Combination therapy using KRAS G12D inhibitors and PD-1 inhibitors or PD-L1 inhibitors

Abstract

This article provides a method for treating cancer by administering combination therapy containing KRAS G12D inhibitors and PD-1 inhibitors or PD-L1 inhibitors.

Description

[0001] Related applications

[0002] This application relates to U.S. Provisional Application No. 63 / 588,924, filed October 9, 2023, and U.S. Provisional Application No. 63 / 680,218, filed August 7, 2024, the entire contents of each of which are incorporated herein by reference. 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 when activated by its upstream receptor tyrosine kinase (D. Uprety et al., Cancer Treat. Rev., 2020, 89, 102070). The KRAS protein exists in a GTP-binding “on” state and a GDP-binding “off” state. When GTP binds, the signal is transduced through activation of, among other things, the mitogen-activated protein kinase pathway and the PI3K pathway. 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. KRAS G12D mutations impair GTP hydrolysis, leading to overactivation of the KRAS subtype, which in turn drives high levels of oncogenic ERK and PI3K signaling (M. Malumbres et al., Nat. Rev. Cancer., 2003, 3, 459-65).

[0004] Inhibiting KRAS G12D by binding to the KRAS G12D switch-II pocket (which leads to conformational changes unfavorable to GTP binding and RAF association) is presumably intended to eliminate KRAS signaling and halt tumor growth in KRAS G12D-mutant tumors. In addition to direct antitumor effects, inhibition of mutant KRAS signaling with small molecule inhibitors has induced immunomodulatory changes in the tumor microenvironment in preclinical models. These changes include increased tumor cell antigen presentation, increased frequency of tumor-infiltrating T cells, and decreased frequency of myeloid-derived suppressor cells (SB Kemp et al., CancerDiscov. 2023, 13(2), 298-311). Furthermore, in published preclinical studies, combining mutant KRAS inhibitors with immune checkpoint blockade (particularly PD-1 / PD-L1 blockade) in mutant KRAS tumor models has produced enhanced antitumor activity and durable responses (DM Briere et al., Mol. Cancer Ther., 2021, 20(6), 975-85). Summary of the Invention

[0005] This article provides a method for treating cancer in a subject of need, comprising administering to the subject a KRAS G12D inhibitor or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor or a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof. Targeting KRAS G12D-mutant tumors with a combination of a selective and reversible inhibitor and a PD-1 / PD-L1 disruptor may be a promising cancer treatment for patients with KRAS G12D mutations. Attached Figure Description

[0006] Figure 1 The antitumor activity of compound 1 ± retifanlimab in the CT-26 clone 299 model was demonstrated.

[0007] Figure 2 The study demonstrated delayed tumor growth in the CT-26 clone 299 model after discontinuation of treatment with compound 1 ± revilimab.

[0008] Figure 3 The changes in body weight of CT-26 clone 299 tumor-bearing mice treated with compound 1 ± revivalmab are shown.

[0009] Figure 4 The study demonstrated the inhibition of pERK in CT-26 clone 299 tumors by compound 1 ± revilimab after 5 days of treatment.

[0010] Figure 5 The antitumor activity of compound 1 ± compound 2 in the CT-26 clone 299 model is shown.

[0011] Figure 6 The study demonstrated delayed tumor growth in the CT-26 clone 299 model after treatment with compound 1 ± compound 2 was discontinued.

[0012] Figure 7 The changes in body weight of CT-26 clone 299 tumor-bearing mice after administration of compound 1 ± compound 2 are shown.

[0013] Figure 8 The inhibition of pERK in CT-26 clone 299 tumors by compound 1 ± compound 2 was shown after 5 days of treatment.

[0014] Figure 9 The antitumor activity of compound 1 ± anti-mouse PD-1 antibody RMP1-14 was demonstrated in the KPCY-013 (2838c3) model.

[0015] Figure 10 The antitumor activity of compound 1 ± anti-mouse PD-L1 antibody 10F.9G2 was demonstrated in the KPCY-013 (2838c3) model.

[0016] Figure 11 The antitumor activity of compound 3 ± revilimab in the CT-26 clone 299 model was demonstrated.

[0017] Figure 12 The antitumor activity of compound 3 ± compound 2 in the CT-26 clone 299 model was demonstrated. Detailed Implementation

[0018] 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, the KRAS G12D mutation is predominant 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). A wealth of in vivo experimental evidence further supports the role of mutant KRAS as a driver of oncogenesis, with evidence suggesting 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).

[0019] The immune system plays a crucial role in controlling and eradicating diseases such as cancer. However, cancer cells often develop strategies to evade or suppress the immune system in a way that favors their growth. One such mechanism involves altering the expression of costimulatory and co-inhibitory molecules on immune cells (MA Postow et al., J. Clin. Oncol., 2015, 33(17), 1974-82). Blocking the signaling of inhibitory immune checkpoints, such as PD-1, has proven to be a promising and effective therapeutic approach.

[0020] Programmed death-1 (“PD-1”, also known as “CD279”) is a 31 kD type I membrane protein member of the extended CD28 / CTLA-4 family of T cell regulators that broadly negatively regulates immune responses (Y. Ishida et al., EMBO J., 1992, 11, 3887-95). PD-1 is expressed on activated T cells, B cells, and monocytes (T. Yamazaki et al., J. Immunol., 2002, 169(10), 5538-45) and at low levels on natural killer (NK) T cells (N. Martin-Orozco et al., Semin. Cancer Biol., 2007, 17(4), 288-98).

[0021] Multiple pieces of evidence from preclinical animal studies indicate that PD-1 and its ligands negatively regulate immune responses. PD-1-deficient mice have been shown to develop lupus-like glomerulonephritis and dilated cardiomyopathy (H. Nishimura et al., Science, 2001, 291(5502), 319–22). Using a chronically infected LCMV model, results showed that the PD-1 / PD-L1 interaction inhibits the activation, expansion, and gain of effector function of virus-specific CD8 T cells (DL Barber et al., Nature, 2006, 439, 682–87). In summary, these data support the development of a therapeutic approach to block the PD-1-mediated inhibitory signaling cascade to enhance or “rescue” T cell responses. Therefore, novel approaches to blocking the PD-1 / PD-L1 protein / protein interaction are needed, and thereby to treat cancer in subjects.

[0022] This disclosure relates to a method of treating cancer in a subject in need, the method comprising administering to the subject a KRASG12D inhibitor or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor or a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof.

[0023] The following describes some of the terms used herein. The compounds of this disclosure 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.

[0024] definition

[0025] The following lists the definitions of various terms used herein. These definitions apply to terms used throughout this specification and claims, unless otherwise limited, either individually or as part of a larger group, in particular.

[0026] 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.

[0027] As used herein, the articles “a” and “an” refer to one or more (i.e., at least one) of the grammatical objects of an article. 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.

[0028] The term "about" when used in conjunction with a numerical value means including a set or range of values. For example, "about X" includes a range of values ​​of ±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.

[0029] As used herein, “drug combination” or “combination” means a formulation or combination product of individual compounds, with or without instructions for use in combination. Thus, combination compounds can be completely separate drug dosage forms or drug compositions that are also sold independently of each other, and wherein instructions for their combined use are provided in the packaging device (e.g., leaflets, etc.) or in other information (e.g., provided to physicians and medical personnel (e.g., oral communication, written communication, etc.)) for simultaneous or sequential use to work together.

[0030] 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 exposing KRAS or PD-1 to an effective amount of the compounds disclosed herein for cancer-related symptoms.

[0031] 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.

[0032] 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.

[0033] As used herein, the term "free base equivalent" refers to the amount of free base of an active agent or a pharmaceutically acceptable salt of an active agent (e.g., compound 1) equivalent to the dose of the active agent. In other words, the term "free base equivalent" refers to the amount of free base of compound 1, or the equivalent amount of free base of compound 1 provided by the salt of said compound.

[0034] 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 may 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.

[0035] 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.

[0036] 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 described herein include, for example, conventional non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts discussed herein can be synthesized from parent compounds containing basic or acidic moieties 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 diethyl 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., A. Adejare (ed.), 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).

[0037] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound with a pharmaceutically acceptable carrier. A pharmaceutical composition facilitates the administration of the composition 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.

[0038] 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 relates to 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; tragacanth gum 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 solutions; and other non-toxic and compatible substances used in pharmaceutical formulations.

[0039] As used herein, "pharmaceuticalally acceptable carrier" also includes any and all coatings, 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 a pharmaceutical composition are known in the art and 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., (ed.), Handbook of Pharmaceutical Excipients, 6th edition; (Pharmaceutical Press, 2009); PJ Shesky et al., (ed.), Handbook of Pharmaceutical Excipients, 9th edition; (The Pharmaceutical Press, 2020); M. Ash et al., (ed.), Handbook of Pharmaceutical Additives, 3rd edition; (Gower Publishing Company: 2007); and M. Gibson (ed.), Pharmaceutical Preformulation and Formulation, 2nd edition (CRC Press LLC, 2007). (2009).

[0040] 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 agent 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.

[0041] The term "combination therapy" refers to the administration of two or more therapeutic compounds to treat the conditions or ailments described in this disclosure. Such administration encompasses the co-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) targeting 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 effects of the combination of drugs in treating the conditions or ailments described herein.

[0042] The combination of drugs described herein can exhibit a synergistic effect. As used herein, the term "synergistic effect" refers to an effect produced by two drugs, such as a KRAS inhibitor (e.g., a KRAS inhibitor of Formula I) and a PD-1 or PD-L1 inhibitor, that is greater than the simple sum of the effects of each drug administered individually. Synergistic effects can be calculated using appropriate methods such as the Sigmoid-Emax equation (NHG Holford et al., Clin. Pharmacokinet., 1981, 6: 429-53), the Loewe additive equation (S. Loewe et al., Arch. Exp. Pathol Pharmacol., 1926, 114, 313-26), the intermediate-effect equation (TC Chou et al., Adv. EnzymeRegul., 1984, 22: 27-55), or based on the Bliss definition of drug independence (E. Demidenko et al., PLoSONE, 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 exponential curves.

[0043] As used herein, the term "synergistic effect" refers to the effect achieved when the active ingredient, namely a KRAS inhibitor, is used in combination with a PD-1 inhibitor or a PD-L1 inhibitor, which is greater than the sum of the effects of using these compounds alone.

[0044] In this embodiment, a combination therapy comprising an effective amount of a KRAS inhibitor and a PD-1 inhibitor or a PD-L1 inhibitor is provided. An “effective amount” of the combination of agents (i.e., a KRAS inhibitor and a PD-1 inhibitor or a PD-L1 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.

[0045] This article provides combinations of therapeutic agents and the administration of such combinations 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 a combination of two types of agents: a KRAS inhibitor or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor or a pharmaceutically acceptable salt thereof, or a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof. Use of racemic mixtures of individual agents is also provided. Pharmacologically active metabolites include those that are inactive but are converted into their pharmacologically active form in vivo after administration.

[0046] As used herein, the term "alkyl" itself, or as part of another substituent, unless otherwise stated, refers to 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 the examples, 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.

[0047] 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 connection points between the alkylene group and 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, ethyl-1,2-diyl, ethyl-1,1-diyl, propion-1,3-diyl, propion-1,2-diyl, propion-1,1-diyl, bution-1,4-diyl, bution-1,3-diyl, bution-1,2-diyl, 2-methyl-propion-1,3-diyl, etc.

[0048] 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 the examples, C1-C3, C1-C4, and C1-C6 alkoxy groups are provided herein.

[0049] The term "amino" as used alone or in combination with other terms refers to a group of the formula –NH2, wherein the hydrogen atom may be substituted by the substituents described herein. For example, "alkylamino" can refer to –NH (alkyl) and –N (alkyl)2.

[0050] As used herein, unless otherwise stated, the terms “halogenated” or “halogen” alone or as part of another substituent mean a fluorine, chlorine, bromine, or iodine atom.

[0051] 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 {2(n to m) + 1} halogen atoms. n-m Alkyl 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. Examples of haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, etc. In some embodiments, the haloalkyl group is a fluoroalkyl group.

[0052] 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.

[0053] 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 is present (i.e., attached or formed) by having two adjacent atoms shared (i.e., common) with the first ring. Cycloalkyl also includes bicyclic structures that may be inherently bridged or spirocyclic, wherein each individual ring within the bicyclic structure differs by 3–10, 3–8, 3–7, 3–6, and 5–10 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 the examples, 3–10 membered cycloalkyl groups are provided herein.

[0054] As used herein, the term "heterocyclic alkyl" means a non-aromatic carbocyclic system containing 1, 2, 3, or 4 independent heteroatoms 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 structure differs in number from 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, epoxidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxetanyl, 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]hexyl, 5-azabicyclo[2.1.1]hexyl, 6-azabicyclo[3.1.1]heptyl, 2-azabicyclo-[2.2.1]heptyl, 3-azabicyclo [3.1.1]Heptyl, 2-azabicyclo[3.1.1]Heptyl, 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-aza-bicyclo[2.2.1]heptyl, 6-oxa-3-aza-bicyclo[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-oxa-bicyclo[3.2.1]octyl. In the examples, 3- to 10-membered heterocyclic alkyl groups are provided herein. In another example, 5- to 10-membered heterocyclic alkyl groups are provided herein. In yet another example, 4- to 6-membered heterocyclic alkyl groups are provided herein.

[0055] The term "aromatic" refers to a polyunsaturated ring having one or more aromatic characteristics (i.e., having (4n + 2) delocalized elements). (pi) electrons, where n is an integer) carbon ring or heterocycle.

[0056] 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.

[0057] As used herein, the term "heteroaryl" refers to an aromatic carbocyclic system containing one, two, three, or four heteroatoms independently selected from N, O, and S, and having one, two, or three rings, wherein such rings can be fused, as defined above. The term "heteroaryl" Including but not limited to furanyl, thiophene, oxazolyl, thiazolyl, imidazole, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridinyl, pyrazinyl, imidazole[1,2-a]pyridyl, pyrazol[1,5-a]pyridyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopentadien[b]pyridyl, 6,7-dihydro-5H-cyclopentadien[c]pyridyl, 1,4,5,6- Tetrahydrocyclopentadieno[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopentadieno[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 the examples, 5- to 10-membered heteroaryl groups are provided herein.

[0058] It should be understood that if a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl moiety can be attached to a specified moiety by different ring atom bonds or otherwise (i.e., shown or described without indicating a specific attachment point), it means all possible points, whether by a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridinyl" means 2-, 3-, or 4-pyridinyl, and the term "thiophenyl" means 2- or 3-thiophenyl, and so on.

[0059] As used herein, the term “substituted” means that an atom or group of atoms replaces hydrogen as a “substituent” attached to another group.

[0060] 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.

[0061] KRAS G12D inhibitors

[0062] This disclosure relates to a combination therapy comprising a KRAS G12D inhibitor and a PD-1 inhibitor or a PD-L1 inhibitor. This combination therapy can be used to treat a variety of conditions associated with abnormal KRAS or PD-1 / PD-L1 activity.

[0063] In the examples, the KRAS G12D inhibitor is a compound of formula I:

[0064]

[0065] Or its pharmaceutically acceptable salt, wherein:

[0066] Y is N or CR 6 ;

[0067] 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 derived from one or two independently selected from R g Substituents of the substituents;

[0068] R 2 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, 4-6 membered heterocyclic alkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5-6-membered heteroaryl-C 1-3 Alkylene, Halogenated, D, CN, and OR a2 ; wherein C 1-3 Alkyl, 4-6 membered heterocyclic alkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5-6-membered heteroaryl-C 1-3 Each alkylene group is optionally derived from one or two independently selected from R g Substituents of the substituents;

[0069] Cy1 Selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 aryl and 6-10-membered heteroaryl; wherein the 4-10-membered heterocyclic alkyl and the 6-10-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 6-10-membered heteroaryl and the 4-10-membered heterocyclic alkyl are optionally oxysubstituted to form a carbonyl group; and wherein C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 The aryl and 6-10 heteroaryl groups are each optionally selected from R by 1, 2, 3 or 4 independent selections. 10 Substituents of the substituents;

[0070] R 3 Selected from H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5-6-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, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5-6-membered heteroaryl-C 1-3 Each alkylene group is optionally derived from one, two, or three independently selected from R 30 Substituents of the substituents;

[0071] 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 derived from one or two independently selected from R g Substituents of the substituents;

[0072] R 6 Selected from H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-9 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5-6-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, 4-9 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5-6-membered heteroaryl-C 1-3 Each alkylene group is optionally derived from one or two independently selected from R 60 Substituents of the substituents;

[0073] 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 derived from one or two independently selected from R g Substituents of the substituents;

[0074] Cy 2 Selected from

[0075]

[0076] Where n is 0, 1, or 2;

[0077] 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 ;

[0078] Each R 20 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN and OR a20 ;

[0079] Each R 30 Selected independently from C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 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, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected R 31 Substituents of the substituents;

[0080] 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 ;

[0081] 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, 5-6-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 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected from R 31Substituents of the substituents;

[0082] Each R 60 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, 4-6 membered heterocyclic alkyl, 5-6 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, 4-6-membered heterocyclic alkyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected R 61 Substituents of the substituents;

[0083] 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 ;

[0084] R a1 Selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0085] Each R a2 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0086] 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, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 1, 2 or 3 independently selected from R 30 Substituents of the substituents;

[0087] Or R attached to the same N atom c3 and R d3 Together with the attached N atom, 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 ;

[0088] R j3 Selected from C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 1, 2 or 3 independently selected from R 30 Substituents of the substituents;

[0089] Or R attached to the same N atom c3 and R j3 Together with the attached N atom, 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 ;

[0090] R f3 Selected from C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein the C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 1, 2 or 3 independently selected from R 30 Substituents; or

[0091] R f3 Selected from

[0092]

[0093] Where R x Is it H or C? 1-2 Alkyl and R y It is C 1-2 alkyl;

[0094] Or R x and R y Together with the C atoms to which they are attached, they form 3- or 4-membered cycloalkyl groups;

[0095] R a5 Selected from H, C 1-3 Alkyl and C 1-3Halogenated alkyl groups;

[0096] 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, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected R 60 Substituents of the substituents;

[0097] R a7 Selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0098] 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;

[0099] Each R a20 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0100] R b20 Selected from NH2, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0101] 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;

[0102] 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;

[0103] Each R a60 R b60 R c60 and R d60 Independently selected from H and C 1-3 Alkyl, C1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 The cycloalkyl, 4-6-membered heterocycloalkyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected R 61 Substituents of the substituents;

[0104] Or any R attached to the same N atom c60 and R d60 Together with the attached N atom, 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 ;

[0105] 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

[0106] 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.

[0107] In examples of Formula I or its pharmaceutically acceptable salts,

[0108] Y is CR 6 ;

[0109] R 1 Selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0110] 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 derived from one or two independently selected from R g Substituents of the substituents;

[0111] Cy 1 Selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10aryl and 6-10-membered heteroaryl; wherein the 4-10-membered heterocyclic alkyl and the 6-10-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 6-10-membered heteroaryl and the 4-10-membered heterocyclic alkyl are optionally oxysubstituted to form a carbonyl group; and wherein C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 The aryl and 6-10 heteroaryl groups are each optionally selected from R by 1, 2, 3 or 4 independent selections. 10 Substituents of the substituents;

[0112] R 3 Selected from H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 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, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 1, 2 or 3 independently selected from R 30 Substituents of the substituents;

[0113] R 5 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and halogenated groups;

[0114] R 6 Selected from H, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halogenated, D, CN, OR a6 and C(O)NR c6 R d6 ; wherein C 3-6 Cycloalkyl, 4-8-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected R 60 Substituents of the substituents;

[0115] R 7 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, halogenated groups, and CN groups;

[0116] Cy 2 Selected from

[0117]

[0118] Where n is 0, 1, or 2;

[0119] 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 ;

[0120] Each R 20 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN and OR a20 ;

[0121] Each R 30 Selected independently from C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 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, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected R 31 Substituents of the substituents;

[0122] 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 ;

[0123] Each R 60 Selected independently from C1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, 4-6 membered heterocyclic alkyl, 5-6 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, 4-6-membered heterocyclic alkyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected R 61 Substituents of the substituents;

[0124] 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 ;

[0125] Each R a2 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0126] 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, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 1, 2 or 3 independently selected from R 30 Substituents of the substituents;

[0127] Or R attached to the same N atom c3 and R d3 Together with the attached N atom, 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 ;

[0128] 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, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected R 60 Substituents of the substituents;

[0129] 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;

[0130] Each R a20 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0131] R b20 Selected from NH2, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0132] 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;

[0133] 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;

[0134] 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, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6The cycloalkyl, 4-6-membered heterocycloalkyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected R 61 Substituents of the substituents;

[0135] Or any R attached to the same N atom c60 and R d60 Together with the attached N atom, 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 ;as well as

[0136] 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

[0137] Each R g Independently selected from D, CN, halogenated, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0138] In another embodiment of Formula I or a pharmaceutically acceptable salt thereof

[0139] Y is CR 6 ;

[0140] R 1 It is H;

[0141] R 2 Selected from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, CN and -CH2CH2CN;

[0142] Cy 1 Selected from C 3-10 cycloalkyl, C 6-10 Aryl and 6-10 heteroaryl; wherein the 6-10 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 and 6-10 heteroaryl groups are each optionally derived from one or two independent selections from R 10 Substituents of the substituents;

[0143] R 3 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, 4-6 membered heterocyclic alkyl groups, phenyl groups, and 5-6 membered heteroaryl groups; wherein the C 1-3 Alkyl, 4-6-membered heterocyclic alkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 1, 2 or 3 independently selected from R30 Substituents of the substituents;

[0144] R 5 Selected from H and halogenated;

[0145] R 6 Selected from H, C 1-3 Halogenated alkyl, 4-8-membered heterocyclic alkyl, and 5-6-membered heteroaryl; wherein the 4-8-membered heterocyclic alkyl and 5-6-membered heteroaryl are each optionally derived from one or two independently selected from R 60 Substituents; or

[0146] R 7 It is a halogenated product;

[0147] Cy 2 yes

[0148] ;

[0149] Cy 2 -b

[0150] Each R 10 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, D, CN and OR a10 ;

[0151] Each R 30 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, 4-6 membered heterocyclic alkyl, halogenated, D, CN, OR a30 C(O)NR c30 R d30 and NR c30 R d30 ; wherein C 1-3 Alkyl groups and 4-6-membered heterocyclic alkyl groups are each optionally derived from one or two independently selected from R 31 Substituents of the substituents;

[0152] Each R 31 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, CN, OR a31 and NR c31 R d31 ;

[0153] Each R 60 Selected independently from C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, 4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, halogenated, D, CN, OR a60C(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, 4-6-membered heterocyclic alkyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected R 61 Substituents of the substituents;

[0154] Each R 61 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, halogenated groups, and CN groups;

[0155] Each R a10 Independently selected from H and C 1-3 alkyl;

[0156] Each R a30 R c30 and R d30 Independently selected from H and C 1-3 alkyl;

[0157] Each R a31 R c31 and R d31 Independently selected from H and C 1-3 alkyl;

[0158] 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, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 The cycloalkyl, 4-6-membered heterocycloalkyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected R 61 Substituents of the substituents;

[0159] Or any R attached to the same N atom c60 and R d60Together with the attached N atom, 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 .

