Method and composition for treating cardiopulmonary disorders

Abstract

Novel methods and compositions for the prevention, treatment, and / or improvement of heart disease, heart disorder, heart tissue damage, lung disease, and / or lung disorder are described herein, comprising administering a therapeutically effective amount of a compound of the present disclosure to a subject who requires prevention, treatment, and / or improvement of heart disease, heart disorder, heart tissue damage, lung disease, and / or lung disorder.

Description

Technology Field

[0001] Cross-reference of related applications

[0002] This application claims priority to PCT application PCT / CN2023 / 124511 filed on October 13, 2023, the contents of which are incorporated by reference in their entirety for all purposes. Background Technology

[0003] Coronary artery disease, the most common cardiovascular disease, often leads to myocardial infarction or cardiac arrest and is a leading cause of death in the United States. Consequently, there is an urgent need for improved treatments to prevent, treat, and / or mitigate cardiac tissue damage caused by myocardial infarction, cardiac arrest, and other cardiovascular diseases and disorders. Coronary artery bypass grafting (CABG) has become the gold-standard treatment for coronary artery disease. Despite significant advancements in surgical techniques that have improved survival rates, patients still suffer cardiac damage (ischemia-reperfusion injury) resulting from ischemia when the heart is isolated from systemic circulation and reperfusion when circulation is restored. High-risk patients, namely those with comorbidities such as hypertension, obesity, and diabetes, are particularly vulnerable to this type of perioperative myocardial injury and postoperative myocardial infarction (PMI). Despite the significant need to protect vulnerable patients from postoperative cardiac damage and to treat cardiac damage caused by myocardial infarction and other cardiovascular disorders or diseases, there are currently no approved treatments, and numerous compounds have demonstrated a lack of efficacy in clinical trials.

[0004] Furthermore, the cardiovascular system has a complex and intertwined relationship with the pulmonary system. Individuals with respiratory disorders often exhibit pulmonary vascular abnormalities. These abnormalities may include, but are not limited to, fibrosis, lung disease, sarcoidosis, neuromuscular or chest wall disorders, and ventilatory dysregulation. In particular, patients with interstitial lung diseases, such as idiopathic pulmonary fibrosis, have been shown to experience a decline in quality of life and an increased risk of death. Moreover, an increased risk of cardiac death has been observed in patients with systemic signs of lung disease. Therefore, there remains a need to address these interconnected systems through small molecule therapies.

[0005] Hibernating mammals are a treasure trove of information regarding transient genetic resistance, the state of which can be monitored by body temperature. They can completely prevent or reverse pathological conditions very similar to human diseases, including ischemia-reperfusion injury caused by heart attacks. During deep hibernation, model hibernating animals such as ground squirrels have a heart rate equivalent to 1% of normal and their body temperature drops to 4°C. On at least 25 occasions during winter hibernation, they rapidly raise their body temperature to 37°C in just 2–3 hours; surprisingly, by the time their core body temperature reaches only 7°C, their heart rate increases 100-fold (MacCannell et al., 2018). This phenotype mimics ischemia-reperfusion events similar to heart attacks or strokes, but they are protected from associated tissue damage. Studies show that when ischemia-reperfusion events are surgically simulated, winter squirrels are significantly protected from damage compared to summer squirrels (reduced plasma levels of troponin I, cardiomyocyte apoptosis, and left ventricular systolic dysfunction) (Quinones et al., 2016). Therefore, studying hibernating animals can help identify potential therapeutic compounds to protect and treat cardiac tissue.

[0006] The present disclosure includes a compound of formula (I) or a salt thereof that is permitted by the constraints:

[0007]

[0008] Here

[0009] Ring A is selected from the group consisting of a 4-7 member monocyclic heterocyclil ring having 1-3 cyclic heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, a 7-10 member cyclic heterocyclil ring having 1-3 cyclic heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, or a 5-6 member heteroaryl ring, wherein Ring A has 1, 2, or 3 R 3 It can be substituted by;

[0010] Ring B is a 5-7-membered heterocyclil ring containing 1-3 cyclic heteroatoms, including the cyclic nitrogen to which it is attached, wherein additional cyclic heteroatoms can each be independently selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein ring B is 1 or 2 R 2 It can be substituted by;

[0011] W is selected from the group consisting of -C(O)-, -C(O)O-, -C(O)N(H)-, -C(O)OCH2-, -C(O)N(H)CH2-, and 5-membered heteroaryls having 1-3 cyclic heteroatoms;

[0012] Z is CR 1 or N and;

[0013] R 1 In each case, independently hydrogen, halogen, -OH, C1-C3 alkyl (optionally substituted with 1, 2, or 3 halogens), C 3-7 Selected from the group consisting of cycloalkyl; and 3-7-membered heterocyclyl rings containing 1-3 nitrogen atoms;

[0014] R 2In each case, is independently selected from hydrogen, halogen, C1-C3 alkyl (optionally substituted with 1, 2, or 3 halogens), -C(O)-(C1-C3 alkyl (optionally substituted with 1, 2, or 3 halogens)), and -C(O)O-(C1-C3 alkyl (optionally substituted with 1, 2, or 3 halogens));

[0015] R 3 In each case, independently are halogens, C1-C3 alkyls (optionally substituted with 1, 2, or 3 halogens), C 3-7 Selected from the group consisting of 4-6 member monocyclic heterocyclyl rings having 1-3 cyclic heteroatoms, each independently selected from the group consisting of cycloalkyl, nitrogen, oxygen, and sulfur (optionally substituted with 1, 2, or 3 halogens);

[0016] m is 1, 2, or 3.

[0017] In a particular aspect, a method comprising administering a therapeutically effective amount of the compound of the present disclosure to a subject in need thereof as a method for treating, improving, or preventing cardiovascular disease, cardiovascular disorder, or heart damage is described herein. In certain embodiments, heart damage is ischemia-reperfusion (I / R) damage. In certain embodiments, ischemia-reperfusion damage is the result of myocardial infarction or ischemic stroke. In certain embodiments, the subject is at high risk of developing the disease or condition.

[0018] In some embodiments, the proposed compounds disclosed herein have no known association with cardiac IR damage. Although further studies on the mechanism of action are required for verification, the compounds disclosed herein are potentially the first in class drugs for multiple clinical applications involving cardiac tissue damage.

[0019] In certain embodiments, the cardiovascular disease or cardiovascular disorder is selected from the group consisting of arrhythmia, aortic disease, cardiomyopathy, congenital heart disease, coronary artery disease, deep vein thrombosis, heart valve disease, hypertension, Marfan syndrome, pericardial disease, pulmonary embolism, rheumatic heart disease, vascular disease, and drug-induced cardiotoxicity. In certain embodiments, the subject is expected to undergo coronary artery bypass graft (CABG) surgery. In certain embodiments, the subject has undergone CABG surgery.

[0020] In certain embodiments, after administration of the compound of the present disclosure, the subject exhibits a reduction in symptoms selected from the group consisting of arrhythmia, microvascular dysfunction, myocardial fainting, and cardiomyocyte death. In certain embodiments, the subject's cardiomyocytes exhibit reduced reactive oxygen species production after administration of the compound of the present disclosure compared to cardiomyocytes prior to administration of the compound of the present disclosure or compared to a control sample of cardiomyocytes. In certain embodiments, cardiomyocytes from the subject exhibit reduced troponin I release after administration of the compound of the present disclosure compared to cardiomyocytes or heart tissue prior to administration of the compound of the present disclosure or compared to a control sample of cardiomyocytes or heart tissue from the subject not administered the compound of the present disclosure. In certain embodiments, cardiomyocytes from the subject exhibit cellular responses selected from the group consisting of reduced cell death, increased cell viability, reduced cell damage, and reduced oxidative stress after administration of the compound of the present disclosure compared to cardiomyocytes prior to administration of the compound of the present disclosure or compared to a control sample of cardiomyocytes or heart tissue from the subject not administered the compound of the present disclosure. In certain embodiments, administration of the compound of the present disclosure results in an increased aortic velocity in a subject compared to before administration of the compound of the present disclosure or compared to a subject not administered the compound of the present disclosure. In certain embodiments, administration of the compound of the present disclosure results in an improved cardiac output in a subject compared to before administration of the compound of the present disclosure or compared to a subject not administered the compound of the present disclosure.In certain embodiments, administration of the compound of the present disclosure results in a reduction of an indicator of cardiovascular disease selected from the group consisting of reduced collagen deposition, reduced differentiation of fibroblasts into myofibroblasts, increased or reduced Smad binding factor (SBE) expression, increased cardiac contractility generation or contractility, increased or enhanced calcium processing maintenance, reduced hypertrophy (cell size), and reduced expression of cardiac hypertrophy marker genes.

[0021] In a specific aspect, a method for treating a subject who has experienced a myocardial infarction or cardiac arrest and requires treatment is described herein, comprising administering a sufficient amount of the compound of the present disclosure to the subject after the myocardial infarction or cardiac arrest. In specific embodiments, the compound of the present disclosure results in a reduced infarct size in the subject's heart tissue compared to a subject who has not been administered the compound of the present disclosure after the myocardial infarction or cardiac arrest. In specific embodiments, the compound of the present disclosure results in reduced thinning of the heart tissue walls after the myocardial infarction or cardiac arrest. In specific embodiments, the compound of the present disclosure results in reduced granulation tissue formation in the heart tissue after the myocardial infarction or cardiac arrest. In specific embodiments, the compound of the present disclosure results in reduced neovascularization in the heart tissue after the myocardial infarction or cardiac arrest. In specific embodiments, the compound of the present disclosure results in reduced neovascularization in the heart tissue after the myocardial infarction or cardiac arrest. In specific embodiments, the compound of the present disclosure is administered in more than one dose. In certain embodiments, the effective amount is less than 300 µg / kg. In certain embodiments, the effective amount is 0.3-30 µg / kg. In certain embodiments, the compound of the present disclosure is administered in combination with at least one additional therapeutic agent.

[0022] A method for preventing or minimizing cardiac damage in a subject at risk of myocardial infarction or cardiac arrest, comprising administering an effective amount of the compound of the present disclosure to the subject prior to myocardial infarction or cardiac arrest, thereby preventing or improving cardiovascular damage. In certain embodiments, the subject at risk of myocardial infarction or cardiac arrest has a cardiovascular disease or condition selected from the group consisting of arrhythmia, aortic disease, cardiomyopathy, congenital heart disease, coronary artery disease, deep vein thrombosis, heart valve disease, hypertension, Marfan syndrome, pericardial disease, pulmonary embolism, rheumatic heart disease, and vascular disease. In certain embodiments, the compound of the present disclosure is administered in more than one dose.

[0023] In a specific aspect, a method for reducing cardiac damage in a subject due to coronary artery bypass graft (CABG) surgery is described herein, comprising administering a therapeutically effective amount of the compound of the present disclosure to the subject before, after, and / or during surgery. In a specific aspect, a method for reducing cardiac damage in a subject due to cardiopulmonary bypass surgery is described herein, comprising administering a therapeutically effective amount of the compound of the present disclosure to the subject before, after, and / or during surgery. In a specific embodiment, the compound of the present disclosure is administered in more than one dose. In a specific embodiment, the compound of the present disclosure is administered before, after, or both before and after surgery.

[0024] In a specific aspect, a method for treating a subject who has heart tissue damage and requires treatment is described herein, comprising administering a sufficient amount of the compound of the present disclosure to the subject and thereby improving the heart tissue damage. In a specific embodiment, the compound of the present disclosure brings about reduced neovascularization in the damaged heart tissue. In a specific embodiment, the compound of the present disclosure is administered in combination with at least one additional therapeutic agent. In a specific embodiment, the additional therapeutic agent is an agent selected from the group consisting of an agent that reduces cholesterol, an agent that reduces low-density lipoprotein, an agent that reduces systemic blood pressure, and an agent that reduces blood glucose levels. In a specific embodiment, the method increases the overall survival rate of the subject compared to a subject who has not been administered the compound of the present disclosure.

[0025] In a particular aspect, pharmaceutical compositions formulated for a route of administration selected from the group consisting of intravenous administration, intracardiac administration, and administration in a cardiac arrest solution, comprising the compounds of the present disclosure and pharmaceutically acceptable excipients, are described herein. Specific details for implementing the invention

[0026] definition

[0027] "Treating" includes any effect that results in the improvement of a condition, disease, disability, etc., e.g., alleviation, reduction, adjustment, or elimination.

[0028] As used herein, the term "alkoxy" refers to a straight-chain or branched-chain alkyl group (alkyl-O-) attached to oxygen. Exemplary alkoxy groups include, but are not limited to, alkoxy groups having 1-6 or 2-6 carbon atoms, and respectively C as described herein 1- C6 alkoxy and C 2- It is referred to as a C6 alkoxy. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, etc.

[0029] As used herein, the term "alkyl" refers to saturated straight-chain or branched-chain hydrocarbons. Exemplary alkyl groups include, but are not limited to, straight-chain or branched-chain hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, and each C herein 1- C6alkyl, C 1- C4alkyl, and C 1- It is referred to as a C3 alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0030] The term "cyano" as used herein refers to the radical -CN.

[0031] As used herein, the terms "cycloalkyl" or "carbocyclic group" refer to, for example, saturated or partially unsaturated hydrocarbon groups of 3-6 or 4-6 carbons, and respectively C 3- C6-cycloalkyl or C 4- It is referred to as a C6-cycloalkyl. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.

[0032] As used herein, the term "cycloalkylalkyl" refers to a saturated straight-chain or branched-chain hydrocarbon substituted by, for example, a saturated or partially unsaturated hydrocarbon group of 3-6 or 4-6 carbons.

[0033] The terms "halo" or "halogen" as used herein refer to F, Cl, Br, or I.

[0034] The terms “heterocyclyl” or “heterocyclic group” refer to a saturated or partially unsaturated 4- to 10-membered ring structure that includes a cross-linked or fused ring recognized in the relevant art, the ring structure of which includes 1 to 3 heteroatoms, e.g., nitrogen, oxygen, and sulfur. Where possible, the heterocyclyl ring may be connected to an adjacent radical through carbon or nitrogen. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, or dihydrofuran.

[0035] The terms "hydroxy" and "hydroxyl" as used herein refer to the radical -OH.

[0036] "Pharmaceutical or pharmacologically acceptable" includes molecular entities and compositions that do not cause harmful, allergic, or other unwanted reactions when administered to animals or, where appropriate, to humans. For human administration, the formulation must meet the standards of sterility, pyrogenity, general safety, and purity required by the FDA Office of Biological Products Standards.

[0037] As used herein, the terms "pharmaceutical acceptable carrier" or "pharmaceutical acceptable excipient" refer to all solvents, dispersion media, coatings, isotonic and absorption-retarding agents, etc. that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutical active substances is widely known in the relevant art. The composition may also contain other active compounds that provide supplementary, additional, or enhanced therapeutic functions.

[0038] As used herein, the term “pharmaceutical composition” refers to a composition comprising at least one compound as disclosed herein, formulated with one or more pharmaceutically acceptable carriers.

[0039] "Individual," "patient," or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, most preferably humans. The compounds of the present invention may be administered to mammals such as humans, but may also be administered to other mammals, such as animals requiring veterinary treatment, e.g., domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammals treated in the method of the present invention are preferably mammals for whom treatment of mental illness or disorder is desired. "Adjustment" includes antagonism (e.g., inhibition), agonism, partial antagonism, and / or partial agonism.

[0040] As used herein, the term "therapeutic effective dose" refers to an amount of a target compound sought by a researcher, veterinarian, physician, or other clinician to elicit a biological or medical response in a tissue, system, or animal (e.g., mammal or human). The compounds of the present invention are administered at a therapeutic effective dose to treat a disease. Alternatively, the therapeutic effective dose of a compound is an amount necessary to achieve a desired therapeutic and / or preventive effect, such as an amount that brings about a reduction in the symptoms of a mental disorder.

[0041] As used herein, the term "pharmaceutical acceptable salt(s)" refers to salts of acidic or basic groups that may be present in the compounds used in the composition. Compounds included in the composition of the present invention that are essentially basic may form a wide variety of salts with various inorganic and organic acids. Acids that may be used to produce pharmaceutically acceptable acid addition salts of such basic compounds include, but are not limited to, non-toxic acid addition salts, namely maleates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, bisulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbates, succinates, maleates, genticinates, fumarates, gluconates, glucaronates, saccharates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The purpose is to form a salt containing a pharmacologically acceptable anion. Compounds included in the compositions of the present invention, which are essentially acidic, may form various pharmacologically acceptable cations and basic salts. Examples of such salts include alkali metal or alkaline earth metal salts, in particular calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the compositions of the present invention, which contain basic or acidic moiety, may also form various amino acids and pharmaceutically acceptable salts. Compounds of the present disclosure may contain both acidic and basic groups; for example, may include one amino and one carboxylic acid group. In such cases, the compound may exist as an acid addition salt, a zwitterion, or a basic salt.

[0042] The compounds of the present disclosure may contain one or more chiral centers and thus exist as stereoisomers. As used herein, the term "stereoisomer" consists of all enantiomers or diastereomers. These compounds may be designated by the symbols "(+)," "(-)," "R," or "S" according to the arrangement of substituents around the stereogenic carbon atom, but a person skilled in the art will recognize that the structure may implicitly represent a chiral center. The present invention encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated by "(±)" in nomenclature, but a person skilled in the art will recognize that the structure may implicitly represent a chiral center.

[0043] The compounds of the present disclosure may contain one or more double bonds and thus exist as geometric isomers resulting from the arrangement of substituents around the carbon-carbon double bond. Symbol represents a bond that may be a single, double, or triple bond as described herein. Substituents around the carbon-carbon double bond are designated as "Z" or "E" arrangements, where the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures illustrating the double bond include both "E" and "Z" isomers. Substituents around the carbon-carbon double bond may alternatively be referred to as "cis" or "trans," where "cis" indicates a substituent on the same side of the double bond and "trans" indicates a substituent on the opposite side of the double bond.

[0044] Compounds of the present disclosure may contain carbocyclic or heterocyclic rings and thus exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around the carbocyclic or heterocyclic ring is designated as a "Z" or "E" arrangement, wherein the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures illustrating carbocyclic or heterocyclic rings include both "Z" and "E" isomers. Substituents around the carbocyclic or heterocyclic ring may also be referred to as "cis" or "trans," wherein the term "cis" indicates a substituent on the same side of the ring plane and the term "trans" indicates a substituent on the opposite side of the ring plane. Mixtures of compounds in which substituents are placed on both the same and opposite sides of the ring plane are designated as "cis / trans".

[0045] The individual enantiomers and diastereomers of the compounds of the present invention may be synthesized from commercially available starting materials containing asymmetric or stereogenic centers, or may be prepared by a separation method widely known to those skilled in the art following the preparation of a racemic mixture. Such separation methods are exemplified by (1) attaching a mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography, and liberating the optically pure product from the auxiliary, (2) salt formation using an optically active separating agent, (3) direct separation of a mixture of optical enantiomers on a chiral liquid chromatography column, or (4) kinetic separation using stereoselective chemical or enzymatic reagents. A racemic mixture may also be separated into its constituent enantiomers by widely known methods such as chiral-phase liquid chromatography or crystallization of the compounds in a chiral solvent. Stereoselective synthesis, that is, chemical or enzymatic reactions in which a single reactant forms a mixture of heterogeneous stereoisomers during the formation of a new stereocenter or the transformation of an existing stereocenter, is widely known in the relevant art. Stereoselective synthesis encompasses both enantiomerotic and diastereoselective transformations and may involve the use of chiral auxiliaries. For example, see the literature [Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009].

[0046] The compounds disclosed herein may exist in a solvated form as well as a non-solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc., and the present invention is intended to encompass both the solvated and non-solvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a monomorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is a crystalline form.

[0047] The present invention also encompasses isotope-labeled compounds of the same invention as those listed herein, except that one or more atoms are replaced with atoms having an atomic mass or mass number different from that which is ordinarily found in nature. Examples of isotopes that may be incorporated into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluoro, and chlorine, e.g., each 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 It contains Cl. For example, in the compound of the present invention, one or more H atoms may be replaced with deuterium.

[0048] Specific isotope-labeled initiated compounds (e.g., 3 H and 14 C-labeled) is useful for assessing the distribution of compounds and / or substrate tissues. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) Isotopes are particularly desirable due to their ease of manufacture and detectability. In addition, deuterium (i.e., 2Substitution with heavier isotopes, such as H), can provide specific therapeutic benefits resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be desirable in some situations. The isotope-labeled compounds of the present invention can generally be prepared by following a procedure similar to that disclosed in the embodiments of this invention by substituting a non-isotope-labeled reagent with an isotope-labeled reagent.

[0049] compound

[0050] The present disclosure includes a compound of formula (I) or a salt thereof that is permitted by the constraints:

[0051]

[0052] Here

[0053] Ring A is selected from the group consisting of a 4-7 member monocyclic heterocyclil ring having 1-3 cyclic heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, a 7-10 member cyclic heterocyclil ring having 1-3 cyclic heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, or a 5-6 member heteroaryl ring, wherein Ring A has 1, 2, or 3 R 3 It can be substituted by;

[0054] Ring B is a 5-7-membered heterocyclil ring containing 1-3 cyclic heteroatoms, including the cyclic nitrogen to which it is attached, wherein additional cyclic heteroatoms can each be independently selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein ring B is 1 or 2 R 2 It can be substituted by;

[0055] W is selected from the group consisting of -C(O)-, -C(O)O-, -C(O)N(H)-, -C(O)OCH2-, -C(O)N(H)CH2-, and 5-membered heteroaryls having 1-3 cyclic heteroatoms;

[0056] Z is CR 1 or N and;

[0057] R 1 In each case, independently hydrogen, halogen, -OH, C1-C3 alkyl (optionally substituted with 1, 2, or 3 halogens), C 3-7 Selected from the group consisting of cycloalkyl; and 3-7-membered heterocyclyl rings containing 1-3 nitrogen atoms;

[0058] R 2 In each case, is independently selected from hydrogen, halogen, C1-C3 alkyl (optionally substituted with 1, 2, or 3 halogens), -C(O)-(C1-C3 alkyl (optionally substituted with 1, 2, or 3 halogens)), and -C(O)O-(C1-C3 alkyl (optionally substituted with 1, 2, or 3 halogens));

[0059] R 3 In each case, independently are halogens, C1-C3 alkyls (optionally substituted with 1, 2, or 3 halogens), C 3-7 Selected from the group consisting of 4-6 member monocyclic heterocyclyl rings having 1-3 cyclic heteroatoms, each independently selected from the group consisting of cycloalkyl, nitrogen, oxygen, and sulfur (optionally substituted with 1, 2, or 3 halogens);

[0060] m is 1, 2, or 3.

[0061] The present disclosure comprises a compound of the formula (Ia), (Ib), (Ic), or (Id) or a salt thereof that is pharmaceutically acceptable:

[0062]

[0063] Here, R 1, R 2 , A, W, and m are as defined herein.

[0064] In some embodiments, the present disclosure comprises a compound of formula (II) or a salt thereof that is permitted by the constraints:

[0065]

[0066] Here

[0067] X is selected from the group consisting of -C(R")2-, -O-, and -N(H)-;

[0068] W is selected from the group consisting of -C(O)O-, -C(O)N(H)-, and 5-membered heteroaryls having 1-3 cyclic heteroatoms;

[0069] R 1 is independently hydrogen or halogen in each case;

[0070] R 2 is hydrogen or C1-C3 alkyl;

[0071] R" is independently selected from hydrogen, halogen, and methyl in each case;

[0072] m is 1, 2, or 3 and;

[0073] n is 0, 1, 2, or 3, and;

[0074] p is 0, 1, 2, 3.

