 mmol) was stirred at 60 °C for 0.5 h in toluene (1 mL) and tert-butanol (9 mL) to provide a homogeneous solution. In a separate vial, the previously prepared copper-containing solution was added to a mixture of (E)-4-chloro-6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid ethyl ester (4.5 g, 9.70 mmol) and polymethylhydrosiloxane (3.5 g, 58.2 mmol) in toluene (12 mL) at 60 °C. The mixture was stirred at 60 °C for 0.5 h. Upon completion, the reaction mixture was filtered through diatomaceous earth and concentrated. The crude product was purified using FCC (0%–40% EtOAc / DCM) to give a mixture of two transisomers (2.0 g, 44% yield). Chiral supercritical fluid chromatography (ChiralPak IJ column, eluted with 40% MeOH dissolved in CO2 at a flow rate of 70 mL / min; the title compound eluted after its transisomer) was performed. LC-MS, C122 H 17 Cl3FN2O2 (M+H) + Calculated value: m / z = 465.0; Measured value: 465.0.

[0653] Intermediate 2. (1R,4R,5S)-5-(((R)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

[0654]

[0655] Step 1. (1R,4R,5S)-5-(((R)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

[0656]

[0657] Ethyl (1R,4R,5S)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (tert-butyl ester) (5.52 g, 27.8 mmol) and DIPEA (8.1 mL, 46.4 mmol) were added to a solution of (R)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate (intermediate 1, 7.2 g, 15.5 mmol) in N-methyl-2-pyrrolidone (21 mL). The resulting mixture was heated at 80 °C for 18 hours. After this, the reaction mixture was cooled to room temperature and poured into a mixture of 1 NHCl (300 mL) and ice. After stirring for 0.5 hours, the solid was collected on a sintering filter, washed with water followed by hexane, and dried under reduced pressure to give a white solid (8.2 g, 85% yield). The crude product was used in the next step without further purification. LC-MS, C 32 H 34 Cl2FN4O4 (M+H) + The calculated value is m / z = 627.2; the measured value is 627.1.

[0658] Step 2. (R)-4-(((1R,4R,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-yl)amino)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid

[0659]

[0660] To a solution of (1R,4R,5S)-5-(((R)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-8-fluoro-2-methylquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (4.0 g, 6.37 mmol) dissolved in MeCN (13 mL), 1 N NaOH (16 mL, 15.94 mmol) was added. The mixture was heated at 50 °C for 2 hours. After completion, the reaction mixture was cooled to room temperature and acidified to pH 5 with 1 N HCl. Organic volatiles were removed under reduced pressure. The residual aqueous phase was extracted three times with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow solid (3.70 g, 97% yield). The crude material was used for the next step without further purification. LC-MS, C 30 H 30 Cl2FN4O4 (M+H) + Calculated value: m / z = 599.2; measured value: 599.1.

[0661] Step 3. (1R,4R,5S)-5-(((R)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

[0662] Potassium phosphate (2.62 g, 12.34 mmol) and N-iodosuccinimide (2.50 g, 11.1 mmol) were added to a solution of (R)-4-(((1R,4R,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid (3.70 g, 6.17 mmol) dissolved in MeCN (6.2 mL). The mixture was stirred at room temperature for 1 h. Once complete, the reaction mixture was poured into a saturated Na2S2O3 solution. After stirring for 10 min, the mixture was extracted three times with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was further purified by FCC (0%-100% EtOAc / hexane) to give the title compound as a grayish-white solid (1.95 g, 46% yield). LC-MS, C 29 H 29 Cl2FIN4O2 (M+H) + Calculated value: m / z = 681.1; measured value: 681.0.

[0663] Intermediate 3. (1R,3R,4S)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylic acid methyl ester

[0664]

[0665] Step 1. Methyl 2-hydroxy-2-methoxyacetate

[0666]

[0667] A solution of glyoxylic acid monohydrate (41.4 g, 450 mmol) dissolved in anhydrous MeOH (200 mL) was heated to 70 °C overnight. After cooling to room temperature, the mixture was stirred with solid NaHCO3 for 10 minutes. The resulting mixture was filtered and concentrated under reduced pressure to give an oily residue. The residue was dissolved in CH2Cl2, dried over Na2SO4, filtered, and concentrated to provide the product (40.0 g, 82% yield). The product was used in the next step without further purification.

[0668] Step 2. Methyl (S,E)-2-((1-phenylethyl)imino)acetate

[0669]

[0670] (S)-1-phenylethane-1-amine (40.4 g, 333 mmol) was slowly added to a solution of methyl 2-hydroxy-2-methoxyacetate (40.0 g, 333 mmol) dissolved in toluene (95 mL). The mixture was stirred at room temperature for 1 hour and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to a yellow oil. The crude product was used in the next step without further purification.

[0671] Step 3. Methyl (1R,3R,4S)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate

[0672] TFA (25.5 mL, 333 mmol) was added to a solution of (S,E)-2-((1-phenylethyl)imino)acetic acid methyl ester (63.7 g, 333 mmol) dissolved in 2,2,2-trifluoroethanol (800 mL) at -10 °C. The reaction mixture was stirred at -10 °C for 1 hour before the slow addition of cyclopentadiene (24.2 g, 366 mmol). The mixture was stirred at -10 °C for another 0.5 hours, then allowed to warm to room temperature. After removing volatiles, the residue was diluted with 2 N hydrochloric acid (500 mL) and washed with diethyl ether. The organic layer was extracted with 2 N hydrochloric acid (100 mL). The combined aqueous layers were neutralized with 28% ammonium hydroxide and extracted three times with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was purified fractionally by FCC (0%-10% EtOAc / hexane) to give the title compound as a colorless solid. LC-MS, C 16 H 20 NO2 (M+H) + Calculated value: m / z = 258.1; measured value: 258.2. 1 H NMR (500 MHz, CDCl3) δ 7.32–7.27 (m, 2H), 7.25 (m, 2H), 7.22–7.16 (m, 1H), 6.44 (ddd, J=5.7, 3.1, 1.2 Hz, 1H), 6.29 (dd, J=5.7, 2.0Hz, 1H), 4.33 (h, J=1.5 Hz, 1H), 3.37 (s, 3H), 3.06 (q, J=6.5 Hz, 1H), 2.93 (dq, J=3.3, 1.6 Hz, 1H), 2.24 (d, J=0.9 Hz, 1H), 2.13 (dt, J=8.4, 1.7 Hz,1H), 1.48–1.41 (m, 4H).

[0673] Intermediate 4,2-(tert-butyl)-3-methyl(1R,3R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate

[0674]

[0675] Step 1. Methyl (1R,3R,4R,5S)-5-hydroxy-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate

[0676]

[0677] At 0 °C, a solution of 0.5 N 9-boronbicyclo[3.3.1]nonane (51.5 mL, 25.7 mmol) in THF was added to a solution of methyl (1R,3R,4S)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]hept-5-en-3-carboxylate (intermediate 3, 5.3 g, 20.6 mmol) dissolved in THF (70 mL). The reaction mixture was heated to room temperature and stirred for 18 h. The reaction mixture was then cooled to 0 °C, and a 2 N NaOH solution (36.0 mL, 72.1 mmol) was added, followed by hydrogen peroxide (30% aqueous solution, 10.5 mL, 103 mmol). The reaction mixture was heated to room temperature and stirred for 1 h. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (50%–70% EtOAc / hexane) to give the subtitle compound (2.0 g, 38% yield). LC-MS, C 16 H 22 NO3 (M+H) + Calculated value: m / z = 276.2; Measured value: 276.2.

[0678] Step 2. Methyl (1R,3R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylate

[0679]

[0680] 20% Pd(OH)₂ / C (0.58 g) was added to a solution of (1R,3R,4R,5S)-5-hydroxy-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (2.00 g, 7.26 mmol) in EtOH (35 mL). The mixture was stirred for 18 h under a H₂ atmosphere. The resulting mixture was filtered through diatomaceous earth and concentrated to provide the subtitle compound. The crude material was used for the next step without further purification. LC-MS, C₈H₂O 14 NO3 (M+H) + Calculated value: m / z = 172.1; Measured value: 172.1.

[0681] Step 3. 2-(tert-butyl)-3-methyl(1R,3R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate

[0682] DIPEA (5.10 mL, 29.1 mmol) and Boc₂O (3.96 g, 18.2 mmol) were added to methyl (1R,3R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylate (1.24 g, 7.26 mmol) dissolved in THF (10 mL). The reaction mixture was stirred at room temperature for 0.5 h and diluted with EtOAc. After washing with 0.01 N HCl and brine, the organic fraction was dried over Na₂SO₄, filtered, and concentrated. The crude product was further purified by FCC (0%–100% EtOAc / hexane) to give the title compound (1.88 g, 95% yield). LC-MS, C₁₆H₁₆H₂O 14 NO5 (M- t Bu+2H) + Calculated value: m / z = 216.1; Measured value: 216.1.

[0683] Intermediate 5. (1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0684]

[0685] Step 1. 2-(tert-butyl)-3-methyl(1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate

[0686]

[0687] tert-butylchlorodiphenylsilane (2.08 g, 7.64 mmol) and imidazole (1.40 g, 20.8 mmol) were added to a solution of 2-(tert-butyl)-3-methyl(1R,3R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (intermediate 4, 1.88 g, 6.92 mmol) in DMF (140 mL). The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with EtOAc, washed five times with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0%–40% EtOAc / hexane) to give the subtitle compound. LC-MS, C 25 H 32 NO5Si (M- t Bu+2H) + The calculated value is m / z = 454.2; the measured value is 454.2.

[0688] Step 2. (1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0689]

[0690] A solution of 2-(tert-butyl)-3-methyl(1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1.53 g, 3.01 mmol) in THF (15 mL) was added to a solution of 2N THF containing LiBH4 (3.8 mL, 7.52 mmol). The mixture was stirred at room temperature for 8 hours, followed by quenching with a saturated NH4Cl solution. The mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC (0%–60% EtOAc / hexane) to give the subtitle compound (1.39 g, 96% yield). LC-MS, C 24 H 32 NO4Si(M- t Bu+2H) + Calculated value: m / z = 426.2; Measured value: 426.2.

[0691] Step 3. (1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-formyl-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0692]

[0693] DMSO (0.61 mL, 8.64 mmol) was slowly added to a solution of oxaloyl chloride (0.73 g, 5.76 mmol) dissolved in DCM (5.3 mL) cooled to −78 °C. After stirring for 10 min, a solution of (1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.39 g, 2.88 mmol) in DCM (1 mL) was added. The reaction mixture was stirred at −78 °C for 1 h before adding DIPEA (1.5 mL). The reaction mixture was then warmed to room temperature and stirred for another 0.5 h. The reaction mixture was then poured into a mixture of DCM (15 mL) / 28% ammonium hydroxide (1.5 mL). After stirring for 10 min, the mixture was diluted with water. The organic phase was separated, dried over Na₂SO₄, filtered, and concentrated to obtain a crude product, which was used in the next step without further purification. LC-MS, C₂ 24 H 30 NO4Si(M- t Bu+2H) + Calculated value: m / z = 424.2; measured value: 424.3.

[0694] Step 4. (1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0695] To a solution of (1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-formyl-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.38 g, 2.88 mmol) in MeOH (15 mL), dimethyl phosphonate (1-diazo-2-oxopropyl)phosphonate (0.61 g, 3.17 mmol) and K₂CO₃ (1.19 g, 8.64 mmol) were added. After stirring for 18 hours, the reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated. The residue was extracted with EtOAc, filtered through diatomaceous earth, and concentrated. The crude product was purified by FCC (0%–40% EtOAc / hexane) to give the title compound (0.20 g, 51% yield in 2 steps). LC-MS, C 25 H 30 NO3Si (M- t Bu+2H) + Calculated value: m / z = 420.2; Measured value: 420.2.

[0696] Example 2. Synthesis of cyclopropyl((1R,3R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexan-2-yl) ketone (step 17 in Example 1)

[0697] Step 1. 1-(tert-butyl)-2-ethyl(R)-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate:

[0698]

[0699] A solution of 1-(tert-butyl)-2-ethyl(R)-5-oxopyrrolidine-1,2-dicarboxylate (241 g, 0.938 mol) in anhydrous toluene (1.6 L) was added dropwise to tetrahydrofuran with 1M triethylborohydride (1.01 L, 1.01 mol). After addition, the mixture was stirred at approximately -50 °C for 1 h. DIPEA (726 mL, 4.17 mol) was added dropwise to the mixture over 1 h. 4-Dimethylaminopyridine (1.49 g, 12.2 mmol, 0.013 eq.) was added to the mixture, followed by the dropwise addition of trifluoroacetic anhydride (156.5 mL, 1.126 mol) over 1.5 h. After addition, the mixture was stirred at approximately -50 °C for 1 h, then slowly heated to room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0°C and slowly diluted with water (2.41 L), while maintaining the temperature below 10°C during addition. The organic layer was separated and washed with water (2.41 L) and saturated brine (720 mL). The organic layer was dried over sodium sulfate (120 g). The solution was concentrated under reduced pressure to give the desired product (230 g, quantitative) as a yellow oil. GCMS, C 12 H 19 Calculated value of NO4: 241.1; Measured value: 214.2 (M + ). 1 H-NMR (400 MHz, CDCl3) δ 6.70-6.48 (m, 1H), 4.99-4.86 (m, 1H), 4.70-4.52 (m, 1H), 4.30-4.11 (m, 2H), 3.15-2.98 (m, 1H), 2.73-2.57 (m, 1H), 1.53-1.38 (m, 9H), 1.34-1.21 (m, 4H).