[0160] In yet another embodiment of Formula I or its pharmaceutically acceptable salt,

[0161] Y is CR 6 ;

[0162] R 1 It is H;

[0163] R 2 It is -CH2CH2CN;

[0164] Cy 1 It is a phenyl group; wherein the phenyl group is optionally derived from one or two independently selected from R 10 Substituents of the substituents;

[0165] R 3 Selected from H, C 1-3 Alkyl, phenyl, and 5-6-membered heteroaryl; wherein the C 1-3 Alkyl, phenyl, and 5-6 heteroaryl groups are each optionally derived from 1, 2, or 3 independently selected from R 30 Substituents of the substituents;

[0166] R 5 Selected from H and halogenated;

[0167] R 6 Selected from 4-8 membered heterocyclic alkyl groups; wherein the 4-8 membered heterocyclic alkyl group is optionally derived from one or two independently selected from R 60 Substituents; or

[0168] R 6 Selected from C 1-3 Alkyl; wherein the C 1-3 Alkyl groups are selected from one or two independently from R 60 Substituents of the substituents;

[0169] R 7 It is a halogenated product;

[0170] Cy 2 yes

[0171] ;

[0172] Cy 2 -b

[0173] Each R 10 Selected independently from C 1-3 Alkyl and halogenated;

[0174] Each R30 Selected independently from C 1-3 Alkyl, halogenated, D, OH and C(O)NR c30 R d30 ; wherein C 1-3 Alkyl group optionally via one independently selected from R 31 Substituents of the substituents;

[0175] Each R 31 Is it OR a31 ;

[0176] Each R 60 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkoxy, 4-6 membered heterocyclic alkyl, 5-6 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, 4-6-membered heterocyclic alkyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected R 61 Substituents of the substituents;

[0177] Each R 61 Selected independently from C 1-3 Alkyl and halogenated;

[0178] Each R c30 and R d30 Independently selected from H and C 1-3 alkyl;

[0179] Each R a31 Independently selected from H and C 1-3 Alkyl groups; and

[0180] 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, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 The cycloalkyl, 4-6-membered heterocycloalkyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected R61 Substituents of the substituents;

[0181] Or any R attached to the same N atom c60 and R d60 Together with the attached N atom, 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 .

[0182] In another embodiment of Formula I or a pharmaceutically acceptable salt thereof

[0183] Y is CR 6 ;

[0184] R 1 It is H;

[0185] R 2 It is -CH2CH2CN;

[0186] Cy 1 It is a phenyl group; wherein the phenyl group is optionally derived from one or two independently selected from R 10 Substituents of the substituents;

[0187] R 3 Selected from H, methyl, ethyl, phenyl, 1,2,4-triazolyl, pyrazinyl, and pyridyl; wherein the methyl, phenyl, 1,2,4-triazolyl, pyrazinyl, and pyridyl groups are each optionally selected from 1, 2, or 3 independently from R 30 Substituents of the substituents;

[0188] R 5 Selected from H and chlorine;

[0189] 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-tetrahydroindazine-3-yl; wherein the pyrrolidinyl, 2-azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.1]heptyl, and 5-oxo-1,2,3,5-tetrahydroindazine-3-yl are optionally derived from one or two independently selected from R 60 Substituents of the substituents;

[0190] R 7 It is fluorine;

[0191] Cy 2 yes

[0192] ;

[0193] Cy 2 -b

[0194] Each R 10 Independently selected from methyl, fluorine, and chlorine;

[0195] Each R 30 Independently selected from methyl, fluorine, OH, D and C(O)NR c30 R d30 ; wherein the methyl group is optionally via one R 31 Substituents of the substituents;

[0196] Each R 31 Is it OR a31 ;

[0197] 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 and 2-oxopyrazin-1(2H)- group are each optionally derived from one or two independently selected R 61 Substituents of the substituents;

[0198] Each R 61 Independently selected from methyl and fluorine;

[0199] Each R c30 and R d30 Independently selected from H and methyl;

[0200] Each R a31 Independently selected from H and methyl; and

[0201] 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 derived from one or two independently selected from R 61 Substituents of the substituents;

[0202] Or any R attached to the same N atom c60 and R d60Together with the N atoms to which they are attached, they form optionally via one or two independent atoms selected from R 61 The substituents are nitrogen-containing heterocyclic butyl groups.

[0203] In the embodiments, the compound of formula I is the compound of formula II:

[0204]

[0205] Or its pharmaceutically acceptable salt.

[0206] In another embodiment, the compound of formula I is the compound of formula III:

[0207]

[0208] Or its pharmaceutically acceptable salt.

[0209] In embodiments of Formula I or its pharmaceutically acceptable salts, Y is CR 6 In another embodiment of Formula I or a pharmaceutically acceptable salt thereof, R 1 It is H. In yet another embodiment of Formula I or a pharmaceutically acceptable salt thereof, Cy 1 It is a phenyl group optionally substituted with one or two independent substituents selected from halogenation. In another embodiment of Formula I or a pharmaceutically acceptable salt thereof, R 3 It is methyl. In examples of Formula I or its pharmaceutically acceptable salts, R 5 It is H. In one embodiment of Formula I or a pharmaceutically acceptable salt thereof, R 6 It is through 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 yet another embodiment of Formula I or a pharmaceutically acceptable salt thereof, Cy 2 It is Cy 2 -b. In yet another embodiment, R 60 It is C(O)cyclopropyl.

[0210] In one embodiment, the KRAS G12D inhibitor is selected from...

[0211] 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;

[0212] 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;

[0213] 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;

[0214] 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;

[0215] 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;

[0216] 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;

[0217] 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;

[0218] 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;

[0219] 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;

[0220] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-4-(((S)-1-(dimethylamino)prop-2-yl)oxy)-6-fluoro-7-(7-fluoronaphth-1-yl)-2-((2-oxopyrrolidine-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0221] 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;

[0222] 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;

[0223] 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;

[0224] 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;

[0225] 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;

[0226] 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;

[0227] 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;

[0228] 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;

[0229] 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;

[0230] 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;

[0231] 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;

[0232] 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;

[0233] 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;

[0234] 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;

[0235] 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;

[0236] 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;

[0237] 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;

[0238] (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;

[0239] (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;

[0240] (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;

[0241] 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-tetrahydroindazine-3-yl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0242] (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;

[0243] (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;

[0244] 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;

[0245] 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;

[0246] 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-methylpyridinecarboxamide;

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

[0248] 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;

[0249] (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)pyrrolidin-1-carboxylic acid methyl ester;

[0250] (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-hydroxypropyl-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-1-carboxylic acid methyl ester;

[0251] (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-hydroxypropyl-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-1-carboxylic acid ethyl ester;

[0252] 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;

[0253] 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;

[0254] 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;

[0255] 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-methylpyridinecarboxamide;

[0256] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphth-1-yl)-4-(6-(2-hydroxypropyl-2-yl)pyridin-3-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0257] 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;

[0258] (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;

[0259] 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;

[0260] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropyl-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

[0261] (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-hydroxypropyl-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)-4-fluoropyrrolidine-1-carboxylic acid methyl ester;

[0262] (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-hydroxypropyl-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)-5-methylpyrrolidine-1-carboxylic acid methyl ester;

[0263] (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-hydroxypropyl-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-1-carboxylic acid methyl ester;

[0264] 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;

[0265] ((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;

[0266] 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;

[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-methyl-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-2,2-difluoroacetamide;

[0268] (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;

[0269] 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;

[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)thiazolyl-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)-N-methylcyclopropaneformamide;

[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-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-2-yl)ethyl)-1-methylcyclopropane-1-carboxamide;

[0273] 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;

[0274] 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;

[0275] 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;

[0276] 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;

[0277] 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;

[0278] 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;

[0279] 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;

[0280] 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;

[0281] 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;

[0282] 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;

[0283] 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-dimethylpyridinecarboxamide; and

[0284] (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;

[0285] And its pharmaceutically acceptable salts.

[0286] 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.

[0287] 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]quinolin-8-yl)propionitrile hydrochloride dihydrate (“Compound 1*”).

[0288] In yet another embodiment, the KRAS G12D inhibitor is 3-((R a Compound 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:

[0289] .

[0290] In the examples, 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”):

[0291] .

[0292] In another respect, KRAS G12D inhibitors are compounds of formula IV:

[0293]

[0294] Or its pharmaceutically acceptable salt, wherein:

[0295] Cy 1 It is a phenyl group 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;

[0296] R 1 It is halogen;

[0297] 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, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5-6-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 3-5Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5-6-membered heteroaryl-C 1-3 Each alkylene group is optionally derived from one, two, or three independently selected from R 2A Substituents are substituted; wherein R is formed 2 4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene and 4-6 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 4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene and 4-6 membered heterocyclic alkyl-C 1-3 The cyclic carbon atom of the alkylene group is optionally oxidically substituted 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 derived from one, two, or three independently selected from R 2B Substituents of the substituents;

[0298] 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, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein R is formed a2 C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 1, 2 or 3 independently selected from R 2A Substituents are substituted; wherein R is formed a2 The cyclic atoms of the 4-6 membered heterocyclic alkyl and 5-6 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 4-6-membered heterocyclic alkyl and 5-6-membered heteroaryl groups are optionally oxidized 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 derived from one, two, or three independently selected from R2B Substituents of the substituents;

[0299] 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, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein R is formed b2 R c2 and R d2 C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 1, 2 or 3 independently selected from R 2A Substituents are substituted to form R. b2 R c2 and R d2 The cyclic atoms of the 4-6 membered heterocyclic alkyl and 5-6 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 4-6-membered heterocyclic alkyl and 5-6-membered heteroaryl groups are optionally oxidized 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 derived from one, two, or three independently selected from R 2B Substituents; or

[0300] Any R attached to the same N atom c2 and R d2 Together with the attached N atom, 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 ;

[0301] 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, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein R is formed e2 C 3-6Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 1, 2 or 3 independently selected from R 2A Substituents are substituted; wherein R is formed e2 The cyclic atoms of the 4-6 membered heterocyclic alkyl and 5-6 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 4-6-membered heterocyclic alkyl and 5-6-membered heteroaryl groups are optionally oxidized 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 derived from one, two, or three independently selected from R 2B Substituents; or

[0302] R attached to the same N atom c2 and R e2 Together with the attached N atom, 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 ;

[0303] 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 derived from one, two, or three independently selected from R 2B Substituents of the substituents;

[0304] Each R 2B Selected independently from C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, 5-6 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, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 1, 2 or 3 independently selected from R 2C Substituents of the substituents;

[0305] 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, 4-6 membered heterocycloalkyl, phenyl, 5-6 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 ;

[0306] 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;

[0307] 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;

[0308] R 3 Selected from C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl, 5-10 heteroaryl, OR 3A and NR 3B R 3C ; where R is formed 3 C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl C 1-3 Each alkyl group is optionally derived from one, two, or three independently selected from R 3D Substituents are substituted; wherein R is formed 3 The cyclic atoms of the 4-10 membered heterocyclic alkyl and 5-10 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 3The cyclic carbon atom of the 4-10-membered heterocyclic alkyl or 5-10-membered heteroaryl group is optionally oxidically substituted 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 derived from one, two, or three independently selected from R 3E Substituents of the substituents;

[0309] R 3A Selected from C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 membered heteroaryl; wherein R is formed 3A C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl C 1-3 Each alkyl group is optionally derived from one, two, or three independently selected from R 3D Substituents are substituted; wherein R is formed 3A The cyclic atoms of the 4-10 membered heterocyclic alkyl and 5-10 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 4-10-membered heterocyclic alkyl or 5-10-membered heteroaryl group is optionally oxidically substituted 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 derived from one, two, or three independently selected from R 3E Substituents of the substituents;

[0310] R 3B Selected from H, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 membered heteroaryl; wherein R is formed 3B C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally selected from R by one, two, or three independent selections. 3D Substituents are substituted; wherein R is formed 3B The cyclic atoms of the 4-10 membered heterocyclic alkyl and 5-10 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 forms3B The cyclic carbon atoms of the 4-10-membered heterocyclic alkyl and 5-10-membered heteroaryl groups are optionally oxidized 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 derived from one, two, or three independently selected from R 3E Substituents of the substituents;

[0311] 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 ;

[0312] 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 derived from one, two, or three independently selected from R 3E Substituents of the substituents;

[0313] 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 2-3 Each of the ynyl groups is optionally derived from one, two, or three independently selected from R 3E Substituents of the substituents;

[0314] 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 c3C(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 ;

[0315] 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, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Alkyl groups; wherein R is formed a3 R b3 R c3 and R d3 C 6-10 Aryl-C 1-3 Alkyl, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Each alkyl group is optionally substituted by one, two, three, four, or five independent substituents selected from the following: C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 Alkyne, Halogenated, CN, OR a3A SR a3AC(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 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-3 Alkyl and 4-10 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 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 The cyclic carbon atom of the alkyl group may be optionally substituted with an oxo group to form a carbonyl group; or

[0316] R attached to the same N atom c3 and R d3 Together with the N atom attached to both, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl group or a 5-membered heteroaryl group, each of which is optionally substituted by one, two, or three independent substituents selected from the following: C1-3 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 ;

[0317] 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, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Alkyl groups; wherein R is formed a3A R b3A R c3A and R d3A C1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl C 6-10 Aryl-C 1-3 Alkyl, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Each alkyl group may optionally be substituted by one, two, or three independent substituents selected from the following: 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 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-3 Alkyl and 4-10 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 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 The cyclic carbon atom of the alkyl group may be optionally substituted with an oxo group to form a carbonyl group; or

[0318] R attached to the same N atom c3A and R d3A Together with the N atom attached to both, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl group or a 5-membered heteroaryl group, each of which is optionally substituted by one, two, or three independent substituents 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;

[0319] 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 ;

[0320] Each R a4 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0321] An R 5 It is 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 Alkynyl group; or optionally, two other R groups attached to the same carbon atom. 5 Together with the carbon atoms attached to both, they form a spiral C. 3-6 Cycloalkyl rings, wherein the rings are optionally composed of 1, 2, 3 or 4 rings each selected from D, C 1-3 Alkyl and halogenated substituents; or optionally, two other R groups attached to adjacent carbon atoms. 5 Together with the carbon atoms to which they are attached, they form fused C 3-6 Cycloalkyl rings, wherein the rings are optionally composed of 1, 2, 3 or 4 rings each selected from D, C 1-3 Alkyl and halogenated substituents;

[0322] R 5A It is 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 derived from 1, 2, 3 or 4 alkyl groups, each selected from R 5B Substituents and optionally Cy 2 Substitution, or optionally, attachment of R to the same carbon atom 5A and R 5 Together with the carbon atoms attached to both, they form a spiral C. 3-6 Cycloalkyl rings, wherein the rings are optionally composed of 1, 2, 3 or 4 rings each selected from D, C 1-3Alkyl and halogenated substituents; 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 3-6 Cycloalkyl rings, wherein the rings are optionally composed of 1, 2, 3 or 4 rings each selected from D, C 1-3 Alkyl and halogenated substituents;

[0323] Each R 5B Independently selected from D and halogenated;

[0324] Each R a5 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0325] 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 derived from 1, 2, 3 or 4 alkyl groups, each selected from R 5B Substituents and optionally Cy 2 replace;

[0326] Cy 2 Selected from C 3-7 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl groups; wherein Cy is formed 2 C 3-7 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 6-10 Aryl and 5-10 heteroaryl groups are optionally selected from R by 1, 2, 3 or 4 independent selections. Cy2 Substituents are substituted; wherein Cy is formed 2 The cyclic atoms of the 4-10 membered heterocyclic alkyl and 5-10 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 4-10-membered heterocyclic alkyl and 5-10-membered heteroaryl groups are optionally oxidized to form carbonyl groups;

[0327] 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, 4-10 membered heterocyclic alkyl, C 6-10Aryl, 5-10 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, 4-10 membered heterocyclic alkyl, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally selected from R by 1, 2, 3 or 4 independent selections. Cy2A Substituents are substituted; wherein R is formed Cy2 The cyclic atoms of the 4-10 membered heterocyclic alkyl and 5-10 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 4-10-membered heterocyclic alkyl and 5-10-membered heteroaryl groups are optionally oxidized 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 derived from one, two, or three independently selected from R Cy2B Substituents of the substituents;

[0328] Each R Cy2A Selected independently from C 1-3Alkyl, 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 derived from one, two, or three independently selected from R Cy2B Substituents of the substituents;

[0329] 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 ,

[0330] 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 3-7Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 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, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Each alkyl group is optionally substituted by one, two, or three independent substituents selected from the following: 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 ; where R is formedaCy21 R bCy21 R cCy21 and R dCy21 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, 5-10-membered heteroaryl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Each alkyl group consists of at least one carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and R is formed therein. aCy21 R bCy21 R cCy21 and R dCy21 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, 5-10-membered heteroaryl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 The cyclic carbon atom of the alkyl group may be optionally substituted with an oxo group to form a carbonyl group;

[0331] Or R attached to the same N atom cCy21 and R dCy21 Together with the N atom attached to both, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl group or a 5-membered heteroaryl group, each of which is optionally substituted by one, two, or three independent substituents selected from the following: 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 cCy22R dCy22 S(O)2R bCy22 NR cCy22 S(O)2R bCy22 and S(O)2NR cCy22 R dCy22 ;

[0332] 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, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 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, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Each alkyl group may optionally be substituted by one, two, or three independent substituents selected from the following: 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 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, 5-10-membered heteroaryl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Each alkyl group consists of at least one carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and R is formed therein. aCy22 R bCy22 RcCy22 and R dCy22 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, 5-10-membered heteroaryl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 The cyclic carbon atom of the alkyl group may be optionally substituted with an oxo group to form a carbonyl group; or

[0333] R attached to the same N atom cCy22 and R dCy22 Together with the N atom attached to both, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl group or a 5-membered heteroaryl group, each of which is optionally substituted by one, two, or three independent substituents 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

[0334] R eCy21 and R eCy22 Each can be H, CN, or NO2 independently.

[0335] In the embodiment of formula IV,

[0336] Cy 1 It is a phenyl group optionally substituted with one or two substituents selected from the following: D, C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, OH and C 1-3 Alkoxy;

[0337] R 1 It is a halogenated product;

[0338] R 2 C is optionally substituted with OH 1-3 alkyl;

[0339] R 3 C is optionally halogenated. 3-10 cycloalkyl;

[0340] Each R 4 It is H;

[0341] An R 5 It is R 5A ; and each other R 5 Independently selected from H, D, halogenated, C 1-3 Alkyl, OC 1-3 Alkyl, C 1-3Haloalkyl; 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 3-6 Cycloalkyl rings, wherein the rings are optionally fused with one or two ions each selected from D, C 1-3 Alkyl and halogenated substituents; and

[0342] R 5A Is it H, halogenated, or OR? a5A ;

[0343] 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

[0344] Cy 2 Selected from C 6-10 Aryl and 5-10 heteroaryl compounds.