[0075] In some embodiments, the compound is a compound of formula (II-a) or a salt thereof that is permitted by the constraints:

[0076] .

[0077] In some embodiments, the compound is a compound of formula (II-a') or a salt thereof that is permitted by the formula:

[0078]

[0079] Here, each R 1 It may be the same or different.

[0080] In some embodiments, the compound is a compound of the formula (II-a) or a salt thereof that is pharmaceutically acceptable:

[0081] .

[0082] In some embodiments, the present disclosure comprises a compound of formula (II-b) or a salt thereof that is permitted by limitation:

[0083] .

[0084] In some embodiments, the present disclosure comprises a compound of formula (III) or a salt thereof that is permitted by the constraints:

[0085]

[0086] Here

[0087] X is selected from the group consisting of -C(R")2-, -O-, and -N(H)-;

[0088] W is selected from the group consisting of -C(O)O-, -C(O)N(H)-, and 5-membered heteroaryls having 1-3 cyclic heteroatoms;

[0089] R 1 is independently hydrogen or halogen in each case.

[0090] R 2 is hydrogen or C1-C3 alkyl;

[0091] R 3 It is selected from the group consisting of hydrogen, halogens, and C1-C3 alkyls (optionally substituted with 1, 2, or 3 halogens);

[0092] m is 1, 2, or 3 and;

[0093] n is 0, 1, 2, or 3, and;

[0094] p is 0, 1, 2, 3.

[0095] In some embodiments, the present disclosure comprises a compound of formula (III-a) or formula (III-b) or a salt thereof that is permitted by the constraints:

[0096] .

[0097] In some embodiments, the present disclosure comprises a compound of formula (III-a') or formula (III-b') or a salt thereof that is permitted by the constraints:

[0098] .

[0099] Ring A

[0100] In some embodiments, ring A is selected from the group consisting of a 4-7-membered monocyclic heterocyclil ring having 1-3 cyclic heteroatoms each independently selected from the group consisting of nitrogen, oxygen, and sulfur, a 7-10-membered cyclic heterocyclil ring having 1-3 cyclic heteroatoms each independently selected from the group consisting of nitrogen, oxygen, and sulfur, or a 5-6-membered heteroaryl ring, wherein ring A has 1, 2, or 3 R 3 It can be replaced by.

[0101] In some embodiments, ring A is a 4-7-membered monocyclic heterocyclil ring having 1-3 cyclic heteroatoms each independently selected from the group consisting of nitrogen, oxygen, and sulfur, wherein ring A has 1, 2, or 3 R 3 It may be substituted by. In some embodiments, ring A is selected from the group consisting of azetidinyl, pyrrolidinyl, and piperidinyl, wherein ring A has 1, 2, or 3 R 3 It can be substituted by. In some embodiments, ring A is selected from the group consisting of:

[0102] .

[0103] In some embodiments, ring A is a 7-10 cyclic heterocyclil ring having 1-3 cyclic heteroatoms each independently selected from the group consisting of nitrogen, oxygen, and sulfur, wherein ring A has 1, 2, or 3 R 3 It may be substituted by. In some embodiments, ring A is selected from the group consisting of bicyclo[2.2.2]heterocyclyl ring, bicyclo[4.4.0]heterocyclyl ring, bicyclo[3.3.1]heterocyclyl, bicyclo[2.2.1]heterocyclyl ring, bicyclo[3.2.1]heterocyclyl ring, quinuclidinyl, and 3-oxa-9-azabicyclo[3.3.1]nonanyl.

[0104] In some embodiments, ring A is a 5-6-membered heteroaryl ring, where ring A has 1, 2, or 3 R 3 It can be replaced by.

[0105] In some embodiments, ring A is selected from the group consisting of:

[0106]

[0107]

[0108] .

[0109] In some embodiments, ring A is selected from the group consisting of:

[0110]

[0111]

[0112] .

[0113] Ring B

[0114] In some embodiments, ring B is a 5-7-membered heterocyclil ring containing 1-3 cyclic heteroatoms, including the cyclic nitrogen to which it is attached, wherein additional cyclic heteroatoms may each be independently selected from the group consisting of nitrogen, oxygen, and sulfur, and ring B has 1 or 2 R 2 It may be substituted by. In some embodiments, ring B is a 5-membered heterocyclil ring containing 1 to 3 cyclic heteroatoms, including the cyclic nitrogen to which it is attached, wherein additional cyclic heteroatoms may each be independently selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein ring B is 1 or 2 R 2 It may be substituted by. In some embodiments, ring B is a 6-membered heterocyclil ring containing 1 to 3 cyclic heteroatoms, including the cyclic nitrogen to which it is attached, wherein additional cyclic heteroatoms may each be independently selected from the group consisting of nitrogen, oxygen, and sulfur, and ring B has 1 or 2 R 2 It may be substituted by. In some embodiments, ring B is a 7-membered heterocyclil ring containing 1 to 3 cyclic heteroatoms, including the cyclic nitrogen to which it is attached, wherein additional cyclic heteroatoms may each be independently selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein ring B is 1 or 2 R 2 It can be replaced by.

[0115] In some embodiments, ring B is selected from the group consisting of:

[0116] .

[0117] In some embodiments, ring B is a 6-membered heterocyclil ring containing 1 to 3 cyclic heteroatoms, including the cyclic nitrogen to which it is attached, wherein additional cyclic heteroatoms may each be independently selected from the group consisting of nitrogen, oxygen, and sulfur, and ring B has 1 or 2 R 2 It may be substituted by. In some embodiments, ring B is a 6-membered heterocyclil ring containing two cyclic heteroatoms, including the cyclic nitrogen to which it is attached, wherein the additional cyclic heteroatom is nitrogen, and where ring B has one or two R 2 It can be replaced by.

[0118] In some embodiments, ring B is a 7-membered heterocyclil ring containing 1 to 3 cyclic heteroatoms, including the cyclic nitrogen to which it is attached, wherein additional cyclic heteroatoms may each be independently selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein ring B is 1 or 2 R 2 It can be replaced by.

[0119] W

[0120] In some embodiments, W is selected from the group consisting of -C(O)-, -C(O)O-, -C(O)N(H)-, -C(O)OCH2-, -C(O)N(H)CH2-, and 5-membered heteroaryl rings having 1-3 cyclic heteroatoms. In some embodiments, W is -C(O)-. In some embodiments, W is -C(O)O-. In some embodiments, W is -C(O)N(H)-. In some embodiments, W is -C(O)OCH2-. In some embodiments, W is -C(O)N(H)CH2-. In some embodiments, W is a 5-membered heteroaryl ring having 1-3 cyclic heteroatoms. In some embodiments, W is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, and thiadiazolyl. In some embodiments, W is oxadiazole.

[0121] R 1

[0122] In some embodiments, R 1 In each case, independently hydrogen, halogen, -OH, C1-C3 alkyl (optionally substituted with 1, 2, or 3 halogens), C 3-7 It is selected from the group consisting of cycloalkyl; and 3-7-membered heterocyclyl rings containing 1-3 nitrogen atoms. In some embodiments, R 1 is hydrogen or a halogen. In some embodiments, R 1 is a C1-C3 alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is trifluoromethyl. In some embodiments, R 1 It is a fluoro.

[0123] R 2

[0124] In some embodiments, R 2In each case, is independently selected from hydrogen, halogen, C1-C3 alkyl (optionally substituted with 1, 2, or 3 halogens), -C(O)-(C1-C3 alkyl (optionally substituted with 1, 2, or 3 halogens)), and -C(O)O-(C1-C3 alkyl (optionally substituted with 1, 2, or 3 halogens)). In some embodiments, R 2 is a C1-C3 alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is hydrogen.

[0125] R 3

[0126] In some embodiments, R 3 In each case, independently are halogens, C1-C3 alkyls (optionally substituted with 1, 2, or 3 halogens), C 3-7 It is selected from the group consisting of 4-6 member monocyclic heterocyclil rings having 1-3 cyclic heteroatoms, each independently selected from the group consisting of cycloalkyl, nitrogen, oxygen, and sulfur (optionally substituted with 1, 2, or 3 halogens). In some embodiments, R 3 is a halogen. In some embodiments, R 3 is a C1-C3 alkyl (optionally substituted with 1, 2, or 3 halogens). In some embodiments, R 3 C 3-7 It is a cycloalkyl. In some embodiments, R 3 It is a 4-6 member monocyclic heterocyclil ring having 1-3 cyclic heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur (optionally substituted with 1, 2, or 3 halogens).

[0127] In some embodiments, the present disclosure includes the compounds of Table 1 or salts that are pharmaceutically acceptable thereto.

[0128] Table 1

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151] Diseases, disabilities, and injuries

[0152] Cardiovascular disease, cardiovascular disorder, and / or heart damage are improved, prevented, and / or treated by the methods described herein. In certain embodiments, the cardiovascular disease or cardiovascular disorder is selected from the group consisting of arrhythmia, aortic disease, cardiomyopathy, congenital heart disease, coronary artery disease, deep vein thrombosis, heart valve disease, hypertension, ischemic stroke, Marfan syndrome, pericardial disease, pulmonary embolism, rheumatic heart disease, vascular disease, and drug-induced cardiotoxicity. In certain embodiments, heart tissue damage resulting from cardiovascular surgery or procedures (e.g., coronary artery bypass graft (CABG) surgery or cardiopulmonary bypass surgery) is improved, prevented, and / or treated by the methods described herein.

[0153] In certain embodiments, heart damage or heart tissue damage resulting from ischemia-reperfusion injury is improved, prevented, and / or treated by the method described herein. In certain embodiments, heart damage or heart tissue damage resulting from one or more events, including but not limited to myocardial infarction, cardiac arrest, or ischemic stroke, is improved, prevented, and / or treated by the method described herein.

[0154] In certain embodiments, heart damage or heart tissue damage caused by cardiotoxicity or cardiomyopathy is improved, prevented, and / or treated by the methods described herein. In certain embodiments, cardiotoxicity is caused by chemicals or toxins (e.g., chemotherapy, e.g., anthracyclines, side effects of heavy metals, stimulants, e.g., cocaine abuse, alcohol abuse, and incorrectly administered bupivacaine). In certain embodiments, cardiotoxicity is caused by infection (e.g., viral or bacterial), starvation (e.g., anorexia nervosa), diabetes, hypertension, thyroid disease (e.g., hypothyroidism), thiamine or vitamin B deficiency, and genetic defects that cause cardiomyopathy. In certain embodiments, the compounds of the disclosure are administered to a subject when one or more symptoms of cardiotoxicity or cardiomyopathy are present in the subject, including but not limited to hypertrophied myocardium, abnormal heart or lung sounds, edema of the hands, abnormal weight gain, fatigue, chronic cough, dyspnea, and / or congestive heart failure.

[0155] In certain embodiments, the disease or disorder improved, prevented, and / or treated by the method described herein is selected from the group consisting of pulmonary arterial hypertension, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis, cystic fibrosis), coronavirus infection (e.g., SARS-COV2 infection), acute lung injury, respiratory distress syndrome, respiratory failure, small cell lung cancer, interstitial lung disease, chronic obstructive pulmonary disease, and chronic thromboembolic pulmonary hypertension. In some embodiments, the disease or disorder improved, prevented, and / or treated by the method described herein is chronic thromboembolic pulmonary hypertension.

[0156] In certain embodiments, the disease or disorder improved, prevented, and / or treated by the method described herein is fibrosis. Pulmonary fibrosis is a process occurring in the interstitium. Pulmonary fibrosis may be localized, segmental, lobular, or affect the entire lung(s). In some embodiments, the disease is pulmonary fibrosis. In some embodiments, the condition associated with pulmonary fibrosis improved, prevented, and / or treated by the method described herein is selected from the group consisting of severe acute injury to the lungs, adult respiratory distress syndrome due to severe lung infection, post-COVID fibrosis (particularly in patients admitted to the ICU who require intubation / mechanical ventilation), and diffuse alveolar injury from any cause.

[0157] In some embodiments, the pulmonary fibrosis-associated condition improved, prevented, and / or treated by the method described herein is a condition resulting from an inhaled substance. In some embodiments, the inhaled substance is coal / silica (progressive massive fibrosis) or asbestos (asbestos-associated pulmonary fibrosis). In some embodiments, the pulmonary fibrosis is radiation-induced pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is congenital. In some embodiments, the congenital fibrosis is cystic fibrosis or Hermanski-Pudlach syndrome. In some embodiments, the pulmonary fibrosis is an autoimmune condition. In some embodiments, the pulmonary fibrosis is a connective tissue disorder. In some embodiments, the pulmonary fibrosis is a granulomatous condition. In some embodiments, the granulomatous condition is selected from the group consisting of sarcoidosis, tuberculosis, and granulomatosis. In some embodiments, the pulmonary fibrosis is central interstitial fibrosis of the airways. In some embodiments, the pulmonary fibrosis is chronic. In some embodiments, the fibrosis is chronic hypersensitivity pneumonia or chronic eosinophilic pneumonia. In some embodiments, pulmonary fibrosis is polymyalgia rheumatica. In some embodiments, pulmonary fibrosis is a drug-induced lung disease. In some embodiments, pulmonary fibrosis includes emphysema. In some embodiments, pulmonary fibrosis includes one or more atelectasis-related lung conditions.

[0158] In some embodiments, the disease or disorder improved, prevented, and / or treated by the method described herein is an autoimmune disease with lung involvement. In some embodiments, the autoimmune disease with lung involvement is selected from the group consisting of systemic sclerosis, Sjögren's syndrome, sarcoidosis, and amyloidosis.

[0159] In some embodiments, the disease or disorder improved, prevented, and / or treated by the method described herein is a B-cell-related pulmonary disorder.

[0160] Methods for treating, improving, or preventing heart damage

[0161] A method for improving, preventing, and / or treating cardiovascular disease, cardiovascular disorder, and / or heart damage is described herein, comprising administering a therapeutically effective amount of the compound of the present disclosure to a subject in need thereof. In certain embodiments, a method for treating a subject who has experienced a myocardial infarction or cardiac arrest and requires treatment is described herein, comprising administering a sufficient amount of the compound of the present disclosure to the subject after the myocardial infarction or cardiac arrest. In certain embodiments, a method for preventing or minimizing heart damage in a subject at risk of myocardial infarction or cardiac arrest is described herein, comprising administering an effective amount of the compound of the present disclosure to the subject before the myocardial infarction or cardiac arrest, thereby preventing or improving cardiovascular damage. In certain embodiments, a method for reducing heart damage in a subject due to coronary artery bypass graft (CABG) surgery is described herein, comprising administering a therapeutically effective amount of the compound of the present disclosure to the subject before, after, and / or during surgery. In certain embodiments, the compound of the present disclosure is administered before, after, or both before and after CABG surgery. In certain embodiments, a method for reducing cardiac damage to a subject caused by cardiopulmonary bypass surgery is described herein, comprising administering a therapeutically effective amount of the compound of the present disclosure to the subject before, after, and / or during surgery.

[0162] In a particular aspect, a method for preventing heart damage in a subject at risk of myocardial infarction or cardiac arrest is described herein, comprising administering an effective amount of the compound of the present disclosure to the subject prior to myocardial infarction or cardiac arrest, thereby preventing or improving cardiovascular damage. In a particular embodiment, the subject at risk of myocardial infarction or cardiac arrest has a cardiovascular disease or condition selected from the group consisting of arrhythmia, aortic disease, cardiomyopathy, congenital heart disease, coronary artery disease, deep vein thrombosis, heart valve disease, hypertension, Marfan syndrome, pericardial disease, pulmonary embolism, rheumatic heart disease, and vascular disease. In a particular embodiment, the subject has a disorder or disease associated with an increased risk of heart disease, including but not limited to hypertension, elevated cholesterol, obesity, diabetes, drug abuse, and tobacco use. In a particular embodiment, the subject has a family history of heart disease and / or has a higher risk of developing heart disease due to factors (but not limited to) such as age, race, sex, diet, substance abuse, physical activity, stress, and / or depression.

[0163] In a specific embodiment of the method described herein, the compound of the present disclosure is administered to a subject by a route selected from the group consisting of intravenous administration, intracardiac administration, and administration into a cardiac arrest solution.

[0164] Unless otherwise specified, the term “object” includes any mammalian animal, including but not limited to both human and non-human animals, and includes but not limited to human, non-human primates, dogs, cats, murine, cattle, horses, and pigs.

[0165] In this invention, a method for improving, preventing, and / or treating lung disease, lung disorder, and / or lung damage is described, comprising administering a therapeutically effective amount of a compound of the present disclosure to a subject who requires improvement, prevention, and / or treatment of lung disease, lung disorder, and / or lung damage.

[0166] In some embodiments, the lung disease or disorder is selected from the group consisting of pulmonary arterial hypertension PAH, asthma, chronic obstructive pulmonary disease COPD, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis IPF, cystic fibrosis), coronavirus infection (e.g., SARS-COV2 infection), acute lung injury, respiratory distress syndrome, respiratory failure, small cell lung cancer, interstitial lung disease, chronic obstructive pulmonary disease, and chronic thromboembolic pulmonary hypertension.

[0167] In some embodiments, the lung disease or disorder is an obstructive lung disease or a restrictive lung disease. In some embodiments, the lung disease or disorder is selected from the group consisting of asthma, bronchiolitis obstructive organizing pneumonia (BOOP), chronic obstructive pulmonary disease (COPD), emphysema, pulmonary fibrosis, and sarcoidosis. In some embodiments, lung disease or disorder is acute chest syndrome, acute respiratory distress syndrome, alpha-1 antitrypsin deficiency, asbestosis, aspergillosis, asthma, bronchiectasis, bronchiolitis, obstructive bronchiolitis, bronchitis, bronchopulmonary dysplasia, chronic cough, chronic obstructive pulmonary disease (COPD), coccidioidomycosis, latent organizing pneumonia, cystic fibrosis, lung injury associated with electronic cigarette or vaping product use (EVALI), emphysema, eosinophilic granulomatosis with polyangiitis (EGPA), common cold, hantavirus pulmonary syndrome (HPS), histoplasmosis, human metapneumovirus (hMPV), hypersensitivity pneumonitis, idiopathic pulmonary fibrosis (IPF), infectious lung disease, influenza, interstitial lung disease (ILD), Legionellosis, lung cancer, LAM, MAC lung disease, mesothelioma, NTM lung disease, occupational lung disease, pertussis, It is selected from a group consisting of pneumonia, pneumothorax, primary ciliary dyskinesia (PCD), pulmonary arterial hypertension (PAH), pulmonary embolism, pulmonary fibrosis, pulmonary hypertension, respiratory syncytial virus, sarcoidosis, silicosis, sleep apnea, coronavirus-related diseases and tuberculosis.

[0168] In some embodiments, the lung disorder is bronchitis. In some embodiments, the bronchitis is acute bronchitis or chronic bronchitis.

[0169] In some embodiments, the lung disease or disorder is selected from the group consisting of aspergillosis, asthma, bronchiectasis, bronchitis, chronic cough, chronic obstructive pulmonary disease (COPD), common cold, croup, cystic fibrosis, hantavirus pulmonary syndrome (HPS), idiopathic pulmonary fibrosis (IPF), influenza, lung cancer, LAM, MAC lung disease, pertussis, pleuritis, pneumonia, pulmonary embolism, pulmonary hypertension, respiratory syncytial virus, sarcoidosis, sleep apnea, spirometry, sudden infant death syndrome, tobacco cessation, and tuberculosis.

[0170] Therapeutic improvement resulting from treatment with the compounds of the present disclosure

[0171] In certain embodiments, after administering one or more doses of the compound of the present disclosure by the method described herein, the subject exhibits reduced symptoms of cardiac injury, including but not limited to arrhythmia, microvascular dysfunction, myocardial fainting, and cardiomyocyte death. In certain embodiments, the subject's cardiomyocytes exhibit reduced reactive oxygen species production after administration of the compound of the present disclosure compared to cardiomyocytes before administration of the compound of the present disclosure or compared to a control sample of cardiomyocytes. In certain embodiments, the subject's cardiomyocytes exhibit reduced troponin I release after administration of the compound of the present disclosure compared to cardiomyocytes or heart tissue before administration of the compound of the present disclosure or compared to a control sample of cardiomyocytes or heart tissue from a subject not administered the compound of the present disclosure. In certain embodiments, the cardiomyocytes of a subject exhibit a cellular response selected from the group consisting of reduced apoptosis, increased cell viability, reduced cell damage, and reduced oxidative stress after administration of the compound of the present disclosure, compared to the cardiomyocytes before administration of the compound of the present disclosure or to a control sample of cardiomyocytes or heart tissue from a subject not administered the compound of the present disclosure. Any method known in the art may be used to detect the described cellular response in vivo or in vitro.

[0172] In certain embodiments, the method described herein brings about an increased aortic velocity in a subject compared to before administration of the compound of the present disclosure or compared to a subject not administered the compound of the present disclosure. In certain embodiments, the method described herein brings about an improved cardiac output in a subject compared to before administration of the compound of the present disclosure or compared to a subject not administered the compound of the present disclosure. Any method known in the relevant art may be used to detect aspects of cardiac function (e.g., aortic velocity or cardiac output). In certain embodiments, administration of the compound of the present disclosure according to the method described herein brings about an improvement in cardiac function as evidenced by changes in parameters, such as, but not limited to, shortening rate, left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), and stroke volume.

[0173] In certain embodiments, the method described herein results in a reduction of indicators of cardiovascular disease and / or impairment selected from the group consisting of reduced collagen deposition, reduced differentiation of fibroblasts into myofibroblasts, increased or reduced Smad binding factor (SBE) expression, increased cardiac contractility generation or contractility, increased or enhanced calcium processing maintenance, reduced hypertrophy (cell size), reduced expression of cardiac hypertrophy marker genes, reduced apoptosis, reduced angiogenesis markers, and reduced troponin I.

[0174] In certain embodiments, the method described herein brings about reduced thinning of the heart tissue walls (e.g., anterior wall thickening or posterior wall thickening) after myocardial infarction or cardiac arrest. In certain embodiments, the method described herein brings about granulation tissue formation in reduced heart tissue after myocardial infarction or cardiac arrest. In certain embodiments, the method described herein brings about improved organization of heart tissue after myocardial infarction or cardiac arrest. In certain embodiments, the compound of the present disclosure brings about neovascularization in reduced heart tissue after myocardial infarction or cardiac arrest. In certain embodiments, the method described herein brings about neovascularization in reduced heart tissue after myocardial infarction or cardiac arrest.

[0175] In certain embodiments, the method described herein results in a reduced risk of myocardial infarction or cardiac arrest in a subject compared to a subject not administered the compound of the present disclosure. In certain embodiments, for a subject who has experienced at least one previous myocardial infarction or cardiac arrest, the method described herein results in a reduced risk of subsequent myocardial infarction or cardiac arrest in a subject compared to a subject not administered the compound of the present disclosure. In certain embodiments, the method described herein results in an increased overall survival rate in a subject compared to a subject not administered the compound of the present disclosure.

[0176] Additional therapeutic compounds

[0177] In certain embodiments, the method disclosed herein comprises administering the compound of the disclosure in combination with at least one additional therapeutic agent. In certain embodiments, the additional therapeutic agent is an agent used to lower blood pressure (e.g., angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor inhibitors, or vasodilators, e.g., isosorbide dinitrate), an agent used to reduce heart rate or modify cardiac output (e.g., beta-blockers), cholesterol-lowering drugs (e.g., statins), calcium channel blockers, diuretics (e.g., hydrochlorthiazide), anticoagulants, antiplatelet agents, and / or an agent used to prevent or reduce the occurrence and severity of cardiac damage caused by drug-induced cardiotoxicity (e.g., dexrazoxane hydrochloride).