[0700] Step 2. 2-(tert-butyl)-3-ethyl(1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate

[0701]

[0702] 1.1M diethylzinc in toluene (1.7 L, 1.87 mol) was added to a solution of 1-(tert-butyl)-2-ethyl(R)-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (230 g, 0.938 mol) in toluene (2.3 L) for 1 h at -30 °C to -25 °C. Chloroiodoform (273 mL, 3.752 mol) was added dropwise to the mixture for 2 h at approximately -30 °C to -20 °C, and the mixture was stirred for 16 h. Semi-saturated sodium bicarbonate (2.3 L) was added to the mixture, and the mixture was heated to room temperature. The mixture was filtered through diatomaceous earth to remove white solids, and the filter bed was washed with toluene (1.5 L). The organic layer was separated from the filtrate and washed with water (2 × 1.15 L) and saturated brine (1.15 L). The toluene solution was concentrated under reduced pressure to give a 6:1 mixture (231 g) of 2-(tert-butyl)-3-ethyl(1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate and 2-(tert-butyl)-3-ethyl(1S,3R,5S)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate, as determined by GCMS analysis.

[0703] An aqueous solution of methylamine (40%, 344 g) was added to the crude mixture product obtained above (226 g), and the mixture was stirred at room temperature for 16 h. Water (340 mL) and methyl tert-butyl ether (340 mL) were added to the mixture. The organic layer was separated and washed with water (340 mL) and saturated brine (230 mL). The solution was concentrated under reduced pressure to give 2-(tert-butyl)-3-ethyl(1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (177 g, calculated yield 73%) as a yellow oil containing 2% 2-(tert-butyl)-3-ethyl(1S,3R,5S)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate, as determined by GCMS analysis. GCMS, C 13 H 21 Calculated value of NO4: 255.1; Measured value: 255.1 (M + ). 1 H-NMR (400 MHz, CDCl3) δ 4.56-4.39 (m, 1H), 4.18-4.01 (m, 2H), 3.51-3.36 (m, 1H), 2.60-2.42 (m, 1H), 2.00-1.92 (m, 1H), 1.45-1.32 (m, 9H), 1.23-1.15 (m, 4H), 0.87-0.79 (m, 1H), 0.70-0.56 (m, 1H).

[0704] Step 3. (1R,3R,5R)-3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester

[0705]

[0706] A solution of 2-(tert-butyl)-3-ethyl(1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (177 g, 0.694 mol) in tetrahydrofuran (1.56 L) was added to a 1M lithium aluminum hydride solution in tetrahydrofuran (777 mL, 0.777 mol, 1.12 eq.). After addition, the mixture was stirred at 3 °C for 2 h. Water (27 mL) was added dropwise to the mixture to quench the reaction. Sodium hydroxide solution (15%, 27 mL) and water (80 mL) were added dropwise sequentially to the mixture. The mixture was stirred at room temperature for 1 h. DCM (2.35 L) was added to the mixture. The suspension was filtered through a diatomaceous earth (100 g) bed and washed with DCM (300 mL). The filtrate was concentrated under reduced pressure and dried in a vacuum oven at 40 °C for 18 h to give (1R,3R,5R)-3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (133 g, 90% yield), a yellow oil containing 2% isomers, as determined by GC-MS analysis. GC-MS, C 11 H 19 Calculated value of NO3: 213.1; Measured value: 213.2 (M + ). 1 H-NMR (400 MHz, CDCl3) δ 4.83(brs, 1H), 4.34 (brs, 1H), 2.45 (ddd, 1H), 1.55-1.43 (m, 12H), 0.80 (q, 1H), 0.40 (brs, 1H).

[0707] Step 4. (1R,3R,5R)-3-formyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester

[0708]

[0709] DMSO (42.7 mL, 0.603 mol) was added dropwise to oxaloyl chloride (26.4 mL, 0.301 mol) in DCM (535 mL) for 30 min at -78 °C, while maintaining the temperature below -60 °C during the addition. After stirring at -78 °C for 30 min, (1R,3R,5R)-3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (53.5 g, 0.251 mol) in DCM (535 mL) was added dropwise to the solution for 40 min at -78 °C. After stirring at -78 °C for 30 min, NEt3 (104.9 mL, 0.753 mol) was added dropwise to the solution for 40 min at -78 °C. After stirring at -78 °C for 1 h, the reaction mixture was heated to 0 °C and stirred for 30 min. Water (888 mL) was added to the mixture and stirred for 20 min. The aqueous layer was separated and extracted with DCM (2 × 888 mL). The combined organic layers were washed sequentially with 1 M HCl (888 mL), water (888 mL), and saturated brine (888 mL). The organic layers were concentrated under reduced pressure to give (1R,3R,5R)-3-formyl-2-azabicyclo[3.1.0]hexane-2-carboxylate tert-butyl ester (44 g, 83% yield), a yellow oil. GCMS, C 11 H 17 Calculated value of NO3: 213.1; Measured value: 213.2 (M + ). 1 H-NMR (400 MHz, CDCl3) δ 9.54-9.31 (m, 1H),4.64-4.39 (m, 1H), 3.68-3.45 (m, 1H), 2.68-2.33 (m, 1H), 2.24-2.10 (m, 1H),1.53-1.41 (m, 10H), 0.88-0.71 (m, 1H), 0.39-0.28 (m, 1H).

[0710] Step 5. (1R,3R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester

[0711]

[0712] K₂CO₃ (28.8 g, 0.209 mol, 2 eq.) was added to a solution of (1R,3R,5R)-3-formyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (22 g, 0.104 mol) in methanol (352 mL) at 0 °C to 5 °C. Dimethyl (18.3 mL, 0.110 mol) phosphonate was added dropwise to the mixture at 0 °C to 5 °C over 30 min, while maintaining the temperature < 5 °C during the addition. After stirring at 0 °C to 5 °C for 15 min, the reaction mixture was warmed to room temperature and stirred for 2 h. Water (372 mL) and EtOAc (930 mL) were added to the mixture, and the mixture was stirred for 15 min. The aqueous layer was separated and extracted with EtOAc (372 mL). The combined organic layers were washed with water (560 mL) and saturated brine (560 mL). The organic solution was concentrated under reduced pressure and purified by silica gel elution with a gradient of 0% to 10% EtOAc in heptane to give a 7:1 mixture (82 g, calculated yield 74%) of (1R,3R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-carboxylate tert-butyl ester and (1R,3S,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-carboxylate tert-butyl ester, which appeared as a pale yellow oil. GCMS, C 12 H 17 Calculated value of NO2: 207.1; Measured value: 207.0 (M + ). 1 H-NMR (400 MHz, CDCl3) δ 4.78-4.54 (m, 1H), 3.60-3.46 (m, 1H), 2.52-2.40 (m, 1H), 2.30-2.22(m, 1H), 2.18-2.08 (m, 1H), 1.50-1.48 (m, 9H), 1.16-1.05 (m, 1H), 0.91-0.80 (m, 1H), 0.78-0.66 (m, 1H).

[0713] Step 6. Cyclopropyl((1R,3R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-yl) methyl ketone

[0714]

[0715] A mixture of (1R,3R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-carboxylate tert-butyl ester and (1R,3S,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-carboxylate tert-butyl ester (82 g, 0.39 mol) and 4M HCl in dioxane (297 mL, 1.19 mol, 3 eq.) was stirred at room temperature for 4 h. The reaction mixture was diluted with THF (1.23 L) and cooled to 0 °C. NEt3 (275.8 mL, 1.98 mol) was added dropwise to the reaction mixture over 1.5 h at 0 °C while maintaining the temperature <10 °C. Cyclopropaneformyl chloride (45.4 g, 0.43 mol) was added to the reaction mixture at 0 °C. The reaction mixture was then heated to room temperature and stirred for 3 h. 1M HCl (410 mL, 5 vol) and DCM (820 mL) were added. The aqueous layer was separated and extracted with DCM (2 × 820 mL). The combined organic layers were washed with water (820 mL) and saturated brine (820 mL). The organic layers were concentrated under reduced pressure to give a crude residue (60 g). Diatomaceous earth (120 g) was added to the crude residue, and the mixture was dried under reduced pressure to give a dry loaded powder (186 g). The dried loaded powder was purified on a silica gel column (1.5 kg) and eluted with a gradient of 15% to 40% EtOAc in heptane. The desired fraction was concentrated under reduced pressure and dried under vacuum at 30 °C for 18 h to give the title compound (40.8 g, 59% yield) as a brown oil. GCMS, C 12 H 17 Calculated value of NO2: 175.1; Measured value: 175.0 (M + ). 1 H-NMR (400 MHz, DMSOd6) δ 5.14 (dt, 0.45H), 4.81 (dt, 0.55H), 3.82 (t, 0.55H), 3.71 (t, 0.45H), 3.42 (d, 0.45H), 3.15 (d,0.55H), 2.57 (ddd, 0.45H), 2.44 (ddd, 0.55H), 2.09 (dd, 0.45H), 2.04 (ddd,0.55H), 1.97 (dd, 0.55H), 1.86-1.69 (m, 1H), 1.62 (dddd, 0.45H), 1.01 (td,0.55H), 0.90 (td, 0.45H), 0.87-0.68 (m, 5H).

[0716] Example 3. Synthesis of (1R,4R,5S)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl oxalate (step 14a in Example 1)

[0717] Step 1. (E)-4-methoxybut-3-en-2-one:

[0718]

[0719] A mixture of 4,4-dimethoxy-2-butanone (350 g, 1.0 eq) and sodium acetate (11 g, 0.05 eq.) was heated to 145 °C to 150 °C under a nitrogen atmosphere, with the resulting methanol purged during heating. When the reaction was complete, the mixture was cooled to 70 °C to 80 °C. The product was distilled under vacuum to give the desired product (130 g, 50% yield). ¹H NMR (CD₂Cl₂ / CHDOD, 400 MHz): δ 7.60 (d, ¹H, J=12.8 Hz), 5.53 (d, ¹H, J=12.8 Hz), 3.81 (s, ³H), 2.17 (s, ³H). 13C NMR (CD2Cl2 / CD3OD, 100.6 MHz): δ 27.1, 58.0, 107.0, 165.2, 199.6.

[0720] Step 2. (E)-4-(allylamino)but-3-en-2-one:

[0721]

[0722] A mixture of (E)-4-methoxybut-3-en-2-one (150 g) and NEt3 (182 g) in DCM (450 mL) was added and stirred under nitrogen at 10-15 °C. An aqueous solution of allylamine hydrochloride (60%, 234 g) was slowly added to the mixture at 10-15 °C. After addition, the mixture was stirred for 30 min. When the reaction was complete, water (150 g) was added to the reaction mixture. The organic phase was separated, and the aqueous phase was extracted with DCM (300 mL). The combined organic phases were washed with brine (150 mL) and concentrated under vacuum to give a crude product (175 g, 93% yield) as a yellow oil. 1H NMR (500MHz, CDCl3): δ 9.75 (bs, 1H); 6.58 (dd, 1H, J=16.8, 2); 5.78-5.86 (m,1H); 5.19 (d, 1H, J=16.8)); 5,14 (d, 1H, J=10, 1)); 5.00 (d, 1H, J=10, 1); 3.74-3.77 (m, 2H); 2.03, (s, 3H). 13C NMR (125 Hz, CDCl3): 197.5; 153.2; 165.3; 117.6; 94.9; 51.1; 29.2.

[0723] Step 3. (E)-Allyl (3-oxobut-1-en-1-yl)carbamate tert-butyl ester:

[0724]

[0725] Will (A mixture of E)-4-(allylamino)but-3-en-2-one (130 g), trimethylamine (105 g), and N,N-dimethylaminopyridine (13 g) in toluene (390 mL) was heated to 50°C to 55°C. (Boc)₂O (259 g) was added in parts while maintaining the reaction temperature between 50°C and 55°C. The reaction mixture was stirred at 50°C to 55°C for 2 h to complete the reaction. The mixture was cooled to 10°C to 15°C, and a 3 M HCl aqueous solution was added to the mixture until the pH reached 5 to 6. The organic phase was separated, and the aqueous phase was extracted with toluene (260 mL). The combined organic phases were washed with water (260 mL). Activated carbon (1 g) was added. The mixture was stirred at 50°C to 55°C for 1 h, and then cooled to 20°C to 30°C. The mixture was filtered through a diatomaceous earth bed, and the diatomaceous earth bed was washed with toluene. The filtrate was concentrated to the residue, which was then co-evaporated with MeCN to give a yellow oily residue (189 g, 80% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.11 (d, ¹H, J=15); 5.68–5.73 (m, ¹H); 5.49 (d, ¹H, J=15); 5.14 (d, ¹H, J=18); 5.09 (d, ¹H, J=10); 4.13 (t, 2H); 2.20 (s, 3H); 1.50 (s, 9H). 13C NMR (125 MHz, CDCl3): 198.6; 153.0; 143.2; 131.8; 117.8; 109.5; 84.0; 47.0; 28.3; 28.1.

[0726] Step 4. 5-Acetyl-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester:

[0727]

[0728] A solution of (E)-allyl(3-oxobut-1-en-1-yl)carbamate tert-butyl in MeCN (3240 mL) was subjected to a UV photoreactor. Upon completion of the reaction, the yellow oily residue (a mixture of major and minor isomers) was used for the next step without further purification. The sample was purified by column chromatography to obtain analytical data. ¹H NMR (500 MHz, CDCl₃) δ 4.62–6.78 (bd, ¹H); 3.40 (bt, ¹H); 3.16 (bs, ¹H); 3.06 (bs, ¹H); 2.69 (s, ¹H); 1.97 (s, ³H); 1.70–1.73 (m, ¹H); 1.46 (s, ⁹H).