[0345] In another embodiment of formula IV,

[0346] Cy 1 It is a phenyl group optionally substituted with one or two substituents selected from the following: D, C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, OH and C 1-3 Alkoxy;

[0347] R 1 It is a halogenated product;

[0348] R 2 C is optionally substituted with OH 1-3 alkyl;

[0349] R 3 OR is arbitrarily halogenated 3A Or C 3-10 cycloalkyl;

[0350] R 3A It is C 1-3 alkyl;

[0351] Each R 4 It is H;

[0352] An R 5 It is R 5A ; and each other R 5 Independently selected from H, D, halogenated, C 1-3 Alkyl, OC1-3 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 3-6 Cycloalkyl rings, wherein the rings are optionally fused with one or two ions each selected from D, C 1-3 Alkyl and halogenated substituents;

[0353] R 5A Is it H, halogenated, or OR? a5A ;

[0354] 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

[0355] Cy 2 Selected from C 6-10 Aryl and 5-10 heteroaryl compounds.

[0356] In another embodiment of formula IV,

[0357] Cy 1 It is a phenyl group optionally substituted with one or two substituents each selected from the following: C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, OH and C 1-3 Alkoxy;

[0358] R 1 It is a halogenated product;

[0359] R 2 C is optionally substituted with OH 1-3 alkyl;

[0360] R 3 OR is arbitrarily halogenated 3A Or C 3-10 cycloalkyl;

[0361] R 3A It is C 1-3 alkyl;

[0362] Each R 4 It is H;

[0363] An R 5 It is R 5A ; and each other R 5 Independently selected from H, halogen, C1-3 Alkyl, OC 1-3 Alkyl, C 1-3 Halogenated alkyl groups;

[0364] R 5A Is it H, halogenated, or OR? a5A ;as well as

[0365] 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.

[0366] In the embodiments, the compound of formula IV is a compound of formula IV-A or IV-B:

[0367]

[0368] Or its pharmaceutically acceptable salt.

[0369] In another embodiment, the compound of formula IV is selected from:

[0370] 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;

[0371] 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;

[0372] 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;

[0373] 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;

[0374] 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;

[0375] 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;

[0376] 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;

[0377] 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;

[0378] 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;

[0379] 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;

[0380] 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-dimethylpyridinecarboxamide;

[0381] 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-hydroxypropyl-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile;

[0382] 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;

[0383] 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;

[0384] 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;

[0385] 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;

[0386] 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;

[0387] 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;

[0388] 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;

[0389] 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;

[0390] 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;

[0391] 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;

[0392] 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;

[0393] 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;

[0394] 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;

[0395] 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;

[0396] 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;

[0397] 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

[0398] 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;

[0399] And its pharmaceutically acceptable salts.

[0400] 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 3”) or a pharmaceutically acceptable salt thereof.

[0401] 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]quinoline-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid methyl ester:

[0402] .

[0403] In the examples, 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:

[0404] .

[0405] 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.

[0406] In some embodiments, the inhibitor of the KRAS G12D inhibitor is selected from the 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.

[0407] KRAS currently in use G12D suppression Other suppression selection WO2016161361; WO2020212895; WO2021041671; WO2021081212; WO2021 106231; WO2021107160; WO2021126799; WO2021215544; WO2021248079; WO2021248082 W O2022105857; WO2022105859; WO2022173033; WO2022177917; WO2022184178; WO2022188729; WO2022192794; WO2022194066; WO2 022194191; WO2022194192; WO2022198905; WO2022199170; WO2022199586; WO2022206723; WO2022206724; WO2022212947; WO20 22214102; WO2022217042; WO2022221739; WO2022223020; WO2022227987; WO2022228543; WO2022232331; WO2022232332; WO2022 234639; WO2022234851; WO2022240971; WO2022261154; WO2022262686; WO2022262838; WO2022266069; WO2022268051; WO20230 01123; WO2023001141; WO2023018810; WO2023018812; WO2023020347; WO2023025116; WO2023030495; WO2023051586; WO2023056 951; WO2023059594; WO2023059596; WO2023059597; WO2023059598; WO2023059600; WO2023061294; WO2023061463; WO202307218 8; WO2023085657; WO2023098425; WO2023098426; WO2023098832; WO2023101928; WO2023103523; WO2023103906; WO2023104018;WO2023113739; WO2023122662; WO2023125627; WO2023125989; WO2023133183; WO2023134465; WO2023143312; WO2023159086 WO2023159087; WO2023179629; WO2023179703; WO2023274324; WO2023274383; WO2023278600; WO2023280026; WO202328028 The compounds disclosed in WO2023283933; WO2023284537; WO2023284881; US11453683; US20180086752; US20180201610; US20220323614; US20220402971; US20230077225; US20230083431; US20230174518; US20230242544; and US20230279025, the contents of which are incorporated herein by reference in their entirety.

[0408] In yet another embodiment, the KRAS G12D inhibitor is a proteolytic targeting chimera (PROTAC). PROTAC is a heterobifunctional compound consisting of a ligand for the target protein (e.g., KRAS with a G12D mutation) and a ligand for an E3 ligase linked via a linker.

[0409] In some embodiments, the inhibitor of the KRAS G12D proteolytic target chimera (PROTAC) is selected from compounds disclosed in WO2022148421; WO2022148422; WO2022173032; WO2023077441; WO2023081476; WO2023119677; WO2023120742; WO2023138524; and WO2023171781; the contents of these patents are incorporated herein by reference in their entirety.

[0410] In one embodiment, the disclosed compound may exist as a tautomer. All tautomers are included within the scope of the compounds described herein.

[0411] The compounds described herein can exist as transisomeric (i.e., conformationally diastereomers) that are stable at room temperature and can be separated by, for example, chromatography. For instance, compounds of Formula I can exist as transisomeric (i.e., diastereomers) that can be separated by surrounding a Cy group. 1(or any of the examples thereof) interchanges with the bonds of the rest of the molecule through rotation. References to the compounds described herein or any of the examples should be understood to include all such transisomers of the compound. Without being limited by any theory, it should be understood that, for a given compound, one transisomer may generally be more potent as a KRAS (including the G12D mutant form of KRAS) inhibitor than another transisomer. For example, as described herein, Cy... 1 Compounds of formula I, which are 2,3-dichlorophenyl, can exist as trans-restricted isomers, wherein the conformation of the dichlorophenyl relative to the rest of the molecule is as shown by partial formula IV-A or IV-B. The asymmetry of the trans-restricted isomer is designated 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.

[0412]

[0413] 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... 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 result in 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.

[0414] In another embodiment, isotopes (such as positron emission tomography) are emitted using positrons. 11 C18 F, 15 O and 13 N) can be used to replace positron emission tomography (PET) studies that can be used to examine substrate acceptor occupancy. Isotope-labeled compounds are prepared by any suitable method or by a process that uses an appropriate isotope-labeled reagent instead of an unlabeled reagent.

[0415] The specific compounds described herein and compounds with different substituents covered by one or more of the formulas described herein were synthesized using the techniques and materials described herein and, for example, in the following references: 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); E.M. 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, Methoden der OrganischenChemie, 4th edition, Volumes 1–67 (Thieme, 1952-1987); Houben-Weyl, Methoden der Organischen Chemie, E series, Volumes 1-23 (Thieme, 1982-2003); ARKatritzky 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. (eds.), Comprehensive Heterocyclic Chemistry IV, Volumes 1-14 (Elsevier Science, 2008). 2022); MB Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th ed. (Wiley, 2007); MB Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8th ed. (Wiley, 2020); BM Trost et al. (eds.), Comprehensive Organic Synthesis, Volumes 1-9 (Pergamon Press, 1991); and Patai's Chemistry of Functional Groups, 100 Vols.(Wiley 1964–2022) (All of these references are incorporated herein by reference into this publication). 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.

[0416] The compounds described herein can be synthesized from commercially available compounds using any suitable procedure, or prepared using the procedure described herein.

[0417] PD-1 inhibitors and PD-L1 inhibitors

[0418] The combination therapy described in this article may include a KRAS G12D inhibitor and any of a variety of PD-1 inhibitors or PD-L1 inhibitors.

[0419] The amino acid sequence of human PD-1 protein (Genbank accession number NP_005009) is: MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAI SLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL (SEQ ID NO:1).

[0420] PD-1 has two ligands: PD-L1 and PD-L2 (RV Parry et al., Mol. Cell Biol., 2005, 25(21), 9543–53), and they express in different patterns. PD-L1 protein is upregulated on macrophages and dendritic cells in response to lipopolysaccharide and GM-CSF treatment, and on T cells and B cells according to T cell receptor and B cell receptor signaling. PD-L1 is also highly expressed on almost all tumor cells, and its expression is further increased after IFN-γ treatment (RVBlank et al., Cancer Res., 2004, 64(3):1140-45). In fact, tumor PD-L1 expression status has been shown to have a prognostic role in a variety of tumor types (R. Sabatier et al., Oncotarget, 2015, 6(7): 5449–64). Conversely, PD-L2 expression is more restricted and is primarily expressed by dendritic cells (Y. Komiyama et al., J. Immunol., 2006, 177(1), 566-73). The binding of PD-1 with its ligands PD-L1 and PD-L2 on T cells transmits signals that inhibit the production of IL-2 and IFN-γ, as well as cell proliferation induced upon T cell receptor activation (LL. Carter et al., Eur. J. Immunol., 2002, 32(3), 634-43). This mechanism involves recruiting SHP-2 or SHP-1 phosphatases to inhibit T cell receptor signaling, such as Syk and Lck phosphorylation (AH. Sharpe et al., Nat Immunol., 2007, 8(1), 239–45). Activation of the PD-1 signaling axis also attenuates phosphorylation of the PKC-θ activation loop, which is essential for activating the NF-κB and AP1 pathways and for the production of cytokines such as IL-2, IFN-γ, and TNF.

[0421] In some embodiments, the PD-1 / PD-L1 inhibitors that can be used in combination therapy are compounds selected from the following: nivolumab (OPDIVO®, BMS-936558, MDX1106, or MK-34775), pembrolizumab (KEYTRUDA®, MK-3475, SCH-900475, pembrolizumab, CAS Reg. No. 1374853-91-4), and atezolizumab (Tecentriq®, CAS Reg. No.). 1380723-44-3), durvalumab, acitumb (Bavencio®), cimiprimab, AMP-224, AMP-514 / MEDI-0680, atezolizumab, acitumb, BGB-A317, BMS936559, durvalumab, JTX-4014, SHR-1210, pildizumab (CT-011), REGN2810, BGB-108, BGB-A317, SHR-1 210 (HR-301210, SHR1210, or SHR-1210), BMS-936559, MPDL3280A, MEDI4736, MSB0010718C, MDX1105-01, and one or more of the PD-1 / PD-L1 blockers described below: U.S. Patent Nos. 7,488,802, 7,943,743, 8,008,449, 8,168,757, 8,217,149, or Publication No. WO 03042402、WO 2008 / 156712、WO 2010 / 089411、WO 2010 / 036959、WO 2011 / 066342、WO2011 / 159877、WO 2011 / 082400、WO 2011 / 161699、WO 2017 / 070089、WO 2017 / 087777、WO2017 / 106634、WO 2017 / 112730、WO 2017 / 192961、WO 2017 / 205464、WO 2017 / 222976、WO2018 / 013789、WO 2018 / 04478、WO 2018 / 119236、WO WO 2018 / 119266, WO 2018 / 119221, WO 2018 / 119286, WO 2018 / 119263, WO 2018 / 119224, WO 2019 / 191707 and WO 2019 / 217821 and any combination thereof. The disclosure of each of the foregoing patents, applications and publications is incorporated herein by reference in its entirety.

[0422] In some embodiments, the PD-1 / PD-L1 inhibitor is selected from compounds disclosed in WO 2018 / 119266, such as,

[0423] (S)-1-((7-chloro-2-(2'-chloro-3'-(5-((((2-hydroxyethyl)amino)methyl)pyridinamido)-2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid or a pharmaceutically acceptable salt thereof;

[0424] (S)-1-((7-chloro-2-(3'-(7-chloro-5-(((S)-3-hydroxypyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof;

[0425] (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthidin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidin-3-carboxylic acid or a pharmaceutically acceptable salt thereof;

[0426] (S)-1-((2-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof;

[0427] (R)-1-((7-cyano-2-(2,2'-dimethyl-3'-(4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof;

[0428] (R)-1-((7-cyano-2-(3'-(5-(2-(dimethylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazo-2-yl)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidin-3-carboxylic acid or a pharmaceutically acceptable salt thereof; and

[0429] 1-((7-cyano-2-(3'-(5-(2-(dimethylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazolyl-2-yl)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof.

[0430] In some embodiments, the inhibitor of PD-1 / PD-L1 is I-1-((7-cyano-2-(3'-(3-(((I-3-hydroxypyrrolidone-1-yl)methyl)-1,7-naphthidone-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof. The synthesis and characterization of I-1-((7-cyano-2-(3'-(3-((I-3-hydroxypyrrolidone-1-yl)methyl)-1,7-naphthidone-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid are disclosed in WO 2018 / 119266, which is hereby incorporated herein by reference in its entirety.

[0431] In some embodiments, the PD-1 / PD-L1 inhibitor is selected from:

[0432] (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthidin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid hydrobromide;

[0433] (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthidin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid oxalate;

[0434] (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthidin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylate salt;

[0435] (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthid-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid L-tartrate;

[0436] (R)-1-((7-cyano-2-(3'-(3-((((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthidin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid malonate; and

[0437] (R)-1-((7-cyano-2-(3'-(3-((((R)-3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthid-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid phosphate.

[0438] In some embodiments, the PD-1 / PD-L1 inhibitor is selected from compounds disclosed in WO 2018 / 119224, such as,

[0439] (S)-1-((2-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof;

[0440] (R)-1-((2-(2'-chloro-3'-(6-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof;

[0441] (S)-N-(2-chloro-3'-(5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide)-2'-methylbiphenyl-3-yl)-5-isopropyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide or a pharmaceutically acceptable salt thereof;

[0442] Cis-4-((2-((2,2'-dichloro-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-carboxymethyl)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid or a pharmaceutically acceptable salt thereof;

[0443] trans-4-(2-(2-((2,2'-dichloro-3'-(5-(2-hydroxyethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-carboxymethyl)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid or a pharmaceutically acceptable salt thereof;

[0444] trans-4-(2-(2-((2-chloro-2'-methyl-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-carboxymethylamino)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid or a pharmaceutically acceptable salt thereof; and

[0445] Cis-4-((2-(2-chloro-3'-(5-(2-(ethyl(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazolyl-2-yl)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexane-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

[0446] In some embodiments, the PD-1 / PD-L1 inhibitor is selected from compounds disclosed in WO 2019 / 191707, such as,

[0447] (R)-1-((7-cyano-2-(3'-(7-(((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyridino[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidin-4-carboxylic acid or a pharmaceutically acceptable salt thereof;

[0448] (R)-1-((7-cyano-2-(3'-(7-(((S)-1-hydroxypropyl-2-ylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof;

[0449] (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidin-4-carboxylic acid or a pharmaceutically acceptable salt thereof;

[0450] (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-N,N-dimethylpiperidin-4-carboxamide or a pharmaceutically acceptable salt thereof;

[0451] (R)-1-((7-cyano-2-(3'-(2-cyclopropyl-7-((((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof; and

[0452] (R)-1-((7-cyano-2-(3'-(3-((((R)-3-hydroxypyrrolidine-1-yl)methyl)-6-methyl-1,7-naphthidin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof.

[0453] In some embodiments, the PD-1 / PD-L1 inhibitor is selected from compounds disclosed in WO 2019 / 217821, such as,

[0454] 4-(2-(2-((2,2'-dichloro-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-carboxymethylamino)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid or a pharmaceutically acceptable salt thereof;

[0455] 4-(2-(2-((3'-(5-(((1H-pyrazol-3-yl)methyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-carboxyamino)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid or a pharmaceutically acceptable salt thereof;

[0456] I-4-(2-(2-((2,2'-dichloro-3'-(5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-carboxymethyl)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid or a pharmaceutically acceptable salt thereof;

[0457] 4,4'-(((((2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid) or a pharmaceutically acceptable salt thereof;

[0458] 4-(2-(2-((2-chloro-2'-methyl-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid or a pharmaceutically acceptable salt thereof;

[0459] 4-(2-(2-((2,2'-dimethyl-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-carboxymethylamino)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid or a pharmaceutically acceptable salt thereof; and

[0460] 4-(2-(2-((3'-(5-(trans-4-carboxy-4-methylcyclohexyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-carboxamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

[0461] In some embodiments, the PD-1 / PD-L1 inhibitor is an antibody or antigen-binding fragment thereof that binds to human PD-1. In some embodiments, the antibody or antigen-binding fragment thereof that binds to human PD-1 is a humanized antibody.

[0462] In some embodiments, the PD-1 / PD-L1 inhibitor is revilimab (i.e., MGA-012).

[0463] Refulimab is a humanized IgG4 monoclonal antibody that binds to human PD-1. See hPD-1 mAb 7(1.2) in U.S. Patent No. 10,577,422, which is incorporated herein by reference in its entirety. The amino acid sequences of the mature refulimab heavy and light chains are shown below. The complementarity-determining regions (CDRs) 1, 2, and 3 of the variable heavy chain (VH) and variable light chain (VL) domains are shown in N-to-C-terminus order of the mature VL and VH sequences, and are all underlined and bold. The antibody consisting of the mature heavy chain (SEQ ID NO:2) and mature light chain (SEQ ID NO:3) listed below is referred to as refulimab.

[0464] Mature rivasmab heavy chain (HC)

[0465] QVQLVQSGAEVKKPGASVKVSCKASGYSFT SYWMN WVRQAPGQGLEWIG VIHPSDSETWLDQKFKD RVTITVDKSTSTAYMELSSLRSEDTAVYYCAR EHYGTSPFAY WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYV DGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG(SEQ ID NO:2)

[0466] Mature rivasuma antibody light chain (LC)

[0467] EIVLTQSPATLSLSPGERATLSC RASESVDNYGMSFMNW FQQKPGQPPKLLIH AASNQGS GVPSRFSGSGSGTDFTLTISSLEPEDFAVYFC QQSKEVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:3)

[0468] The variable heavy chain (VH) domain of revivalimab has the following amino acid sequence:

[0469] QVQLVQSGAEVKKPGASVKVSCKASGYSFT SYWMN WVRQAPGQGLEWIG VIHPSDSETWLDQKFKD RVTITVDKSTSTAYMELSSLRSEDTAVYYCAR EHYGTSPFAY WGQGTLVTVSS (SEQ ID NO:4)

[0470] The variable light chain (VL) domain of rivastigmine has the following amino acid sequence:

[0471] EIVLTQSPATLSLSPGERATLSC RASESVDNYGMSFMNW FQQKPGQPPKLLIH AASNQGS GVPSRFSGSGSGTDFTLTISSLEPEDFAVYFC QQSKEVPYT FGGGTKVEIK (SEQ ID NO:5)

[0472] The following is the amino acid sequence of the VH CDR of revivalimab:

[0473] VH CDR1:SYWMN (SEQ ID NO:6);

[0474] VH CDR2:VIHPSDSETWLDQKFKD (SEQ ID NO:7);

[0475] VH CDR3:EHYGTSPFAY (SEQ ID NO:8)

[0476] The following is the amino acid sequence of the VL CDR of revivalimab:

[0477] VL CDR1:RASESVDNYGMSFMNW (SEQ ID NO:9);

[0478] VL CDR2: AASNQGS (SEQ ID NO: 10); and

[0479] VL CDR3: QQSKEVPYT (SEQ ID NO:11).

[0480] In one embodiment, the PD-1 inhibitor is a PD-1 immune checkpoint inhibitor. In another embodiment, the PD-1 inhibitor is an anti-PD-1 antibody. In yet another embodiment, the PD-1 inhibitor is selected from revivalimab, nivolumab, pembrolizumab, cimiprimab, and dotalimab. In yet another embodiment, the PD-1 inhibitor is revivalimab.

[0481] In the examples, the PD-1 inhibitor is a small molecule inhibitor.

[0482] In one embodiment, the PD-L1 inhibitor is a small molecule inhibitor. In another embodiment, the PD-L1 inhibitor is...

[0483] (“Compound 2”)

[0484] Or its pharmaceutically acceptable salt.

[0485] Treatment

[0486] In one respect, this article provides a method for treating cancer in a subject in need, comprising administering to the subject a KRAS G12D inhibitor or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor or a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof.

[0487] In another aspect, this article provides a method for treating cancer in subjects in need, which includes administering to the subject:

[0488] A pharmaceutical composition comprising a KRAS G12D inhibitor or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient; and

[0489] A pharmaceutical composition comprising a PD-1 inhibitor or a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

[0490] In the examples, the KRAS G12D inhibitor is a compound of Formula I or a pharmaceutically acceptable salt thereof. In another example, the KRAS G12D inhibitor is selected from the compounds listed above. In yet another example, 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.

[0491] 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]quinolin-8-yl)propionitrile hydrochloride dihydrate (“Compound 1*”).

[0492] 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”).

[0493] In the examples, 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”).

[0494] In the examples, the KRAS G12D inhibitor is a compound of formula IV or a pharmaceutically acceptable salt thereof. In another example, the KRAS G12D inhibitor is selected from the compounds of formula IV listed above. In yet another example, 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 3”) or a pharmaceutically acceptable salt thereof.

[0495] 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.

[0496] 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.