[0178] In certain embodiments, an additional therapeutic agent is administered simultaneously with one or more doses of the compound of the present disclosure. In certain embodiments, an additional therapeutic agent is administered before one or more doses of the compound of the present disclosure. In certain embodiments, an additional therapeutic agent is administered after one or more doses of the compound of the present disclosure.

[0179] In certain embodiments, the additional therapeutic agent is one of a small molecule, a nucleic acid, or a protein (e.g., an antibody). In certain embodiments, the nucleic acid is RNA. In certain embodiments, the RNA is antisense RNA. In certain embodiments, the RNA is shRNA. In certain embodiments, the therapeutic compound alters the expression of at least one gene target identified by the method described herein.

[0180] The term percent “identity” refers to two or more sequences or subsequences having a specific percentage of identical nucleotide or amino acid residues when compared and aligned for maximum correspondence, as measured by one of the sequence comparison algorithms described below (e.g., BLASTP and BLASTN or other algorithms available to a person skilled in the art) or by visual inspection in the context of two or more nucleic acid or polypeptide sequences. Depending on the application, percent “identity” may exist across regions of the sequences being compared, for example, across functional domains, or alternatively, across the entire length of the two sequences being compared.

[0181] For sequence comparison, typically one sequence serves as the reference sequence against which the test sequence is compared. When using the sequence comparison algorithm, the test and reference sequences are input into a computer, subsequence coordinates are specified if necessary, and sequence algorithm program parameters are specified. Subsequently, the sequence comparison algorithm calculates the percentage sequence identity of the test sequence(s) with respect to the reference sequence based on the specified program parameters.

[0182] Optimal alignment of sequences for comparison can be performed, for example, by a local homology algorithm [Smith & Waterman, Adv. Appl. Math. 2:482 (1981)], by a homology alignment algorithm [Needleman & Wunsch, J. Mol. Biol. 48:443 (1970)], by a similarity search method [Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988)], by a computer implementation of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (generally by referring to the following literature [Ausubel et al.]).

[0183] An example of an algorithm suitable for determining percent sequence identity and sequence similarity is the BLAST algorithm, which is described in the literature [Altschul et al., J. Mol. Biol. 215:403-410 (1990)]. Software for performing BLAST analysis is publicly available through the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov / ).

[0184] Pharmaceutical composition

[0185] The therapeutic compounds described herein may be formulated into pharmaceutical compositions. In addition to one or more therapeutic compounds, such compositions may include pharmaceutically acceptable excipients, carriers, buffers, stabilizers, or other substances widely known to those skilled in the art. These substances must be non-toxic and must not interfere with the efficacy of the active ingredient. The specific properties of the carrier or other substances may vary depending on the route of administration, e.g., oral, intravenous, skin or subcutaneous, nasal, intramuscular, intraperitoneal, intracardiac, and in a cardiac solution.

[0186] Pharmaceutical compositions for oral administration may be in the form of tablets, capsules, powders, or liquids. Tablets may include a solid carrier, such as gelatin or an adjuvant. Liquid pharmaceutical compositions generally include a liquid carrier, such as water, petroleum, animal or vegetable oil, mineral oil, or synthetic oil. They may include a physiological saline solution, dextrose or other saccharide solution, or a glycol, such as ethylene glycol, propylene glycol, or polyethylene glycol.

[0187] For intravenous, cutaneous or subcutaneous injection, or injection at the site of infection, the active ingredient shall be in the form of a parenterally acceptable aqueous solution that is free of pyrogens and possesses suitable pH, isotonicity, and stability. A person skilled in the art can prepare a suitable solution using, for example, an isotonic vehicle, such as sodium chloride injection, Ringer's injection, or lactated Ringer's injection. Preservatives, stabilizers, buffers, antioxidants, and / or other additives may be included as needed.

[0188] Therapeutic compounds containing nucleic acids may be formulated by any method known in the relevant art, including but not limited to formulations using polymer nanoparticles (e.g., cationic polymers), lipid nanoparticles, and / or other hydrophobic moiety (e.g., cholesterol).

[0189] When administering a polypeptide, antibody, nucleic acid, small molecule, or other pharmaceutically useful compound according to the present disclosure to an individual, the administration is preferably made at a "therapeutic effective dose" sufficient to produce a benefit to the individual. A "prophylactic effective dose" may also be administered if sufficient to produce a benefit to the individual. The actual amount administered, and the rate and course of administration, will depend on the nature and severity of the protein aggregation disorder being treated. Decisions regarding the prescription of treatment, e.g., dosage, etc., are within the scope of responsibility of the general practitioner and other physicians, taking into account the disorder being treated, the individual patient's condition, the delivery site, the method of administration, and other factors known to the specialist. Examples of the aforementioned techniques and protocols can be found in the literature [Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed), 1980].

[0190] The composition may be administered simultaneously or sequentially, either alone or in combination with other treatments, depending on the condition being treated.

[0191] Examples

[0192] The following are examples of specific embodiments for carrying out the present invention. The embodiments are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way. While efforts have been made to ensure accuracy with respect to the numerical values ​​used (e.g., quantities, temperatures, etc.), some experimental error and deviation should, of course, be allowed.

[0193] Practice of the present invention will utilize conventional methods of protein chemistry, biochemistry, recombinant DNA technology, and pharmacology within the relevant art, unless otherwise indicated. These techniques are described in detail in the literature. For example, refer to the following: TE Creighton, Proteins: Structures and Molecular Properties (WH Freeman and Company, 1993); AL Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Sambrook, et al., Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3 rd Ed. (Plenum Press) Vols A and B (1992).

[0194] Example 1. Synthesis of I-1 and I-2

[0195]

[0196] Step 1

[0197] H2SO4 (4 mL) was added to a solution of 2-(2-nitrophenyl)acetic acid (3.6 g, 0.02 mol) in EtOH (50 ml) stirred at 0°C, and the reaction mixture was stirred at 60°C for 12 hours. The reaction mixture was slowly poured into ice water (200 ml) and extracted with EA (100 mL x 3). The organic layers were combined, washed with H2O (100 mL x 3), and concentrated under vacuum to obtain ethyl 2-(2-nitrophenyl)acetate (3.8 g, 91%) as a white solid.

[0198] MS (ESI): C 10 H 11 Calculated value for NO4 209.07, m / z measured value 232.1 [M+Na].

[0199] Step 2

[0200] Pd / C (100 mg) was added to a solution of ethyl 2-(2-nitrophenyl)acetate (3.8 g, 0.018 mol) in EtOH (50 ml), and the reaction mixture was stirred under an H2 balloon at 25°C for 4 hours. The mixture was filtered through Celite, and the filtrate was concentrated to obtain ethyl 2-(2-aminophenyl)acetate (3.1 g, 95%) as a white solid.

[0201] MS (ESI): C 10 H 13 Calculated value for NO2 179.09, m / z measured value 180.2 [M+H] + .

[0202] Step 3

[0203] 4-chlorobutanoyl chloride (2.43 g, 0.017 mol) was added at 0°C to a solution of ethyl 2-(2-aminophenyl)acetate (2.2 g, 0.012 mol) and TEA (2.49 g, 0.025 mol) in THF (30 ml), and the reaction mixture was stirred at 25°C for 4 hours. The mixture was quenched with water (100 mL) and extracted with EA (100 mL x 3). The organic layer was concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE:EA = 3:1) to obtain ethyl 2-(2-(4-chlorobutanamido)phenyl)acetate (3 g, 85%) as a white solid.

[0204] MS (ESI): C 14 H 18 Calculated value for ClNO3 283.10, m / z measured value 284.4 [M+H] + .

[0205] Step 4

[0206] A solution of t-BuOK (3.36 g, 30 mmol) in THF (20 mL) was added to a solution of ethyl 2-(2-(4-chlorobutanamido)phenyl)acetate (2.84 g, 10 mmol) in THF (40 ml) at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The mixture was quenched with water (200 mL) and extracted with EA (200 mL x 3). The organic layer was concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE:EA = 3:1) to obtain ethyl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate (588 mg, 26%) as a white solid.

[0207] MS (ESI): C 14 H 15 Calculated value for NO2 229.11, m / z measured value 230.1 [M+H] + .

[0208] Step 5

[0209] KOH (220.3 mg, 3.93 mmol) was added to a mixture of ethyl 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylate (300 mg, 1.30 mmol) in EtOH (15 mL) and H2O (5 mL). The reaction mixture was stirred at 80°C for 10 hours. The reaction mixture was concentrated to remove EtOH, and then the pH was adjusted to 2 with 1 M HCl. The mixture was diluted with water and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (200 mg, crude product) as a white solid, which was used directly in a subsequent step.

[0210] MS (ESI): C 12 H 11 Calculated value for NO2 201.08, m / z measured value 202.1 [M+H] + .

[0211] Step 6

[0212] HATU (226.8 mg, 0.60 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (100 mg, 0.50 mmol), (3R)-1-azabicyclo[2.2.2]octan-3-amine (62.7 mg, 0.50 mmol) and DIEA (192.7 mg, 1.49 mmol) in DMF (10 mL). After stirring at 20°C for 6 hours, the mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by HPLC for purification (X-bridge purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain N-[(3R)-1-azabicyclo[2.2.2]octane-3-yl]-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide formate (64.6 mg, 42%) as a white solid.

[0213] MS (ESI): C 19 H 23 Calculated value for N3O 309.18, m / z measured value 310.2 [M+H] + .

[0214] 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.89 - 7.87 (m, 1H), 7.38 - 7.35 (m, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.15 - 7.08 (m, 2H), 4.13 - 4.10 (m, 3H), 3.39 (t, J = 12.0 Hz, 1H), 3.28 - 3.24 (m, 2H), 3.13 - 3.08 (m, 1H), 2.97 - 2.94 (m, 4H), 2.62 - 2.55 (m, 2H), 2.08 - 1.98 (m, 2H), 1.78 - 1.76 (m, 2H), 1.60 - 1.54 (m, 1H).

[0215] Step 7

[0216] HATU (226.8 mg, 0.60 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (100 mg, 0.50 mmol), (3S)-1-azabicyclo[2.2.2]octan-3-amine (62.7 mg, 0.50 mmol) and DIEA (192.7 mg, 1.50 mmol) in DMF (10 mL). The reaction mixture was stirred at 20°C for 6 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-bridge purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain N-[(3S)-1-azabicyclo[2.2.2]octane-3-yl]-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide formate (75.6 mg, 49%) as a white solid.

[0217] MS (ESI): C 19 H 23Calculated value for N3O 309.18, m / z measured value 310.2 [M+H] + .

[0218] 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 0.5H), 7.89 - 7.87 (m, 1H), 7.38 - 7.36 (m, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.15 - 7.08 (m, 2H), 4.17 - 4.10 (m, 3H), 3.39 (t, J = 12.0 Hz, 1H), 3.26 (t, J = 8.0 Hz, 2H), 3.15 - 3.11 (m, 1H), 3.03 - 2.96 (m, 4H), 2.63 - 2.56 (m, 2H), 2.12 - 2.01 (m, 2H), 1.81 - 1.75 (m, 2H), 1.64 - 1.61 (m, 1H).

[0219] Example 2. Synthesis of I-3 and I-4:

[0220]

[0221] Experimental Procedure:

[0222] Step 1

[0223] SOCl2 (2.4 g, 20 mmol) was added to (5-fluoro-2-nitrophenyl)acetic acid (2 g, 10 mmol) in EtOH (5 mL), and the reaction mixture was stirred at 80°C for 2 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography eluted with PE / EtOAc (20:1) to obtain ethyl 2-(5-fluoro-2-nitrophenyl)acetate (2 g, 83%) as a white solid.

[0224] MS (ESI): C 10 H 10Calculated value for FNO4 227.06, m / z measured value 228.1 [M+H] + .

[0225] Step 2

[0226] Pd / C (80 mg, 0.8 mmol) was added to ethyl 2-(5-fluoro-2-nitrophenyl)acetate (2 g, 8.8 mmol) in MeOH (20 mL) under N2, and the mixture was stirred under H2 at 25°C for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated to obtain ethyl 2-(2-amino-5-fluorophenyl)acetate (1.8 g, 93%) as a white solid.

[0227] MS (ESI): C 10 H 12 Calculated value for FNO2 197.09, m / z measured value 198.1 [M+H] + .

[0228] Step 3

[0229] 4-chlorobutanoyl chloride (1.4 g, 9.7 mmol) was added to a mixture of ethyl 2-(2-amino-5-fluorophenyl)acetate (1.6 g, 8.1 mmol) and DIEA (3.2 g, 24.3 mmol) in THF (20 mL). The mixture was stirred at 25°C for 2 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography eluted with DCM / MeOH (20:1) to obtain ethyl 2-[2-(4-chlorobutanamido)-5-fluorophenyl]acetate (2.4 g, 86%) as a white solid.

[0230] MS (ESI): C 14 H 17 Calculated value for ClFNO3 301.09, m / z measured value 302.1 [M+H] + .

[0231] Step 4

[0232] Ethyl 2-[2-(4-chlorobutanamido)-5-fluorophenyl]acetate (200 mg, 0.66 mmol) in THF (2 mL) was added to a mixture of t-BuOK (160 mg, 1.66 mmol) in THF (2 mL) under N2. After stirring at 25°C for 2 hours, the mixture was diluted with water (20 mL) and extracted with EA (20 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography eluted with DCM / MeOH (10:1) to obtain ethyl 7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-carboxylate (100 mg, 51%) as a white solid.

[0233] MS (ESI): C 14 H 14 Calculated value for FNO2 247.1, m / z measured value 248.1 [M+H] + .

[0234] Step 5

[0235] Sodium hydroxide (30 mg, 0.73 mmol) was added to ethyl 7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-carboxylate (60 mg, 0.24 mmol) in DMSO (2 mL) and H2O (0.5 mL). After stirring at 100°C for 1 hour, the mixture was adjusted to pH = 6-7 with 1 M HCl (aq.). The mixture was diluted with water (10 mL) and extracted with EA (5 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (50 mg, 80%) as a white solid.

[0236] MS (ESI): C 12 H 10Calculated value for FNO2 219.07, m / z measured value 220.1 [M+H] + .

[0237] Step 6

[0238] HATU (208.2 mg, 0.55 mmol) was added to a mixture of 7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (100 mg, 0.46 mmol), (3R)-1-azabicyclo[2.2.2]octan-3-amine (57.6 mg, 0.46 mmol) and DIEA (176.9 mg, 1.37 mmol) in DMF (10 mL). After stirring at 20°C for 6 hours, the mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by HPLC for purification (X-bridge purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain N-[(3R)-1-azabicyclo[2.2.2]octane-3-yl]-7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide formate (62.5 mg, 42%) as a white solid.

[0239] MS (ESI): C 19 H 22 Calculated value for FN3O 327.17, m / z measured value 328.1 [M+H] + .

[0240] 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 0.70 H), 7.59 (dd, J = 12.0, 4.0 Hz, 1H), 7.39 (dd, J = 12.0, 4.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.00 - 6.95 (m, 1H), 4.13 (t, J = 8.0 Hz, 3H), 3.45 - 3.34 (m, 1H), 3.30 - 3.25 (m, 2H), 3.12 - 3.08 (m, 1H), 2.96 - 2.90 (m, 4H), 2.63 - 2.54 (m, 2H), 2.07 - 1.97 (m, 2H), 1.77 - 1.73 (m, 2H), 1.60 - 1.54 (m, 1H).

[0241] Step 7

[0242] HATU (208.2 mg, 0.55 mmol) was added to a mixture of 7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (100 mg, 0.46 mmol), (3S)-1-azabicyclo[2.2.2]octan-3-amine (57.6 mg, 0.46 mmol) and DIEA (176.9 mg, 1.37 mmol) in DMF (10 mL). After stirring at 20°C for 6 hours, the mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by HPLC for purification (X-bridge purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain N-[(3S)-1-azabicyclo[2.2.2]octane-3-yl]-7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide formate (55.6 mg, 36%) as a white solid.

[0243] MS (ESI): C 19 H 22 Calculated value for FN3O 327.17, m / z measured value 328.1 [M+H] + .

[0244] 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 0.70 H), 7.59 (dd, J = 12.0, 4.0 Hz, 1H), 7.39 (dd, J = 8.0, 4.0 Hz, 1H), 7.25 (d, J = 4.0 Hz, 1H), 7.00 - 6.95 (m, 1H), 4.14 - 4.11 (m, 3H), 3.44 - 3.39 (m, 1H), 3.30 - 3.25 (m, 2H), 3.13 - 3.11 (m, 1H), 2.99 - 2.97 (m, 4H), 2.62 - 2.55 (m, 2H), 2.10 - 1.99 (m, 2H), 1.79 - 1.77 (m, 2H), 1.62 - 1.57 (m, 1H).

[0245] Example 3. Synthesis of I-5 and I-6:

[0246]

[0247] Experimental Procedure:

[0248] Step 1

[0249] LiAlH4 (1.5 g, 39.64 mmol) was added to a mixture of ethyl 1H-indole-2-carboxylate (5 g, 26.43 mmol) in THF (60 mL) at 0°C, and the reaction mixture was stirred at 60°C for 3 hours. The reaction mixture was quenched with H2O (3 mL) and 15% NaOH (4.5 mL). The mixture was filtered, the filtrate was diluted with water (200 mL), and extracted with EA (100 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash chromatography (PE / EA 100:1→1:1) to obtain (1H-indole-2-yl)methanol (3 g, 77%) as a yellow solid.

[0250] MS (ESI): Calculated value for C9H9NO 147.07, m / z measured value 148.1 [M+H] + .

[0251] Step 2

[0252] KOH (1.05 g, 0.019 mol) was added to a mixture of 1H-indole-2-ylmethanol (1.1 g, 0.0075 mol) in DCM (20 mL) at 0°C, and the reaction mixture was stirred at 0°C for 0.5 hours. Ethenyldiphenylsulfanium trifluoromethanesulfonate (3.26 g, 0.0079 mol) was added. The reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue, which was purified by flash chromatography (PE / EA 100:1→10:1) to obtain 1H,3H,4H-[1,4]oxazino[4,3-a]indole (0.57 g, 41%) as a yellow solid.

[0253] MS (ESI): C 11 H 11 Calculated NO 173.08, m / z measured 174.1 [M+H] + .

[0254] Step 3

[0255] TFAA (760.3 mg, 3.62 mmol) was added to a solution of 1H,3H,4H-[1,4]oxazino[4,3-a]indole (570 mg, 3.29 mmol) and TEA (399.6 mg, 3.95 mmol) in DCE (20 mL) at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. The mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash chromatography (PE / EA 100:1→2:1) to obtain difluoromethyl 1H,3H,4H-[1,4]oxazino[4,3-a]indole-10-carbonyl fluoride (700 mg, 75%) as a yellow solid.

[0256] MS (ESI): C 13 H 10 Calculated value for F3NO2 269.07, m / z measured value 270.0 [M+H] + .

[0257] Step 4

[0258] NaH (373.0 mg, 15.54 mmol) and H2O (233.3 mg, 12.95 mmol) were added to a solution of difluoromethyl 1H,3H,4H-[1,4]oxazino[4,3-a]indole-10-carbonyl fluoride (700 mg, 2.59 mmol) in DMF (10 mL). The reaction mixture was stirred at 20°C for 2 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL). The aqueous solution was adjusted to pH = 2 with 1N HCl and extracted with EA (50 mL x 2). The combined organic layer was dried over Na2SO4 and concentrated to obtain the residue. The residue was purified by a reverse-phase column (phase A: H2O; phase B: ACN, 5–100%), the fraction with MS signal of the target product was collected and concentrated to obtain 1H,3H,4H-[1,4]oxazino[4,3-a]indole-10-carboxylic acid (400 mg, 68%) as a yellow solid.

[0259] MS (ESI): C 12 H 11 Calculated value for NO3 217.07, m / z measured value 218.1 [M+H] + .

[0260] Step 5

[0261] HATU (105.0 mg, 0.28 mmol) was added to a mixture of 1H,3H,4H-[1,4]oxazino[4,3-a]indole-10-carboxylic acid (50 mg, 0.23 mmol), (3R)-1-azabicyclo[2.2.2]octan-3-amine (29.1 mg, 0.23 mmol) and DIEA (89.3 mg, 0.69 mmol) in DMF (5 mL). After stirring at 20°C for 6 hours, the mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by HPLC for purification (Welch 10u C18 250 x 21.2 mm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 25 ml / min, wavelength: 214 / 254 nm) to obtain N-[(3R)-1-azabicyclo[2.2.2]octane-3-yl]-1H,3H,4H-[1,4]oxazino[4,3-a]indole-10-carboxamide (42.3 mg, 56%) as a white solid.

[0262] MS (ESI): C 19 H 23 Calculated value for N3O2 325.18, m / z measured value 326.1 [M+H] + .

[0263] 1 H NMR (400 MHz, DMSO-d6) δ 7.81 - 7.78 (m, 1H), 7.50 - 7.47 (m, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.23 - 7.19 (m, 2H), 5.13 (s, 2H), 4.13 (s, 4H), 3.94 - 3.92 (m, 1H), 3.11 - 2.85 (m, 2H), 2.69 - 2.65 (m, 4H), 1.92 - 1.80 (m, 2H), 1.61 - 1.55 (m, 2H), 1.38 - 1.32 (m, 1H).

[0264] Step 6

[0265] HATU (105.0 mg, 0.28 mmol) was added to a mixture of 1H,3H,4H-[1,4]oxazino[4,3-a]indole-10-carboxylic acid (50 mg, 0.23 mmol), (3S)-1-azabicyclo[2.2.2]octan-3-amine (29.1 mg, 0.23 mmol) and DIEA (89.3 mg, 0.69 mmol) in DMF (5 mL). After stirring at 20°C for 6 hours, the mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC for purification (Welch 10u C18 250 x 21.2 mm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 25 ml / min, wavelength: 214 / 254 nm) to obtain N-[(3S)-1-azabicyclo[2.2.2]octane-3-yl]-1H,3H,4H-[1,4]oxazino[4,3-a]indole-10-carboxamide (47.5 mg, 63%) as a white solid.

[0266] MS (ESI): C 19 H 23 Calculated value for N3O2 325.18, m / z measured value 326.1 [M+H] + .

[0267] 1 H NMR (400 MHz, DMSO-d6) δ 7.81 - 7.78 (m, 1H), 7.50 - 7.46 (m, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.23 - 7.19 (m, 2H), 5.13 (s, 2H), 4.13 (s, 4H), 3.94 - 3.92 (m, 1H), 3.10 - 2.84 (m, 2H), 2.68 - 2.61 (m, 4H), 1.92 - 1.81 (m, 2H), 1.61 - 1.52 (m, 2H), 1.38 - 1.32 (m, 1H).

[0268] Example 4. Synthesis of I-8 to I-12:

[0269]

[0270] Experimental Procedure:

[0271] Step 1

[0272] Sodium hydride (3.8 g, 0.16 mol) was added to a solution of ethyl 1H-indole-2-carboxylate (20.0 g, 0.11 mol) in DMF (100 mL) at 0°C. After stirring for 0.5 hours, 2-bromoacetonitrile (25.4 g, 0.21 mol) was added, and the reaction mixture was stirred at room temperature for 6 hours. The mixture was quenched with an aqueous NH4Cl solution and extracted with EA (300 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain the residue, which was purified by silica gel column chromatography (EA / PE=1 / 10) to obtain ethyl 1-(cyanomethyl)indole-2-carboxylate (22 g, 91%) as a brown solid.