[0729] Step 5. (1R,4R,5S)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl oxalate:

[0730]

[0731] A mixture of 150 g of 5-acetyl-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester in MeCN (1500 mL) was added to a 30% sodium hydroxide solution (1500 mL) containing 173.5 g of sodium hypochlorite at 30-40°C. The mixture was stirred at 30-40°C for 30 min to complete the reaction. The mixture was cooled to 10-15°C, and a 6M HCl aqueous solution was added to adjust the pH of the mixture to 8-9. The mixture was concentrated under vacuum at 50-55°C to remove MeCN, and methanol (90 mL) was added to the residue. The mixture was cooled to 10-15°C, and 6M HCl was added to adjust the pH of the mixture to 2-3 (the solid precipitated during pH adjustment), and stirred for another 2-3 h. The solid was separated and washed with water (300 mL). The wet solid was dried under vacuum at 50-55°C.

[0732] Recrystallization: The mixture of solids in toluene (1500 mL) was heated to 60-70°C to form a solution. (R)-(+)-1-phenylethylamine (80.7 g) was added at 40-70°C. After 90 min, the solution was cooled to 30-35°C (the solid gradually precipitated) and stirred for 1 h. After 90 min, the suspension was cooled to 20-25°C and stirred for 2 h. The solids were separated and washed with toluene (40 mL). The mixture of filter cake and toluene (1200 mL) was heated to 100-105°C to form a solution. After 90 min, the mixture was cooled to 75-85°C (the solid precipitated) and stirred for 1 h. After 2 h, the mixture was cooled to 20-25°C and stirred for 2 h. The solids were separated and washed with toluene (40 mL). The recrystallization process was repeated once more.

[0733] Free base: Add 30% NaOH aqueous solution to a mixture of wet cake in toluene (225 mL) and water (225 mL) at 10°C to 15°C until the pH is 9 to 10. Stir the mixture for 30 min and separate the organic phase. Add 6 M HCl aqueous solution to the aqueous phase at 10°C to 15°C until the pH is 2 to 3 (solids expected). Then cool the mixture to 3°C to 8°C and stir for 1 h. Separate the solids and wash with water (40 mL). Dry the wet filter cake under vacuum at 50°C to 55°C to give the desired (1R,4S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (25 g, yield 18%).

[0734] Add (Boc)₂O (310 g) to a mixture of acid (245 g), pyridine (86 g), and ammonium carbonate (111 g) in MeCN (3700 mL) at 15°C to 25°C. Stir the mixture for 5 h to complete the reaction. Separate the solid and wash with MeCN (250 mL). Combine the filtrate and wash, concentrate under vacuum at 40°C to 45°C, and azeotropically react with heptane. Add EtOAc (130 mL) and n-heptane (650 mL) to the residue at 40°C to 45°C. Cool the mixture to 10°C to 15°C (solid precipitate) and stir for 2 h. Separate the solid and wash with n-heptane (250 mL). The wet filter cake was dried under vacuum at 50°C to 55°C to quantitatively obtain the desired product (1R,4S,5S)-5-carbamoyl-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester.

[0735] (1R,4S,5S)-5-carbamoyl-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (214 g) was added to a cooled 15% NaOH aqueous solution (800 mL) at 10°C to 15°C. Sodium hypochlorite (91.2 g) was added at 10°C to 20°C, and the mixture was stirred for 2 h. The mixture was heated to 40°C to 45°C for 4 h to complete the reaction. The reaction mixture was cooled to 15°C to 20°C, and citric acid was added to adjust the pH to 5 to 6. The mixture was alkalized to pH 14 by adding sodium hydroxide. The alkalized mixture was extracted with 2-methyltetrahydrofuran (2 × 1000 mL). The combined organic phases were concentrated under vacuum, and the residue was azeotropically reacted with MeCN. The residue was dissolved in (140 mL), and activated carbon (2 g) was added. The mixture was stirred at 25°C to 30°C for 2 h. The mixture was filtered, and the filter bed was rinsed with MeCN (85 mL). The combined filtrate and rinsing solution were added to a solution of oxalic acid (120 g) in MeCN (850 mL) at 40-45 °C. The solution was cooled to 3-7 °C and stirred for 1 h. The solid was separated and rinsed with MeCN (110 mL). The wet filter cake was dried under vacuum at 40-50 °C to give the desired (1R,4R,5S)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl oxalate (248 g, 91% yield) as a white solid. HPLC-MS, C 10 H 18 Calculated value of N2O2: 198.14; Measured value (M+H): 199.1. 1 H NMR (500 MHz, DMSO-d6): δ8.44 (s, 3H); 3.34, (m, 1H); 4.24, dt, 1H, J=6.9, 1.7 Hz); 3.20-3.31 (m, 2H); 2.84, (dt, 1H, J=6.5, 3.0); 1.65-1.71 (m,1H); 1.42 (s, 9H); 1.19 (d, 1H, J=8.1). 13 C NMR (125 Hz, DMSO-d6): δ 165.0;155.8;79.5;61.5;50.6;44.9;40.8;33.8;28.6.

[0736] Example 4: Antitumor efficacy and pharmacodynamics of compound 1 ± cetuximab and compound 2 ± cetuximab in an LS513 colorectal cancer xenograft mouse model

[0737] LS513 xenotransplantation efficacy model

[0738] Female NSG-SCID mice (Jackson Labs, 8 to 10 weeks old) were simultaneously subcutaneously injected with a solution of 50% phosphate-buffered saline and 50% Matrigel. ® (354234 Corning ® 5 × 10 6 LS513 cells. For the efficacy portion of these studies—note that compound 1 (monotherapy and combination) and compound 2 (monotherapy and combination) were tested in independent studies—treatment of tumor-bearing mice was initiated 11 days (in combination with compound 1) or 13 days (in combination with compound 2) post-inoculation, at which point the tumor volume reached approximately 250 mm. 3 Mice inoculated with LS513 were randomly assigned to groups of n=10 based on tumor volume. They were then treated with: monotherapy with compound 1 (30 mg / kg QD PO or 100 mg / kg QD PO), compound 2 (10 mg / kg QD PO or 30 mg / kg QD PO), or cetuximab (3 mg / kg BIW IP); combination of compound 1 and cetuximab (30 mg / kg QD or 100 mg / kg QD PO of compound 1); combination of compound 2 and cetuximab (10 mg / kg QD or 30 mg / kg QD of compound 2); or mediator PO. Treatment was continuous throughout the study and ended on day 31 (compound 1) or day 33 (compound 2) post-tumor implantation. Mice were weighed and tumors were measured twice weekly until the end of the study, the day after the final treatment dose (day 32 or 33 post-tumor implantation). Tumor volume was calculated in two dimensions using the following equation:

[0739] Volume = [Length × (Width)] 2 )] / 2.

[0740] Tumor growth inhibition (TGI) is calculated using the formula (1 – [V]). T / V C ]) × 100, where V T The mean tumor volume of the treatment group on the last day of treatment, and V C This represents the mean tumor volume in the control group on the last day of treatment. Partial response was defined as tumor volume ≤ 50% of the initial tumor volume based on two follow-up measurements, and complete response was defined as tumor volume ≤ 3 mm x 3 mm (or ≤ 27 mm) based on two follow-up measurements. 3Statistical analyses were performed using GraphPad Prism software (v9.3.1; GraphPad software, Boston, MA). Two-way ANOVA with Dunnett's multiple comparison test was used to determine statistical differences between the treatment group and the mediator control group and the monotherapy group.

[0741] LS513 pharmacodynamic model

[0742] Female NSG-SCID mice (Jackson Labs, 8 to 10 weeks old) were simultaneously subcutaneously injected with a solution of 50% phosphate-buffered saline and 50% Matrigel. ® (354234 Corning ® 5 × 10 6 LS513 cells. For the pharmacodynamic portion of this study, treatment of tumor-bearing mice began 22 days (4-hour collection) and 28 days (24-hour collection) post-inoculation, at which point the tumor volume reached approximately 700 mm. 3 (4hr) or 560 mm 3 (24hr). The tumor volume was calculated in two dimensions using the following equation:

[0743] Volume = [Length × (Width)] 2 )] / 2.

[0744] Mice inoculated with LS513 were randomly assigned to n = 4 groups based on tumor volume. They were then administered either a single-dose monotherapy of compound 1 (30 mg / kg QD PO or 100 mg / kg QD PO) or cetuximab (3 mg / kg BIW IP), a combination of the two agents at two dose concentrations of compound 1, or cetuximab PO. Plasma and tumor samples were collected at 4 and 24 hours post-administration following CO2 asphyxia. Blood was collected into ethylenediaminetetraacetic acid (EDTA) tubes (450480 Greiner Bio-One). Plasma was analyzed for drug levels. Tumor fragments were collected from each individual, weighed, placed in Omni Bead Ruptor tubes (19-628 Omni International), and rapidly frozen. A tumor fragment was lysed at a 1:5 ratio with a homogenization solution (water:acetonitrile:formic acid, 95:5:0.1, v:v:v) for drug concentration analysis. The second tumor mass was then lysed at a 1:5 ratio using lysis buffer (64KL1FD, Cisbio) supplemented with protease inhibitors (A32957 and A32965, Thermo Fisher) and blocking reagent (64KB1AAC, Cisbio) on a Bead Ruptor Elite homogenizer (19-042E, Omni International, Kennesaw, GA). The tumor lysates were rotated at 10,000 rpm for 10 minutes at 4°C. Protein concentrations were determined using the Pierce™ BCA protein assay method according to the manufacturer's protocol (23227 Thermo Fisher Scientific). The lysates were diluted to a final concentration of 0.4 μg / μL with additional lysis buffer. The samples were analyzed using the MesoScale Discovery platform on the Phospho / Total ERK1 / 2 Whole Cell Lysate Kit (K15107D, MesoScale Discovery, Rockville, MD). First, the pERK level was normalized to the total ERK for each sample, and then normalized to the mean pERK / tERK ratio of the mediator control group.

[0745] Pharmacokinetic Sample Analysis

[0746] Plasma and tumor concentrations of compound 1 were determined using calibration curves prepared in plasma. A quality control sample prepared in a tumor homogenate was included to confirm the accuracy of plasma as a substitute matrix for tumor homogenate samples. Plasma and tumor homogenate study samples were aliquoted (25 μL volume) and deproteinized by vigorous mixing of 200 µL of 50 nM compound 1 in acetonitrile. After centrifugation, 100 μL of the supernatant was transferred to a 96-well plate containing 200 μL of water, thoroughly mixed, and analyzed by LC-MS / MS. Chromatography was performed using an ACE C18-AR HPLC column (50 × 2.1 mm, 3 μm, at 45 °C) under gradient conditions (see Table 1) at a flow rate of 0.75 mL / min, injecting 5 µL of the extract. All tumor samples were above the limit of quantitation (5000 nM) for compound 1, and the signal for compound 1 was saturated on the mass spectrometer. Therefore, all samples for compound 1 were re-injected in 2 µL increments. All tumor samples with concentrations exceeding the upper limit of quantitation were re-injected at 0.5 µL (plus a QC) to ensure peak areas remained within the linear range. Water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid were used for mobile phases A and B, respectively. LC-MS / MS analysis was performed using a Shimadzu Nexera ultra-high performance liquid chromatography system coupled to the electrospray ionization source (in positive ion MRM mode) of a SCIEX Triple Quad 6500+ mass spectrometer. Using the MRM ion pair for Compound 1 (628.228 m / z → 517.228 m / z, retention time = 1.18 min) and the MRM ion pair for (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-1-carboxylate (“Compound 2”) as an internal standard for Compound 1, a peak area of ​​370.792 m / z → 296.652 m / z (retention time = 1.30 min) was used to construct a peak with 1 / x 2 The linear regression calibration equation for the weights. (Using SCIEX Analyst) ® The software (v1.7.2) is used to acquire raw data and calculate calibration curves and study sample concentrations. The measurement range is adjusted to 1 to 5000 nM for the expected study concentration.

[0747] Table 1: Gradient elution protocols for high performance liquid chromatography

[0748]

[0749] Note: Post-column split valve: 0.8 to 1.6 minutes of the solution is sent to the mass spectrometer for analysis, and all the rest is sent to waste liquid.

[0750] result

[0751] Antitumor activity of compound 1 ± cetuximab in the LS513 colorectal xenograft tumor model

[0752] The antitumor activity of the combination of compound 1 and cetuximab was evaluated in the LS513 colorectal model. Mice were administered either compound 1 (30 mg / kg QD PO, 100 mg / kg QD PO) or cetuximab (3 mg / kg BIW IP) as monotherapy, either the two agents at two dose concentrations of compound 1, or the mediator PO. When evaluated on day 32 after the last treatment, 30 mg / kg compound 1 caused a 73% TGI compared to the mediator (p < 0.0001), while 100 mg / kg compound 1 caused a 93% TGI compared to the mediator (p < 0.0001). All 10 mice in the 100 mg / kg compound 1 monotherapy group achieved partial remission. Cetuximab IP BIW produced a 64% TGI (p = 0.0001). Compared with the mediator, the combination of 3 mg / kg cetuximab BIW IP and 30 mg / kg compound 1 induced 96% TGI (p < 0.0001) (see [link to relevant documentation]). Figure 1 The combination of 3 mg / kg cetuximab BIW IP with 100 mg / kg compound 1 resulted in 100% TGI (p < 0.0001) and caused complete remission in all animals (n=10 out of 10). The combination with cetuximab significantly reduced tumor growth compared to compound 1 monotherapy (p ≤ 0.0001 when comparing 30 mg / kg compound 1 monotherapy with 30 mg / kg compound 1 + cetuximab combination, and p = 0.0006 when comparing 100 mg / kg compound 1 monotherapy with 100 mg / kg compound 1 + cetuximab combination). Each treatment modality was tolerable, as demonstrated by the absence of weight loss across treatment groups (see [link to treatment guidelines]). Figure 2 (and Table 2).