[0497] In one embodiment, the PD-1 inhibitor is a PD-1 immune checkpoint inhibitor. In another embodiment, the PD-1 inhibitor is an anti-PD-1 antibody. In yet another embodiment, the PD-1 inhibitor is selected from revivalimab, nivolumab, pembrolizumab, cimiprimab, and dotalimab. In yet another embodiment, the PD-1 inhibitor is revivalimab.

[0498] In the examples, the PD-1 inhibitor is a small molecule inhibitor.

[0499] In this embodiment, the PD-L1 inhibitor is a small molecule inhibitor. In another embodiment, the PD-L1 inhibitor is compound 2 or a pharmaceutically acceptable salt thereof.

[0500] In another embodiment, a KRAS G12D inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof. In yet another embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody. In still another embodiment, the PD-L1 inhibitor is selected from atezolizumab, avermab, and durvalumab.

[0501] In another aspect, this article provides a method for treating cancer in a subject in need, the method comprising administering to the subject:

[0502] A pharmaceutical composition comprising compound 1 and at least one pharmaceutically acceptable carrier or excipient; and

[0503] A pharmaceutical composition comprising revivalimab and at least one pharmaceutically acceptable carrier or excipient.

[0504] In another aspect, this article provides a method for treating cancer in subjects in need, which includes administering to the subject:

[0505] A pharmaceutical composition comprising compound 1* and at least one pharmaceutically acceptable carrier or excipient; and

[0506] A pharmaceutical composition comprising revivalimab and at least one pharmaceutically acceptable carrier or excipient.

[0507] In another aspect, this article provides a method for treating cancer in subjects in need, which includes administering to the subject:

[0508] A pharmaceutical composition comprising compound 1* and at least one pharmaceutically acceptable carrier or excipient; and

[0509] A pharmaceutical composition comprising compound 2 and at least one pharmaceutically acceptable carrier or excipient.

[0510] On another front, this article also provides a method for treating cancer in subjects in need, which includes administering the following to the subject:

[0511] A pharmaceutical composition comprising compound 1 and at least one pharmaceutically acceptable carrier or excipient; and

[0512] A pharmaceutical composition comprising compound 2 and at least one pharmaceutically acceptable carrier or excipient.

[0513] On another front, this article also provides a method for treating cancer in subjects in need, which includes administering the following to the subject:

[0514] A pharmaceutical composition comprising compound 1* and at least one pharmaceutically acceptable carrier or excipient; and

[0515] A pharmaceutical composition comprising compound 2 and at least one pharmaceutically acceptable carrier or excipient.

[0516] In yet another embodiment, the KRAS G12D inhibitor has an IC50 of approximately 100 nM or less. 50 In another embodiment, the KRAS G12D inhibitor selectively inhibits G12D relative to wild-type KRAS.

[0517] In another embodiment, the KRAS G12D inhibitor is administered to the subject in the form of a pharmaceutical composition comprising a KRAS G12D inhibitor or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

[0518] In yet another embodiment, a PD-1 inhibitor or a PD-L1 inhibitor is administered to a subject in the form of a pharmaceutical composition comprising a PD-1 inhibitor or PD-L1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

[0519] In another aspect, this article provides a method for treating cancer in subjects in need, comprising administering to the subject a KRAS G12D inhibitor of 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 a PD-1 inhibitor of revivalimab.

[0520] In the examples, 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 (“Compound 1*”).

[0521] 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”).

[0522] 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”).

[0523] In another aspect, this article provides a method for treating cancer in subjects in need, comprising administering to the subject a KRAS G12D inhibitor as (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 3”) or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor as revivalimab.

[0524] In another aspect, this article provides a method for treating cancer in subjects in need, comprising administering to the subject a KRAS G12D inhibitor as (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 3”) or a pharmaceutically acceptable salt thereof, and a PD-L1 inhibitor as Compound 2.

[0525] 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).

[0526] In one embodiment, the PD-1 inhibitor is administered twice weekly (BIW). In another embodiment, the PD-1 inhibitor is administered via intraperitoneal injection (IP).

[0527] In yet another embodiment, the cancer is selected from carcinoma, hematologic malignancies, sarcomas, and glioblastoma. In still another embodiment, the cancer is a cancer comprising abnormally proliferating cells with a KRAS G12D mutation.

[0528] In an embodiment, the method further includes identifying the presence of abnormally proliferating cells with a KRAS G12D mutation.

[0529] In another embodiment, the cancer is selected from blood cancers such as myeloproliferative neoplasms, myelodysplastic syndromes, chronic and juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and multiple myeloma.

[0530] In another embodiment, 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. In yet another embodiment, the cancer is colorectal cancer. In still another embodiment, the cancer is lung cancer. In some embodiments, the cancer is pancreatic cancer.

[0531] In another embodiment, the cancer is colorectal cancer.

[0532] In yet another embodiment, the cancer is non-small cell lung cancer (NSCLC).

[0533] In another embodiment, the cancer is pancreatic ductal adenocarcinoma.

[0534] In another aspect, this article provides a method for treating colorectal cancer in subjects in need, comprising administering to the subject a KRAS G12D inhibitor of 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 a PD-1 inhibitor of revilimab.

[0535] In another aspect, this article provides a method for treating colorectal cancer in subjects in need, comprising administering to the subject a KRAS G12D inhibitor of 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 a PD-1 inhibitor of compound 2.

[0536] In the examples, 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 (“Compound 1*”).

[0537] 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”).

[0538] 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”).

[0539] In another aspect, this article provides a method for treating pancreatic cancer in subjects in need, comprising administering to the subject a KRAS G12D inhibitor of 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 a PD-1 inhibitor of revivalimab.

[0540] In another aspect, this article provides a method for treating pancreatic cancer in subjects in need, comprising administering to the subject a KRAS G12D inhibitor of 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 a PD-1 inhibitor of compound 2.

[0541] In the examples, 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 (“Compound 1*”).

[0542] 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”).

[0543] 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”).

[0544] In another aspect, this article provides a method for treating colorectal cancer in subjects in need, comprising administering to the subject a KRASG12D inhibitor of (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 3”) or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor of revivalimab.

[0545] In another aspect, this article provides a method for treating colorectal cancer in subjects in need, comprising administering to the subject a KRASG12D inhibitor as (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 3”) or a pharmaceutically acceptable salt thereof, and a PD-L1 inhibitor as Compound 2.

[0546] In another aspect, this article provides a method for treating pancreatic cancer in subjects in need, comprising administering to the subject a KRASG12D inhibitor of (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 3”) or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor of revivalimab.

[0547] In another aspect, this article provides a method for treating pancreatic cancer in subjects in need, comprising administering to the subject a KRASG12D inhibitor as (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 3”) or a pharmaceutically acceptable salt thereof, and a PD-L1 inhibitor as Compound 2.

[0548] In one embodiment, the cancer is metastatic.

[0549] In embodiments of the method, KRAS inhibitors and PD-1 inhibitors or PD-L1 inhibitors are administered alone.

[0550] In another embodiment of the method, the cancer is a myeloproliferative tumor.

[0551] 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 blood cell production, progressive cytopenia, risk of progression to acute leukemia, or morphologically and maturing impaired bone marrow cells (myelodysplastic 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.

[0552] In yet 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, generalized mastocytosis, atypical chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). In yet another embodiment, the cancer is myelofibrosis (MF).

[0553] In embodiments of the method, cancer is selected from the group consisting of: primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis.

[0554] In another embodiment of the method, the subject is a human being.

[0555] In yet another embodiment of the method, the treatment comprises substantially simultaneous administration of a KRAS inhibitor and a PD-1 inhibitor or a PD-L1 inhibitor.

[0556] In another embodiment of the method, the treatment includes administering a KRAS inhibitor and a PD-1 inhibitor or a PD-L1 inhibitor at different times.

[0557] In one embodiment of the method, a KRAS inhibitor is administered to the subject, followed by a PD-1 inhibitor or a PD-L1 inhibitor. In another embodiment, a PD-1 inhibitor or a PD-L1 inhibitor is administered to the subject, followed by a KRAS inhibitor.

[0558] In another embodiment of the method, the KRAS inhibitor and / or PD-1 inhibitor or PD-L1 inhibitor are administered at doses that would be ineffective when the KRAS inhibitor and PD-1 inhibitor or PD-L1 inhibitor are administered alone, but are effective when these doses are combined.

[0559] In embodiments 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) requiring treatment (including subjects identified as requiring treatment).

[0560] In another embodiment of the method, the treatment comprises co-administering a certain amount of a KRAS inhibitor and a certain amount of a PD-1 inhibitor or PD-L1 inhibitor. In this embodiment, the amounts of the KRAS inhibitor and the PD-1 inhibitor or PD-L1 inhibitor are in a single formulation or unit dosage form. In still other embodiments, the amounts of the KRAS inhibitor and the PD-1 inhibitor or PD-L1 inhibitor are in separate formulations or unit dosage forms.

[0561] In the aforementioned methods, treatment may include substantially simultaneous administration of a certain amount of a KRAS inhibitor and a certain amount of a PD-1 inhibitor or PD-L1 inhibitor, or administration of a certain amount of a KRAS inhibitor and a certain amount of a PD-1 inhibitor or PD-L1 inhibitor at different times. In some embodiments of the aforementioned methods, the amount of the KRAS inhibitor and / or the amount of the PD-1 inhibitor or PD-L1 inhibitor is administered at a dose that would be ineffective if the KRAS inhibitor and one or both of the PD-1 inhibitor or PD-L1 inhibitor were administered alone, but would be effective when these amounts are combined.

[0562] Drug combination

[0563] In one aspect, this document provides a pharmaceutical combination comprising a KRAS G12D inhibitor or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor or a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof. In embodiments, 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 exert synergistic activity. In yet another embodiment, the pharmaceutical combination may comprise individual components or components together in a single unit dose.

[0564] In the examples, the KRAS G12D inhibitor is a compound of Formula I or a pharmaceutically acceptable salt thereof. In another example, the KRAS G12D inhibitor is selected from the compounds listed above. In yet another example, 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.

[0565] 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]quinolin-8-yl)propionitrile hydrochloride dihydrate (“Compound 1*”).

[0566] 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”).

[0567] In the examples, 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”).

[0568] In the examples, the KRAS G12D inhibitor is a compound of formula IV or a pharmaceutically acceptable salt thereof. In another example, the KRAS G12D inhibitor is selected from the compounds of formula IV listed above. In yet another example, 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 3”) or a pharmaceutically acceptable salt thereof.

[0569] 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.

[0570] 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.

[0571] In one embodiment, the PD-1 inhibitor is a PD-1 immune checkpoint inhibitor. In another embodiment, the PD-1 inhibitor is an anti-PD-1 antibody. In yet another embodiment, the PD-1 inhibitor is selected from revivalimab, nivolumab, pembrolizumab, cimiprimab, and dotalimab. In yet another embodiment, the PD-1 inhibitor is revivalimab.

[0572] In the examples, the PD-1 inhibitor is a small molecule inhibitor.

[0573] In this embodiment, the PD-L1 inhibitor is a small molecule inhibitor. In another embodiment, the PD-L1 inhibitor is compound 2 or a pharmaceutically acceptable salt thereof.

[0574] 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).

[0575] In one embodiment, the PD-1 inhibitor is administered twice weekly (BIW). In another embodiment, the PD-1 inhibitor is administered via intraperitoneal injection (IP).

[0576] Compared to monotherapy that uses only one of the active pharmaceutical ingredients used in the combination of the present invention, the administration of the pharmaceutical combination provided herein can produce beneficial effects, such as synergistic therapeutic effects, for example, regarding the reduction, delay of progression or inhibition of symptoms, and can also produce further surprising beneficial effects, such as fewer side effects, improved quality of life or reduced morbidity.

[0577] Pharmaceutical Composition

[0578] In one aspect, this article provides a pharmaceutical composition comprising:

[0579] a) KRAS G12D inhibitors or pharmaceutically acceptable salts thereof;

[0580] b) PD-1 inhibitors or PD-L1 inhibitors or their pharmaceutically acceptable salts; and

[0581] c) At least one pharmaceutically acceptable carrier or excipient.

[0582] In the examples, the KRAS G12D inhibitor is a compound of Formula I or a pharmaceutically acceptable salt thereof. In another example, the KRAS G12D inhibitor is selected from the compounds listed above. In yet another example, 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.

[0583] 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]quinolin-8-yl)propionitrile hydrochloride dihydrate (“Compound 1*”).

[0584] 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”).

[0585] In the examples, 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”).

[0586] In the examples, the KRAS G12D inhibitor is a compound of formula IV or a pharmaceutically acceptable salt thereof. In another example, the KRAS G12D inhibitor is selected from the compounds of formula IV listed above. In yet another example, 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 3”) or a pharmaceutically acceptable salt thereof.

[0587] 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.

[0588] 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.

[0589] In one embodiment, the PD-1 inhibitor is a PD-1 immune checkpoint inhibitor. In another embodiment, the PD-1 inhibitor is an anti-PD-1 antibody. In yet another embodiment, the PD-1 inhibitor is selected from revivalimab, nivolumab, pembrolizumab, cimiprimab, and dotalimab. In yet another embodiment, the PD-1 inhibitor is revivalimab.

[0590] In the examples, the PD-1 inhibitor is a small molecule inhibitor.

[0591] In this embodiment, the PD-L1 inhibitor is a small molecule inhibitor. In another embodiment, the PD-L1 inhibitor is compound 2 or a pharmaceutically acceptable salt thereof.

[0592] Packaging ingredients

[0593] 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 a PD-1 inhibitor or a PD-L1 inhibitor. The combination of compounds in a formulated form is contained in a container. The packaging typically includes instructions for using the formulation to treat animals (or typically human patients) with cancer.

[0594] In some embodiments, the packaged pharmaceutical formulation or pharmaceutical product contains a combination of the compounds described herein in a container along with instructions for administration of a dosage form at a fixed schedule. In some of these embodiments, the combination of compounds is provided in individual unit dosage forms.

[0595] In specific embodiments, the combined compounds can be administered according to the same schedule, either by administering a single or unit dosage form containing all the compounds in the combination, or by administering a separate formulation or unit dosage form of the combined compounds. However, some compounds used in the combination may be administered more frequently than once daily, or at a different frequency than the other compounds in the combination. Thus, in one embodiment, the packaged medicine comprises a formulation or unit dosage form containing all the compounds in the combination in a container, and an additional formulation or unit dosage form containing one of the compounds in the medicine combination, without additional active compounds, as per the instructions for administration of the dosage form according to a fixed schedule.

[0596] The packaged formulations described herein include, for example, prescribing information for patients or healthcare providers, or as labels within packaged drug formulations. Prescribing information may include, for example, information regarding the efficacy, dosage and administration, contraindications, and adverse reactions of the drug formulation.

[0597] In all the foregoing, the combination of compounds of the present invention can be applied alone, as a mixture, or with other active agents.

[0598] Application / Dosage / Formulation

[0599] On the other hand, this article provides a pharmaceutical composition or combination of pharmaceuticals comprising the compounds described herein and a pharmaceutically acceptable carrier.

[0600] Combination administration includes administering the combination as a single formulation or unit dosage form, administering individual agents of the combination simultaneously but separately, or administering individual agents of the combination sequentially via any suitable route. The dosage of an individual agent in the combination may require more frequent administration compared to the other agents in the combination. Therefore, to allow for appropriate dosage, packaged pharmaceutical products may contain one or more dosage forms containing a combination of agents, and one or more dosage forms containing one of the agents in the combination but not the other agents in that combination.

[0601] 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.

[0602] Specifically, the selected dose level will depend on a variety of factors, including the activity of the particular compound used, the time 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 age, sex, weight, condition, general health and prior medical history of the patient being treated, and similar factors well known in the medical field.

[0603] A physician or veterinarian with ordinary skills in the art can easily determine and prescribe the required effective amount of the pharmaceutical composition. For example, a physician or veterinarian may begin administering the pharmaceutical composition to dossier at a level lower than required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[0604] In the examples, the free base equivalent of compound 1 was administered at a dose of about 50 mg to about 2000 mg. In the examples, the free base equivalent of compound 1 was administered at a dose of about 200 mg to about 1600 mg. In the examples, the free base equivalent of compound 1 was administered at a dose of about 200 mg to about 1200 mg.

[0605] In the examples, the free base equivalent of compound 1 was 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.

[0606] In the examples, compound 1 was administered once, twice, three times, or four times daily.

[0607] In the examples, compound 1* free base equivalent was administered at a dose of about 50 mg to about 2000 mg. In the examples, compound 1* free base equivalent was administered at a dose of about 200 mg to about 1600 mg. In the examples, compound 1* free base equivalent was administered at a dose of about 200 mg to about 1200 mg.

[0608] In the examples, compound 1* was administered in 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.

[0609] In the examples, the free base equivalent of compound 3 was administered at a dose of about 50 mg to about 2000 mg. In the examples, the free base equivalent of compound 3 was administered at a dose of about 200 mg to about 1600 mg. In the examples, the free base equivalent of compound 3 was administered at a dose of about 200 mg to about 1200 mg.

[0610] In the examples, the free base equivalent of compound 3 was 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.

[0611] In the examples, compound 1* was applied once, twice, three times, or four times daily.

[0612] In some examples, revilimab is administered at a dose of about 100 mg to about 1000 mg. In some examples, revilimab is administered at a dose of about 300 mg to about 800 mg. In some examples, revilimab is administered at a dose of about 400 mg to about 600 mg.

[0613] In the examples, rivarimab was 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.

[0614] In this embodiment, revilimab is administered intravenously (IV). In this embodiment, revilimab is administered once every four weeks (q4w).

[0615] 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 physically discrete units suitable as a uniform dose for 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 characteristics 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.

[0616] In one embodiment, the compounds provided herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions provided herein comprise a therapeutically effective amount of the disclosed compound and a pharmaceutically acceptable carrier.

[0617] The pharmaceutical compounds provided herein (e.g., KRAS inhibitors and PD-1 inhibitors or PD-L1 inhibitors) are present in the combinations, dosage forms, pharmaceutical compositions, and pharmaceutical formulations disclosed herein at a ratio ranging from 100:1 to 1:100. For example, the ratio of a PD-1 inhibitor or PD-L1 inhibitor to a KRAS inhibitor may be in the range of 1:100 to 1:1, such as 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 of a PD-1 inhibitor or PD-L1 inhibitor to a KRAS inhibitor. In another instance, the ratio of KRAS inhibitor to PD-1 inhibitor or PD-L1 inhibitor can be in the range of 1:100 to 1:1, such as 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:PD-1 inhibitor or PD-L1 inhibitor.

[0618] 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 utilization of the active ingredient to the target site and using methods known to those skilled in the art.

[0619] Routes of administration for any composition 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, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical application. In one embodiment, oral administration is preferred.

[0620] Suitable compositions and dosage forms include, for example, tablets, capsules, microcapsules, 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.

[0621] For oral applications, tablets, sugar-coated pills, liquids, drops, suppositories or capsules, sac tablets, and capsule tablets 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; binders 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.

[0622] 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 or continuous infusion administration. Suspensions, solutions, or emulsions in oily or aqueous media may be used, optionally containing other formulation agents such as suspending agents, stabilizers, or dispersants.

[0623] 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 modifications to reaction conditions, including but not limited to reaction time, reaction size / volume, and experimental reagents such as solvents, catalysts, pressure, atmospheric conditions, such as a nitrogen atmosphere, and reducing / oxidizing agents, using art-recognized alternatives and employing only conventional experiments, are all within the scope of this application.

[0624] It should be understood that whatever values ​​and ranges are provided herein, all values ​​and ranges encompassed by these values ​​and ranges are meant to be covered 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.

[0625] 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.

[0626] Example

[0627] The compounds and methods disclosed herein are further illustrated by the following examples, which should not be construed as further limitations. Unless otherwise indicated, 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.

[0628] The KRAS inhibitors described herein, their synthesis, and their bioactivity against KRAS can be found in WO 2023 / 064857, which is incorporated herein by reference in its entirety. The KRAS inhibitors described herein, their synthesis, and their bioactivity against KRAS can be found in PCT / US2024 / 025160, which is incorporated herein by reference in its entirety. The PD-1 and PD-L1 inhibitors described herein, their synthesis, and their bioactivity against PD-1 / PD-L1 can be found in WO 2022 / 147092, which is incorporated herein by reference in its entirety.

[0629] The following abbreviations may be used in this document: AcOH (acetic acid); Ac2O (acetic anhydride); aq. (aqueous); atm. (atmosphere); Boc (tert-butyloxycarbonyl); BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate); br (broad); Cbz (carboxybenzyl); calc. (calculation); 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); Et (Ethyl); EtOAc (ethyl acetate); FCC (Fast Column Chromatography); g (gram); h (hour); HATU (N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea 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 (multiplex); M (molar) ); 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 (nanomolar); NMP (N-methylpyrrolidone); NMR (nuclear magnetic resonance spectroscopy); OTf (trifluoromethanesulfonate); Ph (phenyl); pM (picomolar); PPT (precipitate); RP-HPLC (reversed-phase high-performance liquid chromatography); rt (room temperature); s (single peak); t (triple or tertiary); TBS (tert-butyldimethylsilyl); tert (tertiary); tt (triple triplet); TFA (trifluoroacetic acid); THF (tetrahydrofuran); µg (microgram); µL (microliter); µM (micromolar); wt% (weight percentage). The brine is a saturated aqueous solution of sodium chloride. In a vacuum is under a vacuum.