[0273] MS (ESI): C 13 H 12 Calculated value for N2O2 228.09, m / z measured value 229.1 [M+H] + .

[0274] Step 2

[0275] LiAlH4 (109.5 mL, 109.5 mmol) in THF was added to a solution of ethyl 1-(cyanomethyl)indole-2-carboxylate (10.0 g, 43.8 mmol) in THF (50 mL) at 0°C, and the mixture was refluxed for 4 hours. The mixture was quenched with water and filtered. The filtrate was concentrated to obtain crude 1H,2H,3H,4H-pyrazino[1,2-a]indole, which was used in subsequent steps without further purification.

[0276] MS (ESI): C 11 H 12Calculated value for N2 172.10, m / z measured value 173.1 [M+H] + .

[0277] Step 3

[0278] A mixture of 1H,2H,3H,4H-pyrazino[1,2-a]indole (5.5 g, 32 mmol), Boc2O (8.35 g, 38 mmol), and TEA (3.87 g, 38 mmol) in DCM (60 mL) was stirred at room temperature for 12 hours. The mixture was diluted with water (200 mL) and extracted with DCM (100 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash chromatography (PE / EA = 100 / 1 to 4 / 1) to obtain tert-butyl {1H,3H,4H-pyrazino[1,2-a]indole-2-yl} formate (3.2 g, 35%) as a yellow solid.

[0279] MS (ESI): C 16 H 20 Calculated value for N2O2 272.15, m / z measured value 273.2 [M+H] + .

[0280] Step 4

[0281] TFAA (2.7 g, 12.8 mmol) was added to a mixture of tert-butyl {1H,3H,4H-pyrazino[1,2-a]indole-2-yl} formate (3.2 g, 12 mmol) and TEA (1.42 g, 14 mmol) in DCE (40 mL) at 0°C, and the reaction mixture was stirred at this temperature for 1 hour. The mixture was diluted with water (200 mL) and extracted with DCM (100 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash chromatography (PE / EA = 100 / 1 to 2 / 1) to obtain tert-butyl (10-{[(difluoromethyl)-$l^{2}-fluoranyl]carbonyl}-1H,3H,4H-pyrazino[1,2-a]indole-2-yl) formate (3.5 g, 77%) as a yellow solid.

[0282] MS (ESI): C 18 H 19 Calculated value for F3N2O3 368.13, m / z measured value 369.1 [M+H] + .

[0283] Step 5

[0284] A mixture of tert-butyl (10-{[(difluoromethyl)-$l^{2}-fluoranyl]carbonyl}-1H,3H,4H-pyrazino[1,2-a]indole-2-yl) formate (3.5 g, 9.5 mmol) and NaOH (1.14 g, 28 mmol) in DMSO (20 mL) and H2O (20 mL) was stirred at 100°C for 1 hour. Subsequently, the mixture was diluted with water (200 mL) and extracted with EA (100 mL). The aqueous solution was acidified with HCl (1N) to pH = 2 and then extracted with EA (100 mL x 2). The combined organic layer was dried and concentrated over Na2SO4 to obtain 2-(tert-butyl-$l^{3}-oxy)-1H,3H,4H-pyrazino[1,2-a]indole-10-carboxylic acid (1.7 g, raw material) as a yellow solid, which was used directly in a subsequent step.

[0285] MS (ESI): C 17 H 20 Calculated value for N2O4 316.14, m / z measured value 339.1 [M+Na].

[0286] Step 6

[0287] HATU (575 mg, 1.51 mmol) was added to a mixture of 2-(tert-butyl-$l^{3}-oxy)-1H,3H,4H-pyrazino[1,2-a]indole-10-carboxylic acid (400 mg, 1.26 mmol), (3R)-1-azabicyclo[2.2.2]octan-3-amine (159 mg, 1.26 mmol) and DIEA (489 mg, 3.78 mmol) in DMF (10 mL), and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with water (200 mL) and extracted with EA (100 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by HPLC for purification (X-Bridge Purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain (10-{[(3R)-1-azabicyclo[2.2.2]octane-3-yl]carbamoyl}-1H,3H,4H-pyrazino[1,2-a]indole-2-yl) tert-butyl formate (250 mg, 45%) as a white solid.

[0288] MS (ESI): C 24 H 32 Calculated value for N4O3 424.25, m / z measured value 425.2 [M+H] + .

[0289] 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.82 - 7.78 (m, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.50 - 7.47 (m, 1H), 7.23 - 7.18 (m, 2H), 4.99 (s, 2H), 4.17 - 4.14 (m, 2H), 4.10 - 4.08 (m, 1H), 3.88 - 3.85 (m, 2H), 3.34 - 3.28 (m, 1H), 3.04 - 3.02 (m, 1H), 2.86 - 2.84 (m, 4H), 2.03 - 1.97 (m, 2H), 1.75 - 1.71 (m, 2H), 1.51 - 1.47 (m, 1H), 1.44 (s, 9H).

[0290] Step 7

[0291] TFA (4 mL) was added at 0°C to a solution of (10-{[(3R)-1-azabicyclo[2.2.2]octan-3-yl]carbamoyl}-1H,3H,4H-pyrazino[1,2-a]indole-2-yl) tert-butyl formate (200 mg, 0.47 mmol) in DCM (12 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain the residue, which was purified by HPLC for purification (X-Bridge purification c18 10 µm OBD 19*150 mm / Welch's Xtimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain N-[(3R)-1-azabicyclo[2.2.2]octane-3-yl]-1H,2H,3H,4H-pyrazino[1,2-a]indole-10-carboxamide formate (150 mg, 94%) as a yellow solid.

[0292] MS (ESI): C 19 H 24 Calculated value for N4O 324.20, m / z measured value 325.2 [M+H] + .

[0293] 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.14 (s, 0.2H), 7.88 - 7.83 (m, 2H), 7.56 - 7.52 (m, 1H), 7.28 - 7.23 (m, 2H), 4.61 (s, 2H), 4.33 - 4.20 (m, 3H), 3.71 - 3.66 (m, 1H), 3.61 - 3.54 (m, 2H), 3.39 - 3.32 (m, 1H), 3.26 - 3.22 (m, 4H), 2.26 - 2.14 (m, 2H), 1.94 - 1.90 (m, 2H), 1.80 - 1.75 (m, 1H).

[0294] Step 8

[0295] Acetyl chloride (24 mg, 0.31 mmol) was added at 0°C to a mixture of N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1H,2H,3H,4H-pyrazino[1,2-a]indole-10-carboxamide (10 mL) and TEA (94 mg, 0.92 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by HPLC for purification (Xbridge purification c18 10 µm OBD 19*150 mm / Welch's Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain 2-acetyl-N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1H,3H,4H-pyrazino[1,2-a]indole-10-carboxamide (22.8 mg, 20%) as a white solid.

[0296] MS (ESI): C 21 H 26Calculated value for N4O2 366.21, m / z measured value 367.2 [M+H] + .

[0297] 1 H NMR (400 MHz, DMSO-d6) δ 7.81 - 7.77 (m, 1H), 7.51 - 7.44 (m, 2H), 7.23 - 7.18 (m, 2H), 5.13 - 5.05 (m, 2H), 4.24 - 4.12 (m, 2H), 3.99 - 3.97 (m, 3H), 3.15 - 3.10 (m, 1H), 2.88 - 2.85 (m, 1H), 2.69 - 2.66 (m, 4H), 2.16 - 2.13 (m, 3H), 1.93 - 1.86 (m, 2H), 1.62 - 1.58 (m, 2H), 1.37 - 1.35 (m, 1H).

[0298] Step 9

[0299] HATU (503 mg, 1.32 mmol) was added to a mixture of 2-(tert-butyl-$l^{3}-oxy)-1H,3H,4H-pyrazino[1,2-a]indole-10-carboxylic acid (350 mg, 1.10 mmol), (3S)-1-azabicyclo[2.2.2]octan-3-amine (139.2 mg, 1.10 mmol) and DIEA (428 mg, 3.31 mmol) in DMF (10 mL). After stirring at room temperature for 6 hours, the mixture was diluted with water (30 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by HPLC for purification (X-Bridge Purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain (10-{[(3S)-1-azabicyclo[2.2.2]octane-3-yl]carbamoyl}-1H,3H,4H-pyrazino[1,2-a]indole-2-yl) tert-butyl formate (250 mg, 52%) as a white solid.

[0300] MS (ESI): C 24 H 32 Calculated value for N4O3 424.25, m / z measured value 425.2 [M+H] + .

[0301] 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.82 - 7.78 (m, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.50 - 7.47 (m, 1H), 7.23 - 7.18 (m, 2H), 4.99 (s, 2H), 4.17 - 4.14 (m, 2H), 4.10 - 4.08 (m, 1H), 3.88 - 3.85 (m, 2H), 3.33 - 3.27 (m, 1H), 3.03 - 3.01 (m, 1H), 2.87 - 2.85 (m, 4H), 2.03 - 1.96 (m, 2H), 1.75 - 1.70 (m, 2H), 1.50 - 1.47 (m, 1H), 1.44 (s, 9H).

[0302] Step 10

[0303] TFA (4 mL) was added at 0°C to a solution of (10-{[(3S)-1-azabicyclo[2.2.2]octane-3-yl]carbamoyl}-1H,3H,4H-pyrazino[1,2-a]indole-2-yl) tert-butyl formate (200 mg, 0.47 mmol) in DCM (12 mL). After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to obtain the residue, which was purified by HPLC for purification (Xbridge purification c18 10 µm OBD 19*150 mm / Welch's Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain N-[(3S)-1-azabicyclo[2.2.2]octane-3-yl]-1H,2H,3H,4H-pyrazino[1,2-a]indole-10-carboxamide (150 mg, 98%) as a yellow solid.

[0304] MS (ESI): C 19 H 24 Calculated value for N4O 324.20, m / z measured value 325.2 [M+H] + .

[0305] 1H NMR (400 MHz, DMSO-d6) δ 7.79 - 7.75 (m, 1H), 7.45 - 7.40 (m, 1H), 7.30 (s, 1H), 7.18 - 7.14 (m, 2H), 4.27 (s, 2H), 4.00 - 3.94 (m, 3H), 3.56 - 3.54 (m, 1H), 3.16 - 3.10 (m, 2H), 2.91 - 2.85 (m, 1H), 2.70 - 2.65 (m, 4H), 1.92 - 1.85 (m, 2H), 1.62 - 1.54 (m, 2H), 1.40 - 1.34 (m, 1H).

[0306] Step 11

[0307] Acetyl chloride (24 mg, 0.31 mmol) was added to a mixture of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1H,2H,3H,4H-pyrazino[1,2-a]indole-10-carboxamide (100 mg, 0.31 mmol) and TEA (94 mg, 0.92 mmol) in DCM (10 mL) at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by HPLC for purification (X-Bridge Purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain 2-acetyl-N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1H,3H,4H-pyrazino[1,2-a]indole-10-carboxamide formate (60.6 mg, 53%) as a white solid.

[0308] MS (ESI): C 21 H 26Calculated value for N4O2 366.21, m / z measured value 367.2 [M+H] + .

[0309] 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.83 - 7.79 (m, 1H), 7.60 - 7.55 (m, 1H), 7.51 - 7.48 (m, 1H), 7.24 - 7.20 (m, 2H), 5.13 - 5.05 (m, 2H), 4.25 - 4.22 (m, 1H), 4.13 - 4.07 (m, 2H), 4.00 - 3.97 (m, 2H), 3.31 - 3.25 (m, 1H), 3.03 - 2.99 (m, 1H), 2.85 - 2.83 (m, 4H), 2.16 - 2.13 (m, 3H), 2.04 - 1.95 (m, 2H), 1.70 - 1.68 (m, 2H), 1.51 - 1.48 (m, 1H).

[0310] Example 5. Synthesis of I-13 and I-14:

[0311]

[0312] Experimental Procedure:

[0313] Step 1

[0314] H2SO4 (4 mL) was added to a solution of 2-(2-nitrophenyl)acetic acid (3.6 g, 0.02 mol) in EtOH (50 ml) stirred at 0°C, and the reaction mixture was stirred at 60°C for 12 hours. The reaction mixture was slowly poured into ice water (200 ml) and extracted with EA (100 mL x 3). The organic layers were combined, washed with H2O (100 mL x 3), and concentrated under vacuum to obtain ethyl 2-(2-nitrophenyl)acetate (3.8 g, 91%) as a white solid.

[0315] MS (ESI): C 10 H 11 Calculated value for NO4 209.07, m / z measured value 232.1 [M+Na].

[0316] Step 2

[0317] Pd / C (100 mg) was added to a solution of ethyl 2-(2-nitrophenyl)acetate (3.8 g, 0.018 mol) in EtOH (50 ml), and the reaction mixture was stirred under an H2 balloon at 25°C for 4 hours. The mixture was filtered through Celite, and the filtrate was concentrated to obtain ethyl 2-(2-aminophenyl)acetate (3.1 g, 95%) as a white solid.

[0318] MS (ESI): C 10 H 13 Calculated value for NO2 179.09, m / z measured value 180.2 [M+H] + .

[0319] Step 3

[0320] 5-chloropentanoyl chloride (2.69 g, 0.021 mol) was added to a mixture of ethyl 2-(2-aminophenyl)acetate (2.5 g, 0.014 mol) and DIEA (2.69 g, 0.021 mol) in THF (40 mL). After stirring at 20°C for 2 hours, the mixture was quenched with water (200 mL) and extracted with EA (200 mL x 3). The organic layer was concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE:EA = 3:1) to obtain ethyl 2-[2-(5-chloropentanamido)phenyl]acetate (2.5 g, 58%) as a white solid.

[0321] MS (ESI): C 15 H 20 Calculated value for ClNO3 297.11, m / z measured value 298.1 [M+H] + .

[0322] Step 4

[0323] t-BuOK (2.36 g, 0.021 mol) was added to a mixture of ethyl 2-[2-(5-chloropentanamido)phenyl]acetate (2.5 g, 0.0084 mol) in THF (40 mL). After stirring at 20°C for 2 hours, the mixture was quenched with water (200 mL) and extracted with EA (200 mL x 3). The organic layer was concentrated to obtain the residue, which was purified by silica gel column chromatography (PE:EA = 3:1) to obtain ethyl 1H,2H,3H,4H-pyrido[1,2-a]indole-10-carboxylate (500 mg, 24%) as a white solid.

[0324] MS (ESI): C 15 H 17 Calculated value for NO2 243.13, m / z measured value 244.1 [M+H] + .

[0325] Step 5

[0326] KOH (345.9 mg, 6.17 mmol) was added to a mixture of ethyl 1H,2H,3H,4H-pyrido[1,2-a]indole-10-carboxylate (500 mg, 2.06 mmol) in EtOH (15 mL) and H2O (5 mL). The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated to remove EtOH. The mixture was adjusted to pH = 2 with 1 M HCl. The mixture was diluted with water and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 1H,2H,3H,4H-pyrido[1,2-a]indole-10-carboxylic acid (400 mg, 89%) as a white solid, which was used directly in a subsequent step.

[0327] MS (ESI): C 13 H 13 Calculated value for NO2 215.09, m / z measured value 216.1 [M+H] + .

[0328] Step 6

[0329] HATU (106.0 mg, 0.28 mmol) was added to a mixture of 1H,2H,3H,4H-pyrido[1,2-a]indole-10-carboxylic acid (50 mg, 0.23 mmol), (3R)-1-azabicyclo[2.2.2]octan-3-amine (29.3 mg, 0.23 mmol) and DIEA (90.1 mg, 0.70 mmol) in DMF (5 mL). The reaction mixture was stirred at 20°C for 6 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-bridge purification c18 5 µm OBD 19*150 mm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 20 ml / min, wavelength: 214 / 254 nm) to obtain N-[(3R)-1-azabicyclo[2.2.2]octane-3-yl]-1H,2H,3H,4H-pyrido[1,2-a]indole-10-carboxamide formate (28.7 mg, 38%) as a white solid.

[0330] MS (ESI): C 20 H 25 Calculated value for N3O 323.20, m / z measured value 324.1 [M+H] + .

[0331] 1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 0.7 H), 7.78 - 7.74 (m, 1H), 7.48 (d, J = 4.0 Hz, 1H), 7.43 - 7.40 (m, 1H), 7.17 - 7.12 (m, 2H), 4.14 - 4.05 (m, 3H), 3.42 - 3.36 (m, 1H), 3.17 (t, J = 8.0 Hz, 2H), 3.12 - 3.05 (m, 1H), 2.96 - 2.88 (m, 4H), 2.09 - 2.00 (m, 4H), 1.88 - 1.73 (m, 4H), 1.59 - 1.53 (m, 1H).

[0332] Step 7

[0333] HATU (106.0 mg, 0.28 mmol) was added to a mixture of 1H,2H,3H,4H-pyrido[1,2-a]indole-10-carboxylic acid (50 mg, 0.23 mmol), (3S)-1-azabicyclo[2.2.2]octan-3-amine (29.3 mg, 0.23 mmol) and DIEA (90.1 mg, 0.70 mmol) in DMF (5 mL). The reaction mixture was stirred at 20°C for 6 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-bridge purification c18 5 µm OBD 19*150 mm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 20 ml / min, wavelength: 214 / 254 nm) to obtain N-[(3S)-1-azabicyclo[2.2.2]octane-3-yl]-1H,2H,3H,4H-pyrido[1,2-a]indole-10-carboxamide formate (35 mg, 46%) as a white solid.

[0334] MS (ESI): C 20 H 25 Calculated value for N3O 323.20, m / z measured value 324.1 [M+H]+ .

[0335] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 0.8 H), 7.78 - 7.74 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.44 - 7.40 (m, 1H), 7.17 - 7.12 (m, 2H), 4.14 - 4.07 (m, 3H), 3.40 - 3.35 (m, 1H), 3.17 (t, J = 8.0 Hz, 2H), 3.12 - 3.05 (m, 1H), 2.95 - 2.88 (m, 4H), 2.08 - 1.99 (m, 4H), 1.88 - 1.73 (m, 4H), 1.59 - 1.53 (m, 1H).

[0336] Example 6. Synthesis of I-15:

[0337]

[0338] Experimental Procedure:

[0339] Step 1

[0340] AcOH (14.8 mg, 0.25 mmol) was added to a mixture of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1H,2H,3H,4H-pyrazino[1,2-a]indole-10-carboxamide (80 mg, 0.25 mmol) and paraformaldehyde (153.1 mg, 2.47 mmol) in methanol (5 mL). After stirring at 20°C for 4 hours, NaBH3CN (46.5 mg, 0.7398 mmol) was added, and the reaction mixture was stirred at 20°C for 12 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-bridge purification c18 5 µm OBD 19*150 mm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 20 ml / min, wavelength: 214 / 254 nm) to obtain N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-2-methyl-1H,3H,4H-pyrazino[1,2-a]indole-10-carboxamide (33.5 mg, 40%) as a white solid.

[0341] MS (ESI): C 20 H 26 Calculated value for N4O 338.21, m / z measured value 339.3 [M+H] + .

[0342] 1H NMR (400 MHz, DMSO-d6) δ 7.77 - 7.73 (m, 1H), 7.46 - 7.39 (m, 2H), 7.20 - 7.16 (m, 2H), 4.11 (t, J = 5.6 Hz, 2H), 3.96 - 3.92 (m, 3H), 3.14 - 3.08 (m, 1H), 2.89 - 2.84 (m, 3H), 2.72 - 2.64 (m, 4H), 2.43 (s, 3H), 1.91 - 1.81 (m, 2H), 1.62 - 1.55 (m, 2H), 1.38 - 1.32 (m, 1H).

[0343] Example 7. Synthesis of I-16:

[0344]

[0345] Experimental Procedure:

[0346] Step 1

[0347] 1,3-dibromopropane (1130.3 mg, 5.60 mmol) was added to a mixture of 5-(benzyloxy)-1H-indole (500 mg, 2.24 mmol), bis(acetonitrile)dichloropalladium(II) (58.1 mg, 0.22 mmol), norbornene (1054.2 mg, 11.20 mmol) and Cs2CO3 (1459.3 mg, 4.48 mmol) in DMA (10 mL) and H2O (0.1 mL). After stirring at 80°C for 12 hours, the mixture was filtered through Celite, the filtrate was diluted with water (200 mL), and extracted with EA (100 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash chromatography (PE / EA, 100 / 1 to 10 / 1) to obtain 7-(benzyloxy)-1H,2H,3H-benzo[b]pyrrolizine (200 mg, 31%) as a yellow solid.

[0348] MS (ESI): C 18 H 17Calculated NO 263.13, m / z measured 264.1 [M+H] + .

[0349] Step 2

[0350] TFAA (175.5 mg, 0.84 mol) was added to a solution of 7-(benzyloxy)-1H,2H,3H-benzo[b]pyrrolizine (200 mg, 0.76 mmol) and TEA (92.2 mg, 0.91 mmol) in DCE (10 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The mixture was diluted with water (200 mL) and extracted with DCM (100 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash chromatography (PE / EA, 100 / 1 to 2 / 1) to obtain difluoromethyl 7-(benzyloxy)-1H,2H,3H-benzo[b]pyrrolizine-9-carbonyl fluoride (200 mg, 69%) as a yellow solid.

[0351] MS (ESI): C 20 H 16 Calculated value for F3NO2 359.11, m / z measured value 360.1 [M+H] + .

[0352] Step 3

[0353] A mixture of difluoromethyl 7-(benzyloxy)-1H,2H,3H-benzo[b]pyrrolizine-9-carbonyl fluoride (200 mg, 0.56 mmol) and NaOH (44.4 mg, 1.1 mmol) in DMSO (5 mL) and H2O (5 mL) was stirred at 100°C for 1 hour. The mixture was diluted with water (100 mL) and extracted with EA (50 mL). The aqueous phase was adjusted to pH = 2 with 1N HCl and extracted with EA (50 mL x 2). The combined organic layer was dried over Na2SO4 and concentrated to obtain 7-(benzyloxy)-1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (100 mg, 54%) as a yellow solid.

[0354] MS (ESI): C 19 H 17 Calculated value for NO3 307.12, m / z measured value 308.0 [M+H] + .

[0355] Step 4

[0356] HATU (148.5 mg, 0.39 mmol) was added to a mixture of 7-(benzyloxy)-1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (100 mg, 0.33 mmol), (3S)-1-azabicyclo[2.2.2]octan-3-amine (41.1 mg, 0.33 mmol) and DIEA (126.2 mg, 0.98 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 6 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain N-[(3S)-1-azabicyclo[2.2.2]octane-3-yl]-7-(benzyloxy)-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (100 mg, 70%) as a yellow solid.

[0357] MS (ESI): C 26 H 29Calculated value for N3O2 415.23, m / z measured value 416.2 [M+H] + .

[0358] Step 5

[0359] Pd / C (25.6 mg, 0.24 mmol) and ammonium formate (30.4 mg, 0.48 mmol) were added under N2 to a mixture of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-7-(benzyloxy)-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (100 mg, 0.24 mmol) in EtOH (10 mL). The reaction mixture was stirred under N2 at 20°C for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (Xbridge purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-7-hydroxy-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide formate (32.4 mg, 41%) as a gray solid.

[0360] MS (ESI): C 19 H 23 Calculated value for N3O2 325.18, m / z measured value 326.1 [M+H] + .