[0753] exist Figure 1In this study, NSG-SCID mice carrying subcutaneous LS513 tumors were treated with monotherapy of compound 1 (30 mg / kg PO QD, 100 mg / kg PO QD) or cetuximab (3 mg / kg IP BIW), either at two different dose concentrations of compound 1 or as a mediator PO. Dosing began on day 11 and ended on day 31. n = 10 mice / group. Cetuximab was administered on days 11, 15, 18, 22, 25, and 29 post-tumor implantation. PR – Partial remission – Tumors with a volume ≤ 50% of the initial tumor volume in two follow-up measurements. CR – Complete remission – Tumors with a measurement ≤ 3 mm x 3 mm (or ≤ 27 mm³) in two follow-up measurements. ** - p-value = 0.0019; *** - p-value = 0.0001; **** - p-value < 0.0001 (all compared to group 1 (mediator)). # - Cetuximab + 30 mg / kg Compound 1 - p-value < 0.0001 compared to Compound 1 monotherapy (30 mg / kg QD). & - Cetuximab + 100 mg / kg Compound 1 - p-value = 0.0003 compared to Compound 1 monotherapy (100 mg / kg QD).

[0754] exist Figure 2 Throughout the study, body weight was measured. No toxicity was observed with compound 1 ± cetuximab when measured by weight loss. SEM = standard error of the mean. n = 10 mice / group.

[0755] Table 2: Mean (± SEM) body weight of LS513 tumor-bearing mice treated with compound 1 ± cetuximab

[0756]

[0757] Pharmacodynamics of Compound 1 ± Cetuximab in LS513 Tumor-Bearing Mice

[0758] Plasma and tumor samples were collected 4 and 24 hours after administration of compound 1 (30 mg / kg QD PO, 100 mg / kg QD PO) or cetuximab (3 mg / kg BIW IP), either as a single therapy at two different dose concentrations of compound 1, or as a single oral or IP administration of cetuximab. Total ERK and phosphorylated ERK levels were measured from tumor samples. In this model, treatment with compound 1 at 30 or 100 mg / kg induced dose-dependent pERK inhibition. Under this single-dose setting, at 4 hours (close to C... max The pERK inhibition was lower at 24 hours than at 24 hours (C). 谷(Stronger) Cetuximab as monotherapy had little effect on pERK levels up to 4 hours after administration, but induced pERK inhibition comparable to that of compound 1 as a monotherapy up to 24 hours after administration. Combination therapy with compound 1 plus cetuximab tended to increase the observed degree of pERK inhibition, but not by a statistically significant amount. Figure 3 These results were summarized in NSG-SCID mice carrying subcutaneous LS513 tumors treated with monotherapy of compound 1 (at 30 mg / kg PO QD, 100 mg / kg PO QD) or cetuximab (at 3 mg / kg IP BIW), a combination of the two agents at two dose concentrations of compound 1, or the mediator PO. Tumor samples were collected at 4 and 24 hours after monotherapy or IP administration. The percentage inhibition of pERK / ERK relative to the mediator control is plotted as bars. n = 4 mice / group

[0759] Pharmacodynamics of Compound 1 ± Cetuximab in LS513 Tumor-Bearing Mice

[0760] Following CO2 asphyxiation, plasma and tumor samples were collected from N = 4 mice from each group treated with compound 1 after a single oral administration at 4 and 24 hours post-administration. The collected data are shown in Table 3.

[0761] Table 3: Plasma and tumor concentrations relative to pERK inhibition

[0762]

[0763] Data indicate that combination administration of compound 1 with cetuximab induced additional tumor growth inhibition in the LS513 xenograft model. Cetuximab and compound 1 exhibited a synergistic effect (at both dose levels of compound 1), as determined using “survival curves” described in E. Demidenko, et al., PLoS ONE, 2019, 14(11): e0224137. The increased efficacy from the combination was due to activity unrelated to the inhibition of pERK signaling.

[0764] result

[0765] Antitumor activity of compound 2 ± cetuximab in the LS513 colorectal xenograft tumor model

[0766] The antitumor activity of the combination of compound 2 and cetuximab was evaluated in the LS513 colorectal model. Mice were administered compound 2 (10 mg / kg QD PO, 30 mg / kg QD PO) or cetuximab (3 mg / kg BIW IP) as monotherapy, a combination of the two agents at two dose concentrations of compound 2, or a mediator PO. When evaluated on day 34, all treatment groups showed significant inhibition of tumor growth compared to the mediator control (p ≤ 0.0002). The combination of compound 2 and cetuximab produced superior efficacy compared to the respective monotherapy groups. The combination of 10 mg / kg compound 2 + cetuximab significantly inhibited tumor growth compared to either compound 2 (10 mg / kg) or cetuximab monotherapy (p ≤ 0.0008). Similarly, compared with either monotherapy of compound 2 (30 mg / kg) or cetuximab, the combination of compound 2 (30 mg / kg) and cetuximab significantly inhibited tumor growth (p ≤ 0.0003).

[0767] Example 5: Antitumor efficacy and pharmacodynamics of compound 1 ± cetuximab in HPAFII pancreatic cancer xenograft mouse model

[0768] HPAFII xenotransplantation efficacy model

[0769] Female NCr nude mice (Taconic Biosciences, 8 to 10 weeks old) were simultaneously subcutaneously inoculated with a suspension of 50% phosphate-buffered saline and 50% Matrigel. ® (354234 Corning ® 1 × 10 7 HPAFII cells. For the efficacy portion of the study, treatment of tumor-bearing mice began 13 days post-inoculation, at which point the tumor volume reached approximately 280 mm². 3 Mice inoculated with HPAFII were randomly assigned to groups of n = 10 based on tumor volume. They were then administered: monotherapy with compound 1 (30 mg / kg QDPO or 100 mg / kg QD PO) or cetuximab (3 mg / kg BIW IP), a combination of both agents (compound 2 at 30 mg / kg QD or 100 mg / kg QD), or mediator PO. Treatment was continuous throughout the study and ended on day 32 post-tumor implantation. Mice were weighed and tumors were measured twice weekly until the end of the study on day 32 post-tumor implantation. Tumor volume was calculated in two dimensions using the following equation:

[0770] Volume = [Length × (Width)] 2 )] / 2.

[0771] Tumor growth inhibition (TGI) is calculated using the formula (1 – [V]). T / V C ]) × 100, where V T The mean tumor volume of the treatment group on the last day of treatment, and V C This represents the mean tumor volume in the control group on the last day of treatment. Partial response was defined as tumor volume ≤ 50% of the initial tumor volume based on two follow-up measurements, and complete response was defined as tumor volume ≤ 3 mm x 3 mm (or ≤ 27 mm) based on two follow-up measurements. 3 Statistical analyses were performed using GraphPad Prism software (v9.3.1; GraphPad software, Boston, MA). Two-way ANOVA with Tukey's multiple comparison test was used to determine statistical differences between the treatment group and the mediator control group and the monotherapy group.

[0772] result

[0773] Antitumor activity of compound 1 ± cetuximab in an HPAFII pancreatic cancer xenograft tumor model

[0774] The antitumor activity of the combination of compound 1 and cetuximab was evaluated in an HPAFII pancreatic cancer model. Mice were administered compound 1 (30 mg / kg QD PO, 100 mg / kg QD PO) or cetuximab (3 mg / kg BIW IP) as monotherapy, a combination of the two agents at two dose concentrations of compound 1, or mediator PO. When evaluated on day 32, animals treated with 100 mg / kg compound 1 monotherapy or compound 2 (at 30 or 100 mg / kg) + cetuximab had significantly reduced tumor growth compared to the mediator control (p ≤ 0.0202); animals treated with 30 mg / kg compound 1 monotherapy had reduced tumor growth compared to the mediator control, but the reduction was not statistically significant. Figure 5 Tumor growth in the group treated with cetuximab monotherapy was not significantly different from that in the mediator control group. Combining compound 1 with cetuximab produced superior efficacy compared to the relevant monotherapy groups, but this did not reach statistical significance due to intragroup variability and the high tumor growth inhibition produced by compound 1 monotherapy (TGI of 82% for 100 mg / kg of compound 1). In other words, treatment with compound 1 (100 mg / kg) plus cetuximab did indeed result in a significant reduction in tumor growth compared to the lower-dose combination group (30 mg / kg of compound 1 + cetuximab).

[0775] The scope of the disclosed subject matter is not limited to the specific embodiments and examples described herein. In fact, various modifications to this disclosure, in addition to those described, will become apparent to those skilled in the art from the foregoing description and drawings. Such modifications are intended to fall within the scope of the appended claims.

[0776] All references cited herein (e.g., publications, patents, or patent applications) are incorporated herein by reference in their entirety and for all purposes, to the extent that each individual reference (e.g., publications, patents, or patent applications) is specifically and individually indicated by reference in its entirety for all purposes. Other embodiments are within the scope of the following claims.

Claims

1. A method of treating cancer in a subject with this need, the method comprising administering to the subject a KRASG12D inhibitor or a pharmaceutically acceptable salt thereof and an EGFR inhibitor or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein the EGFR inhibitor is an anti-EGFR antibody.

3. The method according to claim 1 or 2, wherein the EGFR inhibitor is selected from cetuximab, mateuzumab, nexituzumab, nimotuzumab, panitumumab, and zalumumab.

4. The method according to any one of claims 1 to 3, wherein the EGFR inhibitor is cetuximab.

5. The method according to claim 1, wherein the EGFR inhibitor is a small molecule inhibitor.

6. The method according to claim 1 or 5, wherein the EGFR inhibitor is selected from afatinib, brigatinib, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, mobocetinib, neratinib, osimertinib, and vandetanib.

7. The method according to any one of claims 1 to 6, wherein the G12D inhibitor has an IC50 of about 100 nM or lower. 50 .

8. The method according to any one of claims 1 to 7, wherein the G12D inhibitor is selective for inhibiting G12D relative to wild-type KRAS.

9. The method according to any one of claims 1 to 8, wherein the KRAS G12D inhibitor is a compound of formula I: I Or its pharmaceutically acceptable salt, wherein: Y is N or CR 6 ; R 1 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, cyclopropyl, halogenated, D, CN and OR a1 ; wherein C 1-3 The alkyl and cyclopropyl groups are each optionally selected independently from R by one or two. g Substituents of the substituents; R 2 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, 4- to 6-membered heterocyclic alkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5- to 6-membered heteroaryl-C 1-3 Alkylene, Halogenated, D, CN, and OR a2 ; wherein C 1-3 Alkyl, 4- to 6-membered heterocyclic alkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5- to 6-membered heteroaryl-C 1-3 Each alkylene group is optionally selected independently from one or two of R. g Substituents of the substituents; Cy 1 Selected from C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl and 6- to 10-membered heteroaryl; wherein each of the 4- to 10-membered heterocyclic alkyl and the 6- to 10-membered heteroaryl has at least one cyclic carbon atom and 1, 2, 3 or 4 cyclic heteroatoms independently selected from N, O and S; wherein the cyclic carbon atom of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocyclic alkyl is optionally substituted with an oxo group to form a carbonyl group; and wherein the C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 The aryl group and the 6- to 10-membered heteroaryl group are each optionally selected independently by 1, 2, 3, or 4 groups from R. 10 Substituents of the substituents; R 3 Selected from H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4- to 6-membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5- to 6-membered heteroaryl-C 1-3 Alkylene, Halogenated, D, CN, OR f3 C(O)NR c3 R d3 NR c3 R j3 and NR c3 C(O)R b3 ; wherein C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4- to 6-membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- to 6-membered heteroaryl-C 1-3 Each alkylene group is optionally selected independently from R by one, two, or three independent groups. 30 Substituents of the substituents; R 5 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, cyclopropyl, halogenated, D, CN and OR a5 ; wherein C 1-3 The alkyl and cyclopropyl groups are each optionally selected independently from R by one or two. g Substituents of the substituents; R 6 Selected from H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 9-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4- to 6-membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5- to 6-membered heteroaryl-C 1-3 Alkylene, Halogenated, D, CN, OR a6 and C(O)NR c6 R d6 ; wherein C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 9-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4- to 6-membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- to 6-membered heteroaryl-C 1-3 Each alkylene group is optionally selected independently from one or two of R. 60 Substituents of the substituents; R 7 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, cyclopropyl, halogenated, D, CN and OR a7 ; wherein C 1-3 The alkyl and cyclopropyl groups are each optionally selected independently from R by one or two. g Substituents of the substituents; Cy 2 Selected from Where n is 0, 1, or 2; Each R 10 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN, OR a10 C(O)R b10 C(O)NR c10 R d10 C(O)OR a10 NR c10 R d10 and S(O)2R b10 ; Each R 20 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN and OR a20 ; Each R 30 Selected independently from C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogenated, D, CN, OR a30 C(O)R b30 C(O)NR c30 R d30 C(O)OR a30 NR c30 R d30 and S(O)2R b30 ; wherein C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R 31 Substituents of the substituents; Each R 31 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN, OR a31 C(O)R b31 C(O)NR c31 R d31 C(O)OR a31 NR c31 R d31 and S(O)2R b31 ; Each R 33 Selected independently from C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogenated, D, CN, OR a30 C(O)NR c30 R d30 and NR c30 R d30 ; wherein C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected independently by one or two of R. 31 Substituents of the substituents; Each R 60 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, 4- to 6-membered heterocyclic alkyl, 5- to 6-membered heteroaryl, halogenated, D, CN, OR a60 C(O)R b60 C(O)NR c60 R d60 NR c60 C(O)R b60 C(O)OR a60 NR c60 C(O)OR a60 NR c60 R d60 NR c60 S(O)2R b60 and S(O)2R b60 ; wherein C 1-3 Alkyl, 4- to 6-membered heterocyclic alkyl and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R 61 Substituents of the substituents; Each R 61 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN, OR a61 and NR c61 R d61 ; R a1 Selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Each R a2 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Each R b3 R c3 and R d3 Independently selected from H and C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by 1, 2, or 3 independently from R 30 Substituents of the substituents; Or R connected to the same N atom c3 and R d3 Together with the N atoms to which they are attached, they form 4-, 5-, or 6-membered heterocyclic alkyl groups optionally substituted with 1, 2, or 3 substituents, wherein the substituents are independently selected from R. 30 ; R j3 Selected from C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by 1, 2, or 3 independently from R 30 Substituents of the substituents; Or R connected to the same N atom c3 and R j3 Together with the N atoms to which they are attached, they form 4-, 5-, or 6-membered heterocyclic alkyl groups optionally substituted with 1, 2, or 3 substituents, wherein the substituents are independently selected from R. 30 ; R f3 Selected from C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; wherein the C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by 1, 2, or 3 independently from R 30 Substituents; or R f3 Selected from Where R x For H or C 1-2 Alkyl, and R y C 1-2 alkyl; Or R x and R y Together with the C atoms they are attached to, they form 3- or 4-membered cycloalkyl groups; R a5 Selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Each R a6 R c6 and R d6 Independently selected from H and C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R 60 Substituents of the substituents; R a7 Selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Each R a10 R b10 R c10 and R d10 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Each R a20 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; R b20 Selected from NH2, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Each R a30 R b30 R c30 and R d30 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Each R a31 R b31 R c31 and R d31 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Each R a60 R b60 R c60 and R d60 Independently selected from H and C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 The cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R. 61 Substituents of the substituents; Or any R connected to the same N atom c60 and R d60 Together with the N atoms to which they are attached, they form 4-, 5-, or 6-membered heterocyclic alkyl groups, optionally substituted with one or two substituents, said substituents being independently selected from R. 61 ;and Each R a61 R c61 and R d61 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; and Each R g Independently selected from D, OH, CN, halogenated, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, amino, C 1-3 Alkylamino and di(C) 1-3 Alkyl)amino.