[0630] Example 1: Synthesis Procedure

[0631] Example 1a: 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

[0632]

[0633] Step 1. Methyl 2-amino-4-bromo-3-fluorobenzoate:

[0634]

[0635] 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-dimethylamide or 1,4-dioxane (6 L) at 5 °C–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 × 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

[0636] Step 2. Methyl 3-amino-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylate:

[0637]

[0638] Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (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 re-purged 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 solid was separated by filtration and the wet filter cake was washed with 50% acetonitrile (2 × 2 L) in water and water (2 × 2 L). The solid was dried under vacuum overnight at about 50 °C to give the desired product (1700 g, 94% yield). C 14 LCMS 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

[0639] Step 3. 3-Amino-6-bromo-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid:

[0640]

[0641] 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–66 °C. After the reaction was complete, acetonitrile (3 L) was removed by rotary evaporation. Water (5.75 L) was added to the concentrated mixture and stirred at room temperature for 2–3 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.14 LCMS calculation of H9BrFCl2NO2: 390.92; Measured value: 391 (M+H). 1 HNMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 1.7 Hz, 1H), 7.79 (dd, J = 8.1, 1.5 Hz, 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.

[0642] Step 4. 3-Amino-6-bromo-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid:

[0643]

[0644] 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). Sodium hydroxide (1.5 M) aqueous solution (5 L) was added to the solution, and the mixture was stirred at approximately 50 °C for 2 hours to complete the saponification reaction. Hydrochloric acid (1.5 M) aqueous solution was gradually added to the mixture to adjust the pH to 3–4, 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 × 1.2 L). The solid was dried overnight under vacuum at approximately 50 °C to give the desired product (1354 g, 97.5% yield in two steps). 13 LCMS calculated value of H7BrCl2FNO2: 376.90; Measured value: 378 (M + H + ). 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J =1.7 Hz, 1H), 7.78 (dd, J = 8.1, 1.5 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.39(dd, J = 7.9, 1.5 Hz, 1H), 6.88. 19 F NMR (376 MHz, DMSO-d6) δ -128.95.

[0645] Step 5.6-Bromo-7-(2,3-dichlorophenyl)-8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione:

[0646]

[0647] Triphosgene (500 g, 1.65 mol) in tetrahydrofuran (THF) (500 mL) was added to 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) at 60 °C, and the mixture was 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 reaction mixture was cooled to room temperature and stirred for 1 hour. The solid was separated by filtration and washed with n-heptane (2 × 1 L). The wet filter cake was dried overnight under vacuum at about 50 °C to give the desired product (1385 g, quantitative yield). 14 LCMS calculated value of H5BrCl2FNO3: 402.88; Measured value: 404 (M + H + ). 1 H NMR (400 MHz, DMSO-d6)δ 12.24 (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.

[0648] Step 6. Ethyl 6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate:

[0649]

[0650] 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 raised to 100 °C and stirred for 1 hour to complete the reaction. The mixture was cooled to approximately 60 °C and water (10 L) was gradually added to precipitate the product. The reaction 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 × 2 L). The wet solid was dried overnight under vacuum at approximately 50 °C to give the desired product (1145 g, 91% yield). 19 H 13 LCMS calculated value of BrCl2FNO2: 470.94; Measured value: 472 (M + H) + ). 1 H NMR (400 MHz, DMSO-d6) δ 12.05 (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.

[0651] Step 6b. Ethyl 6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate:

[0652] Alternatively, the title compound can be prepared 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) is refluxed for 5 hours to remove water via azeotropic extraction. Sodium ethoxide (26 g, 0.381 mol) is added to the mixture, and the mixture is refluxed again for 5 hours. The mixture is cooled to room temperature and poured into dilute hydrochloric acid at pH = 6–7. The organic phase is separated, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are concentrated, and the product is purified by silica gel column chromatography, eluting with ethyl acetate and heptane (0%–30%) to give the desired product (65 g, 54%). 19 H 13 LCMS calculated value of BrCl2FNO3: 470.91; Measured value: 472 (M + H) + ). 1 H NMR (400 MHz, DMSO-d6)δ 12.05 (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 = 7.1Hz, 2H), 2.46 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -124.80.

[0653] Step 7.6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylic acid ethyl ester:

[0654]

[0655] 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 5–6. The solids were separated by filtration and the wet filter cake was washed with water (2 × 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 then heated to about 50 °C. ℃ The product was dried under vacuum overnight to obtain the desired product (210 g, 90% yield). 22 H 15 LCMS calculated 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).

[0656] Step 8. 6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylic acid ethyl ester:

[0657]

[0658] A mixture of ethyl 6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxyl-2-methylquinoline-3-carboxylate (155 g, 348 mmol), pyridine (450 mL), and 1,4-dioxane (450 mL) was heated to 50–60 °C to obtain a homogeneous solution. Sodium borohydride (65.8 g, 1741 mmol) was added to the solution in portions at 50–60 °C. The resulting mixture was stirred at 50–60 °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 1–2. 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%–20% MeOH in DCM) to give the desired product (117.8 g, 76%). 22 H 17 LCMS calculated 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).

[0659] Step 9. 4-Chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid ethyl ester:

[0660]

[0661] 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) was added with phosphorus oxychloride (62 g, 405 mmol) 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 solid was separated by filtration and the wet filter cake was washed with 10% acetonitrile in water (2 × 150 mL). The wet solid was dried overnight under vacuum at about 50 °C to give the desired product (57 g, 90% yield). 22 H 16 LCMS 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).

[0662] Step 10. Ethyl 4-chloro-6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate:

[0663]

[0664] 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-diethylaniline (603 g, 4.04 mol) in acetonitrile (3 L) was added with phosphorus oxychloride (389.7 g, 4.04 mol) 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 (9 L) 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 10% acetonitrile in water (2 × 1.5 L). The wet solids were dried overnight under vacuum at about 50 °C to give the desired product (563 g, 90% yield). 22 H 14 LCMS calculated value of Cl3FN2O2: 462.01; Measured value: 463 (M + H + ). 1 ¹H-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 = 7.4Hz, 4H). 1.41 (t, J = 7.1 Hz, 4H).

[0665] Step 11. 4-Chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid ethyl ester:

[0666]

[0667] 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 diacetoxy hydrate (4.1 g, 0.02 mol), (9,9-dimethyl-9H-xanthon-4,5-diyl)bis(diphenylphosphine) (13.58 g, 0.023 mol), and tert-butanol (483 g, 6.52 mol) in toluene (300 ml) was stirred for 1–2 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. The reaction mixture was concentrated to approximately 2 L by vacuum distillation. Heptane (8 L) was added to the 2 L residue at approximately 50°C for 1 hour. The reaction 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 × 1.2 L). The wet filter cake in dichloromethane (2.7 L) was stirred with silica gel (260 g) 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 × 1.2 L). The wet solids were dried overnight under vacuum at approximately 50 °C to obtain the desired product (476 g, 90% yield). 22 H 16 LCMS 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).

[0668] Step 12. (R) a 4-Chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid ethyl ester:

[0669]

[0670] 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. C 22 H 16 LCMS 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)

[0671] Step 13. Ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate prepared by racemization:

[0672]

[0673] 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 × 200 mL). The wet solid was dried overnight under vacuum at about 50 °C to give the desired product (97 g, 97% yield). 22 H 16LCMS 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)

[0674] 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:

[0675]

[0676] (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 then 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%–10% MeOH in DCM). 32 H 33 LCMS 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).

[0677] 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:

[0678] Alternatively, the title compound can be prepared 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 rt 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 phase was separated. The solvent was removed under reduced pressure to give the product, which can be used in the next step without further purification. The analytical samples were purified by silica gel column chromatography (0%–10% MeOH in DCM). 32 H 33 LCMS calculated value of Cl2FN4O4: 626.19; Measured value: 627 (M + H) + ). 1H-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).

[0679] Alternative 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 obtained via a similar route from (S a Ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate is substituted for (R a It is prepared by a similar process to that starting with ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate.

[0680] 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:

[0681]

[0682] At room temperature, an aqueous solution of sodium hydroxide (2 M) (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). The mixture was heated to 50 °C for 1–1.5 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 × 100 mL). The solid was dried under vacuum at about 50 °C to give the desired product (135 g, quantitative), which could be used for the next step without further purification.

[0683] 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:

[0684] Alternatively, the title compound can be prepared by the following method. At room temperature, sodium trimethylsilanolate (338 g, 95%) is 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). The mixture is heated to 50 °C for 1–3 hours to complete the reaction. The mixture is cooled to room temperature and acidified with 1 M hydrochloric acid aqueous solution to approximately pH 5. The tetrahydrofuran is removed under vacuum. The product is extracted with dichloromethane (6 L). The aqueous phase is separated and extracted with dichloromethane (6 L). The combined organic phases are concentrated under vacuum to give the product (6 L) in DCM solution. A concentrated dichloromethane solution was added to tert-butyl methyl ether (7 L) and then to the residue. 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 × 3 L). The solid was dried under vacuum at approximately 50 °C to obtain the desired product, which could be used for the next step without further purification.

[0685] 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:

[0686]

[0687] A mixture 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) was mixed with N-iodosuccinimide (94 g, 396 mmol) and 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 × 250 mL). The solid was dried under vacuum at approximately 50°C to obtain the desired product (120 g, 80% yield). 39 H28 LCMS 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).

[0688] 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:

[0689]

[0690] A mixture of cyclopropyl ((1R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-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]hexane-2-carboxylic acid tert-butyl ester (136.5 g, 200 mmol) and tetrabutylammonium acetate (242 g, 801 mmol) in DMF (1100 ml) was purged with nitrogen below the liquid surface for 10 min. Tris(dibenzylideneacetone)dipalladium(0) (2.75 g, 3 mmol) was added to the mixture. The mixture was purged with nitrogen under liquid surface for 15 minutes, then heated to 70°C for 1 hour. The reaction mixture was cooled to room temperature and added to a semi-saturated sodium bicarbonate aqueous solution (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%–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).

[0691] 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:

[0692] Alternatively, the title compound can be prepared 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), cuprous iodide (I) (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) is purged with nitrogen below the liquid surface for 30 min. Palladium(II) acetate (60 g, 30 mmol) was added to the mixture. The mixture was then purged with nitrogen under liquid surface for 30 min. It was then heated to 50 °C for more than 10 h. The reaction mixture was cooled to rt and EtOAc (906 L) was added, followed by the slow addition of water (1267 L). The mixture was stirred at rt 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 rt and polished before filtration. The separated aqueous phase was 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 in 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).

[0693] The alternative isomers (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 obtained from (S) via a similar route by performing steps similar to 14-17. a )-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid ethyl ester instead of (R a The preparation begins with ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate.

[0694] 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:

[0695]

[0696] 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 × 300 mL). The wet solid was dried under vacuum. The solid was purified by rapid chromatography with 60%–100% ethyl acetate in dichloromethane. The solvent was removed and the solid in heptane (840 mL) was crystallized from ethyl acetate (420 mL) and tert-butyl methyl ether (420 mL) and heptane (9840 mL) to give the desired product (122 g, 87% yield). 40 H 40 LCMS 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 = 2.7Hz, 4H), 2.34 – 2.20 (m, 1H), 2.21 – 1.97 (m, 2H), 1.73 (dp, J = 15.0, 4.8Hz, 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).

[0697] 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:

[0698]

[0699] At room temperature, towards (1R,4R,5S)-5-((R a8-(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 (167.7 g, 230.1 mmol) was added to a solution of dichloromethane (1.35 L) with trimethyliodosilane (69 g, 345 mmol) and stirred for 1 hour. 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 evaporator and the residue was passed through a silica gel bed (1%–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). C 35 H 32 LCMS 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 = 13.6Hz, 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).

[0700] Alternative transisomers 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 via a similar route by performing steps similar to steps 14-19 from (S a Ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate is substituted for (R a The preparation begins with ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate.

[0701] 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):

[0702]

[0703] At 30℃–50℃, the dissolved 3-((R) a 53.8 g, 85 mmol) of free base (53.8 g, 85 mmol) of propionitrile (53.8 g, 85 mmol) was added to a solution of methanol (110 mL), ethyl acetate (50 mL), water (11 mL), and tert-butyl methyl ether (TBME) (110 mL). 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 5% methanol and 20% ethyl acetate (2 × 110 mL) in TBME. The wet solid was slurryed in ethyl acetate (270 mL) and dried under vacuum at about 50 °C to give the desired product (53.7 g, 90% yield). 35 H 32LCMS calculated 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, 2.6 Hz, 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;56.5;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).

[0704] Alternative transisomers 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 was obtained from 3-((S) via a similar route by performing steps similar to steps 15-21. 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 The preparation begins 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.

[0705] Example 1b: (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidine-l-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidin-4-carboxylic acid (Compound 2)

[0706]

[0707] Step 1: 7-Bromo-2-(difluoromethyl)-4H-pyrido[3,2-d][1,3]oxazin-4-one

[0708]

[0709] A mixture of 3-amino-5-bromopyridinecarboxylic acid (PharmBlock cat#PB0554: 645 mg, 2.97 mmol) and 2,2-difluoroacetic anhydride (4.14 g, 23.8 mmol) was stirred at 60 °C for 3 h. After cooling to rt, volatiles were removed by rotary evaporation using a high vacuum pump. The residue was used directly for the next step. C8H4BrF2N2O2 (M+H) + The calculated LC-MS value is m / z = 276.9; the measured value is 277.0.

[0710] Step 2: 7-Bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-4-ol

[0711]

[0712] A mixture of 7-bromo-2-(difluoromethyl)-4H-pyrido[3,2-d][1,3]oxazin-4-one (801 mg, 2.89 mmol) and an aqueous solution of ammonium hydroxide (8.0 ml, 28%) was sealed in a thick-walled glass tube and stirred at 85 °C for 2 h. After cooling to rt, the solution was evaporated and the residue was redissolved with CH3CN and toluene. The suspension was evaporated again, and the residue was ready for use in the next step without further purification. C8H5BrF2N3O (M+H) + The calculated LC-MS value is m / z = 276.0; the measured value is 276.0.

[0713] Step 3: 7-Bromo-N-(3-chloro-2-methylphenyl)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-4-amine

[0714]

[0715] Phosphoryl chloride (1.52 ml, 16.3 mmol) was added to a mixture of 7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-4-ol (from the crude product of step 2: 750 mg, 2.72 mmol), benzyltriethylammonium chloride (1238 mg, 5.43 mmol), and N,N-diethylaniline (648 μl, 4.08 mmol) in acetonitrile (13.6 ml). The mixture was stirred at 75 °C for 2 h. The reaction was then cooled to rt. Volatiles were removed under reduced pressure.

[0716] Methanesulfonic acid (188 μl, 2.89 mmol) was added to a solution of 3-chloro-2-methylaniline (409 mg, 2.89 mmol) and 7-bromo-4-chloro-2-(difluoromethyl)pyrido[3,2-d]pyrimidine (the residue above) in 2-propanol (14.4 ml). The mixture was stirred at 80 °C for 2 h. The reaction was then cooled to rt. The mixture was carefully quenched with an aqueous solution of NaHCO3. The precipitate was filtered, washed with water, and air-dried. The solid was used directly for the next step. 15 H 11 BrClF2N4 (M+H) + The calculated LC-MS value is m / z = 399.0; the measured value is 399.0.

[0717] Step 4: N-(3-chloro-2-methylphenyl)-2-(difluoromethyl)-7-vinylpyridino[3,2-d]pyrimidine-4-amine

[0718]

[0719] A mixture of 7-bromo-N-(3-chloro-2-methylphenyl)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-4-amine (841 mg, 2.10 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborane (537 μl, 3.16 mmol), tetra(triphenylphosphine)palladium(0) (243 mg, 0.21 mmol), and potassium phosphate (1117 mg, 5.26 mmol) in tert-butanol (7.0 ml) and water (7.0 ml) was purged with N2 and then stirred at 100 °C for 3 h. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated to give a crude residue, which was purified by rapid chromatography (0%–30% EtOAc / DCM). 17 H 14 CIF2N4 (M+H) + The calculated LC-MS value is m / z = 347.1; the measured value is 347.1.

[0720] Step 5: 4-(3-chloro-2-methylphenylamino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-7-carboxaldehyde

[0721]

[0722] N-(3-chloro-2-methylphenyl)-2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidin-4-amine (195 mg, 0.562 mmol), THF (4.5 ml), a stir bar, and water (1.1 ml) were added to a vial. Sodium periodate (601 mg, 2.81 mmol) was added to this solution, followed by osmium tetroxide (4% w / w in water, 221 μl, 0.028 mmol). After stirring at rt for 1 h, the reaction was quenched with a saturated aqueous solution of sodium thiosulfate. The mixture was then extracted with DCM, and the combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated under vacuum. The crude residue was used directly for the next step without further purification. 16 H 12 LC-MS calculated value of CIF2N4O (M+H)+: m / z = 349.1; measured value: 349.1.

[0723] Step 6: (R)-1-((4-(3-chloro-2-methylphenylamino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidine-3-ol

[0724]

[0725] A mixture of 4-((3-chloro-2-methylphenyl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-7-carboxaldehyde (101 mg, 0.290 mmol) and (R)-pyrrolidine-3-ol (30.3 mg, 0.348 mmol) in DCM (1931 μl) was stirred at rt for 30 min. Then, sodium triacetoxyborohydride (92 mg, 0.434 mmol) was added. The mixture was stirred at rt for another 1 h. The reaction was quenched with aqueous NH4OH and extracted with DCM. The organic phases were combined and dried over MgSO4. After filtration, the DCM solution was concentrated to the residue, which was purified by rapid chromatography (0%–12% MeOH / DCM). 20 H 21 CIF2N5O (M+H) + The calculated LC-MS value is m / z = 420.1; the measured value is 420.2.

[0726] Step 7: (R)-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidone-l-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)-5-formylbenzo[d]oxazol-7-carboxynitrile

[0727]

[0728] (R)-1-((4-(3-chloro-2-methylphenylamino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidine-3-ol (34.4 mg, 0.082 mmol), 5-formyl-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)benzo[d]oxazol-7-carboxynitrile (35 mg, 0.090 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (6.5 mg, 8.2 μmol), and potassium phosphate (43.5 mg, 0.205 mmol) were dissolved in water (140 °C). The mixture of 1,4-dioxane (690 μl) and 1,4-dioxane (690 μl) was purged with N2 and then sealed. The reaction was stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with DCM and H2O. The layers were separated. The aqueous layer was extracted three times with DCM. The organic layer was separated, dried over MgSO4, filtered, and concentrated to give a crude residue, which could be used for the next step without further purification. 36 H 30 F2N7O3 (M+H) + The calculated LC-MS value is m / z = 646.2; the measured value is 646.3.

[0729] Step 8: (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidine-l-yl)methyl)pyridino[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidin-4-carboxylic acid

[0730] A mixture of (R)-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidone-l-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)-5-carboxyylbenzo[d]oxazol-7-carboxynitrile (9.5 mg, 0.015 mmol) and tert-butyl piperidine-4-carboxylate (5.45 mg, 0.029 mmol) was stirred at rt for 2 h. Then, sodium triacetoxyborohydride (9.36 mg, 0.044 mmol) was added. The mixture was stirred at rt for 1 h. Then, trifluoroacetic acid (300 μl) was added to the mixture and stirred for 30 min. The evaporation was evaporated and the residue was diluted with MeOH and then purified by preparative HPLC (pH = 2, acetonitrile / water + TFA) to give the desired product as a TFA salt. 42 H 41F2N8O4(M+H) + The calculated LC-MS value is m / z = 759.3; the measured value is 759.6. 1 H NMR (500 MHz, DMSO) δ 10.63 (s,1H), 9.13 (s, 1H), 8.52 (d, J= 2.0 Hz, 1H), 8.39 (d, J= 1.6 Hz, 1H), 8.19(dd, ,7= 7.9, 1.5 Hz, 1H), 8.11 (d, J= 2.1 Hz, 1H), 7.64 (dd, J= 8.1, 1.3 Hz,1H), 7.59 (t, J= 7.7 Hz, 1H), 7.49 (dd, J= 7.5, 1.5 Hz, 1H), 7.41 (t, = 7.8Hz, 1H), 7.16 (dd, = 7.6, 1.3 Hz, 1H), 6.74 (t, J= 54.5 Hz, 1H), 4.85 - 4.65(m, 2H), 4.58 - 4.40 (m, 3H), 3.74 - 3.00 (m, 8H), 2.78 - 2.54 (m, 1H), 2.50(s, 3H), 2.32 - 1.91 (m, 5H), 1.95 (s, 3H), 1.79 - 1.67 (m, 1H).

[0731] Example 1c: (1R,3R,4R,5S)-3-((R a Synthetic procedure for methyl heptan-2-carboxylate (compound 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]quinoline-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0732]

[0733] Step 1. Methyl (1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylic acid

[0734]

[0735] 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. After 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. After completion, 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. C 26 H 32 NO3Si (M+H) + The calculated LC-MS value is m / z = 434.2; the measured value is 434.2.