[0361] 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 6.4 Hz, 1H), 6.60 (dd, J = 8.4, 2.0) Hz, 1H), 4.05 - 4.02 (m, 3H), 3.34 - 3.26 (m, 1H), 3.22 - 3.16 (m, 2H), 3.05 - 3.01 (m, 1H), 2.88 - 2.80 (m, 4H), 2.59 - 2.53 (m, 2H), 2.02 - 1.94 (m, 2H), 1.71 - 1.69 (m, 2H), 1.54 - 1.51 (m, 1H).

[0362] Example 8. Synthesis of I-17 and I-18:

[0363]

[0364] Experimental Procedure:

[0365] Step 1

[0366] 1,3-dibromopropane (43.1 g, 0.21 mol) was added to a mixture of 1H-indole (10 g, 0.085 mol), bis(acetonitrile)dichloropalladium(II) (2.22 g, 0.0085 mol), norbornene (40.2 g, 0.43 mol) and Cs2CO3 (55.65 g, 0.17 mol) in DMA (200 mL) and H2O (2 mL). The reaction mixture was stirred at 80°C for 12 hours. The mixture was filtered through Celite, the filtrate was diluted with water (200 mL), and extracted with EA (100 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash chromatography (PE / EA, 100 / 1 to 10 / 1) to obtain 1H,2H,3H-benzo[b]pyrrolizine (500 mg, 3.4%) as a yellow solid.

[0367] MS (ESI): C11 H 11 Calculated value for N 157.09, m / z measured value 158.1 [M+H] + .

[0368] Step 2

[0369] Ethyl 2-chloro-2-oxoacetate (477.7 mg, 3.50 mol) was added at 0°C to a solution of 1H,2H,3H-benzo[b]pyrrolizine (500 mg, 3.18 mmol) and TEA (386.2 mg, 3.82 mmol) in DCE (10 mL). The reaction mixture was stirred at 0°C for 2 hours. The mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain ethyl 2-{1H,2H,3H-benzo[b]pyrrolizine-9-yl}-2-oxoacetate (180 mg, 18%) as a yellow solid.

[0370] MS (ESI): C 15 H 15 Calculated value for NO3 257.11, m / z measured value 258.1 [M+H] + .

[0371] Step 3

[0372] NaOH (88.8 mg, 2.22 mmol) was added to a mixture of ethyl 2-{1H,2H,3H-benzo[b]pyrrolizine-9-yl}-2-oxoacetate (300 mg, 1.30 mmol) in MeOH (9 mL) and H2O (3 mL). The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated to remove MeOH, and then the pH was adjusted to 2 with 1 M HCl. The mixture was diluted with water and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 1H,2H,3H-benzo[b]pyrrolizine-9-yl(oxo)acetate (90 mg, 50%) as a yellow solid.

[0373] MS (ESI): C 13 H 11 Calculated value for NO3 229.07, m / z measured value 230.1 [M+H] + .

[0374] Step 4

[0375] HATU (89.6 mg, 0.24 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-yl(oxo)acetic acid (45 mg, 0.20 mmol), (3R)-1-azabicyclo[2.2.2]octan-3-amine (24.8 mg, 0.20 mmol) and DIEA (76.1 mg, 0.59 mmol) in DMF (5 mL). The reaction mixture was stirred at 20°C for 6 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-Bridge Purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain N-[(3R)-1-azabicyclo[2.2.2]octane-3-yl]-2-{1H,2H,3H-benzo[b]pyrrolizine-9-yl}-2-oxoacetamide (25.4 mg, 37%) as a white solid.

[0376] MS (ESI): C 20 H 23 Calculated value for N3O2 337.18, m / z measured value 338.1 [M+H] + .

[0377] 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 8.0 Hz, 1H), 8.15 - 8.13 (m, 1H), 7.47 - 7.45 (m, 1H), 7.26 - 7.21 (m, 2H), 4.19 (t, J = 8.0 Hz, 2H), 3.96 - 3.94 (m, 1H), 3.22 - 3.09 (m, 3H), 2.87 - 2.84 (m, 1H), 2.78 - 2.66 (m, 4H), 2.65 - 2.57 (m, 2H), 1.91 - 1.89 (m, 1H), 1.78 - 1.75 (m, 1H), 1.66 - 1.62 (m, 2H), 1.40 - 1.34 (m, 1H).

[0378] Step 5

[0379] HATU (89.6 mg, 0.24 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-yl (oxo)acetic acid (45 mg, 0.20 mmol), (3S)-1-azabicyclo[2.2.2]octan-3-amine (24.8 mg, 0.20 mmol) and DIEA (76.1 mg, 0.59 mmol) in DMF (5 mL). After stirring at 20°C for 6 hours, the mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-bridge purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain N-[(3S)-1-azabicyclo[2.2.2]octane-3-yl]-2-{1H,2H,3H-benzo[b]pyrrolizine-9-yl}-2-oxoacetamide formate (25.0 mg, 32%) as a white solid.

[0380] MS (ESI): C 20 H23 Calculated value for N3O2 337.18, m / z measured value 338.1 [M+H] + .

[0381] 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 8.0 Hz, 1H), 8.28 (s, 1H), 8.15 - 8.13 (m, 1H), 7.47 - 7.44 (m, 1H), 7.26 - 7.21 (m, 2H), 4.19 (t, J = 8.0 Hz, 2H), 3.96 - 3.94 (m, 1H), 3.22 - 3.09 (m, 3H), 2.90 - 2.84 (m, 1H), 2.79 - 2.66 (m, 4H), 2.62 - 2.55 (m, 2H), 1.92 - 1.89 (m, 1H), 1.78 - 1.75 (m, 1H), 1.66 - 1.62 (m, 2H), 1.41 - 1.35 (m, 1H).

[0382] Example 9. Synthesis of I-19:

[0383]

[0384] Experimental Procedure:

[0385] Step 1

[0386] HATU (113.4 mg, 0.30 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (50 mg, 0.25 mmol), endo-9-methyl-9-azabicyclo[3.3.1]nonane-3-amine (38.3 mg, 0.25 mmol) and DIEA (96.4 mg, 0.75 mmol) in DMF (5 mL). The reaction mixture was stirred at 20°C for 6 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-bridge purification c18 5 µm OBD 19*150 mm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 20 ml / min, wavelength: 214 / 254 nm) to obtain N-((1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonane-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate (46.8 mg, 56%) as a white solid.

[0387] MS (ESI): C 21 H 27 Calculated value for N3O 337.22, m / z measured value 338.2 [M+H] + .

[0388] 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 0.8 H), 7.93 - 7.91 (m, 1H), 7.36 - 7.34 (m, 1H), 7.14 - 7.07 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.43 - 4.35 (m, 1H), 4.11 (t, J = 7.2 Hz, 2H), 3.25 - 3.17 (m, 4H), 2.61 - 2.56 (m, 2H), 2.54 (s, 3H), 2.31 - 2.24 (m, 2H), 2.15 - 2.07 (m, 1H), 1.99 - 1.91 (m, 2H), 1.61 - 1.54 (m, 2H), 1.47 - 1.44 (m, 1H), 1.11 - 1.07 (m, 2H).

[0389] Example 10. Synthesis of I-20:

[0390]

[0391] Experimental Procedure:

[0392] Step 1

[0393] HATU (130 mg, 0.34 mmol) and DIEA (88 mg, 0.68 mmol) were added to a mixture of 7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (50 mg, 0.23 mmol) in dimethylformamide (5 mL) at 0°C under N2 protection. After stirring for 30 minutes, 9-methyl-9-azabicyclo[3.3.1]nonane-3-amine (35 mg, 0.23 mmol) was added, and the mixture was subsequently stirred at 50°C for 2 hours. The mixture was extracted with EA (10 ml x 3). The combined organic layer was washed with brine (10 mL x 2), dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-bridge purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA), B (acetonitrile), 20~100% B in A, 10.5 min, flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain 7-fluoro-N-{9-methyl-9-azabicyclo[3.3.1]nonane-3-yl}-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide formate (26.9 mg, 33.2%) as a white solid.

[0394] MS (ESI): C 21 H 26 Calculated value for FN3O 355.21, m / z measured value 356.2 [M+H] + .

[0395] 1H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 7.64 (dd, J = 12.0, 4.0 Hz, 1H), 7.38 (dd, J = 8.0, 4.0 Hz, 1H), 7.00 - 6.91 (m, 2H), 4.72 - 4.64 (m, 1H), 4.11 (t, J = 8.0 Hz, 2H), 3.25 - 3.22 (m, 2H), 3.02 - 3.01 (m, 2H), 2.61 - 2.54 (m, 4H), 2.08 - 1.59 (m, 11H).

[0396] Example 11. Synthesis of I-21:

[0397]

[0398] Experimental Procedure:

[0399] Step 1

[0400] HATU (104.1 mg, 0.27 mmol) was added to a mixture of 7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (50 mg, 0.23 mmol), 9-methyl-9-azabicyclo[3.3.1]nonane-3-amine (35.2 mg, 0.23 mmol) and DIEA (88.4 mg, 0.68 mmol) in DMF (5 mL). After stirring at room temperature for 6 hours, the mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-bridge purification c18 5 µm OBD 19*150 mm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 20 ml / min, wavelength: 214 / 254 nm) to obtain 7-fluoro-N-((1R,3R,5S)-9-methyl-9-azabicyclo[3.3.1]nonane-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate (32.0 mg, 39%) as a white solid.

[0401] MS (ESI): C 21 H 26 Calculated value for FN3O 355.21, m / z measured value 356.2 [M+H] + .

[0402] 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.64 (dd, J = 10.4, 2.4 Hz, 1H), 7.37 (dd, J = 8.8, 4.8 Hz, 1H), 6.99 - 6.94 (m, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.37 - 4.32 (m, 1H), 4.11 (t, J = 7.2 Hz, 2H), 3.24 (t, J = 7.6 Hz, 2H), 3.10 (d, J = 10.8 Hz, 2H), 2.67 - 2.54 (m, 3H), 2.50 - 2.48 (m, 2H), 2.28 - 2.20 (m, 2H), 2.14 - 2.08 (m, 1H), 1.97 - 1.90 (m, 2H), 1.57 - 1.43 (m, 3H), 1.02 (d, J = 13.2 Hz, 2H).

[0403] Example 12. Synthesis of I-22:

[0404]

[0405] Experimental Procedure:

[0406] Step 1

[0407] SOCl2 (520 mg, 4.37 mmol) and one drop of DMF were added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (440 mg, 2.18 mmol) in DCM (5 mL) at 0°C. The reaction mixture was stirred at room temperature under N2 for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was redissolved in DCM (5 mL). Pyridine (864 mg, 10.93 mmol) and endo-tert-butyl (1R,3r,5S)-3-hydroxy-9-azabicyclo[3.3.1]nonane-9-carboxylate (220 mg, 0.91 mmol) were added sequentially at room temperature. The reaction mixture was stirred at 50°C for 16 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (mobile phase A: PE, B: EA; 0 to 35% of A is B) to obtain (1R,3r,5S)-9-(tert-butoxycarbonyl)-9-azabicyclo[3.3.1]nonane-3-yl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate (250 mg, 26%) as a grayish-white solid.

[0408] MS (ESI): C 25 H 32 Calculated value for N2O4 424.24, m / z measured value 447.2 [M+Na] + .

[0409] Step 2

[0410] TFA (2 mL) was added at 0°C to a mixture of endo-(1R,3r,5S)-9-(tert-butoxycarbonyl)-9-azabicyclo[3.3.1]nonane-3-yl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate (250 mg, 0.58 mmol) in DCM (6 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was alkalized to pH 7 with an aqueous NaHCO3 solution and extracted with EA (20 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain endo-(1R,3r,5S)-9-azabicyclo[3.3.1]nonan-3-yl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate (160 mg, 83%) as a pale white solid.

[0411] MS (ESI): C 20 H 24 Calculated value for N2O2 324.18, m / z measured value 325.2 [M+H] + .

[0412] Step 3

[0413] NaBH₃(OAc)₃ (313 mg, 1.47 mmol) was added at room temperature to a mixture of endo-(1R,3r,5S)-9-azabicyclo[3.3.1]nonane-3-yl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate (160 mg, 0.49 mmol) and an aqueous formaldehyde solution (37%, 80 mg, 0.98 mmol) in 5 mL of DCM. The reaction mixture was stirred for 16 hours. After the reaction, the mixture was quenched with an aqueous Na₂S₂O₃ solution (20 mL) and extracted with EA (20 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm; mobile phase A: water (0.1% FA), B: acetonitrile, 22–52% B within 10 min; flow rate: 30 mL / min; wavelength: 214 / 254 nm) to obtain endo-(1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate formate (93.8 mg, 56%) as a white solid.

[0414] MS (ESI): C 21 H 26 Calculated value for N2O2 338.20, m / z measured value 339.2 [M+H] + .

[0415] 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 0.67 H), 8.07 - 8.00 (m, 1H), 7.31 - 7.27 (m, 1H), 7.25 - 7.19 (m, 2H), 5.33 - 5.25 (m, 1H), 4.15 (t, J = 8.0 Hz, 2H), 3.42 (t, J = 4.0 Hz, 2H), 3.31 (t, J = 8.0 Hz, 2H), 2.91 - 2.75 (m, 5H), 2.74 - 2.60 (m, 3H), 2.33 - 2.19 (m, 2H), 2.05 (d, J = 16.0 Hz, 2H), 1.66 (dd, J = 16.0, 4.0 Hz, 2H), 1.58 - 1.49 (m, 1H).

[0416] Example 13. Synthesis of I-23:

[0417]

[0418] Experimental Procedure:

[0419] Step 1

[0420] HATU (68.0 mg, 0.18 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (30 mg, 0.15 mmol), 1-azabicyclo[2.2.1]heptan-3-amine (16.7 mg, 0.15 mmol) and DIEA (57.8 mg, 0.45 mmol) in DMF (5 mL), and the reaction mixture was stirred at room temperature for 6 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-Bridge Purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain N-(1-azabicyclo[2.2.1]heptane-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide (15.7 mg, 36%) as a yellow solid.

[0421] MS (ESI): C 18 H 21 Calculated value for N3O 295.17, m / z measured value 296.1 [M+H] + .

[0422] 1 H NMR (400 MHz, MeOD) δ 8.49 (s, 1H), 7.89 - 7.87 (m, 1H), 7.35 - 7.32 (m, 1H), 7.20 - 7.14 (m, 2H), 4.59 - 4.12 (m, 3H), 3.84 - 3.62 (m, 1H), 3.48 - 3.30 (m, 2H), 3.28 - 3.22 (m, 4H), 3.15 - 3.04 (m, 2H), 2.73 - 2.64 (m, 2H), 2.25 - 1.76 (m, 2H).

[0423] Example 14. Synthesis of I-24:

[0424]

[0425] Experimental Procedure:

[0426] Step 1

[0427] HATU (62.5 mg, 0.16 mmol) was added to a mixture of 7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (30 mg, 0.14 mmol), 1-azabicyclo[2.2.1]heptane-3-amine (15.4 mg, 0.14 mmol), and DIEA (53.1 mg, 0.41 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 6 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-Bridge Purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain N-(1-azabicyclo[2.2.1]heptane-3-yl)-7-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide (14.4 mg, 34%) as a yellow solid.

[0428] MS (ESI): C 18 H 20 Calculated value for FN3O 313.16, m / z measured value 314.1 [M+H] + .

[0429] 1H NMR (400 MHz, MeOD) δ 8.49 (s, 1H), 7.59 - 7.57 (m, 1H), 7.33 - 7.29 (m, 1H), 6.97 - 6.91 (m, 1H), 4.58 - 4.13 (m, 3H), 3.83 - 3.60 (m, 1H), 3.43 - 3.33 (m, 3H), 3.30 - 3.24 (m, 3H), 3.14 - 3.03 (m, 2H), 2.73 - 2.65 (m, 2H), 2.19 - 1.78 (m, 2H).

[0430] Example 15. Synthesis of I-25:

[0431]

[0432] Experimental Procedure:

[0433] Step 1

[0434] HATU (142 mg, 0.37 mmol) was added in portions to a mixture of 7-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylic acid (86 mg, 0.39 mmol) and DIEA (230 mg, 1.78 mmol) in DMF (2 mL), and the mixture was stirred at 25°C for 30 minutes. Hexahydropyrrolizine-7a-ylmethanamine (50 mg, 0.35 mmol) was added at 0°C, and the mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (50 mL) and extracted with EA (50 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm; mobile phase A: water (0.1% FA), B: acetonitrile, 15–45% B within 10 min; flow rate: 30 mL / min; wavelength: 214 / 254 nm) to obtain 7-fluoro-N-((tetrahydro-1H-pyrrolizine-7a(5H)-yl)methyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate (97.3 mg, 79%) as a white solid.

[0435] MS (ESI): C 20 H 24 Calculated value for FN3O 341.19, m / z measured value 342.2 [M+H] + .

[0436] 1 H NMR (400 MHz, DMSO) δ 8.31 (s, 1H), 7.72 (dd, J = 10.8, 2.8 Hz, 1H), 7.39 (dd, J = 8.8, 4.8 Hz, 1H), 7.32 - 7.23 (m, 1H), 7.02 - 6.95 (m, 1H), 4.13 (t, J = 7.2 Hz, 2H), 3.41 (d, J = 6.0 Hz, 2H), 3.26 (t, J = 7.6 Hz, 2H), 3.22 - 3.15 (m, 2H), 2.85 - 2.75 (m, 2H), 2.65 - 2.55 (m, 2H), 1.99 - 1.82 (m, 4H), 1.82 - 1.61 (m, 4H).

[0437] Example 16. Synthesis of I-26:

[0438]

[0439] Experimental Procedure:

[0440] Step 1

[0441] 4-DMAP (60.7 mg, 0.50 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (100 mg, 0.50 mmol), hexahydropyrrolizine-7a-ylmethanol (70.2 mg, 0.50 mmol), 2-chloro-1-methylpyridinium iodide (CMPI) (165.1 mg, 0.65 mmol) and Et3N (75.4 mg, 0.75 mmol) in DMF (10 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction, the mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by HPLC for purification (X-bridge purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain (tetrahydro-1H-pyrrolizine-7a(5H)-yl)methyl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate formate (7 mg, 4%) as a white solid.

[0442] MS (ESI): C 20 H 24 Calculated value for N2O2 324.18, m / z measured value 325.2 [M+H] + .

[0443] 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 0.3H), 7.96 - 7.93 (m, 1H), 7.42 - 7.40 (m, 1H), 7.19 - 7.15 (m, 2H), 4.16 (t, J = 8.0 Hz, 2H), 3.91 (s, 2H), 3.21 (t, J = 8.0 Hz, 2H), 2.96 - 2.91 (m, 2H), 2.64 - 2.52 (m, 4H), 1.92 - 1.86 (m, 2H), 1.85 - 1.69 (m, 4H), 1.62 - 1.56 (m, 2H).

[0444] Example 17. Synthesis of I-27:

[0445]

[0446] Experimental Procedure:

[0447] Step 1

[0448] NH2OH·HCl (193.9 mg, 2.79 mmol) and K2CO3 (578.5 mg, 4.19 mmol) were added to a mixture of 1-azabicyclo[2.2.2]octane-3-carbonitrile (190 mg, 1.40 mmol) in EtOH (20 mL). The reaction mixture was stirred at 80°C for 12 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain N-hydroxyquinuclidin-3-carboximideamide (100 mg, crude product) as a yellow solid, which was used directly in a subsequent step.

[0449] MS (ESI): C8H 15 Calculated value for N3O 169.12, m / z measured value 170.1 [M+H] + .

[0450] Step 2

[0451] HBTU (246.5 mg, 0.65 mmol) and DIEA (229.1 mg, 1.77 mmol) were added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (118.9 mg, 0.59 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 1 hour. N-hydroxy-1-azabicyclo[2.2.2]octan-3-carboximide (100 mg, 0.59 mmol) was added, and the reaction mixture was stirred at 120°C for 8 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-bridge purification c18 5 µm OBD 19*150 mm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 20 ml / min, wavelength: 214 / 254 nm) to obtain 5-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-3-(quinuclidin-3-yl)-1,2,4-oxadiazole trifluoroacetate (13.3 mg, 7%) as a yellow solid.

[0452] MS (ESI): C 20 H 22 Calculated value for N4O 334.18, m / z measured value 335.1 [M+H] + .

[0453] 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 0.8H), 8.06 - 8.04 (m, 1H), 7.53 - 7.50 (m, 1H), 7.29 - 7.24 (m, 2H), 4.25 (t, J = 7.2 Hz, 2H), 3.80 - 3.74 (m, 1H), 3.68 - 3.62 (m, 2H), 3.37 - 3.30 (m, 6H), 2.72 - 2.65 (m, 2H), 2.56 - 2.54 (m, 1H), 2.09 - 1.97 (m, 2H), 1.87 - 1.75 (m, 2H).

[0454] Example 18. Synthesis of I-28:

[0455]

[0456] Experimental Procedure:

[0457] Step 1

[0458] DIEA (3.85 g, 29.82 mmol) and HATU (1.70 g, 4.47 mmol) were added to a solution of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (600 mg, 2.99 mmol) in DMF (12 mL) at room temperature. After stirring for 30 minutes, NH4Cl (0.96 g, 17.89 mmol) was added, and the reaction mixture was stirred at 50°C for 1 hour. The mixture was concentrated to obtain the residue, which was purified by silica gel column chromatography (DCM / MeOH=20:1) to obtain 1H,2H,3H-benzo[b]pyrrolizine-9-carboxyamide (500 mg, 79%) as a white solid.

[0459] MS (ESI): C 12 H 12 Calculated value for N2O 200.09, m / z measured value 201.1 [M+H] + .

[0460] Step 2

[0461] TFAA (1.84 g, 8.75 mmol) was added dropwise at 0°C to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (500 mg, 2.50 mmol) and pyridine (1.97 g, 25 mmol) in DCM (50 mL). After stirring at room temperature for 0.5 hours, the reaction mixture was quenched with water and extracted with DCM (20 mL x 3). The combined organic layer was washed with brine (10 mL x 2), dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE / EA = 1:1) to obtain 1H,2H,3H-benzo[b]pyrrolizine-9-carbonitrile (350 mg, 73%) as a white solid.

[0462] MS (ESI): C 12 H 10 Calculated value for N2 182.08, m / z measured value 183.1 [M+H] + .

[0463] Step 3

[0464] NH2OH / H2O (3.5 mL) was added dropwise to a solution of 1H,2H,3H-benzo[b]pyrrolizine-9-carbonitrile (350 mg, 1.92 mmol) in EtOH (35 mL) at room temperature, and the reaction mixture was stirred at 80°C for 8 hours. The mixture was concentrated under reduced pressure to obtain a crude product (400 mg, crude material) as a white solid.

[0465] MS (ESI): C 12 H 13 Calculated value for N3O 215.11, m / z measured value 216.1 [M+H] + .

[0466] Step 4

[0467] 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (410 mg, 1.28 mmol) and DIEA (450 mg, 3.48 mmol) were added to a solution of (3S)-1-azabicyclo[2.2.2]octane-3-carboxylic acid (180 mg, 1.16 mmol) in dimethylformamide (8 mL) at room temperature. After stirring for 1 hour, N-hydroxy-1H,2H,3H-benzo[b]pyrrolizine-9-carboximide (250 mg, 1.16 mmol) was added, and the reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was quenched with water and extracted with EA (20 ml x 3). The combined organic layer was washed with brine (20 mL x 2), dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (Welch 10u C18 250 x 21.2 mm, mobile phase A: water (0.1% NH3), B (acetonitrile), 70–100% of A, 9 min, flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain (3R)-3-(3-{1H,2H,3H-benzo[b]pyrrolizine-9-yl}-1,2,4-oxadiazole-5-yl)-1-azabicyclo[2.2.2]octane (33 mg, 8%) as a pink solid.