10. The method of claim 9, wherein Y is CR 6 ; R 1 Selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; R 2 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN and OR a2 ; wherein C 1-3 The alkyl group is optionally selected by one or two independently from R. g Substituents of the substituents; Cy 1 Selected from C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl and 6- to 10-membered heteroaryl; wherein each of the 4- to 10-membered heterocyclic alkyl and the 6- to 10-membered heteroaryl has at least one cyclic carbon atom and 1, 2, 3 or 4 cyclic heteroatoms independently selected from N, O and S; wherein the cyclic carbon atom of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocyclic alkyl is optionally substituted with an oxo group to form a carbonyl group; and wherein the C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 The aryl group and the 6- to 10-membered heteroaryl group are each optionally selected independently by 1, 2, 3, or 4 groups from R. 10 Substituents of the substituents; R 3 Selected from H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogenated, D, CN, C(O)NR c3 R d3 and NR c3 C(O)R b3 ; wherein C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by 1, 2, or 3 independently from R 30 Substituents of the substituents; R 5 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and halogenated groups; R 6 Selected from H, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogenated, D, CN, OR a6 and C(O)NR c6 R d6 ; wherein C 3-6 Cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R 60 Substituents of the substituents; R 7 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, halogenated groups, and CN groups; Cy 2 Selected from Where n is 0, 1, or 2; Each R 10 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN, OR a10 C(O)R b10 C(O)NR c10 R d10 C(O)OR a10 NR c10 R d10 and S(O)2R b10 ; Each R 20 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN and OR a20 ; Each R 30 Selected independently from C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogenated, D, CN, OR a30 C(O)R b30 C(O)NR c30 R d30 C(O)OR a30 NR c30 R d30 and S(O)2R b30 ; wherein C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R 31 Substituents of the substituents; Each R 31 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN, OR a31 C(O)R b31 C(O)NR c31 R d31 C(O)OR a31 NR c31 R d31 and S(O)2R b31 ; Each R 60 Selected independently from C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, 4- to 6-membered heterocyclic alkyl, 5- to 6-membered heteroaryl, halogenated, D, CN, OR a60 C(O)R b60 C(O)NR c60 R d60 NR c60 C(O)R b60 C(O)OR a60 NR c60 C(O)OR a60 NR c60 R d60 NR c60 S(O)2R b60 and S(O)2R b60 ; wherein C 1-3 Alkyl, 4- to 6-membered heterocyclic alkyl and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R 61 Substituents of the substituents; Each R 61 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN, OR a61 and NR c61 R d61 ; Each R a2 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Each R b3 R c3 and R d3 Independently selected from H and C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by 1, 2, or 3 independently from R 30 Substituents of the substituents; Or R connected to the same N atom c3 and R d3 Together with the N atoms to which they are attached, they form 4-, 5-, or 6-membered heterocyclic alkyl groups optionally substituted with 1, 2, or 3 substituents, wherein the substituents are independently selected from R. 30 ; Each R a6 R c6 and R d6 Independently selected from H and C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R 60 Substituents of the substituents; Each R a10 R b10 R c10 and R d10 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Each R a20 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; R b20 Selected from NH2, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Each R a30 R b30 R c30 and R d30 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Each R a31 R b31 R c31 and R d31 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Each R a60 R b60 R c60 and R d60 Independently selected from H and C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 The cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R. 61 Substituents of the substituents; Or any R connected to the same N atom c60 and R d60 Together with the N atoms to which they are attached, they form 4-, 5-, or 6-membered heterocyclic alkyl groups, optionally substituted with one or two substituents, said substituents being independently selected from R. 61 ;and Each R a61 R c61 and R d61 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; and Each R g Independently selected from D, CN, halogenated, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

11. The method according to claim 9 or 10, wherein Y is CR 6 ; R 1 For H; R 2 Selected from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, CN and -CH2CH2CN; Cy 1 Selected from C 3-10 cycloalkyl, C 6-10 aryl and 6- to 10-membered heteroaryl; wherein the 6- to 10-membered heteroaryl has at least one cyclic carbon atom and one cyclic heteroatom independently selected from N and S; and wherein the C 3-10 cycloalkyl, C 6-10 The aryl group and the 6- to 10-membered heteroaryl group are each optionally selected independently by one or two of the R groups. 10 Substituents of the substituents; R 3 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, 4- to 6-membered heterocyclic alkyl groups, phenyl groups, and 5- to 6-membered heteroaryl groups; wherein the C 1-3 Alkyl, 4- to 6-membered heterocyclic alkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally represented by 1, 2, or 3 independently selected from R 30 Substituents of the substituents; R 5 Selected from H and halogenated; R 6 Selected from H, C 1-3 Halogenated alkyl, 4- to 8-membered heterocyclic alkyl, and 5- to 6-membered heteroaryl; wherein the 4- to 8-membered heterocyclic alkyl and the 5- to 6-membered heteroaryl are each optionally selected independently by one or two from R 60 Substituents; or R 7 Halogenated; Cy 2 for Each R 10 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN and OR a10 ; Each R 30 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, 4- to 6-membered heterocyclic alkyl, halogenated, D, CN, OR a30 C(O)NR c30 R d30 and NR c30 R d30 ; wherein C 1-3 The alkyl group and the 4- to 6-membered heterocyclic alkyl group are each optionally selected independently by one or two of R. 31 Substituents of the substituents; Each R 31 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, CN, OR a31 and NR c31 R d31 ; Each R 60 Selected independently from C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, 4- to 6-membered heterocyclic alkyl, 5- to 6-membered heteroaryl, halogenated, D, CN, OR a60 C(O)R b60 C(O)NR c60 R d60 NR c60 C(O)R b60 C(O)OR a60 NR c60 C(O)OR a60 NR c60 R d60 NR c60 S(O)2R b60 and S(O)2R b60 ; wherein C 1-3 Alkyl, 4- to 6-membered heterocyclic alkyl and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R 61 Substituents of the substituents; Each R 61 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, halogenated groups, and CN groups; Each R a10 Independently selected from H and C 1-3 alkyl; Each R a30 R c30 and R d30 Independently selected from H and C 1-3 alkyl; Each R a31 R c31 and R d31 Independently selected from H and C 1-3 alkyl; Each R a60 R b60 R c60 and R d60 Independently selected from H and C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 The cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R. 61 Substituents of the substituents; Or any R connected to the same N atom c60 and R d60 Together with the N atoms to which they are attached, they form 4-, 5-, or 6-membered heterocyclic alkyl groups, optionally substituted with one or two substituents, said substituents being independently selected from R. 61 .

12. The method according to any one of claims 9 to 11, wherein Y is CR 6 ; R 1 For H; R 2 -CH2CH2CN; Cy 1 The phenyl group is phenyl; wherein the phenyl group is optionally selected by one or two independently selected from R. 10 Substituents of the substituents; R 3 Selected from H, C 1-3 Alkyl, phenyl, and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally represented by 1, 2, or 3 independently selected from R 30 Substituents of the substituents; R 5 Selected from H and halogenated; R 6 Selected from 4- to 8-membered heterocyclic alkyl groups; wherein the 4- to 8-membered heterocyclic alkyl group is optionally selected by one or two independently from R 60 Substituents; or R 6 Selected from C 1-3 Alkyl; wherein the C 1-3 The alkyl group is selected independently by one or two of R. 60 Substituents of the substituents; R 7 Halogenated; Cy 2 for Each R 10 Selected independently from C 1-3 Alkyl and halogenated; Each R 30 Selected independently from C 1-3 Alkyl, halogenated, D, OH and C(O)NR c30 R d30 ; wherein C 1-3 Alkyl groups are optionally selected independently from R 31 One substituent is substituted; Each R 31 OR a31 ; Each R 60 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkoxy, 4- to 6-membered heterocyclic alkyl, 5- to 6-membered heteroaryl, halogenated, C(O)R b60 C(O)NR c60 R d60 NR c60 C(O)R b60 C(O)OR a60 NR c60 C(O)OR a60 and NR c60 S(O)2R b60 ; wherein C 1-3 Alkyl, 4- to 6-membered heterocyclic alkyl and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R 61 Substituents of the substituents; Each R 61 Selected independently from C 1-3 Alkyl and halogenated; Each R c30 and R d30 Independently selected from H and C 1-3 alkyl; Each R a31 Independently selected from H and C 1-3 Alkyl; and Each R a60 R b60 R c60 and R d60 Independently selected from H and C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 The cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl groups are each optionally selected by one or two independently from R. 61 Substituents of the substituents; Or any R connected to the same N atom c60 and R d60 Together with the N atoms to which they are attached, they form 4-, 5-, or 6-membered heterocyclic alkyl groups, optionally substituted with one or two substituents, said substituents being independently selected from R. 61 .

13. The method according to any one of claims 9 to 12, wherein Y is CR 6 ; R 1 For H; R 2 -CH2CH2CN; Cy 1 The phenyl group is phenyl; wherein the phenyl group is optionally selected by one or two independently selected from R. 10 Substituents of the substituents; R 3 Selected from H, methyl, ethyl, phenyl, 1,2,4-triazolyl, pyrazinyl, and pyridinyl; wherein the methyl, phenyl, 1,2,4-triazolyl, pyrazinyl, and pyridinyl groups are each optionally selected independently by one, two, or three groups selected from R. 30 Substituents of the substituents; R 5 Selected from H and chlorine; R 6 The molecule is selected from pyrrolidinyl, 2-azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.1]heptyl, and 5-oxo-1,2,3,5-tetrahydroindoleazin-3-yl; wherein the pyrrolidinyl, 2-azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.1]heptyl, and 5-oxo-1,2,3,5-tetrahydroindoleazin-3-yl are optionally selected by one or two independently from R 60 Substituents of the substituents; R 7 It is fluorine; Cy 2 for Each R 10 Independently selected from methyl, fluorine, and chlorine; Each R 30 Independently selected from methyl, fluorine, OH, D and C(O)NR c30 R d30 The methyl group is optionally replaced by one substituent, namely R. 31 replace; Each R 31 OR a31 ; Each R 60 Independently selected from methyl, fluorine, C 1-2 Haloalkoxy, 3-oxomorpholino, 2-oxopyrazin-1(2H)-yl), C(O)R b60 C(O)NR c60 R d60 NR c60 C(O)R b60 C(O)OR a60 NR c60 C(O)OR a60 and NR c60 S(O)2R b60 ; wherein the 3-oxomorpholino group and the 2-oxopyrazin-1(2H)- group are each optionally selected independently by one or both from R 61 Substituents of the substituents; Each R 61 Independently selected from methyl and fluorine; Each R c30 and R d30 Independently selected from H and methyl; Each R a31 Independently selected from H and methyl; and Each R a60 R b60 R c60 and R d60 Independently selected from H and C 1-2 Alkyl, C1 haloalkyl, cyclopropyl, tetrahydrofuranyl, and thiazolyl; wherein the C 1-2 Alkyl, cyclopropyl, tetrahydrofuranyl, and thiazolyl groups are each optionally selected independently by one or two of the groups R. 61 Substituents of the substituents; Or any R connected to the same N atom c60 and R d60 Together with the N atoms to which they are attached, they form a nitrogen-containing heterocyclic butyl group optionally substituted with one or two substituents, said substituents being independently selected from R. 61 .