[0736] Step 2. Methyl (1R,3R,4R,5S)-3-ethynyl-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylic acid ester

[0737]

[0738] 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-carboxylic acid methyl ester (1.43 g, 3.30 mmol) dissolved in THF (11 mL). The reaction was stirred at room temperature for 16 h. After completion, volatiles were removed. The crude product was purified by rapid chromatography (0%–10% methanol / DCM) to give the title compound. C 10 H 14 NO3 (M+H) + The calculated LC-MS value is m / z = 196.1; the measured value is 196.1.

[0739] Step 3. Methyl (1R,3R,4R,5S)-5-(difluoromethoxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylic acid ester

[0740]

[0741] 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-carboxylic acid (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. After stirring, 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). 11 H 14 F2NO3 (M+H) + The calculated LC-MS value is m / z = 246.1; the measured value is 246.1.

[0742] 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

[0743]

[0744] 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-carboxylic acid methyl ester (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 hour. Then, cesium carbonate (0.717 g, 2.20 mmol) was added to the reaction mixture. The resulting slurry was stirred at 90 °C for another 18 hours. After 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. C 40 H 41 Cl2F3N5O5 (M+H) + The calculated LC-MS value is m / z = 798.2; the measured value is 798.3.

[0745] 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

[0746] To (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]hexane-2-carboxylic acid tert-butyl ester (0.350 g, 0.439 mmol) was added to a solution in DCM (7 mL) with 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. 35 H 33 Cl2F3N5O3 (M+H) + LC-MS calculated value: m / z = 698.2; measured value: 698.2. TFA salt was collected. 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).

[0747] 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]quinoline-2-yl)-5-(difluoromethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate can be derived from (1R,4R,5S)-5-((S) via a similar route by performing steps similar to those described above. 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 It is prepared by 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]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester.

[0748] Intermediate 1.(R)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid ethyl ester

[0749]

[0750] Step 1. 3-Amino-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid

[0751]

[0752] 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 again for 10 min, 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. 13 H9Cl2FNO2 (M+H) + The calculated LC-MS value is m / z = 300.0; the measured value is 300.0.

[0753] Step 2.3-Amino-6-bromo-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid

[0754]

[0755] 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 min, 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. 13 H8BrCl2FNO2 (M+H) + LC-MS calculated values: m / z = 377.9, 379.9; measured values: 378.0, 380.0.

[0756] Step 3.6-Bromo-7-(2,3-dichlorophenyl)-8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione

[0757]

[0758] 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.

[0759] Step 4. Ethyl 6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylic acid

[0760]

[0761] 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 sintering 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. 19 H 14 BrCl2FNO3 (M+H) + LC-MS calculated values: m / z = 471.9, 473.9; measured values: 471.9, 474.0.

[0762] Step 5. (E)-6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylic acid ethyl ester

[0763]

[0764] 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 bubbled with N2 and heated at 85 °C for 1 h. After completion, the reaction mixture was cooled to rt and poured into 1 N HCl (500 mL). After stirring for 1 h, the solid was collected on a sintering 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. 22 H 16 Cl2FN2O3 (M+H) + The calculated LC-MS value is m / z = 445.0; the measured value is 445.0.

[0765] Step 6. (E)-4-chloro-6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid ethyl ester

[0766]

[0767] At 0 °C, 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). 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). C 22 H 15 Cl3FN2O2 (M+H) + The calculated LC-MS value is m / z = 463.0; the measured value is 463.0.

[0768] Step 7. (R)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid ethyl ester

[0769] 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 obtain 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. Afterward, 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 used. 22H 17 Cl3FN2O2(M+H) + The calculated LC-MS value is m / z = 465.0; the measured value is 465.0.

[0770] 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

[0771]

[0772] 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

[0773]

[0774] 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 completion, the reaction mixture was cooled to room temperature and poured into a mixture of 1 N HCl (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 is used in the next step without further purification. 32 H 34 Cl2FN4O4 (M+H) + The calculated LC-MS value is m / z = 627.2; the measured value is 627.1.

[0775] 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

[0776]

[0777] To a solution of (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 (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. 30 H 30 Cl2FN4O4 (M+H) + The calculated LC-MS value is m / z = 599.2; the measured value is 599.1.

[0778] 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

[0779] 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 rt for 1 h. After stirring, 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). 29 H 29 Cl2FIN4O2 (M+H) + The calculated LC-MS value is m / z = 681.1; the measured value is 681.0.

[0780] Intermediate 3.(1R,3R,4S)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylic acid methyl ester

[0781]

[0782] Step 1. Methyl 2-hydroxy-2-methoxyacetate

[0783]

[0784] 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 min. 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 give the product (40.0 g, 82% yield). The product was used in the next step without further purification.

[0785] Step 2. (S,E)-2-((1-phenylethyl)imino)acetic acid methyl ester

[0786]

[0787] (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.

[0788] Step 3. Methyl (1R,3R,4S)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate

[0789] At -10 °C, 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). 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, and 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 in batches by FCC (0%-10% EtOAc / hexane) to obtain the title compound as a colorless solid. C 16 H 20 NO2 (M+H) + The calculated LC-MS value is m / z = 258.1; the measured value is 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).

[0790] Intermediate 4,2-(tert-butyl)-3-methyl(1R,3R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid ester

[0791]

[0792] Step 1. Methyl (1R,3R,4R,5S)-5-hydroxy-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid

[0793]

[0794] 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 (1R,3R,4S)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]hept-5-en-3-carboxylic acid methyl ester (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 rt 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). 16 H 22 NO3 (M+H) + The calculated LC-MS value is m / z = 276.2; the measured value is 276.2.

[0795] Step 2. (1R,3R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid methyl ester

[0796]

[0797] 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 obtain the subtitle compound. The crude material was used for the next step without further purification. C8H 14 NO3 (M+H) + The calculated LC-MS value is m / z = 172.1; the measured value is 172.1.

[0798] Step 3.2 - (tert-butyl)-3-methyl(1R,3R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid ester

[0799] 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). C₁₈H₂O 14 NO5 (M- t Bu+2H) + The calculated LC-MS value is m / z = 216.1; the measured value is 216.1.

[0800] Intermediate 5.(1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0801]

[0802] Step 1.2-(tert-butyl)-3-methyl(1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid ester

[0803]

[0804] To a solution of (1R,3R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-(tert-butyl)3-methyl ester (intermediate 4, 1.88 g, 6.92 mmol) in DMF (140 mL), tert-butylchlorodiphenylsilane (2.08 g, 7.64 mmol) and imidazole (1.40 g, 20.8 mmol) were added. The reaction mixture was stirred at rt 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. C 25 H 32 NO5Si (M- t Bu+2H) + The calculated LC-MS value is m / z = 454.2; the measured value is 454.2.

[0805] Step 2. (1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0806]

[0807] A solution of 2-(tert-butyl)3-methyl ester of (1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid in 2N THF (3.8 mL, 7.52 mmol) was added to a solution of (1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid in 3N THF. The mixture was stirred at room temperature for 8 hours, and then quenched by slow addition of 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). 24 H 32 NO4Si (M- t Bu+2H) + The calculated LC-MS value is m / z = 426.2; the measured value is 426.2.

[0808] Step 3. (1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-formyl-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0809]

[0810] 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 heated to rt 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. 24 H 30 NO4Si (M- t Bu+2H) + The calculated LC-MS value is m / z = 424.2; the measured value is 424.3.

[0811] Step 4. (1R,3R,4R,5S)-5-((tert-butyldiphenylsilyl)oxy)-3-ethynyl-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0812] 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). 25 H 30 NO3Si (M- t Bu+2H) + The calculated LC-MS value is m / z = 420.2; the measured value is 420.2.

[0813] Example 2. Synthesis of cyclopropyl((1R,3R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexan-2-yl) methyl ketone (step 17a in Example 1)

[0814] Step 1. (R)-2,3-dihydro-1H-pyrrole-1,2-dicarboxylic acid 1-(tert-butyl)2-ethyl ester:

[0815]

[0816] 1M triethyllithium borohydride (1.01 L, 1.01 mol) in tetrahydrofuran was added dropwise to a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)-2-ethyl ester (241 g, 0.938 mol) in anhydrous toluene (1.6 L) for 1 h at −50 °C–−40 °C. 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 after 1 h. 4-Dimethylaminopyridine (1.49 g, 12.2 mmol, 0.013 eq.) was added dropwise to the mixture, followed by the 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, and then slowly heated to rt. The mixture was stirred at rt 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. 12 H 19 GCMS 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).

[0817] Step 2. (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-(tert-butyl)3-ethyl ester

[0818]

[0819] 1.1M diethylzinc in toluene (1.7L, 1.87 mol) was added to a solution of (R)-2,3-dihydro-1H-pyrrole-1,2-dicarboxylic acid 1-(tert-butyl)-2-ethyl ester (230 g, 0.938 mol) in toluene (2.3 L) for 1 h at -30 °C to -25 °C. Chloroiodomethane (273 mL, 3.752 mol) was added dropwise to the mixture for 2 h at approximately -30 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 rt. 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 (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-(tert-butyl)3-ethyl ester and (1S,3R,5S)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-(tert-butyl)3-ethyl ester, as determined by GC-MS analysis.

[0820] 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 rt 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 a yellow oily product, (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-(tert-butyl)3-ethyl ester (177 g, 73% calc. yield), containing 2% (1S,3R,5S)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-(tert-butyl)3-ethyl ester, as determined by GC-MS analysis. 13 H 21 GCMS 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).

[0821] Step 3. (1R,3R,5R)-3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester

[0822]

[0823] A solution of (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-(tert-butyl)3-ethyl ester (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 rt 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. 11 H 19 GCMS 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).

[0824] Step 4. (1R,3R,5R)-3-formyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester

[0825]

[0826] DMSO (42.7 mL, 0.603 mol) was added dropwise to oxaloyl chloride (26.4 mL, 0.301 mol) in DCM (535 mL) over 30 min at -78 °C, while maintaining the temperature below -60 °C during the addition. The mixture was stirred at -78 °C for 30 min, and then (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 over 40 min at -78 °C. After stirring at -78 °C for 30 min, NEt3 (104.9 mL, 0.753 mol) was added dropwise over 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 (2 × 888 mL). The combined organic layers were washed successively 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) as a yellow oil. 11 H 17 GCMS 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).

[0827] Step 5. (1R,3R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester

[0828]

[0829] 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 0–5 °C. Dimethyl phosphonate (18.3 mL, 0.110 mol) was added dropwise to the mixture over 30 min at 0–5 °C, while maintaining the temperature < 5 °C during the addition. After stirring for 15 min at 0–5 °C, the reaction mixture was heated to rt and stirred for 2 h. Water (372 mL) and EtOAc (930 mL) were added to the mixture, and it 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 brine (560 mL). The organic solution was concentrated under reduced pressure and purified by silica gel elution with 0%–10% EtOAc in heptane to give a 7:1 mixture (82 g, 74% calc. yield) 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 as a pale yellow oil. 12 H 17 GCMS 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).

[0830] Step 6. Cyclopropyl ((1R,3R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-yl) methyl ketone

[0831]

[0832] A mixture of (1R,3R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester and (1R,3S,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (82 g, 0.39 mol) and 4M HCl (297 mL, 1.19 mol, 3 eq.) in dioxane was stirred at rt 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 at 0 °C over 1.5 h, while maintaining the temperature < 10 °C during the addition. Cyclopropaneformyl chloride (45.4 g, 0.43 mol) was added to the reaction at 0 °C. The reaction mixture was heated to rt 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 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. 12 H 17 GCMS 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).

[0833] 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)

[0834] Step 1. (E)-4-methoxybut-3-en-2-one:

[0835]

[0836] A mixture of 4,4-dimethoxy-2-butanone (350 g, 1.0 eq) and sodium acetate (11 g, 0.05 eq.) was heated to 145-150 °C under a nitrogen atmosphere, with methanol purged during heating. When the reaction was complete, the mixture was cooled to 70-80 °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.

[0837] Step 2. (E)-4-(allylamino)but-3-en-2-one:

[0838]

[0839] 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.

[0840] Step 3. (E)-Allyl (3-oxobut-1-en-1-yl)carbamate tert-butyl ester:

[0841]

[0842] 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 50–55 °C. (Boc)₂O (259 g) was added in portions while maintaining the reaction temperature between 50 and 55 °C. The reaction mixture was stirred at 50–55 °C for 2 h to complete the reaction. The mixture was cooled to 10–15 °C, and a 3 M HCl aqueous solution was added until the pH reached 5–6. 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 50–55 °C for 1 h, and then cooled to 20–30 °C. The mixture was filtered through a diatomaceous earth bed, and the 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.

[0843] Step 4.5 - Acetyl-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester:

[0844]

[0845] 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, a 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).

[0846] Step 5. (1R,4R,5S)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl oxalate:

[0847]

[0848] A mixture of 150 g of 5-acetyl-2-azabicyclo[2.1.1]hexane-2-carboxylate in MeCN (1500 mL) was added to sodium hypochlorite (173.5 g) in 30% sodium hydroxide solution (1500 mL) at 30 °C–40 °C. The mixture was stirred at 30 °C–40 °C for 30 min to complete the reaction. The mixture was cooled to 10 °C–15 °C, and 6 M HCl aqueous solution was added to adjust the pH of the mixture to 8–9. The mixture was concentrated under vacuum at 50 °C–55 °C to remove MeCN, and methanol (90 mL) was added to the residue. The mixture was cooled to 10 °C–15 °C, and 6 M HCl was added to adjust the pH of the mixture to 2–3 (the solid precipitated out 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 °C–55 °C.

[0849] 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. The solution was cooled to 30–35 °C after 90 min (the solid gradually precipitated) and stirred for 1 h. The suspension was cooled to 20–25 °C after 90 min 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. The mixture was cooled to 75–85 °C after 90 min (the solid precipitated) and stirred for 1 h. The mixture was cooled to 20–25 °C after 2 h and stirred for 2 h. The solids were separated and washed with toluene (40 mL). The recrystallization process was repeated once more.

[0850] Free base: At 10–15 °C, 30% NaOH was added to a mixture of wet filter cake in toluene (225 mL) and water (225 mL) to pH 9–10. The mixture was stirred for 30 min and the organic phase was separated. At 10–15 °C, 6 M HCl aqueous solution was added to the aqueous phase to pH 2–3 (predicted solids). The mixture was then cooled to 3–8 °C and stirred for 1 h. The solids were separated and washed with water (40 mL). The wet filter cake was dried under vacuum at 50–55 °C to give the desired (1R,4S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (25 g, 18% yield).

[0851] A mixture of acid (245 g), pyridine (86 g), and ammonium carbonate (111 g) in MeCN (3700 mL) was added to (Boc)₂O (310 g) at 15 °C–25 °C. The mixture was stirred for 5 h to complete the reaction. The solid was separated and washed with MeCN (250 mL). The filtrate and wash were combined and concentrated under vacuum at 40–45 °C and azeotropically with heptane. EtOAc (130 mL) and n-heptane (650 mL) were added to the residue at 40 °C–45 °C. The mixture was cooled to 10 °C–15 °C (solid precipitate) and stirred for 2 h. The solid was separated and washed with n-heptane (250 mL). The wet filter cake was dried under vacuum at 50 °C–55 °C to quantitatively give the desired product (1R,4S,5S)-5-carbamoyl-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl ester.

[0852] (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℃–15℃. Sodium hypochlorite (91.2 g) was added at 10℃–20℃, and the mixture was stirred for 2 h. The mixture was heated to 40℃–45℃ for 4 h to complete the reaction. The reaction mixture was cooled to 15℃–20℃, and citric acid was added to adjust the pH to 5–6. 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℃–30℃ for 2 h. The mixture was filtered, and the filter bed was washed with MeCN (85 mL). The combined filtrate and washings 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 washed with MeCN (110 mL). The wet filter cake was dried under vacuum at 40–50 °C to give the desired white solid of (1R,4R,5S)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl oxalate (248 g, 91% yield). 10 H 18 HPLC-MS calculated value of N2O2: 198.14; Measured value (M+H): 199.1 1 H NMR (500MHz, 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.

[0853] Example 4: Antitumor efficacy and pharmacodynamic activity of compound 1 and refulimab or compound 3 and refulimab in the CT-26 clone 299 colorectal cancer homologous mouse model.

[0854] CT-26 clone 299 homologous efficacy model

[0855] BALB / c-hPD1 / hPDL1 mice (GemPharmatech, strain #T004025) express human PDCD1 and CD274 (encoding PD-1 and PD-L1 proteins, respectively) from the corresponding mouse loci of these genes. Thus, these mice express the human versions of PD-1 and PD-L1, but not the mouse versions of these genes.

[0856] CT-26 clone 299 cells (generated by Horizon Discovery) are a mouse BALB / c colorectal cancer cell line expressing KRAS G12D, in which both copies of PD-L1 (Cd274) are knocked out and replaced by human CD274 under the control of the endogenous Cd274 promoter.

[0857] Note that Compound 1 (monotherapy and combination) and Compound 3 (monotherapy and combination) were tested in independent studies. Female BALB / c-hPD1 / hPDL1 mice (8-10 weeks old) were subcutaneously inoculated with 1.0 × 10⁻⁶ phosphate-buffered saline solution. 6 CT-26 clone 299 cells. Tumor-bearing mice were treated 11 days (in combination with compound 1), 13 days (in combination with compound 2), or 12 days (in combination with compound 3) post-inoculation, at which point the tumor volume reached approximately 120 mm². 3 Mice inoculated with CT-26 clone 299 were randomly assigned to groups of 10 mice based on tumor volume. They were then administered compound 1 (30 mg / kg BID PO or 100 mg / kg QD PO), compound 3 (10 mg / kg BID PO or 30 mg / kg QD PO), or riberilimab 10 mg / kg BIW IP monotherapy, with PO administered as a combination of two doses of compound 1, two doses of compound 3, or a mediator control. Treatment continued throughout the study and ended on day 24 post-tumor implantation. Mice were weighed and tumors measured once or twice weekly until the end of the study on day 60 post-tumor implantation. Tumors were considered complete when the average or individual tumor volume reached 1700 mm². 3 Mice were euthanized. Partial response was defined as two consecutive tumor volumes ≤ 50% of the initial tumor volume, and complete response was defined as two consecutive tumor measurements ≤ 3 mm × 3 mm. Two-dimensional tumor volume was calculated using the following formula:

[0858] Volume = [Length × (Width)] 2 )] / 2.

[0859] For survival (Kaplan-Meier analysis): In the compound 1 study, when the tumor volume reached 1700 mm... 3 Events were recorded when mice met humane endpoint criteria (e.g., weight loss, tumor ulceration, overall condition); in the compound 3 study, events were recorded when the tumor volume reached 2000 mm. 3 Events are recorded when mice meet the humane endpoint criteria or when recurrence is confirmed after a complete response (confirmed recurrence is defined as tumor growth ≤ 100 mm after a complete response as defined above). 3 ).

[0860] Tumor growth inhibition (TGI) uses the formula (1 – [V]). T / V C ]) × 100, where V T It is the average 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. Statistical analysis was performed using GraphPadPrism software (v9.3.1; GraphPad Software, Boston, MA). Two-way ANOVA with Dunnet's multiple comparison test was used to determine statistical differences between the treatment group and the mediator group and other dose groups. Kaplan-Meier analysis was used to determine statistical differences in survival rates among the treatment groups.

[0861] CT-26 clone 299 pharmacodynamic model

[0862] Female BALB / c-hPD1 / hPDL1 mice (GemPharmatech, 8-10 weeks old) were subcutaneously inoculated with 1.0 × 10⁻⁶ phosphate-buffered saline solution. 6 CT-26 clone 299 cells. For the pharmacodynamic portion of this study, tumor-bearing mice began treatment 17 days post-inoculation, at which point the tumor volume reached approximately 680 mm. 3 The 2D tumor volume is calculated using the following formula:

[0863] Volume = [Length × (Width)] 2 )] / 2.

[0864] Mice inoculated with CT-26 clone 299 were randomly assigned to groups of 4 or 6 based on tumor volume. They were then administered either 100 mg / kg QD PO (compound 1) or 10 mg / kg BIW IP (compound rivetrazol monotherapy), with PO administered as a combination of the two agents or a mediator. Oral administration was continued for 5 consecutive days, followed by two doses of rivetrazol. On day 5, plasma and tumor samples were collected after CO2 asphyxiation, 4 hours after oral administration and 24 hours after IP administration. Blood was collected into ethylenediaminetetraacetic acid (EDTA) tubes (450480 Greiner Bio-One). Plasma drug levels were analyzed. Two tumor fragments from each individual were collected, weighed, and placed in Omni Bead Ruptor tubes (19-628 Omni International) and rapidly frozen. One tumor fragment was lysed at a 1:5 ratio with a homogenate solution (water:acetonitrile:formic acid, 95:5:0.1, v:v:v) for drug concentration analysis. The second tumor block 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 Lysis 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.