[0468] MS (ESI): C 20 H 22 Calculated value for N4O 334.18, m / z measured value 335.2 [M+H] + .

[0469] 1H NMR (400 MHz, DMSO-d6) δ 8.04 - 7.94 (m, 1H), 7.50 - 7.39 (m, 1H), 7.24 - 7.11 (m, 2H), 4.18 (t, J = 8.0 Hz, 2H), 3.30 - 3.26 (m, 5H), 2.89 - 2.79 (m, 4H), 2.67 - 2.59 (m, 2H), 2.22 - 2.20 (m, 1H), 1.79 - 1.52 (m, 3H), 1.48 -1.39 (m, 1H).

[0470] Example 19. Synthesis of I-29 and I-30:

[0471]

[0472] Experimental Procedure:

[0473] Step 1

[0474] The product of 3-(3-{1H,2H,3H-benzo[b]pyrrolizine-9-yl}-1,2,4-oxadiazole-5-yl)-1-azabicyclo[2.2.2]octane (30 mg) was purified by SFC (Chiral Cell AD, 250 mm x 30 mm ID, 10 μm, mobile phase: CO2 / MeOH [0.2% NH3 (7 M solution in MeOH)] = 50 / 50, flow rate: 80 g / min, wavelength: UV 214 nm, temperature: 35℃) to obtain the crude product, which was then purified using HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 μm, mobile phase A: water (0.1% TFA), B (acetonitrile), 35–100% B in A, 9.5 min, flow rate: 25 ml / min, (3R)-3-(3-{1H,2H,3H-benzo[b]pyrrolizine-9-yl}-1,2,4-oxadiazole-5-yl)-1-azabicyclo[2,2,2]octane (6 mg, 20%) was obtained as a white solid by purification using HPLC (Welch's Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% TFA), B (acetonitrile), 35–100% B in A, 9.5 min, flow rate: 25 ml / min, wavelength: 214 / 254 nm) (5S)-3,3-difluoro-5-(3-{7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-yl}-1,2,4-oxadiazole-5-yl)piperidine (7 mg, 23.3%) was obtained as a white solid.

[0475] I-29

[0476] MS (ESI): C 20 H 22 Calculated value for N4O 334.18, m / z measured value 335.2 [M+H] + .

[0477] 1H NMR (400 MHz, DMSO) δ 9.63 (s, 1H), 8.00 - 7.97 (m, 1H), 7.48 -7.44 (m, 1H), 7.23 - 7.17 (m, 2H), 4.20 (t, J = 8.0 Hz, 2H), 4.01 - 3.63 (m, 3H), 3.38 - 3.35 (m, 1H), 3.32 - 3.26 (m, 4H), 2.71 - 2.60 (m, 2H), 2.55 - 2.50 (m, 2H), 2.10 - 2.08 (m, 1H), 2.02 - 1.94 (m, 1H), 1.84 - 1.81 (m, 2H).

[0478] I-30

[0479] MS (ESI): C 20 H 22 Calculated value for N4O 334.18, m / z measured value 335.2 [M+H] + .

[0480] 1 H NMR (400 MHz, DMSO) δ 9.63 (s, 1H), 8.00 - 7.97 (m, 1H), 7.48 -7.44 (m, 1H), 7.23 - 7.17 (m, 2H), 4.20 (t, J = 8.0 Hz, 2H), 4.01 - 3.63 (m, 3H), 3.38 - 3.35 (m, 1H), 3.32 - 3.26 (m, 4H), 2.71 - 2.60 (m, 2H), 2.55 - 2.50 (m, 2H), 2.10 - 2.08 (m, 1H), 2.02 - 1.94 (m, 1H), 1.84 - 1.81 (m, 2H).

[0481] Example 20. Synthesis of I-31:

[0482]

[0483] Experimental Procedure:

[0484] Step 1

[0485] [(chlorosulfonyl)imino]methanone (441.2 mg, 3.12 mmol) was added to a 10 mL DMF mixture of 1H,3H,4H-[1,4]oxazino[4,3-a]indole (450 mg, 2.60 mmol) at -20°C, and the reaction mixture was then stirred at room temperature for 8 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 1H,3H,4H-[1,4]oxazino[4,3-a]indole-10-carbonitrile (400 mg, 70%) as a yellow solid, which was used directly in a subsequent step.

[0486] MS (ESI): C 12 H 10 Calculated value for N2O 198.08, m / z measured value 199.1 [M+H] + .

[0487] Step 2

[0488] NH2OH / H2O (116.6 mg, 3.53 mmol) was added to a solution of 1H,3H,4H-[1,4]oxazino[4,3-a]indole-10-carbonitrile (350 mg, 1.77 mmol) in EtOH (10 mL), the reaction mixture was heated to 80°C and stirred for 4 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain N-hydroxy-1H,3H,4H-[1,4]oxazino[4,3-a]indole-10-carboximideamide (350 mg, 69%) as a yellow solid, which was used directly in a subsequent step.

[0489] MS (ESI): C 12 H 13 Calculated value for N3O2 231.10, m / z measured value 232.1 [M+H] + .

[0490] Step 3

[0491] HBTU (196.8 mg, 0.52 mmol) and DIEA (167.7 mg, 1.30 mmol) were added to a mixture of 1-azabicyclo[2.2.2]octane-3-carboxylic acid (67.1 mg, 0.43 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 1 hour. Subsequently, N-hydroxy-1H,3H,4H-[1,4]oxazino[4,3-a]indole-10-carboximideamide (100 mg, 0.43 mmol) was added, the reaction mixture was heated to 90°C, and stirred for 5 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-bridge purification c18 5 µm OBD 19*150 mm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 20 ml / min, wavelength: 214 / 254 nm) to obtain 10-(5-(quinuclidin-3-yl)-1,2,4-oxadiazole-3-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole formate (9.7 mg, 6%) as a white solid.

[0492] MS (ESI): C 20 H 22 Calculated value for N4O2 350.17, m / z measured value 351.1 [M+H] + .

[0493] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 0.5H), 8.09 - 8.07 (m, 1H), 7.56 - 7.54 (m, 1H), 7.30 - 7.24 (m, 2H), 5.27 (s, 2H), 4.21 - 4.09 (m, 4H), 3.37 - 3.32 (m, 1H), 3.28 - 3.26 (m, 2H), 2.89 - 2.74 (m, 4H), 2.20 - 2.19 (m, 1H), 1.73 - 1.42 (m, 4H).

[0494] Example 21. Synthesis of I-32:

[0495]

[0496] Experimental Procedure:

[0497] Step 1

[0498] LiAlH4 (2.2 g, 57.9 mmol) was added to a solution of ethyl 5-fluoro-1H-indole-2-carboxylate (10.0 g, 48 mmol) in THF (200 mL) at 0°C, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with H2O (6 mL) and 15% NaOH (9 mL). The mixture was filtered, the filtrate was diluted with water (500 mL), and extracted with EA (300 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash chromatography (PE / EA = 100 / 1 to 1 / 1) to obtain (5-fluoro-1H-indole-2-yl)methanol (7 g, 87%) as a yellow solid.

[0499] MS (ESI): Calculated value for C9H8FNO 165.06, m / z measured value 166.1 [M+H] + .

[0500] Step 2

[0501] KOH (1.7 g, 30.2 mmol) was added to a solution of (5-fluoro-1H-indole-2-yl)methanol (2.0 g, 12.1 mmol) in DCM (40 mL) at 0°C, and the mixture was stirred at this temperature for 0.5 hours. Ethenyldiphenylsulfanium trifluoromethanesulfonate (5.26 g, 14.5 mmol) was added, the reaction mixture was heated, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by flash chromatography (PE / EA = 100 / 1 to 10 / 1) to obtain 8-fluoro-1H,3H,4H-[1,4]oxazino[4,3-a]indole (1.2 g, 49%) as a yellow solid.

[0502] MS (ESI): C 11 H 10 Calculated FNO 191.07, m / z measured 192.1 [M+H] + .

[0503] Step 3

[0504] [(chlorosulfonyl)imino]methanone (407 mg, 2.88 mmol) was added to a solution of 8-fluoro-1H,3H,4H-[1,4]oxazino[4,3-a]indole (550 mg, 2.88 mmol) in DMF (10 mL) at -20°C. The reaction mixture was heated to room temperature and stirred for 8 hours. The reaction mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (PE / EA = 100 / 1 to 5 / 1) to obtain 8-fluoro-1H,3H,4H-[1,4]oxazino[4,3-a]indole-10-carbonitrile (500 mg, 69%) as a yellow solid.

[0505] MS (ESI): C 12Calculated value for H9FN2O 216.07, m / z measured value 217.1 [M+H] + .

[0506] Step 4

[0507] NH2OH / H2O (137 mg, 4.16 mmol) was added to a solution of 8-fluoro-1H,3H,4H-[1,4]oxazino[4,3-a]indole-10-carbonitrile (450 mg, 2.08 mmol) in EtOH (10 mL), and the reaction mixture was stirred at 80°C for 4 hours. The reaction mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 8-fluoro-N-hydroxy-1H,3H,4H-[1,4]oxazino[4,3-a]indole-10-carboximideamide (450 mg, crude material) as a yellow solid.

[0508] MS (ESI): C 12 H 12 Calculated value for FN3O2 249.09, m / z measured value 250.1 [M+H] + .

[0509] Step 5

[0510] HBTU (183 mg, 0.48 mmol) and DIEA (156 mg, 1.20 mmol) were added to a solution of 1-azabicyclo[2.2.2]octane-3-carboxylic acid (62 mg, 0.40 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 1 hour. 8-fluoro-N-hydroxy-1H,3H,4H-[1,4]oxazino[4,3-a]indole-10-carboximideamide (100 mg, 0.40 mmol) was added, and the reaction mixture was stirred at 90°C for 5 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-bridge purification c18 5 µm OBD 19*150 mm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 20 ml / min, wavelength: 214 / 254 nm) to obtain 8-fluoro-10-(5-(quinuclidin-3-yl)-1,2,4-oxadiazole-3-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole formate (10.2 mg, 7%) as a white solid.

[0511] MS (ESI): C 20 H 21 Calculated value for FN4O2 368.16, m / z measured value 369.1 [M+H] + .

[0512] 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.76 - 7.73 (m, 1H), 7.61 - 7.58 (m, 1H), 7.17 - 7.12 (m, 1H), 5.25 (s, 2H), 4.22 - 4.18 (m, 4H), 3.38 - 3.32 (m, 1H), 3.28 - 3.26 (m, 2H), 2.84 - 2.80 (m, 4H), 2.21 - 2.19 (m, 1H), 1.74 - 1.42 (m, 4H).

[0513] Example 22. Synthesis of I-33:

[0514]

[0515] Experimental Procedure:

[0516] Step 1

[0517] HATU (113.4 mg, 0.30 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (50 mg, 0.25 mmol), exo-(1R,3S,5S)-9-methyl-9-azabicyclo[3.3.1]nonane-3-amine (38.3 mg, 0.25 mmol) and DIEA (96.4 mg, 0.75 mmol) in DMF (5 mL). After stirring at room temperature for 6 hours, the reaction mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-bridge purification c18 5 µm OBD 19*150 mm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 20 ml / min, wavelength: 214 / 254 nm) to obtain N-((1R,3s,5S)-9-methyl-9-azabicyclo[3.3.1]nonane-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate (28.6 mg, 34%) as a white solid.

[0518] MS (ESI): C 21 H 27 Calculated value for N3O 337.22, m / z measured value 338.2 [M+H] + .

[0519] 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.92 - 7.90 (m, 1H), 7.37 - 7.34 (m, 1H), 7.14 - 7.07 (m, 2H), 6.89 (d, J = 8.0 Hz, 1H), 4.73 - 4.67 (m, 1H), 4.11 (t, J = 7.2 Hz, 2H), 3.22 (t, J = 7.2 Hz, 2H), 3.01 (s, 2H), 2.62 - 2.54 (m, 5H), 2.08 - 1.97 (m, 4H), 1.89 - 1.57 (m, 6H).

[0520] Example 23. Synthesis of I-34:

[0521]

[0522] Experimental Procedure:

[0523] Step 1

[0524] SOCl2 (236 mg, 1.98 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (200 mg, 0.99 mmol) in DCM (5 mL) at 0°C, and then one drop of DMF was added dropwise. The reaction mixture was stirred at room temperature under N2 for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was redissolved in DCM (5 mL). Pyridine (393 mg, 4.96 mmol) and tert-butyl (1R,3s,5S)-3-hydroxy-9-azabicyclo[3.3.1]nonane-9-carboxylate (96 mg, 0.39 mmol) were added at room temperature, and the mixture was stirred at 50°C for 16 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by flash chromatography (mobile phase A: PE, B: EA; 0 to 25% of A is B) to obtain (1R,3s,5S)-9-(tert-butoxycarbonyl)-9-azabicyclo[3.3.1]nonane-3-yl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate (214 mg, 48%) as a yellow solid.

[0525] MS (ESI): C 25 H 32 Calculated value for N2O4 424.24, m / z measured value 447.2 [M+Na] + .

[0526] Step 2

[0527] TFA (2 mL) was added at 0°C to a mixture of (1R,3s,5S)-9-(tert-butoxycarbonyl)-9-azabicyclo[3.3.1]nonane-3-yl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate (214 mg, 0.50 mmol) in DCM (6 mL). The reaction mixture was heated to room temperature and stirred for 1 hour. The mixture was neutralized with NaHCO3(aq.) and extracted with EA (20 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain (1R,3s,5S)-9-azabicyclo[3.3.1]nonane-3-yl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate (159 mg, 97%) as a grayish-white solid.

[0528] MS (ESI): C 20 H 24 Calculated value for N2O2 324.18, m / z measured value 325.2 [M+H] + .

[0529] Step 3

[0530] NaBH(OAc)3 (331 mg, 1.56 mmol) was added at room temperature to a mixture of (1R,5S)-9-azabicyclo[3.3.1]nonane-3-yl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate (169 mg, 0.52 mmol) and an aqueous formaldehyde solution (37%, 85 mg, 1.04 mmol) in DCM (5 mL). The reaction mixture was stirred for 16 hours. The mixture was quenched with Na2S2O3 aq. (20 mL) and extracted with EA (20 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm; mobile phase A: water (0.1% FA), B: acetonitrile, 23–33% B within 10 min; flow rate: 30 mL / min; wavelength: 214 / 254 nm) to obtain (1R,3s,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate formate (125.6 mg, 71%) as a grayish-white solid.

[0531] MS (ESI): C 21 H 26 Calculated value for N2O2 338.20, m / z measured value 339.2 [M+H] + .

[0532] 1 H NMR (400 MHz, CDCl3) δ 8.60 (s, 0.86H), 8.10 - 7.99 (m, 1H), 7.30 - 7.27 (m, 1H), 7.25 - 7.18 (m, 2H), 5.89 - 5.74 (m, 1H), 4.14 (t, J = 8.0 Hz, 2H), 3.55 - 3.47 (m, 2H), 3.30 (t, J = 8.0 Hz, 2H), 2.85 (s, 3H), 2.73 - 2.62 (m, 2H), 2.48 - 2.23 (m, 6H), 2.00 - 1.74 (m, 4H).

[0533] Example 24. Synthesis of I-35:

[0534]

[0535] Experimental Procedure:

[0536] Step 1

[0537] SOCl2 (118.3 mg, 0.99 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (100 mg, 0.50 mmol) in dichloromethane (10 mL) and DMF (0.5 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to obtain 1H,2H,3H-benzo[b]pyrrolizine-9-carbonyl chloride (110 mg, crude material) as a yellow solid, which was used directly in a subsequent step.

[0538] Step 2

[0539] Pyridine (108.0 mg, 1.37 mmol) and 1-azabicyclo[2.2.2]octan-4-ol (57.9 mg, 0.46 mmol) were added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carbonyl chloride (100 mg, 0.46 mmol) in DCM (10 mL). After stirring at room temperature for 16 hours, the mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by HPLC for purification (X-bridge purification c18 5 µm OBD 19*150 mm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 20 ml / min, wavelength: 214 / 254 nm) to obtain quinuclidein-4-yl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate trifluoroacetate (12.9 mg, 9%) as a gray solid.

[0540] MS (ESI): C 19 H22 Calculated value for N2O2 310.17, m / z measured value 311.2 [M+H] + .

[0541] 1 H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 0.80 H), 7.88 - 7.86 (m, 1H), 7.44 - 7.41 (m, 1H), 7.20 - 7.15 (m, 2H), 4.16 (t, J = 7.2 Hz, 2H), 3.52 - 3.48 (m, 6H), 3.18 (t, J = 7.6 Hz, 2H), 2.67 - 2.55 (m, 2H), 2.41 - 2.33 (m, 6H).

[0542] Example 25. Synthesis of I-36:

[0543]

[0544] Experimental Procedure:

[0545] Step 1

[0546] HATU (113.4 mg, 0.30 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (50 mg, 0.25 mmol), 1-azabicyclo[2.2.2]octan-4-amine (31.4 mg, 0.25 mmol) and DIEA (96.4 mg, 0.75 mmol) in DMF (5 mL). After stirring at room temperature for 6 hours, the mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-bridge purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain N-(quinuclidin-4-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate (20.7 mg, 27%) as a yellow solid.

[0547] MS (ESI): C 19 H 23 Calculated value for N3O 309.18, m / z measured value 310.1 [M+H] + .

[0548] 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.87 - 7.85 (m, 1H), 7.36 - 7.34 (m, 1H), 7.13 - 7.06 (m, 2H), 6.50 (s, 1H), 4.10 (t, J = 7.2 Hz, 2H), 3.20 (t, J = 7.6 Hz, 2H), 3.01 - 2.97 (m, 6H), 2.61 - 2.54 (m, 2H), 2.02 - 1.98 (m, 6H).

[0549] Example 26. Synthesis of I-37:

[0550]

[0551] Experimental Procedure:

[0552] Step 1

[0553] SOCl2 (118.3 mg, 0.99 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (100 mg, 0.50 mmol) in dichloromethane (10 mL) and DMF (0.5 mL). The reaction mixture was stirred at 20°C for 3 hours. The mixture was concentrated under reduced pressure to obtain 1H,2H,3H-benzo[b]pyrrolizine-9-carbonyl chloride (110 mg, crude material) as a yellow solid, which was used directly in a subsequent step.

[0554] Step 2

[0555] Pyridine (108.0 mg, 1.37 mmol) and (3S)-1-azabicyclo[2.2.2]octan-3-ol (57.9 mg, 0.46 mmol) were added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carbonyl chloride (100 mg, 0.46 mmol) in DCM (10 mL). The reaction mixture was stirred at 20°C for 16 hours. The mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain (S)-quinuclidin-3-yl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate formate (17.4 mg, 12%) as a white solid.

[0556] MS (ESI): C 19 H 22 Calculated value for N2O2 310.17, m / z measured value 311.2 [M+H] + .

[0557] 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 0.70 H), 7.97 - 7.93 (m, 1H), 7.43 - 7.40 (m, 1H), 7.20 - 7.15 (m, 2H), 4.94 - 4.92 (m, 1H), 4.16 (t, J = 7.2 Hz, 2H), 3.29 - 3.18 (m, 2H), 2.88 - 2.85 (m, 2H), 2.75 - 2.57 (m, 6H), 1.91 - 1.89 (m, 1H), 1.70 - 1.47 (m, 4H).

[0558] Example 27. Synthesis of I-38:

[0559]

[0560] Experimental Procedure:

[0561] Step 1

[0562] SOCl2 (118.3 mg, 0.99 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (100 mg, 0.50 mmol) in dichloromethane (10 mL) and DMF (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain 1H,2H,3H-benzo[b]pyrrolizine-9-carbonyl chloride (100 mg, crude material) as a yellow solid, which was used directly in a subsequent step.

[0563] Step 2

[0564] Pyridine (64.8 mg, 0.82 mmol) and 1-azabicyclo[2.2.1]heptan-3-ol (30.9 mg, 0.27 mmol) were added to a solution of 1H,2H,3H-benzo[b]pyrrolizine-9-carbonyl chloride (60 mg, 0.27 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain 1-azabicyclo[2.2.1]heptane-3-yl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate formate (17.5 mg, 21%) as a yellow solid.

[0565] MS (ESI): C 18 H 20 Calculated value for N2O2 296.15, m / z measured value 297.2 [M+H] + .

[0566] 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.94 - 7.92 (m, 1H), 7.43 - 7.40 (m, 1H), 7.20 - 7.15 (m, 2H), 5.17 - 5.14 (m, 1H), 4.18 - 4.13 (m, 2H), 3.25 - 3.10 (m, 3H), 2.85 - 2.81 (m, 2H), 2.64 - 2.57 (m, 4H), 2.42 - 2.38 (m, 1H), 2.33 - 2.24 (m, 1H), 1.90 - 1.86 (m, 1H), 1.52 - 1.48 (m, 1H).

[0567] Example 28. Synthesis of I-39:

[0568]

[0569] Experimental Procedure:

[0570] Step 1

[0571] HATU (97 mg, 0.25 mmol) was added in several portions at 25°C to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (54 mg, 0.26 mmol) and DIEA (157 mg, 1.21 mmol) in DMF (2 mL), and the mixture was stirred for 30 minutes. Subsequently, (1R,3S,4S)-1-azabicyclo[2.2.1]heptane-3-amine hydrochloride (45 mg, 0.24 mmol) was added at 0°C, and the mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm; mobile phase A: water (0.1% FA), B: acetonitrile, 10–45% B within 10 min; flow rate: 30 mL / min; wavelength: 214 / 254 nm) to obtain N-((1R,3S,4S)-1-azabicyclo[2.2.1]heptane-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate (53.7 mg, 74%) as a white solid.

[0572] MS (ESI): C 18 H 21 Calculated value for N3O 295.17, m / z measured value 296.2 [M+H] + .

[0573] 1H NMR (400 MHz, DMSO) δ 8.17 (s, 0.23H), 7.92 - 7.83 (m, 1H), 7.47 - 7.32 (m, 2H), 7.18 - 7.07 (m, 2H), 4.49 - 4.38 (m, 1H), 4.13 (t, J = 6.8 Hz, 2H), 3.51 (t, J = 11.2 Hz, 1H), 3.25 (t, J = 7.2 Hz, 2H), 3.21 - 3.06 (m, 3H), 3.03 - 2.94 (m, 2H), 2.87 - 2.77 (m, 1H), 2.64 - 2.55 (m, 2H), 2.02 - 1.89 (m, 1H), 1.85 - 1.77 (m, 1H).

[0574] Example 29. Synthesis of I-40:

[0575]

[0576] Experimental Procedure:

[0577] Step 1

[0578] DIEA (1729.02 mg, 13.37 mmol) was added to a stirred solution of (5-methyl-1H-imidazole-4-yl)methanol (500 mg, 4.4591 mmol) in anhydrous DMF (13 mL), followed by the addition of SEMCl (892.11 mg, 5.35 mmol). The resulting solution was heated to 80°C for 3 hours and then cooled to room temperature. The reaction mixture was poured into brine (15 mL) and diluted with H2O (6 mL) and EA (40 mL). The organic phase was washed with brine (20 mL x 4), dried over Na2SO4, and concentrated under reduced pressure. The orange oil was purified by silica gel flash chromatography (DCM / MeOH / NH4OH, 95:4:1) to obtain (5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}imidazole-4-yl)methanol (450 mg, 39.4%).