14. The method according to any one of claims 9 to 13, wherein the compound of formula I is a compound of formula II: II Or its pharmaceutically acceptable salt.

15. The method according to any one of claims 9 to 14, wherein the compound of formula I is a compound of formula III: III Or its pharmaceutically acceptable salt.

16. The method according to any one of claims 1 to 15, wherein the KRAS G12D inhibitor is selected from... 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(7-chloro-3-hydroxynaphth-1-yl)-6-fluoro-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(5,7-difluoro-1H-indol-3-yl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(6-fluoro-5-methyl-1H-indol-3-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(2-(3-(azacyclobutan-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-((1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(3-hydroxynaphth-1-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-2-yl)methyl)oxazolidin-2-one; 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-2,8-dimethyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile; 1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-7-(8-cyanonaphthal-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidone-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-8-carboxynitrile; 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-2-((3-oxomorpholino)methyl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile; 3-(7-(benzo[b]thiophene-3-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-2-((2-oxopyrrolidine-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-4-(((S)-1-(dimethylamino)propane-2-yl)oxy)-6-fluoro-7-(7-fluoronaphthyl-1-yl)-2-((2-oxopyrrolidine-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-6-fluoro-4-((3-fluoro-1-methylazacyclobutane-3-yl)methoxy)-7-(3-hydroxynaphthyl-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropionamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(3-hydroxynaphth-1-yl)-2-methyl-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphth-1-yl)-4-methyl-2-((4-methyl-2-oxoperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-4-ethoxy-6-fluoro-2-((4-isopropyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-4-(3-(dimethylamino)-3-methylazacyclobutane-1-yl)-6-fluoro-7-(7-fluoronaphthyl)-2-((3-oxomorpholino)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphth-1-yl)-2-(1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(3-hydroxynaphth-1-yl)-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-2-(pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(2-(3-(azacyclobutan-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7,8-difluoronaphthyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(2-(3-(azacyclobutan-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(6,7-difluoronaphthyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphth-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 1-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-7-yl)isoquinoline-8-carboxynitrile; 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinoline-7-yl)-1-naphthonitrile; 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-7-yl)-1-naphthonitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphth-1-yl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphthyl-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)-N,N-dimethylpyrrolidine-1-carboxamide; (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2-chloro-3-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidin-1-carboxylic acid methyl ester; (1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-(5-oxo-1,2,3,5-tetrahydroindoleazine-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-1-carboxylic acid methyl ester; (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-1-carboxylic acid methyl ester; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2-chloro-3-fluorophenyl)-2-((R)-1-(cyclopropanecarbonyl)pyrrolidine-2-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 8-(2-((R)-1-acetylpyrrolidine-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-8-methyl-4-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxynitrile; 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(3-chloro-2-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinoline-4-yl)-N-methylpyridineamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphth-1-yl)-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(5-fluoro-6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-1-carboxylic acid methyl ester; (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-1-carboxylic acid methyl ester; (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-1-carboxylic acid ethyl ester; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazabicyclobutane-1-carbonyl)pyrrolidine-2-yl)-6-fluoro-4-(methyl-d3)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazabicyclobutane-1-carbonyl)pyrrolidine-2-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphth-1-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinoline-4-yl)-N-methylpyridineamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphth-1-yl)-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphth-1-yl)-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; (1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; (2R,4S)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)-4-fluoropyrrolidine-1-carboxylic acid methyl ester; (2R,5R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)-5-methylpyrrolidin-1-carboxylic acid methyl ester; (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-3-chloro-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidin-1-carboxylic acid methyl ester; 4-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinoline-4-yl)-2-fluoro-N-methylbenzamide; ((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)carbamate; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-2,2-difluoroacetamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-2,2-difluoroacetamide; (2S)-N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)tetrahydrofuran-2-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)cyclopropanesulfonamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)thiazolyl-4-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-N-methylcyclopropaneformamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-1-methylcyclopropane-1-carboxamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-1-fluorocyclopropane-1-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-1-fluorocyclobutane-1-carboxamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(3-chloro-2-methylphenyl)-2-(1-(2,6-dimethyl-3-oxo-2,3-dihydropyridazin-4-yl)ethyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)pyrimidin-4-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)pyridazine-3-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-3,3-difluoroazabicyclobutane-1-carboxamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-((R)-1-((1-methyl-1H-pyrazol-4-yl)amino)ethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-fluorocyclopropane-1-carbonyl)pyrrolidine-2-yl)-1H-pyrrolo[3,2-c]quinoline-4-yl)-N,N-dimethylpyridineamide; and (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(4-((dimethylamino)methyl)-2,3-difluorophenyl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidin-1-carboxylic acid methyl ester; And its pharmaceutically acceptable salts.

17. The method according to any one of claims 1 to 16, wherein the KRAS G12D inhibitor is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile or a pharmaceutically acceptable salt thereof.

18. The method according to any one of claims 1 to 17, wherein the KRAS G12D inhibitor is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate.

19. The method according to any one of claims 1 to 18, wherein the KRAS G12D inhibitor is 3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate.

20. The method according to any one of claims 1 to 18, wherein the KRAS G12D inhibitor is 3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate.