[0865] Pharmacokinetic Sample Analysis

[0866] Plasma and tumor concentrations of compound 1 were determined using calibration curves prepared in plasma. A mass control sample prepared in a tumor homogenate was included to confirm the accuracy of plasma as a substitute matrix for the tumor homogenate sample. Plasma and tumor homogenate study samples were deproteinized with 200 µL of a 50 nM solution of compound 1 in acetonitrile under vigorous mixing. 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 of compound 1 were re-injected at 2 µL. All tumor samples with concentrations exceeding the upper limit of quantitation were re-injected at 0.5 µL (plus a set of QCs) to ensure peak areas remained within the linear range. Mobile phases A and B used water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid, respectively. LC-MS / MS analysis was performed using a Shimadzu Nexera ultra-high performance liquid chromatography system coupled to the electrospray ionization source (positive ion MRM mode) of a SCIEX Triple Quad 6500+ mass spectrometer. The MRM transition of compound 1 from 628.228 m / z to 517.228 m / z (retention time = 1.18 min) and the peak areas of (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 3”) from 370.792 m / z to 296.652 m / z (retention time = 1.30 min) were used to construct a 1 / x 2 The linear regression calibration equation for the weights. (Using SCIEX Analyst) ® The software (v1.7.2) acquires raw data and calculates calibration curves and study sample concentrations. The measurement range is adjusted according to the expected study concentration, ranging from 1 to 5000 nM.

[0867] Table 1: Gradient elution protocols for high performance liquid chromatography

[0868]

[0869] Note: Post-column switching valve: Flow to mass spectrometry analysis is initiated every 0.8 to 1.6 minutes; otherwise, all flow is wasted.

[0870] result

[0871] Antitumor activity of compound 1 ± revilimab in the CT-26 clone 299 colorectal homologous tumor model

[0872] The antitumor activity of the combination of compound 1 and revilimab was evaluated in the CT-26 clone 299 colorectal model. Mice were treated with revilimab monotherapy with either 30 mg / kg BID PO, 100 mg / kg QD PO of compound 1, or 10 mg / kg BIW IP, with PO administered as either a combination of two dose concentrations of compound 1 or a carrier. When evaluated on day 25 after the last treatment, 30 mg / kg compound 1 BID PO produced a 33% TGI compared to the carrier, while 100 mg / kg compound 1 QD PO produced a 62% TGI compared to the carrier (p = 0.0008). The revilimab IP BIW group produced a 52% TGI. The combination of 10 mg / kg revilimab BIW IP and 30 mg / kg compound 1 BID PO produced a 53% TGI compared to the carrier (p = 0.010) (see [link to relevant documentation]). Figure 1 ).

[0873] exist Figure 1 In this study, BALB / c-hPD1 / hPDL1 mice carrying subcutaneous CT-26 clone 299 tumors were treated with 30 mg / kg POBID, 100 mg / kg PO QD of compound 1, or 10 mg / kg IP BIW of revivalimab monotherapy, or two agents or mediators of compound 1 in combination at two different dose concentrations. Dosing began on day 11 and ended on day 24. Revivalimab was administered on days 11, 15, 18, 19, and 23 post-tumor implantation.

[0874] Compared with the mediator, the combination of 10 mg / kg revivalimab BIW IP and 100 mg / kg compound 1 QD PO increased the TGI to 83% (p < 0.0001). Complete tumor regression was observed in 2 cases in the 10 mg / kg revivalimab BIW IP and 30 mg / kg compound 1 BID PO combination group. Complete tumor regression was observed in 6 cases in the 10 mg / kg revivalimab BIW IP and 100 mg / kg compound 1 QD PO combination group (see [link to relevant documentation]). Figure 2 Dosing ended on day 24 post-vaccination, and tumor and body weight measurements continued until day 60. The mean tumor volume of any group of individuals reached 1700 mm.3 Mice were euthanized. Overall, all treatment groups showed delayed tumor growth compared to the mediator control group (p < 0.005 in all groups). Furthermore, compared to treatment groups treated with compound 1 alone, the combination of revivalimab and compound 1 showed a significantly longer delay in tumor growth after treatment cessation on day 24, and this effect was statistically significant at the 100 mg / kg compound 1 dose level plus revivalimab (see [link to relevant documentation]). Figure 2 Tolerability of each dose was determined based on the absence of weight loss in any treatment group (see [reference]). Figure 3 ).

[0875] Pharmacodynamics and pharmacokinetics of compound 1 ± revilimab in CT-26 clone 299 tumor-bearing mice

[0876] Plasma and tumor samples were collected 4 hours after oral administration and 24 hours after IP administration of 10 mg / kg QD PO of compound 1 or 10 mg / kg IP BIW of reviflimab monotherapy, a combination of the two agents, or reviflimab PO after 5 days of treatment. Reviflimab was collected 24 hours after the second administration. The levels of total ERK and phosphorylated ERK in tumor samples were measured. Compound 1 at 100 mg / kg QD produced a 79% KRAS inhibition rate (see [link to relevant documentation]). Figure 4 ). Refulimab at 10 mg / kg BIW IP produced only an 18% pERK inhibition rate. Combination therapy with compound 1 and refulimab produced an 81% KRAS inhibition rate, indicating that PD1 inhibition has little effect on ERK signaling in this model. Also... Figure 4 As shown, 4 hours after administration, the drug concentration of compound 1 in both plasma and tumor samples was higher than the internally defined IC50 of compound 1. 90 .

[0877] Table 2: Plasma and tumor concentrations associated with pERK inhibition

[0878]

[0879] Data indicate that combination administration of compound 1 with rivarimab resulted in additional tumor growth inhibition in the CT-26 clone 299 homology model. The enhanced efficacy of the combination was due to activity independent of pERK signaling inhibition.

[0880] Antitumor activity of compound 1 ± revilimab in the CT-26 clone 299 colorectal homologous tumor model

[0881] The antitumor activity of the combination of compound 3 and rivabimab was evaluated in the CT-26 clone 299 colorectal model. Figure 11Mice were treated with 10 mg / kg BID or 30 mg / kg QD of compound 3 or 10 mg / kg BIW of riverilimab monotherapy, with PO administered as a combination of two doses of compound 3 or a mediator. When evaluated on day 34 after the last treatment day, 10 mg / kg compound 3 BID PO resulted in a reduction in tumor growth compared to mediator control animals, but this was not statistically significant (p = 0.1127, TGI 47%). Treatment with 30 mg / kg compound 3 BID PO resulted in a significant reduction in tumor growth compared to mediator control (p = 0.0411, 92% TGI). Reriverilimab monotherapy itself was relatively effective, significantly reducing tumor growth compared to mediator control (p = 0.0263, 74% TGI). Although at higher dose levels of compound 3 (30 mg / kg BID), the combination therapy of compound 3 plus revilimab only further reduced tumor growth compared to monotherapy, this effect was not statistically significant. Study animals were further evaluated and monitored for tumor growth after aggressive treatment to assess tumor growth delay and the durability and duration of the antitumor activity induced by these treatment regimens. In this case, the combination of compound 3 at 30 mg / kg BID (but not 10 mg / kg BID) with revilimab provided a significant therapeutic benefit in terms of long-term and relapse-free survival compared to monotherapy. At lower dose levels, there was no significant difference in survival probability between animals treated with compound 3 (10 mg / kg BID) plus revilimab and those treated with revilimab monotherapy (p = 0.1884). At higher dose levels (compound 3 30 mg / kg BID), animals treated with combination therapy showed improved relapse-free survival probability compared with rivarimab monotherapy, but this was not statistically significant, and the relapse-free survival probability was significantly higher over time compared with compound 3 monotherapy at 30 mg / kg BID (p = 0.0004).

[0882] Example 5: Antitumor efficacy and pharmacodynamic activity of compounds 1 and 2 or compounds 3 and 2 in the CT-26 clone 299 colorectal cancer homologous mouse model.

[0883] CT-26 clone 299 homologous efficacy model

[0884] BALB / c-hPD1 / hPDL1 mice (GemPharmatech, strain #T004025) express human PDCD1 and CD274 (encoding PD-1 and PD-L1 proteins, respectively) from the corresponding mouse loci of these genes. Thus, these mice express the human versions of PD-1 and PD-L1, but not the mouse versions of these genes.

[0885] CT-26 clone 299 cells (generated by Horizon Discovery) are a mouse BALB / c colorectal cancer cell line expressing KRAS G12D, in which both copies of PD-L1 (Cd274) are knocked out and replaced by human CD274 under the control of the endogenous Cd274 promoter.

[0886] Note that Compound 1 (monotherapy and combination) and Compound 3 (monotherapy and combination) were tested in independent studies. Female BALB / c-hPD1 / hPDL1 mice (8-10 weeks old) were subcutaneously inoculated with 1.0 × 10⁻⁶ phosphate-buffered saline solution. 6 CT-26 clone 299 cells. Tumor-bearing mice were treated 11 days (in combination with compound 1), 13 days (in combination with compound 2), or 12 days (in combination with compound 3) post-inoculation, at which point the tumor volume reached approximately 120 mm². 3 Mice inoculated with CT-26 clone 299 were randomly assigned to groups of 10 mice based on tumor volume. They were then administered single therapy with compound 1 (30 mg / kg BID PO or 100 mg / kg QD PO), compound 3 (10 mg / kg BID PO or 30 mg / kg QD PO), or compound 2 (25 mg / kg BID PO), with PO administered as a combination of two doses of compound 1, two doses of compound 3, or a mediator control. Treatment continued throughout the study and ended on day 24 post-tumor implantation. Mice were weighed and tumors measured once or twice weekly until the end of the study. Partial response was defined as two consecutive tumor measurements ≤ 50% of the initial tumor volume, and complete response was defined as two consecutive tumor measurements ≤ 3 mm × 3 mm. Two-dimensional tumor volume was calculated using the following formula:

[0887] Volume = [Length × (Width)] 2 )] / 2.

[0888] For survival (Kaplan-Meier analysis): In the compound 1 study, when the tumor volume reached 1700 mm... 3Events were recorded when mice met humane endpoint criteria (e.g., weight loss, tumor ulceration, overall condition); in the compound 3 study, events were recorded when the tumor volume reached 2000 mm. 3 Events are recorded when mice meet the humane endpoint criteria or when recurrence is confirmed after a complete response (confirmed recurrence is defined as tumor growth ≤ 100 mm after a complete response as defined above). 3 ).

[0889] Tumor growth inhibition (TGI) uses the formula (1 – [V]). T / V C ]) × 100, where V T It is the average 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. Statistical analysis was performed using GraphPadPrism software (v9.3.1; GraphPad Software, Boston, MA). Two-way ANOVA with Dunnet's multiple comparison test was used to determine statistical differences between the treatment group and the mediator group and other dose groups. Kaplan-Meier analysis was used to determine statistical differences in survival rates among the treatment groups.

[0890] Pharmacokinetic Sample Analysis

[0891] The plasma and tumor concentrations of compounds 1 and 2 were determined using calibration curves prepared in plasma. Mass control samples prepared in tumor homogenates were included to confirm the accuracy of plasma as a substitute matrix for tumor homogenate samples. Plasma and tumor homogenate study samples were deproteinized with 200 µL of a 50 nM solution of compounds 3 and 2-d5 in acetonitrile under vigorous mixing. 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 3) with a flow rate of 0.75 mL / min for 5 µL of 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 of compound 1 were re-injected at 2 µL. All tumor samples with concentrations exceeding the upper limit of quantitation were re-injected in 0.5 µL (plus a set of QCs) to ensure peak areas remained within the linear range. Mobile phases A and B used water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid, respectively. LC-MS / MS analysis was performed using a Shimadzu Nexera ultra-high performance liquid chromatography system coupled to the electrospray ionization source (positive ion MRM mode) of a SCIEX Triple Quad 6500+ mass spectrometer. The peak areas of the MRM transitions of compound 1 (628.228 m / z → 517.228 m / z, retention time = 1.18 min), compound 2 (380.159 m / z → 530.050 m / z, retention time = 1.18 min), compound 3 (internal standard for compound 1) (370.792 m / z → 296.652 m / z, retention time = 1.30 min), and compound 2-d (internal standard for compound 2) (5764.500 m / z → 545.200 m / z, retention time = 1.18 min) were 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) acquires raw data and calculates calibration curves and study sample concentrations. The measurement range is adjusted according to the expected study concentration, ranging from 1 to 5000 nM.

[0892] Table 3: Gradient elution protocols for high performance liquid chromatography

[0893]

[0894] Note: Post-column switching valve: Flow to mass spectrometry analysis is initiated every 0.8 to 1.6 minutes; otherwise, all flow is wasted.

[0895] result

[0896] Antitumor activity of compound 1 ± compound 2 in the CT-26 clone 299 colorectal homologous tumor model

[0897] The antitumor activity of the combination of compound 1 and compound 2 was evaluated in a CT-26 clone 299 colorectal model. Mice were administered compound 1 at 30 mg / kg BID or 100 mg / kg QD, or compound 2 at 25 mg / kg BID as monotherapy, or in combination of two doses of compound 1, or as a carrier. When evaluated on day 25 after the last treatment, 30 mg / kg compound 1 BID PO resulted in a 33% TGI compared to the carrier, while 100 mg / kg compound 1 QD PO resulted in a 62% TGI compared to the carrier (p = 0.0008). Compound 2 BID PO produced a 17% TGI. Compared to the mediator, the combination of 25 mg / kg compound 2 BID PO and 30 mg / kg compound 1 BID PO showed a TGI of 44%, and the combination of 25 mg / kg compound 2 BID PO and 100 mg / kg compound 1 QD PO increased the TGI to 81% (p < 0.0001) (see [link to relevant documentation]). Figure 5 In the combination group of 25 mg / kg compound 2 BID PO and 100 mg / kg compound 1 QD PO, there was one case of partial tumor response and one case of complete tumor regression. Dosing was discontinued on day 24 post-inoculation, and tumor and body weight measurements continued until day 60. Mice were euthanized when the mean group volume or individual mouse tumor volume reached 1700 mm³. Overall, the treatment groups including compound 2 (i.e., groups 3, 4, 5, and 6) showed delayed tumor growth relative to the mediator control group (p < 0.0005 in all groups). Furthermore, at the 100 mg / kg compound 1 dose level, the combination therapy with compound 2 showed a significantly longer delay in tumor growth after discontinuation of treatment on day 24 compared to either monotherapy alone (p < 0.03) (see [link to relevant documentation]). Figure 6 Tolerability of each dose was determined based on the absence of weight loss in any treatment group (see [reference]). Figure 7 ).

[0898] On day 43 after treatment cessation, 100% of mice treated with monotherapy (compound 1 (100 mg / kg), compound 2) or 90% (refulimab) died due to tumor growth. In contrast, the combination of compound 1 and refulimab completely eliminated tumors in 60% of the treated mice, which remained tumor-free >100 days after initial tumor implantation; 10% of the mice receiving compound 1 + compound 2 achieved complete tumor regression (see [link to article]). Figure 2 and 6 ).

[0899] Surviving mice rejected tumor re-challenge on day 120, while simultaneously challenge-naive mice rapidly developed tumors. Similarly, testing the combination of compound 1 with an antibody targeting PD-1 or PD-L1 also improved long-term tumor-free survival in a mouse model of pancreatic ductal adenocarcinoma (PDAC).

[0900] Pharmacodynamics and pharmacokinetics of compound 1 ± compound 2 in CT-26 clone 299 tumor-bearing mice

[0901] Plasma and tumor samples were collected 4 hours after administration of compound 1 (100 mg / kg QD) or compound 2 (25 mg / kg BID) as monotherapy, in combination of the two agents, or as a mordant PO for 5 days. The levels of total ERK and phosphorylated ERK in the tumor samples were measured. Compound 1 (100 mg / kg QD) produced a 79% KRAS inhibition rate (see [link to relevant documentation]). Figure 8 Compound 2 at a BID of 25 mg / kg produced only a 10% pERK inhibition rate. The combination of compounds 1 and 2 produced an 80% KRAS inhibition rate, indicating that PD-L1 inhibition has little effect on ERK signaling in this model. Also... Figure 8 As shown, 4 hours after administration, the drug concentration of compound 1 in both plasma and tumor samples was higher than the internally defined IC50 of compound 1. 90 .

[0902] Table 4: Plasma and tumor concentrations associated with pERK inhibition

[0903]

[0904] Data indicate that combination administration of compound 1 and compound 2 resulted in additional tumor growth inhibition in the CT-26 clone 299 homology model. As determined using the “survival curves” described by E. Demidenko et al., PLoS ONE, 2019, 14(11): e0224137, both the PD-1 and PD-L1 inhibitors were synergistic with compound 1 (100 mg / kg PO QD). The enhanced combination efficacy was due to activity independent of pERK signaling inhibition.

[0905] These results indicate that compound 1 is a potent, selective, orally bioavailable KRAS G12D inhibitor that can induce major histocompatibility complex (MHC) class I expression in G12D mutant cancer cells in vitro, thereby sensitizing G12D mutant tumors to immune checkpoint blockade and enhancing antitumor activity and tumor clearance.

[0906] Antitumor activity of compound 3 ± compound 2 in the CT-26 clone 299 colorectal homologous tumor model

[0907] The antitumor activity of the combination of compound 3 and compo...

Claims

1. A method of treating cancer in a subject in need, the method comprising administering to the subject a KRASG12D inhibitor or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor or a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein the PD-1 inhibitor is a PD-1 immune checkpoint inhibitor.

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

4. The method according to any one of claims 1 to 3, wherein the PD-1 inhibitor is selected from revivalimab, nivolumab, pembrolizumab, cimiprimab, and dotalimab.

5. The method according to any one of claims 1 to 4, wherein the PD-1 inhibitor is rivanil.

6. The method according to claim 1, wherein the PD-1 inhibitor is a small molecule inhibitor.

7. The method of claim 1, wherein the KRAS G12D inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof.

8. The method according to claim 1 or 7, wherein the PD-L1 inhibitor is an anti-PD-L1 antibody.

9. The method according to claim 8, wherein the PD-L1 inhibitor is selected from atezolizumab, acitumb, and durvalumab.

10. The method according to claim 1 or 7, wherein the PD-L1 inhibitor is a small molecule inhibitor.

11. The method according to claim 7 or 10, wherein the PD-L1 inhibitor is a compound of the following formula Or its pharmaceutically acceptable salt.

12. The method of any one of claims 1 to 11, wherein the KRAS G12D inhibitor has an IC of about 100 nM or less. 50 .

13. The method according to any one of claims 1 to 12, wherein the KRAS G12D inhibitor selectively inhibits G12D relative to wild-type KRAS.

14. The method according to any one of claims 1 to 13, wherein the KRAS G12D inhibitor is a compound of formula 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 derived from one or two independently selected from R g Substituents of the substituents; R 2 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, 4-6 membered heterocyclic alkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5-6-membered heteroaryl-C 1-3 Alkylene, Halogenated, D, CN, and OR a2 ; wherein C 1-3 Alkyl, 4-6 membered heterocyclic alkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5-6-membered heteroaryl-C 1-3 Each alkylene group is optionally derived from one or two independently selected from R g Substituents of the substituents; Cy 1 Selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 aryl and 6-10-membered heteroaryl; wherein the 4-10-membered heterocyclic alkyl and the 6-10-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 6-10-membered heteroaryl and the 4-10-membered heterocyclic alkyl are optionally oxysubstituted to form a carbonyl group; and wherein the C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 The aryl and 6-10 heteroaryl groups are each optionally selected from R by 1, 2, 3 or 4 independent selections. 10 Substituents of the substituents; R 3 Selected from H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5-6-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, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5-6-membered heteroaryl-C 1-3 Each alkylene group is optionally derived from one, two, or three independently selected from R 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 derived from one or two independently selected from R g Substituents of the substituents; R 6 Selected from H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-9 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5-6-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, 4-9 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5-6-membered heteroaryl-C 1-3 Each alkylene group is optionally derived from one or two independently selected from 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 derived from one or two independently selected from R 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, 4-6 membered heterocycloalkyl, phenyl, 5-6 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, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected 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, 5-6-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 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected from R 31 Substituents of the substituents; Each R 60 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkyl, 4-6 membered heterocyclic alkyl, 5-6 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, 4-6-membered heterocyclic alkyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected 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, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 1, 2 or 3 independently selected from R 30 Substituents of the substituents; Or R attached to the same N atom c3 and R d3 Together with the attached N atom, 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. 30 ; R j3 Selected from C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 1, 2 or 3 independently selected from R 30 Substituents of the substituents; Or R attached to the same N atom c3 and R j3 Together with the attached N atom, 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. 30 ; R f3 Selected from C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein the C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 1, 2 or 3 independently selected from R 30 Substituents; or R f3 Selected from Where R x Is it H or C? 1-2 Alkyl and R y It is C 1-2 alkyl; Or R x and R y Together with the C atoms to which they are attached, 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, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected 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, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 The cycloalkyl, 4-6-membered heterocycloalkyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected R 61 Substituents of the substituents; Or any R attached to the same N atom c60 and R d60 Together with the attached N atom, 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 ; 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.

15. The method of claim 14, 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 derived from one or two independently selected from R g Substituents of the substituents; Cy 1 Selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 aryl and 6-10-membered heteroaryl; wherein the 4-10-membered heterocyclic alkyl and the 6-10-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 6-10-membered heteroaryl and the 4-10-membered heterocyclic alkyl are optionally oxysubstituted to form a carbonyl group; and wherein the C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 The aryl and 6-10 heteroaryl groups are each optionally selected from R by 1, 2, 3 or 4 independent selections. 10 Substituents of the substituents; R 3 Selected from H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 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, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 1, 2 or 3 independently selected 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, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halogenated, D, CN, OR a6 and C(O)NR c6 R d6 ; wherein C 3-6 Cycloalkyl, 4-8-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected 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, 4-6 membered heterocycloalkyl, phenyl, 5-6 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, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected 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 Halogenated alkoxy, 4-6 membered heterocyclic alkyl, 5-6 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, 4-6-membered heterocyclic alkyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected 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, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 1, 2 or 3 independently selected from R 30 Substituents of the substituents; Or R attached to the same N atom c3 and R d3 Together with the attached N atom, 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. 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, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected 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, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 The cycloalkyl, 4-6-membered heterocycloalkyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected R 61 Substituents of the substituents; Or any R attached to the same N atom c60 and R d60 Together with the attached N atom, 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.