[0579] MS (ESI): C 11 H 22Calculated value for N2O2Si 242.15, m / z measured value 243.2 [M+H] + .

[0580] Step 2

[0581] Oxalyl chloride (246.03 mg, 1.9383 mmol) and DMF (9.44 mg, 0.1292 mmol) were added to a solution of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (130 mg, 0.646 mmol) in DCM (5 mL) under N2 at 0°C. Subsequently, the mixture was stirred at room temperature under N2 for 1 hour. The mixture was concentrated to obtain a crude product. (5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}imidazole-4-yl)methanol (234.91 mg, 0.969 mmol) and TEA (130.76 mg, 1.2922 mmol) were added to a solution of the crude product in DCM (5 mL), and the mixture was stirred at 50°C under N2 for 16 hours. The mixture was diluted with EtOAc, and the precipitate was removed by filtration. The filtrate was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by a silica gel chromatography column (DCM / MeOH = 5:1) to obtain (5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}imidazole-4-yl)methyl 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylate (130 mg, 47%) as a red oil.

[0582] MS (ESI): C 23 H 31 Calculated value for N3O3Si 425.21, m / z measured value 426.2 [M+H] + .

[0583] Step 3

[0584] TFA (2 ml) was added dropwise to a solution of (5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}imidazole-4-yl)methyl 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylate (130 mg, 0.3047 mmol) in DCM (1 mL) at 0°C under N2, and the mixture was stirred at room temperature under N2 for 2 hours. The mixture was concentrated under reduced pressure to obtain the residue, which was purified by HPLC for purification (X-Bridge purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA), B (acetonitrile), 20~50% of A, B, 10 min, flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain (5-methyl-1H-imidazole-4-yl)methyl 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylate formate (16.8 mg, 18%) as a white solid.

[0585] MS (ESI): C 17 H 17 Calculated value for N3O2 295.13, m / z measured value 296.1 [M+H] + .

[0586] 1 H NMR (400 MHz, DMSO) δ 8.17 (s, 1H), 7.90 - 7.87 (m, 1H), 7.50 (s, 1H), 7.44 - 7.34 (m, 1H), 7.21 - 7.08 (m, 2H), 5.14 (s, 2H), 4.14 (t, J = 8.0 Hz, 2H), 3.14 (t, J = 8.0 Hz, 2H), 2.60 - 2.54 (m, 2H), 2.22 (s, 3H).

[0587] Example 30. Synthesis of I-41:

[0588]

[0589] Experimental Procedure:

[0590] Step 1

[0591] NaH (0.33 g, 0.014 mol) was added to a solution of 5-methyl-1H-imidazole-4-carbaldehyde (1 g, 0.0091 mol) in DMF (20 mL) at 0°C, and the reaction mixture was stirred at 0°C for 2 hours. SEMCl (1.52 g, 9.1 mmol) was added, the reaction mixture was heated to room temperature, and stirred for 4 hours. The mixture was diluted with water (200 mL) and extracted with EA (100 mL x 2). The organic layer was concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE:EA = 1:1) to obtain 5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxaldehyde (1 g, 43%) as a yellow solid.

[0592] MS (ESI): C 11 H 20 Calculated value for N2O2Si 240.13, m / z measured value 241.1 [M+H] + .

[0593] Step 2

[0594] NH2OH·HCl (194.3 mg, 2.80 mmol) and Na2CO3 (592.8 mg, 5.59 mmol) were added to a mixture of 1-[(2-methoxyethyl)trimethyl-$l^{5}-silyl]-5-methylimidazole-4-carbaldehyde (450 mg, 1.86 mmol) in H2O (10 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain (E)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbaldehyde oxime (450 mg, 75%) as a yellow solid, which was used directly in a subsequent step.

[0595] MS (ESI): C 11 H 21Calculated value for N3O2Si 255.14, m / z measured value 256.2 [M+H] + .

[0596] Step 3

[0597] Rani-Ni (91.6 mg, 1.56 mmol) and NH3·H2O (54.7 mg, 1.56 mmol) were added to a mixture of (E)-N-({1-[(2-methoxyethyl)trimethyl-$l^{5}-silyl]-5-methylimidazole-4-yl}methylidene)hydroxylamine (400 mg, 1.56 mmol) in EtOH (10 mL). The reaction mixture was stirred at room temperature under an H2 balloon for 6 hours. After filtration, the filtrate was collected and concentrated under vacuum to obtain (5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-yl)methaneamine (200 mg, crude product) as a yellow solid, which was used directly in a subsequent step.

[0598] MS (ESI): C 11 H 23 Calculated value for N3OSi 241.16, m / z measured value 242.1 [M+H] + .

[0599] Step 4

[0600] HATU (272.1 mg, 0.72 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (120 mg, 0.60 mmol), {1-[(2-methoxyethyl)trimethyl-$l^{5}-silyl]-5-methylimidazole-4-yl}methaneamine (173.5 mg, 0.72 mmol) and DIEA (231.2 mg, 1.79 mmol) in DMF (10 mL). After stirring at room temperature for 6 hours, the mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain N-((5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-yl)methyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide (100 mg, 32%) as a yellow solid, which was used directly in a subsequent step.

[0601] MS (ESI): C 23 H 32 Calculated value for N4O2Si 424.23, m / z measured value 425.2 [M+H] + .

[0602] Step 5

[0603] A DCM / TFA=3 / 1 (12 mL) mixture of N-({1-[(2-methoxyethyl)trimethyl-$l^{5}-silyl]-5-methylimidazole-4-yl}methyl)-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (100 mg, 0.24 mmol) was stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain N-((5-methyl-1H-imidazole-4-yl)methyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide (7.8 mg, 11%) as a white solid.

[0604] MS (ESI): C 17 H 18 Calculated m / z for N4O, 294.15, Measured 295.2 [M+H] + .

[0605] 1 H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 7.96 - 7.94 (m, 1H), 7.45 - 7.08 (m, 5H), 4.37 - 4.31 (m, 2H), 4.10 (t, J = 7.2 Hz, 2H), 3.21 - 3.19 (m, 2H), 2.61 - 2.54 (m, 2H), 2.19 - 2.12 (m, 3H).

[0606] Example 31. Synthesis of I-42:

[0607]

[0608] Experimental Procedure:

[0609] Step 1

[0610] HATU (256 mg, 0.67 mmol) was added in several portions at room temperature to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (142 mg, 0.70 mmol) and DIEA (414 mg, 3.20 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 30 minutes. Hexahydropyrrolizine-7a-ylmethanamine (90 mg, 0.64 mmol) was added to the mixture at 0°C, and the mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (50 mL) and extracted with EA (50 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm; mobile phase A: water (0.1% FA), B: acetonitrile, 20–50% B within 10 min; flow rate: 30 mL / min; wavelength: 214 / 254 nm) to obtain N-(hexahydropyrrolizine-7a-ylmethyl)-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide formate (134.3 mg, 64%) as a white solid.

[0611] MS (ESI): C 20 H 25 Calculated value for N3O 323.20, m / z measured value 324.2 [M+H] + .

[0612] 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.01 - 7.96 (m, 1H), 7.41 - 7.34 (m, 1H), 7.34 - 7.26 (t, J = 4.0 Hz, 1H), 7.19 - 7.06 (m, 2H), 4.12 (t, J = 8.0 Hz, 2H), 3.44 (d, J = 4.0 Hz, 2H), 3.30 - 3.15 (m, 4H), 2.90 - 2.74 (m, 2H), 2.66 - 2.25 (m, 2H), 2.00 - 1.62 (m, 8H).

[0613] Example 32. Synthesis of I-43:

[0614]

[0615] Experimental Procedure:

[0616] Step 1

[0617] MsCl (1.88 g, 16.3 mmol) was added dropwise to a mixture of [(2R,7aS)-2-fluoro-hexahydropyrrolizine-7a-yl]methanol (2.0 g, 12.6 mmol) and Et3N (3.82 g, 37.8 mmol) in DCM at 0°C under N2. The reaction mixture was stirred at room temperature under N2 for 2 hours. The mixture was diluted with water and extracted with DCM. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to obtain (2R,7aS)-7a-(chloromethyl)-2-fluorohexahydro-1H-pyrrolizine (2.2 g, crude product), which was used in subsequent steps without further purification.

[0618] MS (ESI): C8H 13 Calculated value for ClFN 177.07, m / z measured value 178.1 [M+H] + .

[0619] Step 2

[0620] NaN3 (3.67 g, 56.5 mmol) was added to a solution of (2R,7aS)-7a-(chloromethyl)-2-fluoro-hexahydropyrrolizine (2 g, 11.3 mmol) in DMF (40 mL) at room temperature under N2 protection, and the reaction mixture was stirred at 80°C for 16 hours. The mixture was diluted with EA and filtered. The filtrate was washed with water and saturated brine and dried over Na2SO4. The organic layer was concentrated to obtain the residue, which was purified by silica gel column chromatography (PE / EA = 2:1) to obtain (2R,7aS)-7a-(azidomethyl)-2-fluoro-hexahydropyrrolizine (1.6 g, 77%) as a yellow oil.

[0621] MS (ESI): C8H 13 Calculated value for FN4 184.11, m / z measured value 185.1 [M+H] + .

[0622] Step 3

[0623] Pd / C (40 mg) was added to a solution of (2R,7aS)-7a-(azidomethyl)-2-fluoro-hexahydropyrrolizine (200 mg, 1.09 mmol) in MeOH (10 mL), and the reaction mixture was stirred at room temperature under H2 for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methaneamine (200 mg, crude material), which was used directly in a subsequent step.

[0624] MS (ESI): C8H 15 Calculated value for FN2 158.12, m / z measured value 159.2 [M+H] + .

[0625] Step 4

[0626] Oxalyl chloride (189 mg, 1.49 mmol) and one drop of DMF were added to a solution of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (100 mg, 0.50 mmol) in DCM (5 mL) at 0°C under N2. The mixture was then stirred at room temperature for 1 hour. The reaction mixture was concentrated and redissolved in DCM, and this solution was added to a mixture of [(2R,7aS)-2-fluoro-hexahydropyrrolizine-7a-yl]methaneamine (149 mg, 0.94 mmol) and TEA (286 mg, 2.83 mmol). The reaction mixture was stirred at 50°C for 4 hours under N2 protection. The mixture was quenched with water, extracted with DCM, the combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the residue, which was purified by HPLC for purification (X-bridge purification c18 10 µm OBD 19*150 mm / Welch's Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA), B (acetonitrile), 20~100% B in A, 11.5 min, flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain N-{[(2R,7aS)-2-fluoro-hexahydropyrrolizine-7a-yl]methyl}-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (38 mg, 23%) as a white solid.

[0627] MS (ESI): C 20 H 24 Calculated value for FN3O 341.19, m / z measured value 342.2 [M+H] + .

[0628] 1H NMR (400 MHz, DMSO-d6) δ 7.87 - 7.85 (m, 1H), 7.36 -7.34 (m, 1H), 7.17 - 7.03 (m, 2H), 6.44 (s, 1H), 4.87 - 4.74 (m, 1H), 4.10 (t, J = 8.0 Hz, 2H), 3.25 - 3.16 (m, 3H), 3.12 - 2.81 (m, 4H), 2.76 - 2.65 (m, 1H), 2.64 - 2.53 (m, 3H), 2.40 - 2.23 (m, 2H), 2.13 -2.07 (m, 1H), 1.93 - 1.85 (m, 1H), 1.39 - 1.31 (m, 1H).

[0629] Example 33. Synthesis of I-44:

[0630]

[0631] Experimental Procedure:

[0632] Step 1

[0633] 4-DMAP (60.7 mg, 0.50 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (100 mg, 0.50 mmol), [(2R,7aS)-2-fluoro-hexahydropyrrolizine-7a-yl]methanol (79.1 mg, 0.50 mmol), CMPI (165.1 mg, 0.65 mmol), and Et3N (75.4 mg, 0.75 mmol) in DMF (10 mL). The reaction mixture was stirred at 20°C for 16 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-bridge purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methyl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate formate (14.6 mg, 9%)) as a white solid.

[0634] MS (ESI): C 20 H 23 Calculated value for FN2O2 342.17, m / z measured value 343.1 [M+H] + .

[0635] 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 0.2H), 7.96 - 7.92 (m, 1H), 7.43 - 7.39 (m, 1H), 7.20 - 7.15 (m, 2H), 5.34 - 5.21 (m, 1H), 4.16 (t, J = 8.0 Hz, 2H), 4.00 - 3.88 (m, 2H), 3.21 (t, J = 8.0 Hz, 2H), 3.11 - 3.09 (m, 2H), 3.04 - 3.02 (m, 1H), 2.86 - 2.80 (m, 1H), 2.67 - 2.57 (m, 2H), 2.14 - 2.05 (m, 2H), 2.01 - 1.98 (m, 1H), 1.88 - 1.71 (m, 3H).

[0636] Example 34. Synthesis of I-45:

[0637]

[0638] Experimental Procedure:

[0639] Step 1

[0640] HATU (90.7 mg, 0.24 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (40 mg, 0.20 mmol), 1,1-difluoro-6-azaspiro[2.5]octane (29.3 mg, 0.20 mmol) and DIEA (77.1 mg, 0.60 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 6 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-Bridge Purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain (1,1-difluoro-6-azaspiro[2.5]octane-6-yl)(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)methanone (43.8 mg, 67%) as a white solid.

[0641] MS (ESI): Calculated value for C19H20F2N2O 330.15, m / z measured value 331.1 [M+H] + .

[0642] 1 H NMR (400 MHz, DMSO-d6) δ 7.55 - 7.53 (m, 1H), 7.38 - 7.35 (m, 1H), 7.14 - 7.06 (m, 2H), 4.12 (t, J = 7.2 Hz, 2H), 3.65 - 3.62 (m, 2H), 3.52 - 3.44 (m, 2H), 3.05 (t, J = 7.2 Hz, 2H), 2.61 - 2.51 (m, 2H), 1.70 - 1.63 (m, 2H), 1.54 - 1.51 (m, 2H), 1.34 (t, J = 8.4 Hz, 2H).

[0643] Example 35. Synthesis of I-46:

[0644]

[0645] Experimental Procedure:

[0646] Step 1

[0647] HATU (52 mg, 0.13 mmol) was added in several portions at 25°C to a mixture of 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylic acid (28 mg, 0.14 mmol) and DIEA (117 mg, 0.90 mmol) in DMF (1 mL). The mixture was stirred at 25°C for 30 minutes. 1-(azetidine-3-yl)-4-fluoropiperidine dihydrochloride (30 mg, 0.12 mmol) was added to the mixture at 25°C. The mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm; mobile phase A: water (0.1% FA), B: acetonitrile, 15–55% B within 10 min; flow rate: 30 mL / min; wavelength: 214 / 254 nm) to obtain (2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)(3-(4-fluoropiperidin-1-yl)azetidine-1-yl)methanone formate (43.0 mg, 96%) as a white solid.

[0648] MS (ESI): C 20 H 24 Calculated value for FN3O 341.19, m / z measured value 342.2 [M+H] + .

[0649] 1H NMR (400 MHz, DMSO) δ 8.13 (s, 0.31H), 7.74 (d, J = 6.4 Hz, 1H), 7.37 (d, J = 6.8 Hz, 1H), 7.24 - 7.00 (m, 2H), 5.04 - 4.56 (m, 1H), 4.38 - 4.02 (m, 5H), 3.93 - 3.79 (m, 1H), 3.20 - 2.96 (m, 3H), 2.64 - 2.52 (m, 3H), 2.45 - 2.36 (m, 1H), 2.30 - 2.08 (m, 2H), 1.96 - 1.59 (m, 4H).

[0650] Example 36. Synthesis of I-47:

[0651]

[0652] Experimental Procedure:

[0653] Step 1

[0654] HATU (61 mg, 0.16 mmol) and DIEA (69 mg, 0.53 mmol) were added to a mixture of 1H,2H,3H-benzo[b]pyrrolidine-9-carboxylic acid (21 mg, 0.11 mmol) in dimethylformamide (5 mL) at 0°C under N2 protection. After stirring for 30 minutes, 1-(azetidine-3-yl)-3,3-difluoropyrrolidine dihydrochloride (25 mg, 0.11 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 2 hours. LCMS indicated that the reaction was complete. The mixture was extracted with EA (10 ml x 3). The combined organic layer was washed with brine (10 mL x 2), dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-bridge purification c18 10 um OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 um, mobile phase A: H2O (0.1% FA), phase B: ACN, 35~65% of A, 10 min, flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain 1-[1-({1H,2H,3H-benzo[b]pyrrolizine-9-yl}carbonyl)azetidine-3-yl]-3,3-difluoropyrrolidine formate (16.5 mg, 45%) as a white solid.

[0655] MS (ESI): C 19 H 21 Calculated value for F2N3O 345.17, m / z measured value 346.2 [M+H] + .

[0656] 1H NMR (400 MHz, DMSO) δ 8.13 (s, 0.05 H), 7.72 (dd, J = 8.0, 4.0 Hz, 1H), 7.36 (dd, J = 8.0, 4.0 Hz, 1H), 7.20 - 7.01 (m, 2H), 4.12 (t, J = 8.0 Hz, 4H), 3.94 - 3.92 (m, 2H), 3.10 (t, J = 8.0 Hz, 2H), 3.04 - 2.73 (m, 4H), 2.61 -2.54 (m, 3H), 2.30 - 2.23 (m, 2H).

[0657] Example 37. Synthesis of I-48:

[0658]

[0659] Experimental Procedure:

[0660] Step 1

[0661] HATU (90.7 mg, 0.24 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (40 mg, 0.20 mmol), 3,3-difluoro-1-methylpiperidine-4-amine (29.9 mg, 0.20 mmol), and DIEA (77.1 mg, 0.60 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 6 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain N-(3,3-difluoro-1-methylpiperidin-4-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate (36.5 mg, 52%) as a yellow solid.

[0662] MS (ESI): C 18 H21 Calculated value for F2N3O 333.17, m / z measured value 334.1 [M+H] + .

[0663] 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.14 (s, 0.1H), 7.51 (d, J = 7.2 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.18 - 7.10 (m, 2H), 4.45 - 4.40 (m, 1H), 4.21 (d, J = 13.2 Hz, 1H), 4.14 (t, J = 7.2 Hz, 2H), 3.87 - 3.85 (m, 1H), 3.72 - 3.61 (m, 1H), 3.14 - 2.95 (m, 3H), 2.67 - 2.57 (m, 5H), 2.27 - 2.24 (m, 1H), 1.75 - 1.65 (m, 1H).

[0664] Example 38. Synthesis of I-49:

[0665]

[0666] Experimental Procedure:

[0667] Step 1

[0668] HATU (48 mg, 0.12 mmol) was added in several portions at 25°C to a mixture of 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylic acid (27 mg, 0.13 mmol) and DIEA (109 mg, 0.84 mmol) in DMF (1 mL). The mixture was stirred at 25°C for 30 minutes. 1-(3,3-difluorocyclobutyl)piperazine dihydrochloride (30 mg, 0.12 mmol) was added to the mixture at 25°C. The mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm; mobile phase A: water (0.1% FA), B: acetonitrile, 20–60% B within 10 min; flow rate: 30 mL / min; wavelength: 214 / 254 nm) to obtain (4-(3,3-difluorocyclobutyl)piperazine-1-yl)(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)methanone formate (29.9 mg, 68%) as a white solid.

[0669] MS (ESI): C 20 H 23 Calculated value for F2N3O 359.42, m / z measured value 360.2 [M+H] + .

[0670] 1 H NMR (400 MHz, DMSO) δ 8.13 (s, 0.09H), 7.52 (d, J = 7.2 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.16 - 7.03 (m, 2H), 4.12 (t, J = 7.2 Hz, 2H), 3.54 (s, 4H), 3.03 (t, J = 7.2 Hz, 2H), 2.78 - 2.54 (m, 5H), 2.48 - 2.26 (m, 6H).

[0671] Example 39. Synthesis of I-50:

[0672]

[0673] Experimental Procedure:

[0674] Step 1

[0675] HATU (90.7 mg, 0.24 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (40 mg, 0.20 mmol), 4-(3,3-difluoroazetidin-1-yl)piperidine (35.0 mg, 0.20 mmol) and DIEA (77.1 mg, 0.60 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 6 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain (4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl)(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)methanone formate (25.0 mg, 35%) as a white solid.

[0676] MS (ESI): C 20 H 23 Calculated value for F2N3O 359.18, m / z measured value 360.1 [M+H] + .

[0677] 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 0.15H), 7.51 - 7.49 (m, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.13 - 7.06 (m, 2H), 4.11 (t, J = 7.2 Hz, 2H), 3.94 - 3.92 (m, 2H), 3.58 - 3.56 (m, 3H), 3.12 - 3.00 (m, 4H), 2.59 - 2.53 (m, 2H), 2.50 - 2.33 (m, 2H), 1.75 - 1.69 (m, 2H), 1.22 - 1.19 (m, 2H).

[0678] Example 40. Synthesis of I-51:

[0679]

[0680] Experimental Procedure:

[0681] Step 1

[0682] HATU (65 mg, 0.17 mmol) and DIEA (147 mg, 1.14 mmol) were added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (23 mg, 0.11 mmol) in dimethylformamide (5 mL) at 0°C under N2 protection. After stirring for 30 minutes, 4-(3,3-difluoropyrrolidine-1-yl)piperidine hydrochloride (30 mg, 0.11 mmol) was added to the reaction mixture. The mixture was stirred at 50°C for 2 hours. LCMS indicated that the reaction was complete. The mixture was extracted with EA (10 ml x 3). The combined organic layer was washed with brine (10 mL x 2), dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-bridge purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA), B (acetonitrile), 20~60% of A, B, 10 min, flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain 1-({1H,2H,3H-benzo[b]pyrrolizine-9-yl}carbonyl)-4-(3,3-difluoropyrrolidine-1-yl)piperidine formate (27.0 mg, 63%) as a pale yellow solid.

[0683] MS (ESI): C 21 H 25 Calculated value for F2N3O 373.20, m / z measured value 374.2 [M+H] + .

[0684] 1H NMR (400 MHz, DMSO) δ 8.14 (s, 0.13H), 7.52 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.19 - 7.06 (m, 2H), 4.31 - 3.78 (m, 6H), 3.57 - 3.48 (m, 2H), 3.08 - 2.73 (m, 6H), 2.62 - 2.54 (m, 3H), 2.16 - 2.02 (m, 2H), 1.53 - 1.41 (m, 2H).

[0685] Example 41. Synthesis of I-52 and I-53:

[0686]

[0687] Experimental Procedure:

[0688] Step 1

[0689] N-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboximideamide (146 mg, 0.67 mmol) was added to a mixture of 1-(tert-butoxycarbonyl)-5,5-difluoropiperidin-3-carboxylic acid (150 mg, 0.56 mmol), HOBt (114 mg, 0.84 mmol), and EDCI (162 mg, 0.84 mmol) in DMF (3 mL) at 25°C. The reaction mixture was stirred at 50°C under N2 for 16 hours. The mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash chromatography (mobile phase A: PE, B: EA; 0–20% B in A) to obtain tert-butyl 5-(3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole-5-yl)-3,3-difluoropiperidine-1-carboxylate (120 mg, 42%) as a yellow solid. MS (ESI): C 23 H 26Calculated value for F2N4O3 444.20, m / z measured value 467.2 [M+Na] + .