21. The method according to any one of claims 1 to 8, wherein the KRAS G12D inhibitor is a compound of formula IV: (IV) Or its pharmaceutically acceptable salt, wherein: Cy 1 The phenyl group is optionally substituted with 1, 2, 3, or 4 substituents, each of which is selected from D, C, ... 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 Alkyne, Halogen, OH, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; R 1 It is a halogen; R 2 Selected from H, D, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 3-5 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4- to 6-membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5- to 6-membered heteroaryl-C 1-3 Alkylene, Halogenated, CN, OR a2 C(O)R b2 C(O)NR c2 R d2 NR c2 R e2 and NR c2 C(O)R b2 ; where R is formed 2 The C mentioned 3-5 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4- to 6-membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- to 6-membered heteroaryl-C 1-3 Each alkylene group is optionally selected independently from R by one, two, or three independent groups. 2A Substituents are substituted; wherein R is formed 2 The 4- to 6-membered heterocyclic alkyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene and 4- to 6-membered heterocyclic alkyl-C 1-3 The cyclic atoms of the alkylene group consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S; wherein R forms 2 The 4- to 6-membered heterocyclic alkyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene and 4- to 6-membered heterocyclic alkyl-C 1-3 The cyclic carbon atom of the alkylene group is optionally substituted with an oxo group to form a carbonyl group; and R is formed therein. 2 The C mentioned 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. 2B Substituents of the substituents; Each R a2 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- to 6-membered heteroaryl; wherein R is formed a2 The C mentioned 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by 1, 2, or 3 independently from R 2A Substituents are substituted; wherein R is formed a2 The cyclic atoms of the 4- to 6-membered heterocyclic alkyl groups and 5- to 6-membered heteroaryl groups consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S; wherein R forms a2 The cyclic carbon atoms of the 4- to 6-membered heterocyclic alkyl groups and 5- to 6-membered heteroaryl groups are optionally substituted with oxo groups to form carbonyl groups; and wherein R is formed. a2 The C mentioned 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each alkynyl group is optionally composed of one, two, or three independently selected from R. 2B Substituents of the substituents; Each R b2 R c2 and R d2 Independently selected from H and C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- to 6-membered heteroaryl; wherein R is formed b2 R c2 and R d2 The C mentioned 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by 1, 2, or 3 independently from R 2A Substituents are substituted to form R. b2 R c2 and R d2 The cyclic atoms of the 4- to 6-membered heterocyclic alkyl groups and 5- to 6-membered heteroaryl groups consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S; wherein R forms b2 R c2 and R d2 The cyclic carbon atoms of the 4- to 6-membered heterocyclic alkyl groups and 5- to 6-membered heteroaryl groups are optionally substituted with oxo groups to form carbonyl groups; and wherein R is formed. b2 R c2 and R d2 The C mentioned 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. 2B Substituents; or Any R connected to the same N atom c2 and R d2 Together with the N atoms to which they are attached, they form 4-, 5-, or 6-membered heterocyclic alkyl groups optionally substituted with 1, 2, or 3 substituents, wherein the substituents are independently selected from R. 2B ; Each R e2 Selected independently from C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- to 6-membered heteroaryl; wherein R is formed e2 The C mentioned 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by 1, 2, or 3 independently from R 2A Substituents are substituted; wherein R is formed e2 The cyclic atoms of the 4- to 6-membered heterocyclic alkyl groups and 5- to 6-membered heteroaryl groups consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S; wherein R forms e2 The cyclic carbon atoms of the 4- to 6-membered heterocyclic alkyl groups and 5- to 6-membered heteroaryl groups are optionally substituted with oxo groups to form carbonyl groups; and wherein R is formed. e2 The C mentioned 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. 2B Substituents; or R connected to the same N atom c2 and R e2 Together with the N atoms to which they are attached, they form 4-, 5-, or 6-membered heterocyclic alkyl groups optionally substituted with 1, 2, or 3 substituents, wherein the substituents are independently selected from R. 2B ; Each R 2A Selected independently from C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Halogenated alkyl groups and R 2B R is formed 2A The C mentioned 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. 2B Substituents of the substituents; Each R 2B Selected independently from C 3-6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogenated, D, CN, OR a2B C(O)R b2B C(O)NR c2B R d2B C(O)OR a2B NR c2B R d2B and S(O)2R b2B ; wherein C 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally selected by 1, 2, or 3 independently from R 2C Substituents of the substituents; Each R 2C Selected independently from C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogenated, D, CN, OR a2C C(O)R b2C C(O)NR c2C R d2C C(O)OR a2C NR c2C R d2C and S(O)2R b2C ; Each R a2B R b2B R c2B and R d2B Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Each R a2C R b2C R c2C and R d2C Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; R 3 Selected from C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl, 5- to 10-member heteroaryl, OR 3A and NR 3B R 3C ; where R is formed 3 The C mentioned 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl C 1-3 Each alkyl group is optionally selected independently from R by one, two, or three alkyl groups. 3D Substituents are substituted; wherein R is formed 3 The cyclic atoms of the 4- to 10-membered heterocyclic alkyl groups and 5- to 10-membered heteroaryl groups consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S; wherein R forms 3 The cyclic carbon atom of the 4- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl group is optionally substituted with an oxo group to form a carbonyl group; and wherein R is formed. 3 The C mentioned 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. 3E Substituents of the substituents; R 3A Selected from C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; wherein R is formed 3A The C mentioned 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl C 1-3 Each alkyl group is optionally selected independently from R by one, two, or three alkyl groups. 3D Substituents are substituted; wherein R is formed 3A The cyclic atoms of the 4- to 10-membered heterocyclic alkyl groups and 5- to 10-membered heteroaryl groups consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S; wherein R forms 3A The cyclic carbon atom of the 4- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl group is optionally substituted with an oxo group to form a carbonyl group; and wherein R is formed. 3A The C mentioned 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. 3E Substituents of the substituents; R 3B Selected from H, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; wherein R is formed 3B The C mentioned 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group are each optionally selected by one, two, or three independently chosen from R 3D Substituents are substituted; wherein R is formed 3B The cyclic atoms of the 4- to 10-membered heterocyclic alkyl groups and 5- to 10-membered heteroaryl groups consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S; wherein R forms 3B The cyclic carbon atoms of the 4- to 10-membered heterocyclic alkyl groups and 5- to 10-membered heteroaryl groups are optionally substituted with oxo groups to form carbonyl groups; and wherein R is formed. 3B The C mentioned 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. 3E Substituents of the substituents; R 3B and R 3C Together with the N atom attached to both of them, they optionally form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl group, optionally substituted with 1, 2, or 3 substituents, said substituents being independently selected from R. 3D ; R 3C Selected from H, C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Alkyne group; wherein R is formed 3C The C mentioned 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. 3E Substituents of the substituents; Each R 3D Selected independently from C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl and R 3E ; where R is formed 3D The C mentioned 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each of the ynyl groups is optionally selected from 1, 2, or 3 independently from R. 3E Substituents of the substituents; Each R 3E Independently selected from D, halogenated, CN, OR a3 SR a3 C(O)R b3 C(O)NR c3 R d3 C(O)OR a3 OC(O)R b3 OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 C(=NR) e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 S(O)R b3 S(O)NR c3 R d3 S(O)2R b3 NR c3 S(O)2R b3 and S(O)2NR c3 R d3 ; R a3 R b3 R c3 and R d3 Each is independently selected from H and C. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 Alkyl groups; wherein R is formed a3 R b3 R c3 and R d3 The C mentioned 6-10 Aryl-C 1-3 Alkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 Each alkyl group is optionally substituted with 1, 2, 3, 4, or 5 substituents, said substituents being independently selected from C10. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 Alkyne, Halogenated, CN, OR a3A SR a3A C(O)R b3A C(O)NR c3A R d3A C(O)OR a3A OC(O)R b3A OC(O)NR c3A R d3A NR c3A R d3A NR c3A C(O)R b3A NR c3A C(O)NR c3A R d3A NR c3A C(O)OR a3A C(=NR) e3A )NR c3A R d3A NR c3A C(=NR e3A )NR c3A R d3A S(O)R b3A S(O)NR c3A R d3A S(O)2R b3A NR c3A S(O)2R b3A and S(O)2NR c3A R d3A ; where R is formed a3 R b3 R c3 and R d3 The 4- to 10-membered heterocyclic alkyl, 5- to 10-membered heteroaryl, and 5- to 10-membered heteroaryl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 The cyclizing atom of the alkyl group consists of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S; wherein R forms a3 R b3 R c3 and R d3 The 4- to 10-membered heterocyclic alkyl, 5- to 10-membered heteroaryl, and 5- to 10-membered heteroaryl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 The cyclic carbon atom of the alkyl group is optionally substituted with an oxygen to form a carbonyl group; or R connected to the same N atom c3 and R d3 Together with the N atom attached to both of them, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl group or a 5-membered heteroaryl group, each optionally substituted with 1, 2, or 3 substituents, wherein the substituents are independently selected from C. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 Alkyne, Halogenated, CN, OR a3A SR a3A C(O)R b3A C(O)NR c3A R d3A C(O)OR a3A OC(O)R b3A OC(O)NR c3A R d3A NR c3A R d3A NR c3A C(O)R b3A NR c3A C(O)NR c3A R d3A NR c3A C(O)OR a3A C(=NR) e3A )NR c3A R d3A NR c3A C(=NR e3A )NR c3A R d3A S(O)R b3A S(O)NR c3A R d3A S(O)2R b3A NR c3A S(O)2R b3A and S(O)2NR c3A R d3A ; R a3A R b3A R c3A and R d3A Each is independently selected from H and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, aryl, C 6-10 Aryl-C 1-3 Alkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 Alkyl groups; wherein R is formed a3A R b3A R c3A and R d3A The C mentioned 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl-C 1-3 Alkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 Each alkyl group is optionally substituted with one, two, or three substituents, said substituents being independently selected from OH, CN, amino, NH(C) 1-6 Alkyl), N(C) 1-6 Alkyl)2, Halogenated, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy groups; wherein R is formed a3A R b3A R c3A and R d3A The 4- to 10-membered heterocyclic alkyl, 5- to 10-membered heteroaryl, and 5- to 10-membered heteroaryl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 The cyclizing atom of the alkyl group consists of at least one carbon atom and 1, 2, 3, or 4 heteroatoms selected from O, N, and S; and R is formed therein. a3A R b3A R c3A and R d3A The 4- to 10-membered heterocyclic alkyl, 5- to 10-membered heteroaryl, and 5- to 10-membered heteroaryl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 The cyclic carbon atom of the alkyl group is optionally substituted with an oxygen to form a carbonyl group; or R connected to the same N atom c3A and R d3A Together with the N atom attached to both of them, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl group or a 5-membered heteroaryl group, each optionally substituted with 1, 2, or 3 substituents, wherein the substituents are independently selected from OH, CN, amino, NH(C) 1-6 Alkyl), N(C) 1-6 Alkyl)2, Halogenated, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy; R e3 and R e3A Each can be independently H, CN, or NO2; Each R 4 Independently selected from H, D, and C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 Alkyne, halogenated and OR a4 ; Each R a4 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; An R 5 For R 5A ; and each other R 5 Independently selected from H, D, halogenated, C 1-3 Alkyl, OR a5 C 1-3 Haloalkyl, C 2-3 alkenyl and C 2-3 Alkyne group; or, optionally, two other R groups attached to the same carbon atom. 5 Together with the carbon atoms connected to both of them, they form spiroCs that are optionally substituted with 1, 2, 3, or 4 substituents. 3-6 Cycloalkyl ring, wherein each substituent is selected from D, C 1-3 Alkyl and halogenated; or, optionally, two other R atoms attached to adjacent carbon atoms. 5 Together with the carbon atoms to which they are attached, they form fused C atoms optionally substituted with 1, 2, 3, or 4 substituents. 3-6 Cycloalkyl ring, wherein each substituent is selected from D, C 1-3 Alkyl and halogenated; R 5A For H, D, C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 Alkyne, Halogen, OR a5A ,CN or Cy 2 ; where R is formed 5A The C mentioned 1-3 The alkyl group is optionally composed of 1, 2, 3, or 4 each selected from R 5B Substituents are substituted, and optionally Cy is also used. 2 Replace, or, optionally, attach R to the same carbon atom 5A and R 5 Together with the carbon atoms connected to both of them, they form spiroCs that are optionally substituted with 1, 2, 3, or 4 substituents. 3-6 Cycloalkyl ring, wherein each substituent is selected from D, C 1-3 Alkyl and halogenated; or, optionally, R attached to an adjacent carbon atom. 5A and R 5 Together with the carbon atoms to which they are attached, they form fused C atoms optionally substituted with 1, 2, 3, or 4 substituents. 3-6 Cycloalkyl ring, wherein each substituent is selected from D, C 1-3 Alkyl and halogenated; Each R 5B Independently selected from D and halogenated; Each R a5 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; R a5A Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and Cy 2 R is formed a5A The C mentioned 1-3 The alkyl group is optionally composed of 1, 2, 3, or 4 each selected from R 5B Substituents are substituted, and optionally Cy is also used. 2 replace; Cy 2 Selected from C 3-7 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; wherein Cy is formed 2 The C mentioned 3-7 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups are optionally selected by 1, 2, 3, or 4 independently selected from R Cy2 Substituents are substituted; wherein Cy is formed 2 The cyclic atoms of the 4- to 10-membered heterocyclic alkyl groups and 5- to 10-membered heteroaryl groups consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and wherein Cy forms 2 The cyclic carbon atoms of the 4- to 10-membered heterocyclic alkyl groups and 5- to 10-membered heteroaryl groups are optionally substituted with oxygen to form carbonyl groups; Each R Cy2 Independently selected from D and C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 3-6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, halogenated, CN, OR aCy21 SR aCy21 C(O)R bCy21 C(O)NR cCy21 R dCy21 C(O)OR aCy21 OC(O)R bCy21 OC(O)NR cCy21 R dCy21 NR cCy21 R dCy21 NR cCy21 C(O)R bCy21 NR cCy21 C(O)NR cCy21 R dCy21 NR cCy21 C(O)OR aCy21 C(=NR) eCy21 )NR cCy21 R dCy21 NR cCy21 C(=NR eCy21 )NR cCy21 R dCy21 S(O)R bCy21 S(O)NR cCy21 R dCy21 S(O)2R bCy21 NR cCy21 S(O)2R bCy21 and S(O)2NR cCy21 R dCy21 ; where R is formed Cy2 The C mentioned 3-6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group are each optionally selected independently by 1, 2, 3, or 4 groups from R. Cy2A Substituents are substituted; wherein R is formed Cy2 The cyclic atoms of the 4- to 10-membered heterocyclic alkyl groups and 5- to 10-membered heteroaryl groups consist of at least one carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; wherein R forms Cy2 The cyclic carbon atoms of the 4- to 10-membered heterocyclic alkyl groups and 5- to 10-membered heteroaryl groups are optionally substituted with oxo groups to form carbonyl groups; and wherein R is formed. Cy2 The C mentioned 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. Cy2B Substituents of the substituents; Each R Cy2A Selected independently from C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl and R Cy2B ; where R is formed Cy2A The C mentioned 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Each alkynyl group is optionally composed of one, two, or three independently selected from R. Cy2B Substituents of the substituents Each R Cy2B Independently selected from D, halogenated, CN, OR aCy21 SR aCy21 C(O)R bCy21 C(O)NR cCy21 R dCy21 C(O)OR aCy21 OC(O)R bCy21 OC(O)NR cCy21 R dCy21 NR cCy21 R dCy21 NR cCy21 C(O)R bCy21 NR cCy21 C(O)NR cCy21 R dCy21 NR cCy21 C(O)OR aCy21 C(=NR) eCy21 )NR cCy21 R dCy21 NR cCy21 C(=NR eCy21 )NR cCy21 R dCy21 S(O)R bCy21 S(O)NR cCy21 R dCy21 S(O)2R bCy21 NR cCy21 S(O)2R bCy21 and S(O)2NR cCy21 R dCy21 , R aCy21 R bCy21 R cCy21 and R dCy21 Each is independently selected from H and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 Alkyl groups; wherein R is formed aCy21 R bCy21 R cCy21 and R dCy21 The C mentioned 6-10 Aryl-C 1-3 Alkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 Each alkyl group is optionally substituted with one, two, or three substituents, said substituents being independently selected from C10. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 Alkyne, Halogenated, CN, OR aCy22 SR aCy22 C(O)R bCy22 C(O)NR cCy22 R dCy22 C(O)OR aCy22 OC(O)R bCy22 OC(O)NR cCy22 R dCy22 NR cCy22 R dCy22 NR cCy22 C(O)R bCy22 NR cCy22 C(O)NR cCy22 R dCy22 NR cCy22 C(O)OR aCy22 C(=NR) eCy22 )NR cCy22 R dCy22 NR cCy22 C(=NR eCy22 )NR cCy22 R dCy22 S(O)R bCy22 S(O)NR cCy22 R dCy22 S(O)2R bCy22 NR cCy22 S(O)2R bCy22 and S(O)2NR cCy22 R dCy22 ; where R is formed aCy21 R bCy21 R cCy21 and R dCy21 The 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 Each of the alkyl groups consists of at least one carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and wherein R is formed. aCy21 R bCy21 R cCy21 and R dCy21 The 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 The cyclic carbon atom of the alkyl group may be optionally substituted with an oxygen to form a carbonyl group; Or R connected to the same N atom cCy21 and R dCy21 Together with the N atom attached to both of them, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl group or a 5-membered heteroaryl group, each optionally substituted with 1, 2, or 3 substituents, wherein the substituents are independently selected from C. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 Alkyne, Halogenated, CN, OR aCy22 SR aCy22 C(O)R bCy22 C(O)NR cCy22 R dCy22 C(O)OR aCy22 OC(O)R bCy22 OC(O)NR cCy22 R dCy22 NR cCy22 R dCy22 NR cCy22 C(O)R bCy22 NR cCy22 C(O)NR cCy22 R dCy22 NR cCy22 C(O)OR aCy22 C(=NR) eCy22 )NR cCy22 R dCy22 NR cCy22 C(=NR eCy22 )NR cCy22 R dCy22 S(O)R bCy22 S(O)NR cCy22 R dCy22 S(O)2R bCy22 NR cCy22 S(O)2R bCy22 and S(O)2NR cCy22 R dCy22 ; R aCy22 R bCy22 R cCy22 and R dCy22 Each is independently selected from H and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, aryl, C 6-10 Aryl-C 1-3 Alkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 Alkyl groups; wherein R is formed aCy22 R bCy22 R cCy22 and R dCy22 The C mentioned 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 6-10 Aryl-C 1-3 Alkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 Each alkyl group is optionally substituted with one, two, or three substituents, said substituents being independently selected from OH, CN, amino, NH(C) 1-3 Alkyl), N(C) 1-3 Alkyl)2, Halogenated, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 Haloalkoxy groups; wherein R is formed aCy22 R bCy22 R cCy22 and R dCy22 The 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 Each of the alkyl groups consists of at least one carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and wherein R is formed. aCy22 R bCy22 R cCy22 and R dCy22 The 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl-C 1-3 Alkyl and 4- to 10-membered heterocyclic alkyl-C 1-3 The cyclic carbon atom of the alkyl group is optionally substituted with an oxygen to form a carbonyl group; or R connected to the same N atom cCy22 and R dCy22 Together with the N atom attached to both of them, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl group or a 5-membered heteroaryl group, each optionally substituted with 1, 2, or 3 substituents, wherein the substituents are independently selected from OH, CN, amino, NH(C) 1-6 Alkyl), N(C) 1-6 Alkyl)2, Halogenated, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 Halogenated alkoxy groups; and R eCy21 and R eCy22 Each can be H, CN, or NO2 independently.

22. The method according to any one of claims 1 to 8 and 21, wherein Cy 1 The phenyl group is optionally substituted with one or two substituents, each of which is selected from D, C. 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, OH and C 1-3 Alkoxy; R 1 Halogenated; R 2 C that is optionally substituted with OH 1-3 alkyl; R 3 C that is optionally halogenated 3-10 cycloalkyl; Each R 4 For H; An R 5 For R 5A ; and each other R 5 Independently selected from H, D, halogenated, C 1-3 Alkyl, OC 1-3 Alkyl, C 1-3 Haloalkyl; or, optionally, two other R atoms attached to adjacent carbon atoms. 5 Together with the carbon atoms to which they are attached, they form fused C atoms that are optionally substituted with one or two substituents. 3-6 Cycloalkyl ring, wherein each substituent is selected from D, C 1-3 Alkyl and halogenated; and R 5A H, halogenated or OR a5A ; R a5A Selected from C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and Cy 2 R is formed a5A The C mentioned 1-3 The alkyl group is optionally substituted with 1, 2, or 3 D atoms, and is also optionally substituted with Cy atoms. 2 Replace; and Cy 2 Selected from C 6-10 Aryl and 5- to 10-membered heteroaryl groups.

23. The method according to any one of claims 1 to 8, 21 and 22, wherein Cy 1 The phenyl group is optionally substituted with one or two substituents, each of which is selected from D, C. 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, OH and C 1-3 Alkoxy; R 1 Halogenated; R 2 C that is optionally substituted with OH 1-3 alkyl; R 3 OR that is optionally replaced by halogenation 3A Or C 3-10 cycloalkyl; R 3A C 1-3 alkyl; Each R 4 For H; An R 5 For R 5A ; and each other R 5 Independently selected from H, D, halogenated, C 1-3 Alkyl, OC 1-3 Alkyl, C 1-3 Haloalkyl; or, optionally, two other R atoms attached to adjacent carbon atoms. 5 Together with the carbon atoms to which they are attached, they form fused C atoms that are optionally substituted with one or two substituents. 3-6 Cycloalkyl ring, wherein each substituent is selected from D, C 1-3 Alkyl and halogenated; R 5A H, halogenated or OR a5A ; R a5A Selected from C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and Cy 2 R is formed a5A The C mentioned 1-3 The alkyl group is optionally substituted with 1, 2, or 3 D atoms, and is also optionally substituted with Cy atoms. 2 Replace; and Cy 2 Selected from C 6-10 Aryl and 5- to 10-membered heteroaryl groups.