16. The method according to claim 14 or 15, wherein Y is CR 6 ; R 1 It is 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 6-10 heteroaryl; wherein the 6-10 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 and 6-10 heteroaryl groups are each optionally derived from one or two independent selections from R 10 Substituents of the substituents; R 3 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, 4-6 membered heterocyclic alkyl groups, phenyl groups, and 5-6 membered heteroaryl groups; wherein the C 1-3 Alkyl, 4-6-membered heterocyclic alkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 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, 4-8-membered heterocyclic alkyl, and 5-6-membered heteroaryl; wherein the 4-8-membered heterocyclic alkyl and 5-6-membered heteroaryl are each optionally derived from one or two independently selected from R 60 Substituents; or R 7 It is a halogenated product; Cy 2 yes ； Cy 2 -b 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, 4-6 membered heterocyclic alkyl, halogenated, D, CN, OR a30 C(O)NR c30 R d30 and NR c30 R d30 ; wherein C 1-3 Alkyl groups and 4-6-membered heterocyclic alkyl groups are each optionally derived from one or two independently selected from 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 Halogenated alkoxy, 4-6 membered heterocyclic alkyl, 5-6 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, 4-6-membered heterocyclic alkyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected 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, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 The cycloalkyl, 4-6-membered heterocycloalkyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected R 61 Substituents of the substituents; Or any R attached to the same N atom c60 and R d60 Together with the attached N atom, 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 .

17. The method according to any one of claims 14 to 16, wherein Y is CR 6 ; R 1 It is H; R 2 It is -CH2CH2CN; Cy 1 It is a phenyl group; wherein the phenyl group is optionally derived from one or two independently selected from R 10 Substituents of the substituents; R 3 Selected from H, C 1-3 Alkyl, phenyl, and 5-6-membered heteroaryl; wherein the C 1-3 Alkyl, phenyl, and 5-6 heteroaryl groups are each optionally derived from 1, 2, or 3 independently selected from R 30 Substituents of the substituents; R 5 Selected from H and halogenated; R 6 Selected from 4-8 membered heterocyclic alkyl groups; wherein the 4-8 membered heterocyclic alkyl group is optionally derived from one or two independently selected from R 60 Substituents; or R 6 Selected from C 1-3 Alkyl; wherein the C 1-3 Alkyl groups are selected from one or two independently from R 60 Substituents of the substituents; R 7 It is a halogenated product; Cy 2 yes ； Cy 2 -b 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 group optionally via one independently selected from R 31 Substituents of the substituents; Each R 31 OR a31 ; Each R 60 Selected independently from C 1-3 Alkyl, C 1-3 Halogenated alkoxy, 4-6 membered heterocyclic alkyl, 5-6 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, 4-6-membered heterocyclic alkyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected 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, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl; wherein the C 1-3 Alkyl, C 3-6 The cycloalkyl, 4-6-membered heterocycloalkyl and 5-6-membered heteroaryl groups are each optionally derived from one or two independently selected R 61 Substituents of the substituents; Or any R attached to the same N atom c60 and R d60 Together with the attached N atom, 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 .

18. The method according to any one of claims 14 to 17, wherein Y is CR 6 ; R 1 It is H; R 2 It is -CH2CH2CN; Cy 1 It is a phenyl group; wherein the phenyl group is optionally derived from 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 pyridyl; wherein the methyl, phenyl, 1,2,4-triazolyl, pyrazinyl, and pyridyl groups are each optionally selected from 1, 2, or 3 independently 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-tetrahydroindazine-3-yl; wherein the pyrrolidinyl, 2-azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.1]heptyl, and 5-oxo-1,2,3,5-tetrahydroindazine-3-yl are optionally derived from one or two independently selected from R 60 Substituents of the substituents; R 7 It is fluorine; Cy 2 yes ； Cy 2 -b 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 ; wherein the methyl group is optionally via one R 31 Substituents of the substituents; 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 The 3-oxomorpholino group and the 2-oxopyrazin-1(2H)- group are each optionally derived from one or two independently selected 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 derived from one or two independently selected from R 61 Substituents of the substituents; Or any R attached to the same N atom c60 and R d60 Together with the N atoms to which they are attached, they form optionally one or two independent atoms selected from R 61 The substituents are nitrogen-containing heterocyclic butyl groups.

19. The method according to any one of claims 14 to 18, wherein the compound of formula I is a compound of formula II: Or its pharmaceutically acceptable salt.

20. The method according to any one of claims 14 to 19, wherein the compound of formula I is a compound of formula III: Or its pharmaceutically acceptable salt.

21. The method according to any one of claims 1 to 20, 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)prop-2-yl)oxy)-6-fluoro-7-(7-fluoronaphth-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-tetrahydroindazine-3-yl)-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)-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-methylpyridinecarboxamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphth-1-yl)-4-(6-(2-hydroxypropyl-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-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)pyrrolidin-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-hydroxypropyl-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-hydroxypropyl-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-methylpyridinecarboxamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphth-1-yl)-4-(6-(2-hydroxypropyl-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-hydroxypropyl-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-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-hydroxypropyl-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-hydroxypropyl-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)-5-methylpyrrolidine-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-hydroxypropyl-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-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-dimethylpyridinecarboxamide; 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.

22. The method according to any one of claims 1 to 21, 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.

23. The method according to any one of claims 1 to 22, 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.

24. The method according to any one of claims 1 to 22, 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.

25. The method according to any one of claims 1 to 22, 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.

26. The method according to any one of claims 1 to 13, wherein the KRAS G12D inhibitor is a compound of formula IV: Or its pharmaceutically acceptable salt, wherein: Cy 1 It is a phenyl group 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 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, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5-6-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, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocyclic alkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5-6-membered heteroaryl-C 1-3 Each alkylene group is optionally derived from one, two, or three independently selected from R 2A Substituents are substituted; wherein R is formed 2 The 4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene and 4-6 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 4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-C 1-3 Alkylene and 4-6 membered heterocyclic alkyl-C 1-3 The cyclic carbon atom of the alkylene group is optionally oxidically substituted 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 derived from 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, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein R is formed a2 The C mentioned 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 1, 2 or 3 independently selected from R 2A Substituents are substituted; wherein R is formed a2 The cyclic atoms of the 4-6 membered heterocyclic alkyl and 5-6 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 4-6-membered heterocyclic alkyl and 5-6-membered heteroaryl groups are optionally oxidically substituted 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 derived from 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, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein R is formed b2 R c2 and R d2 The C mentioned 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 1, 2 or 3 independently selected from R 2A Substituents are substituted; forming R b2 R c2 and R d2 The cyclic atoms of the 4-6 membered heterocyclic alkyl and 5-6 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 4-6-membered heterocyclic alkyl and 5-6-membered heteroaryl groups are optionally oxidically substituted 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 derived from one, two, or three independently selected from R 2B Substituents; or Any R attached to the same N atom c2 and R d2 Together with the attached N atom, 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 ; 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, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein R is formed e2 The C mentioned 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 1, 2 or 3 independently selected from R 2A Substituents are substituted; wherein R is formed e2 The cyclic atoms of the 4-6 membered heterocyclic alkyl and 5-6 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 4-6-membered heterocyclic alkyl and 5-6-membered heteroaryl groups are optionally oxidically substituted 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 derived from one, two, or three independently selected from R 2B Substituents; or R attached to the same N atom c2 and R e2 Together with the attached N atom, 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 ; 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 derived from one, two, or three independently selected from R 2B Substituents of the substituents; Each R 2B Selected independently from C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, 5-6 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, 4-6-membered heterocycloalkyl, phenyl and 5-6-membered heteroaryl groups are each optionally derived from 1, 2 or 3 independently selected 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, 4-6 membered heterocycloalkyl, phenyl, 5-6 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, 4-10 membered heterocyclic alkyl, C 6-10 Aryl, 5-10 heteroaryl, OR 3A and NR 3B R 3C ; where R is formed 3 The C mentioned 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl C 1-3 Each alkyl group is optionally derived from one, two, or three independently selected from R 3D Substituents are substituted; wherein R is formed 3 The cyclic atoms of the 4-10 membered heterocyclic alkyl and 5-10 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 4-10-membered heterocyclic alkyl or 5-10-membered heteroaryl group is optionally oxidically substituted 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 derived from 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, 4-10 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 membered heteroaryl; wherein R is formed 3A The C mentioned 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl C 1-3 Each alkyl group is optionally derived from one, two, or three independently selected from R 3D Substituents are substituted; wherein R is formed 3A The cyclic atoms of the 4-10 membered heterocyclic alkyl and 5-10 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 4-10-membered heterocyclic alkyl or 5-10-membered heteroaryl group is optionally oxidically substituted 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 derived from 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, 4-10 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 membered heteroaryl; wherein R is formed 3B The C mentioned 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally selected from R by one, two, or three independent selections. 3D Substituents are substituted; wherein R is formed 3B The cyclic atoms of the 4-10 membered heterocyclic alkyl and 5-10 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 4-10-membered heterocyclic alkyl and 5-10-membered heteroaryl groups are optionally oxysubstituted 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 derived from 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 derived from 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 derived from one, two, or three independently selected 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, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 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, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Each alkyl group is optionally substituted by one, two, three, four, or five independent substituents selected from the following: 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 ; where R is formed a3 R b3 R c3 and R d3 The 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-3 Alkyl and 4-10 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 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 The cyclic carbon atom of the alkyl group may be optionally substituted with an oxo group to form a carbonyl group; or R attached to the same N atom c3 and R d3 Together with the N atom attached to both, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl group or a 5-membered heteroaryl group, each of which is optionally substituted by one, two, or three independent substituents selected from the following: 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, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 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 C 6-10 Aryl-C 1-3 Alkyl, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Each alkyl group may optionally be substituted by one, two, or three independent substituents selected from the following: 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 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-3 Alkyl and 4-10 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 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 The cyclic carbon atom of the alkyl group may be optionally substituted with an oxo group to form a carbonyl group; or R attached to the same N atom c3A and R d3A Together with the N atom attached to both, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl group or a 5-membered heteroaryl group, each of which is optionally substituted by one, two, or three independent substituents 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 It is 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 Alkynyl group; or optionally, two other R groups attached to the same carbon atom. 5 Together with the carbon atoms attached to both, they form a spiral C. 3-6 Cycloalkyl rings, wherein the rings are optionally composed of 1, 2, 3 or 4 rings each selected from D, C 1-3 Alkyl and halogenated substituents; or optionally, two other R groups attached to adjacent carbon atoms. 5 Together with the carbon atoms to which they are attached, they form fused C 3-6 Cycloalkyl rings, wherein the rings are optionally composed of 1, 2, 3 or 4 rings each selected from D, C 1-3 Alkyl and halogenated substituents; R 5A It is 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 derived from 1, 2, 3 or 4 alkyl groups, each selected from R 5B Substituents and optionally Cy 2 Substitution, or optionally, attachment of R to the same carbon atom 5A and R 5 Together with the carbon atoms attached to both, they form a spiral C. 3-6 Cycloalkyl rings, wherein the rings are optionally composed of 1, 2, 3 or 4 rings each selected from D, C 1-3 Alkyl and halogenated substituents; 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 3-6 Cycloalkyl rings, wherein the rings are optionally composed of 1, 2, 3 or 4 rings each selected from D, C 1-3 Alkyl and halogenated substituents; 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 derived from 1, 2, 3 or 4 alkyl groups, each selected from R 5B Substituents and optionally Cy 2 replace; Cy 2 Selected from C 3-7 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl groups; wherein Cy is formed 2 The C mentioned 3-7 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 6-10 Aryl and 5-10 heteroaryl groups are optionally selected from R by 1, 2, 3 or 4 independent selections. Cy2 Substituents are substituted; wherein Cy is formed 2 The cyclic atoms of the 4-10 membered heterocyclic alkyl and 5-10 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 is formed. 2 The cyclic carbon atoms of the 4-10-membered heterocyclic alkyl and 5-10-membered heteroaryl groups are optionally oxysubstituted 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, 4-10 membered heterocyclic alkyl, C 6-10 Aryl, 5-10 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, 4-10 membered heterocyclic alkyl, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally selected from R by 1, 2, 3 or 4 independent selections. Cy2A Substituents are substituted; wherein R is formed Cy2 The cyclic atoms of the 4-10 membered heterocyclic alkyl and 5-10 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 4-10-membered heterocyclic alkyl and 5-10-membered heteroaryl groups are optionally oxysubstituted 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 derived from 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 derived from 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, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 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, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Each alkyl group is optionally substituted by one, two, or three independent substituents selected from the following: 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 ; where R is formed aCy21 R bCy21 R cCy21 and R dCy21 The 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, 5-10-membered heteroaryl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Each alkyl group consists of at least one carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and R is formed therein. aCy21 R bCy21 R cCy21 and R dCy21 The 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, 5-10-membered heteroaryl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 The cyclic carbon atom of the alkyl group may be optionally substituted with an oxo group to form a carbonyl group; Or R attached to the same N atom cCy21 and R dCy21 Together with the N atom attached to both, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl group or a 5-membered heteroaryl group, each of which is optionally substituted by one, two, or three independent substituents selected from the following: 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, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 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, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Each alkyl group may optionally be substituted by one, two, or three independent substituents selected from the following: 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 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, 5-10-membered heteroaryl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Each alkyl group consists of at least one carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and R is formed therein. aCy22 R bCy22 R cCy22 and R dCy22 The 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, 5-10-membered heteroaryl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 The cyclic carbon atom of the alkyl group may be optionally substituted with an oxo group to form a carbonyl group; or R attached to the same N atom cCy22 and R dCy22 Together with the N atom attached to both, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl group or a 5-membered heteroaryl group, each of which is optionally substituted by one, two, or three independent substituents 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.

27. The method of claim 26, wherein Cy 1 It is a phenyl group optionally substituted with one or two substituents selected from the following: D, C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, OH and C 1-3 Alkoxy; R 1 It is a halogenated product; R 2 C is optionally substituted with OH 1-3 alkyl; R 3 C is optionally halogenated. 3-10 cycloalkyl; Each R 4 It is H; An R 5 It is 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 3-6 Cycloalkyl rings, wherein the rings are optionally fused with one or two ions each selected from D, C 1-3 Alkyl and halogenated substituents; and R 5A Is it 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 5-10 heteroaryl compounds.

28. The method according to claim 26 or 27, wherein Cy 1 It is a phenyl group optionally substituted with one or two substituents selected from the following: D, C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, OH and C 1-3 Alkoxy; R 1 It is a halogenated product; R 2 C is optionally substituted with OH 1-3 alkyl; R 3 OR is arbitrarily halogenated 3A Or C 3-10 cycloalkyl; R 3A It is C 1-3 alkyl; Each R 4 It is H; An R 5 It is 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 3-6 Cycloalkyl rings, wherein the rings are optionally fused with one or two ions each selected from D, C 1-3 Alkyl and halogenated substituents; R 5A Is it 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 5-10 heteroaryl compounds.

29. The method according to any one of claims 26 to 28, wherein Cy 1 It is a phenyl group optionally substituted with one or two substituents each selected from the following: C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, OH and C 1-3 Alkoxy; R 1 It is a halogenated product; R 2 C is optionally substituted with OH 1-3 alkyl; R 3 OR is arbitrarily halogenated 3A Or C 3-10 cycloalkyl; R 3A It is C 1-3 alkyl; Each R 4 It is H; An R 5 It is 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 Is it 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 may optionally be substituted with 1, 2 or 3 D atoms.

30. The method according to any one of claims 26 to 29, wherein the compound of formula IV is a compound of formula IV-A or formula IV-B: Or its pharmaceutically acceptable salt.

31. The method according to any one of claims 26 to 30, 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-dimethylpyridinecarboxamide; 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-hydroxypropyl-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.

32. The method according to any one of claims 26 to 31, 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-carboxylate or a pharmaceutically acceptable salt thereof.

33. The method according to any one of claims 1 to 32, 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.

34. The method according to any one of claims 1 to 33, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered to the subject in the form of a pharmaceutical composition comprising the PD-1 inhibitor or PD-L1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

35. A method of treating cancer in a subject in 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 a PD-1 inhibitor or a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

36. A method of treating cancer in a subject in need, the method comprising administering to the subject a KRASG12D inhibitor and a PD-1 inhibitor, wherein the KRASG12D 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, and the PD-1 inhibitor is riverimab.

37. The method according to claim 36, 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.

38. The method according to claim 36 or 37, 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.

39. The method according to claim 36 or 37, 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.

40. The method according to any one of claims 1 to 39, wherein the KRAS G12D inhibitor is administered twice daily (BID).

41. The method according to any one of claims 1 to 39, wherein the KRAS G12D inhibitor is administered once daily (QD).

42. The method according to any one of claims 1 to 41, wherein the KRAS G12D inhibitor is administered orally (PO).

43. The method according to any one of claims 1 to 42, wherein the PD-1 inhibitor is administered twice weekly (BIW).

44. The method according to any one of claims 1 to 43, wherein the PD-1 inhibitor is administered by intraperitoneal injection (IP).

45. The method according to any one of claims 1 to 44, wherein the cancer is selected from carcinoma, hematologic malignancies, sarcomas, and glioblastoma.

46. ​​The method according to any one of claims 1 to 45, wherein the cancer is a cancer comprising abnormally proliferating cells having a KRAS G12D mutation.

47. The method according to any one of claims 1 to 45, wherein the method further comprises identifying the presence of abnormally proliferating cells having a KRASG12D mutation.

48. The method according to any one of claims 45 to 47, 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.

49. The method according to any one of claims 45 to 47, wherein the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, bladder cancer, gastric cancer, esophageal cancer, breast cancer, head and neck cancer, cervical cancer, skin cancer, and thyroid cancer.

50. The method of claim 49, wherein the cancer is colorectal cancer.

51. The method of claim 49, wherein the cancer is lung cancer.

52. The method of claim 49, wherein the cancer is pancreatic cancer.

53. The method according to any one of claims 1 to 47, wherein the cancer is colorectal cancer.

54. The method according to any one of claims 1 to 47, wherein the cancer is non-small cell lung cancer (NSCLC).

55. The method according to any one of claims 1 to 47, wherein the cancer is pancreatic ductal adenocarcinoma.

56. The method according to any one of claims 1 to 55, wherein the cancer is metastatic.

57. A pharmaceutical composition comprising a) KRAS G12D inhibitors or pharmaceutically acceptable salts thereof; b) PD-1 inhibitors or PD-L1 inhibitors or their pharmaceutically acceptable salts; and c) At least one pharmaceutically acceptable carrier or excipient.

58. The pharmaceutical composition of claim 57, 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)prop-2-yl)oxy)-6-fluoro-7-(7-fluoronaphth-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-tetrahydroindazine-3-yl)-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)-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-methylpyridinecarboxamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphth-1-yl)-4-(6-(2-hydroxypropyl-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-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)pyrrolidin-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-hydroxypropyl-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-hydroxypropyl-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-methylpyridinecarboxamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphth-1-yl)-4-(6-(2-hydroxypropyl-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-hydroxypropyl-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-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-hydroxypropyl-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-hydroxypropyl-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)-5-methylpyrrolidine-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-hydroxypropyl-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinoline-2-yl)pyrrolidine-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-dimethylpyridinecarboxamide; 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.

59. The pharmaceutical composition according to claim 57 or 58, 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.

60. The pharmaceutical composition according to any one of claims 57 to 59, 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.

61. The pharmaceutical composition according to any one of claims 57 to 60, 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.

62. The pharmaceutical composition according to any one of claims 57 to 60, 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.

63. The pharmaceutical composition of claim 57, wherein the KRAS G12D inhibitor 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-dimethylpyridinecarboxamide; 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-hydroxypropyl-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.

64. The pharmaceutical composition according to claim 57 or 63, 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.

65. The pharmaceutical composition according to any one of claims 57 to 64, wherein the PD-1 inhibitor is rivalimab.

66. The pharmaceutical composition according to any one of claims 57 to 64, wherein the PD-L1 inhibitor is Or its pharmaceutically acceptable salt.

67. A pharmaceutical combination comprising a KRAS G12D inhibitor or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor or a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof.

68. The pharmaceutical combination of claim 67, 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.

69. The pharmaceutical combination according to claim 67 or 68, 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.

70. The pharmaceutical combination according to any one of claims 67 to 69, 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.

71. The pharmaceutical combination according to any one of claims 67 to 69, 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.

72. The pharmaceutical combination according to claim 67, 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-carboxylate or a pharmaceutically acceptable salt thereof.

73. The drug combination according to any one of claims 67 to 72, wherein the PD-1 inhibitor is rivalimab.

74. The drug combination according to any one of claims 67 to 72, wherein the PD-L1 inhibitor is Or its pharmaceutically acceptable salt.

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