24. The method according to any one of claims 1 to 8 and 21 to 23, wherein Cy 1 The phenyl group is optionally substituted with one or two substituents, each of which is selected from C10. 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, OH and C 1-3 Alkoxy; R 1 Halogenated; R 2 C that is optionally substituted with OH 1-3 alkyl; R 3 OR that is optionally replaced by halogenation 3A Or C 3-10 cycloalkyl; R 3A C 1-3 alkyl; Each R 4 For H; An R 5 For R 5A ; and each other R 5 Independently selected from H, halogen, C 1-3 Alkyl, OC 1-3 Alkyl, C 1-3 Halogenated alkyl groups; R 5A H, halogenated or OR a5A ;and R a5A Selected from C 1-3 Alkyl and C 1-3 Halogenated alkyl groups, wherein R is formed a5A The C mentioned 1-3 The alkyl group is optionally substituted with 1, 2 or 3 D atoms.

25. The method according to any one of claims 1 to 8 and 21 to 24, wherein the compound of formula IV is a compound of formula IV-A or formula IV-B: Or its pharmaceutically acceptable salt.

26. The method according to any one of claims 1 to 8 and 21 to 25, wherein the compound of formula IV is selected from... 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-methoxy-2-azabicyclo[2.2.1] heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-fluoro-2-azabicyclo[2.2.1] heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-2-(6-(cyclopropanecarbonyl)-6-azatricyclo[3.2.1.02,4]octane-7-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-(methoxy-d3)-2-azabicyclo[2.2.1] heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-(pyridin-3-yloxy)-2-azabicyclo[2.2.1] heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(2-(5-(benzyloxy)-2-(cyclopropanecarbonyl)-2-azabicyclo[2.2.1]heptane-3-yl)-1-(2-azabicyclo[ 2.1.1] Hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1] heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-(5-fluoro-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1] heptane-3-yl)-4-((R)-1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-(difluoromethyl)-2-azabicyclo[2.2.1] heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-2-azabicyclo[2.2.1] heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 5-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-8-(2-cyanoethyl)-2-(2-(cyclopropanecarbonyl)-2-azabicyclo[2.2.1] heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-4-yl)-N,N-dimethylpyridineamide; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-2-azabicyclo[2.2.1] heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 4-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-8-(2-cyanoethyl)-2-(2-(cyclopropanecarbonyl)-2-azabicyclo[2.2.1] heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-4-yl)-2-fluoro-N-methylbenzamide; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-methyl-2-azabicyclo[2.2.1] heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-hydroxy-2-azabicyclo[2.2.1] heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-(pyridin-2-yloxy)-2-azabicyclo[2.2.1] heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-(pyridin-4-yloxy)-2-azabicyclo[2.2.1] heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-7-(2,3-dichlorophenyl)-2-(5-(difluoromethoxy)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1] heptane-3-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-(5-fluoro-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1] heptane-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-2-(5-chloro-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1] heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-(trifluoromethoxy)-2-azabicyclo[2.2.1] heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-7-(2,3-dichlorophenyl)-2-(5-(difluoromethoxy)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1] heptane-3-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-2-(2-(cyclopropanecarbonyl)-5-cyclopropoxy-2-azabicyclo[2.2.1] heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-7-(2,3-dichlorophenyl)-2-(5-(difluoromethoxy)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1] heptane-3-yl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-2-(5-cyclopropoxy-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1] heptane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)-5-(trifluoromethoxy)-2-azabicyclo[2.2.1] heptane-2-carboxylic acid methyl ester; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-(2-(1-fluorocyclopropane-1-carbonyl)-5-(trifluoromethoxy)-2-azabicyclo[2.2.1] heptane-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)-5-(difluoromethyl)-2-azabicyclo[ 2.2.1] Methyl heptane-2-carboxylate; and 3-(1-(2-azabicyclic[ 2.1.1] Hexane-5-yl)-7-(2,3-dichlorophenyl)-2-(5-(difluoromethyl)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[2.2.1] heptane-3-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; And its pharmaceutically acceptable salts.

27. The method according to any one of claims 1 to 8 and 21 to 26, wherein the compound of formula IV is (1R,3R,4R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof.

28. The method according to any one of claims 1 to 27, wherein the KRAS G12D inhibitor is administered to the subject as a pharmaceutical composition comprising the KRAS G12D inhibitor or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

29. The method according to any one of claims 1 to 28, wherein the EGFR inhibitor is administered to the subject as a pharmaceutical composition comprising the EGFR inhibitor or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

30. A method of treating cancer in a subject with this need, the method comprising administering to the subject: A pharmaceutical composition comprising a KRAS G12D inhibitor or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient; and A pharmaceutical composition comprising an EGFR inhibitor or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

31. A method of treating cancer in a subject with this need, the method comprising administering to the subject: a KRASG12D inhibitor, which is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile or a pharmaceutically acceptable salt thereof; and an EGFR inhibitor, which is cetuximab.

32. The method according to claim 31, wherein the KRAS G12D inhibitor is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate.

33. The method according to claim 31 or 32, wherein the KRAS G12D inhibitor is 3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate.

34. The method according to claim 31 or 32, wherein the KRAS G12D inhibitor is 3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate.

35. A method of treating cancer in a subject with this need, the method comprising administering to the subject: a KRASG12D inhibitor, which is (1R,3R,4R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate or a pharmaceutically acceptable salt thereof; and an EGFR inhibitor, which is cetuximab.

36. The method according to any one of claims 1 to 35, wherein the KRAS G12D inhibitor is administered twice daily (BID).

37. The method according to any one of claims 1 to 35, wherein the KRAS G12D inhibitor is administered once daily (QD).

38. The method according to any one of claims 1 to 37, wherein the KRAS G12D inhibitor is administered orally (PO).

39. The method according to any one of claims 1 to 38, wherein the EGFR inhibitor is administered twice weekly (BIW).

40. The method according to any one of claims 1 to 39, wherein the EGFR inhibitor is administered by intravenous injection (IV).

41. The method according to any one of claims 1 to 40, wherein the cancer is selected from carcinoma, hematologic malignancies, sarcomas, and glioblastoma.

42. The method according to any one of claims 1 to 41, wherein the cancer is a cancer comprising abnormally proliferating cells having a KRAS G12D mutation.

43. The method according to any one of claims 1 to 41, wherein the method further comprises identifying abnormally proliferating cells of the cancer that contain a KRAS G12D mutation.

44. The method according to any one of claims 41 to 43, wherein the cancer is a blood cancer selected from myeloproliferative neoplasms, myelodysplastic syndromes, chronic and juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and multiple myeloma.

45. The method according to any one of claims 41 to 43, wherein the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, bladder cancer, stomach cancer, esophageal cancer, breast cancer, head and neck cancer, cervical cancer, skin cancer, and thyroid cancer.

46. ​​The method of claim 45, wherein the cancer is colorectal cancer.

47. The method of claim 45, wherein the cancer is lung cancer.

48. The method of claim 45, wherein the cancer is pancreatic cancer.

49. The method according to any one of claims 1 to 43, wherein the cancer is colorectal cancer.

50. The method according to any one of claims 1 to 43, wherein the cancer is non-small cell lung cancer (NSCLC).

51. The method according to any one of claims 1 to 43, wherein the cancer is pancreatic ductal adenocarcinoma.

52. The method according to any one of claims 1 to 51, wherein the cancer is metastatic.

53. A pharmaceutical composition comprising a) KRAS G12D inhibitors or pharmaceutically acceptable salts thereof; b) EGFR inhibitors or pharmaceutically acceptable salts thereof; and c) At least one pharmaceutically acceptable carrier or excipient.

54. The pharmaceutical composition of claim 53, wherein the KRAS G12D inhibitor is selected from... 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(7-chloro-3-hydroxynaphth-1-yl)-6-fluoro-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(5,7-difluoro-1H-indol-3-yl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(6-fluoro-5-methyl-1H-indol-3-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(2-(3-(azacyclobutan-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-((1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(3-hydroxynaphth-1-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-2-yl)methyl)oxazolidin-2-one; 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-2,8-dimethyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile; 1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-7-(8-cyanonaphthal-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidone-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-8-carboxynitrile; 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-2-((3-oxomorpholino)methyl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile; 3-(7-(benzo[b]thiophene-3-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-2-((2-oxopyrrolidine-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-4-(((S)-1-(dimethylamino)propane-2-yl)oxy)-6-fluoro-7-(7-fluoronaphthyl-1-yl)-2-((2-oxopyrrolidine-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-6-fluoro-4-((3-fluoro-1-methylazacyclobutane-3-yl)methoxy)-7-(3-hydroxynaphthyl-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropionamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(3-hydroxynaphth-1-yl)-2-methyl-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphth-1-yl)-4-methyl-2-((4-methyl-2-oxoperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-4-ethoxy-6-fluoro-2-((4-isopropyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-4-(3-(dimethylamino)-3-methylazacyclobutane-1-yl)-6-fluoro-7-(7-fluoronaphthyl)-2-((3-oxomorpholino)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphth-1-yl)-2-(1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(3-hydroxynaphth-1-yl)-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-2-(pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(2-(3-(azacyclobutan-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7,8-difluoronaphthyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(2-(3-(azacyclobutan-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(6,7-difluoronaphthyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphth-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 1-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-7-yl)isoquinoline-8-carboxynitrile; 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinoline-7-yl)-1-naphthonitrile; 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-7-yl)-1-naphthonitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphth-1-yl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphthyl-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)-N,N-dimethylpyrrolidine-1-carboxamide; (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2-chloro-3-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidin-1-carboxylic acid methyl ester; (1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-(5-oxo-1,2,3,5-tetrahydroindoleazine-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-1-carboxylic acid methyl ester; (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-1-carboxylic acid methyl ester; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2-chloro-3-fluorophenyl)-2-((R)-1-(cyclopropanecarbonyl)pyrrolidine-2-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 8-(2-((R)-1-acetylpyrrolidine-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-8-methyl-4-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxynitrile; 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(3-chloro-2-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinoline-4-yl)-N-methylpyridineamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphth-1-yl)-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(5-fluoro-6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-1-carboxylic acid methyl ester; (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-1-carboxylic acid methyl ester; (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-1-carboxylic acid ethyl ester; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazabicyclobutane-1-carbonyl)pyrrolidine-2-yl)-6-fluoro-4-(methyl-d3)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazabicyclobutane-1-carbonyl)pyrrolidine-2-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphth-1-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinoline-4-yl)-N-methylpyridineamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphth-1-yl)-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphth-1-yl)-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; (1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; (2R,4S)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)-4-fluoropyrrolidine-1-carboxylic acid methyl ester; (2R,5R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)-5-methylpyrrolidin-1-carboxylic acid methyl ester; (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-3-chloro-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidin-1-carboxylic acid methyl ester; 4-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinoline-4-yl)-2-fluoro-N-methylbenzamide; ((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)carbamate; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-2,2-difluoroacetamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-2,2-difluoroacetamide; (2S)-N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)tetrahydrofuran-2-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)cyclopropanesulfonamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)thiazolyl-4-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-N-methylcyclopropaneformamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-1-methylcyclopropane-1-carboxamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-1-fluorocyclopropane-1-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-1-fluorocyclobutane-1-carboxamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(3-chloro-2-methylphenyl)-2-(1-(2,6-dimethyl-3-oxo-2,3-dihydropyridazin-4-yl)ethyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)pyrimidin-4-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)pyridazine-3-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-3,3-difluoroazabicyclobutane-1-carboxamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-((R)-1-((1-methyl-1H-pyrazol-4-yl)amino)ethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile; 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-fluorocyclopropane-1-carbonyl)pyrrolidine-2-yl)-1H-pyrrolo[3,2-c]quinoline-4-yl)-N,N-dimethylpyridineamide; and (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(4-((dimethylamino)methyl)-2,3-difluorophenyl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidin-1-carboxylic acid methyl ester; And its pharmaceutically acceptable salts.

55. The pharmaceutical composition according to claim 53 or 54, wherein the KRAS G12D inhibitor is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile or a pharmaceutically acceptable salt thereof.

56. The pharmaceutical composition according to any one of claims 53 to 55, wherein the KRAS G12D inhibitor is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate.

57. The pharmaceutical composition according to any one of claims 53 to 56, wherein the KRAS G12D inhibitor is 3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate.

58. The pharmaceutical composition according to any one of claims 53 to 56, wherein the KRAS G12D inhibitor is 3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate.

59. The pharmaceutical composition according to claim 53, wherein the KRAS G12D inhibitor is (1R,3R,4R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof.

60. The pharmaceutical composition according to any one of claims 53 to 59, wherein the EGFR inhibitor is cetuximab.

61. A pharmaceutical combination comprising a KRAS G12D inhibitor or a pharmaceutically acceptable salt thereof and an EGFR inhibitor or a pharmaceutically acceptable salt thereof.

62. The pharmaceutical combination according to claim 61, wherein the KRAS G12D inhibitor is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile or a pharmaceutically acceptable salt thereof.

63. The pharmaceutical combination according to claim 61 or 62, wherein the KRAS G12D inhibitor is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate.

64. The pharmaceutical combination according to any one of claims 61 to 63, wherein the KRAS G12D inhibitor is 3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate.

65. The pharmaceutical combination according to any one of claims 61 to 63, wherein the KRAS G12D inhibitor is 3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate.

66. The pharmaceutical combination according to claim 61, wherein the KRAS G12D inhibitor is (1R,3R,4R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof.

67. The drug combination according to any one of claims 61 to 66, wherein the EGFR inhibitor is cetuximab.

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