[0690] Step 2

[0691] 4 M HCl (2 mL) in EA was added to a mixture of tert-butyl 5-(3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole-5-yl)-3,3-difluoropiperidine-1-carboxylate (115 mg, 0.26 mmol) in DCM (6 mL) at 0°C. The reaction mixture was stirred at 25°C under N2 for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by a reverse-phase column (mobile phase A: H2O (0.1% HCl), B: ACN; 0 to 55% of A is B) to obtain 5-(5,5-difluoropiperidin-3-yl)-3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole (50 mg, 56%) as a white solid.

[0692] MS (ESI): C 18 H 18 Calculated value for F2N4O 344.14, m / z measured value 345.1 [M+H] + .

[0693] Step 3

[0694] 5-(5,5-difluoropiperidin-3-yl)-3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole (50 mg) was separated by chiral purification SFC (Dicel Chiral Cell OJ, 250 mm * 30 mm ID, 10 μm; mobile phase A: CO2, B: MeOH [0.2% NH3 (7 M solution in MeOH)], A / B=65 / 35; flow rate: 70 g / min; wavelength: 214 nm; column temperature: 35°C) to obtain (R)-5-(5,5-difluoropiperidin-3-yl)-3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole hydrochloride (peak 1, 20.1 mg (40%) and (S)-5-(5,5-difluoropiperidin-3-yl)-3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole hydrochloride (peak 2, 21.4 mg, 42%) were obtained as white solids.

[0695] I-52 (Peak 1)

[0696] MS (ESI): C 18 H 18 Calculated value for F2N4O 344.14, m / z measured value 345.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.90 (br, 2H), 8.03 - 7.96 (m, 1H), 7.49 - 7.41 (m, 1H), 7.24 - 7.14 (m, 2H), 4.20 (t, J = 7.2 Hz, 2H), 3.85 - 3.68 (m, 3H), 3.63 - 3.44 (m, 2H), 3.27 (t, J = 7.2 Hz, 2H), 2.89 - 2.78 (m, 1H), 2.70 - 2.55 (m, 3H).

[0697] I-53 (Peak 2)

[0698] MS (ESI): C 18 H 18Calculated value for F2N4O 344.14, m / z measured value 345.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.91 (br, 2H), 8.03 - 7.97 (m, 1H), 7.49 - 7.42 (m, 1H), 7.25 - 7.14 (m, 2H), 4.20 (t, J = 7.2 Hz, 2H), 3.85 - 3.68 (m, 3H), 3.63 - 3.45 (m, 2H), 3.27 (t, J = 7.2 Hz, 2H), 2.89 - 2.78 (m, 1H), 2.70 - 2.55 (m, 3H).

[0699] Example 42. Synthesis of I-54 and I-55:

[0700]

[0701] Experimental Procedure:

[0702] Step 1

[0703] EDCI (130 mg, 0.68 mmol) and HOBt (92 mg, 0.68 mmol) were added at room temperature to a solution of 1-[(tert-butoxy)carbonyl]-5,5-difluoropiperidine-3-carboxylic acid (120 mg, 0.45 mmol) in dimethylformamide (4 mL). After stirring for 1 hour, 7-fluoro-N-hydroxy-1H,2H,3H-benzo[b]pyrrolizine-9-carboximideamide (106 mg, 0.45 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 1 hour. Subsequently, the reaction mixture was stirred at 50°C for 16 hours. LCMS indicated that the reaction was complete. After the reaction, the reaction mixture was quenched with water. The mixture was extracted with EA (20 ml x 3). The combined organic layer was washed with brine (20 mL x 2), dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by a silica gel chromatography column (DCM / MEOH = 20:1) to obtain tert-butyl 3,3-difluoro-5-(3-{7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-yl}-1,2,4-oxadiazole-5-yl)piperidine-1-carboxylate (120 mg, 57.4%) as a white solid.

[0704] MS (ESI): C 23 H 25 Calculated value for F3N4O3 462.19, m / z measured value 485.1 [M+Na] + .

[0705] Step 2

[0706] HCl (4 M, 2 ml) in EA was added dropwise to a solution of tert-butyl 3,3-difluoro-5-(3-{7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-yl}-1,2,4-oxadiazole-5-yl)piperidine-1-carboxylate (120 mg, 0.26 mmol) in DCM (2 mL) at 0°C under N2. The mixture was then stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain the crude product. The residue was purified by SFC (chiral cell AD, 250 mm × 30 mm ID, 10 μm, mobile phase: CO2 / MeOH [0.2% NH3 (7 M solution in MeOH)] = 45 / 55, flow rate: 80 g / min, wavelength: UV 214 nm, temperature: 35°C) to obtain (5R)-3,3-difluoro-5-(3-{7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-yl}-1,2,4-oxadiazole-5-yl)piperidine (34 mg, 36.1%) as a white solid, and (5S)-3,3-difluoro-5-(3-{7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-yl}-1,2,4-oxadiazole-5-yl)piperidine (34.6 mg, 36.8%) was obtained as a white solid.

[0707] I-54

[0708] MS (ESI): C 18 H 17 Calculated value for F3N4O 362.14, m / z measured value 363.1 [M+H] + .

[0709] 1H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 7.68 (dd, J = 12.0, 4.0 Hz, 1H), 7.51 - 7.49 (m, 1H), 7.10 - 7.04 (m, 1H), 4.21 (t, J = 8.0 Hz, 2H), 3.92 - 3.66 (m, 3H), 3.64 - 3.45 (m, 2H), 3.27 (t, J = 8.0 Hz, 2H), 2.88 -2.79 (s, 1H), 2.73 - 2.57 (m, 3H).

[0710] I-55

[0711] MS (ESI): C 18 H 17 Calculated value for F3N4O 362.14, m / z measured value 363.2 [M+H] + .

[0712] 1 H NMR (400 MHz, DMSO) δ 9.89 (s, 1H), 7.68 (dd, J = 12.0, 4.0 Hz, 1H), 7.51 -7.46 (m, 1H), 7.09 - 7.04 (m, 1H), 4.21 (t, J = 8.0 Hz, 2H), 3.88 - 3.69 (m, 3H), 3.65 - 3.50 (m, 2H), 3.27 (t, J = 8.0 Hz, 2H), 2.88 - 2.79 (m, 1H), 2.72 - 2.57 (m, 3H).

[0713] Example 43. Synthesis of I-56:

[0714]

[0715] Experimental Procedure:

[0716] Step 1

[0717] HOBT (150.7 mg, 1.11 mmol) and EDCI (213.7 mg, 1.11 mmol) were added to a mixture of (3R,4S)-1-[(tert-butoxy)carbonyl]-3-fluoropiperidin-4-carboxylic acid (229.7 mg, 0.93 mmol) in ACN (10 mL). The mixture was stirred at room temperature for 1 hour. N-hydroxy-1H,2H,3H-benzo[b]pyrrolizine-9-carboximide (200 mg, 0.93 mmol) was added. The reaction mixture was stirred at 80°C for 3 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE:EA = 1:1) to obtain tert-butyl (3R,4S)-4-(3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole-5-yl)-3-fluoropiperidine-1-carboxylate (40 mg, 8%) as a yellow solid.

[0718] MS (ESI): C 23 H 27 Calculated value for FN4O3 426.21, m / z measured value 449.2 [M+Na].

[0719] Step 2

[0720] A mixture of tert-butyl (3R,4S)-4-(3-{1H,2H,3H-benzo[b]pyrrolizine-9-yl}-1,2,4-oxadiazole-5-yl)-3-fluoropiperidine-1-carboxylate (40 mg, 0.094 mmol) in HCl / EA (4N) (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain 3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-5-((3R,4S)-3-fluoropiperidine-4-yl)-1,2,4-oxadiazole formate (10.4 mg, 32%) as a white solid.

[0721] MS (ESI): C 18 H 19 Calculated value for FN4O 326.15, m / z measured value 327.1 [M+H] + .

[0722] 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 0.8H), 8.01 - 7.98 (m, 1H), 7.45 - 7.43 (m, 1H), 7.22 - 7.16 (m, 2H), 5.16 - 5.03 (m, 1H), 4.18 (t, J = 7.2 Hz, 2H), 3.68 - 3.56 (m, 2H), 3.28 - 3.19 (m, 4H), 3.10 - 3.06 (m, 1H), 2.98 - 2.85 (m, 1H), 2.69 - 2.62 (m, 2H), 2.08 - 1.97 (m, 2H).

[0723] Example 44. Synthesis of I-57 and I-58:

[0724]

[0725] Experimental Procedure:

[0726] Step 1

[0727] 3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-5-((3R,4S)-3-fluoropiperidin-4-yl)-1,2,4-oxadiazole (8 mg, 0.025 mmol) was separated using a purification SFC (Daicel Chiral Cell ID, 250 mm × 30 mm ID, 10 µm mobile phase A / B: CO2 / MeOH [0.2% NH3 (7 M solution in MeOH)] = 50 / 50, flow rate: 80 g / min, column temperature: 35°C), and 3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-5-((3S,4R)-3-fluoropiperidin-4-yl)-1,2,4-oxadiazole formate (1.3 mg, 16%) was obtained as a yellow solid, and 3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-5-((3R,4S)-3-fluoropiperidin-4-yl)-1,2,4-oxadiazole formate (1.2 mg, 15%) was obtained as a yellow solid.

[0728] MS (ESI): C 18 H 19 Calculated value for FN4O 326.15, m / z measured value 327.1 [M+H] + .

[0729] 1 H NMR (400 MHz, MeOD) δ 8.51 (s, 1H), 8.05 - 8.03 (m, 1H), 7.35 - 7.33 (m, 1H), 7.21 - 7.14 (m, 2H), 5.48 - 5.36 (m, 1H), 4.17 (t, J = 7.2 Hz, 2H), 3.73 - 3.58 (m, 2H), 3.47 - 3.43 (m, 2H), 3.38 - 3.31 (m, 2H), 3.16 - 3.06 (m, 1H), 2.77 - 2.62 (m, 2H), 2.50 - 2.29 (m, 2H).

[0730] 1H NMR (400 MHz, MeOD) δ 8.50 (s, 1H), 8.05 - 8.03 (m, 1H), 7.35 - 7.33 (m, 1H), 7.20 - 7.14 (m, 2H), 5.46 - 5.34 (m, 1H), 4.17 (t, J = 7.2 Hz, 2H), 3.69 - 3.58 (m, 2H), 3.48 - 3.42 (m, 2H), 3.38 - 3.31 (m, 2H), 3.12 - 3.05 (m, 1H), 2.74 - 2.66 (m, 2H), 2.49 - 2.31 (m, 2H).

[0731] Example 45. Synthesis of I-59:

[0732]

[0733] Experimental Procedure:

[0734] Step 1

[0735] HOBT (173.8 mg, 1.29 mmol) and EDCI (246.6 mg, 1.29 mmol) were added to a mixture of (3R,4S)-1-[(tert-butoxy)carbonyl]-3-fluoropiperidine-4-carboxylic acid (265.0 mg, 1.07 mmol) in ACN (10 mL). The mixture was stirred at room temperature for 1 hour. 7-fluoro-N-hydroxy-1H,2H,3H-benzo[b]pyrrolizine-9-carboximide (250 mg, 1.07 mmol) was added. The reaction mixture was stirred at 80°C for 3 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE:EA = 1:1) to obtain tert-butyl (3R,4S)-3-fluoro-4-(3-(7-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole-5-yl)piperidine-1-carboxylate (60 mg, 10%) as a yellow solid.

[0736] MS (ESI): C23 H 26 Calculated value for F2N4O3 444.20, m / z measured value 467.2 [M+Na].

[0737] Step 2

[0738] A mixture of tert-butyl (3R,4S)-3-fluoro-4-(3-{7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-yl}-1,2,4-oxadiazole-5-yl)piperidine-1-carboxylate (60 mg, 0.14 mmol) in HCl / EA (4N) (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain 3-(7-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-5-((3R,4S)-3-fluoropiperidine-4-yl)-1,2,4-oxadiazole formate (31.3 mg, 65%) as a yellow solid.

[0739] MS (ESI): C 18 H 18 Calculated value for F2N4O 344.14, m / z measured value 345.1 [M+H] + .

[0740] 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 0.7H), 7.67 (dd, J = 10.0, 2.4 Hz, 1H), 7.48 (dd, J = 8.8, 4.4 Hz, 1H), 7.06 (td,J = 9.2, 2.4 Hz, 1H), 5.18 - 5.06 (m, 1H), 4.19 (t, J = 7.2 Hz, 2H), 3.70 - 3.59 (m, 2H), 3.27 - 3.22 (m, 3H), 3.12 - 3.08 (m, 1H), 3.01 - 2.88 (m, 1H), 2.72 - 2.62 (m, 3H), 2.09 - 2.02 (m, 2H).

[0741] Example 46. Synthesis of I-60 and I-61:

[0742]

[0743] Experimental Procedure:

[0744] Step 1

[0745] 3-(7-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-5-((3R,4S)-3-fluoropiperidin-4-yl)-1,2,4-oxadiazole (28 mg, 0.081 mmol) was separated via a purification SFC (Daicel Chiral Cell ID, 250 mm × 30 mm ID, 10 µm mobile phase A / B: CO2 / MeOH [0.2% NH3 (7 M solution in MeOH)] = 50 / 50, flow rate: 80 g / min, column temperature: 35°C) to obtain 3-(7-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-5-((3S,4R)-3-fluoropiperidin-4-yl)-1,2,4-oxadiazole formate (1.0 mg, 4%) was obtained as a yellow solid and 3-(7-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-5-((3R,4S)-3-fluoropiperidin-4-yl)-1,2,4-oxadiazole formate (2.0 mg, 7%) was obtained as a yellow solid.

[0746] MS (ESI): C 18 H18 Calculated value for F2N4O 344.14, m / z measured value 345.1 [M+H] + .

[0747] 1 H NMR (400 MHz, MeOD) δ 8.51 (s, 1H), 7.75 - 7.68 (m, 1H), 7.34 - 7.31 (m, 1H), 6.99 - 6.91 (m, 1H), 5.36 - 5.24 (m, 1H), 4.18 (t, J = 7.2 Hz, 2H), 3.65 - 3.50 (m, 2H), 3.35 - 3.31 (m, 3H), 3.14 - 2.95 (m, 2H), 2.74 - 2.67 (m, 2H), 2.43 - 2.23 (m, 2H).

[0748] 1 H NMR (400 MHz, MeOD) δ 8.56 (s, 1H), 7.72 - 7.69 (m, 1H), 7.33 - 7.30 (m, 1H), 6.97 - 6.92 (m, 1H), 5.41 - 5.29 (m, 1H), 4.17 (t, J = 7.2 Hz, 2H), 3.67 - 3.53 (m, 2H), 3.40 - 3.31 (m, 3H), 3.26 - 3.00 (m, 2H), 2.73 - 2.66 (m, 2H), 2.46 - 2.27 (m, 2H).

[0749] Example 47. Synthesis of I-62:

[0750]

[0751] Experimental Procedure:

[0752] Step 1

[0753] NMM (171 mg, 1.69 mmol) was added to a mixture of CDMT (119 mg, 0.67 mmol) in dioxane (5 mL) at 25°C. After 30 minutes, 1-(tert-butoxycarbonyl)-3,3-difluoropiperidine-4-carboxylic acid (150 mg, 0.56 mmol) was added to the reaction mixture and stirred at 25°C for 1 hour. N-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxyimideamide (146 mg, 0.67 mmol) was added to the reaction mixture and stirred at 50°C for 16 hours under N2. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by flash chromatography (mobile phase A: PE, B: EA; 0 to 35% of A is B) to obtain tert-butyl 4-(3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole-5-yl)-3,3-difluoropiperidine-1-carboxylate (150 mg, 53%) as a yellow solid.

[0754] MS (ESI): C 23 H 26 Calculated value for F2N4O3 444.20, m / z measured value 467.2 [M+Na] + .

[0755] Step 2

[0756] 4 M HCl (2 mL) in EA was added to a mixture of tert-butyl 4-(3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole-5-yl)-3,3-difluoropiperidine-1-carboxylate (120 mg, 0.27 mmol) in DCM (6 mL) at 0°C. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by flash reverse phase (mobile phase A: H2O (0.1% HCl), B: ACN; 0 to 55% of A is B) to obtain 5-(3,3-difluoropiperidin-4-yl)-3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole hydrochloride (41.2 mg, 44%) as a white solid.

[0757] MS (ESI): C 18 H 18 Calculated value for F2N4O 344.14, m / z measured value 345.1 [M+H] + .

[0758] 1 H NMR (400 MHz, DMSO) δ 10.57 - 9.00 (m, 2H), 8.03 - 7.94 (m, 1H), 7.50 - 7.41 (m, 1H), 7.25 - 7.15 (m, 2H), 4.39 - 4.24 (m, 1H), 4.20 (t, J = 7.2 Hz, 2H), 3.99 - 3.88 (m, 1H), 3.79 - 3.64 (m, 1H), 3.49 - 3.42 (m, 1H), 3.26 (t, J = 7.6 Hz, 2H), 3.22 - 3.11 (m, 1H), 2.70 - 2.60 (m, 2H), 2.57 - 2.52 (m, 1H), 2.43 - 2.31 (m, 1H).

[0759] Example 48. Synthesis of I-63:

[0760]

[0761] Experimental Procedure:

[0762] Step 1

[0763] EDCI (163 mg, 0.85 mmol) and HOBt (115 mg, 0.85 mmol) were added to a solution of 1-[(tert-butoxy)carbonyl]-3,3-difluoropiperidine-4-carboxylic acid (150 mg, 0.57 mmol) in dimethylformamide (5 mL) at room temperature. After stirring for 1 hour, 7-fluoro-N-hydroxy-1H,2H,3H-benzo[b]pyrrolizine-9-carboximidamide (211 mg, 0.90 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 1 hour. Subsequently, the reaction mixture was stirred at 50°C for 16 hours. LCMS indicated that the reaction was complete. After the reaction, the reaction mixture was quenched with water. The mixture was extracted with EA (20 ml x 3). The combined organic layer was washed with brine (20 mL x 2), dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by a silica gel chromatography column (DCM / MEOH = 20:1) to obtain tert-butyl 3,3-difluoro-4-(3-{7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-yl}-1,2,4-oxadiazole-5-yl)piperidine-1-carboxylate (100 mg, 38%) as a yellow solid.

[0764] MS (ESI): C 23 H 25 F3N4O3, 462.19, m / z measured 485.2 [M+Na] + .

[0765] Step 2

[0766] HCl (4 M, 2 ml) in EA was added dropwise to a solution of tert-butyl 3,3-difluoro-4-(3-{7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-yl}-1,2,4-oxadiazole-5-yl)piperidine-1-carboxylate (100 mg, 0.22 mmol) in DCM (2 mL) at 0°C under N2. The mixture was then stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain the crude product. The residue was purified by HPLC for purification (Xbridge purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA), B (acetonitrile), 20~100% B in A, 10.5 min, flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain 3,3-difluoro-4-(3-{7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-yl}-1,2,4-oxadiazole-5-yl)piperidine formate (35 mg, 43.5%) as a white solid.

[0767] MS (ESI): C 18 H 17 Calculated value for F3N4O 362.14, m / z measured value 363.2 [M+H] + .

[0768] 1 H NMR (400 MHz, DMSO) δ 8.14 (s, 1H), 7.66 (dd, J = 12.0, 4.0 Hz, 1H), 7.48 (dd, J = 8.0, 4.0 Hz, 1H), 7.09 - 7.04 (m, 1H), 4.20 (t, J = 8.0 Hz, 2H), 4.08 -3.96 (m, 1H), 3.29 - 3.15 (m, 4H), 3.03 - 2.93 (m, 2H), 2.75 - 2.58 (m, 3H), 2.19 - 2.04 (m, 2H).

[0769] Example 49. Synthesis of I-64:

[0770]

[0771] Experimental Procedure:

[0772] Step 1

[0773] HATU (90.7 mg, 0.60 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (40 mg, 0.20 mmol), tert-butyl 4-amino-2-azabicyclo[2.2.1]heptane-2-carboxylate (42.2 mg, 0.20 mmol) and DIEA (77.1 mg, 0.60 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 6 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain tert-butyl 4-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamido)-2-azabicyclo[2.2.1]heptane-2-carboxylate (60 mg, crude material) as a yellow solid, which was used directly in a subsequent step.

[0774] MS (ESI): C 23 H 29 Calculated value for N3O3 395.22, m / z measured value 396.2 [M+H] + .

[0775] Step 2

[0776] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamido)-2-azabicyclo[2.2.1]heptane-2-carboxylate (60 mg, 0.15 mmol) in HCl / EA (4N) (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain N-(2-azabicyclo[2.2.1]heptane-4-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate (22.2 mg, 50%) as a white solid.

[0777] MS (ESI): C 18 H 21 Calculated value for N3O 295.17, m / z measured value 296.2 [M+H] + .

[0778] 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.91 - 7.89 (m, 1H), 7.51 (s, 1H), 7.38 - 7.36 (m, 1H), 7.15 - 7.08 (m, 2H), 4.11 (t, J = 7.2 Hz, 2H), 3.78 (s, 1H), 3.36 - 3.17 (m, 4H), 2.61 - 2.54 (m, 2H), 2.09 - 2.03 (m, 2H), 1.98 - 1.95 (m, 1H), 1.87 - 1.85 (m, 3H).

[0779] Example 50. Synthesis of I-65:

[0780]

[0781] Experimental Procedure:

[0782] Step 1

[0783] HATU (68.0 mg, 0.18 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (30 mg, 0.15 mmol), tert-butyl 8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylate (37.0 mg, 0.15 mmol) and DIEA (57.8 mg, 0.45 mmol) in DMF (5 mL). The reaction mixture was stirred at 50°C for 12 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain tert-butyl 6-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carbonyl)-8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylate (40 mg, crude material) as a yellow solid, which was used directly in a subsequent step.

[0784] MS (ESI): C 23 H 27 Calculated value for F2N3O3 431.20, m / z measured value 432.2 [M+H] + .

[0785] Step 2

[0786] A mixture of tert-butyl 6-({1H,2H,3H-benzo[b]pyrrolizine-9-yl}carbonyl)-8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylate (40 mg, 0.093 mmol) in HCl / EA (4N) (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-Bridge Purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain (8,8-difluoro-2,6-diazaspiro[3.4]octane-6-yl)(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)methanone formate (19.1 mg, 62%) as a white solid.

[0787] MS (ESI): C 18 H 19 Calculated value for F2N3O 331.15, m / z measured value 332.1 [M+H] + .

[0788] 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 0.7H), 7.59 (d, J = 7.2 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.16 - 7.09 (m, 2H), 4.13 (t, J = 7.2 Hz, 2H), 3.98 - 3.89 (m, 4H), 3.76 - 3.74 (m, 2H), 3.43 - 3.41 (m, 2H), 3.08 (t, J = 7.6 Hz, 2H), 2.62 - 2.55 (m, 2H).

[0789] Example 51. Synthesis of I-66:

[0790]

[0791] Experimental Procedure:

[0792] Step 1

[0793] HATU (68.0 mg, 0.18 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (30 mg, 0.15 mmol), tert-butyl 5,5-difluoro-2,7-diazaspiro[3.5]nonane-2-carboxylate (39.1 mg, 0.15 mmol) and DIEA (57.8 mg, 0.45 mmol) in DMF (5 mL). The reaction mixture was stirred at 50°C for 12 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain tert-butyl 7-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carbonyl)-5,5-difluoro-2,7-diazaspiro[3.5]nonane-2-carboxylate (40 mg, crude product) as a yellow solid, which was used directly in a subsequent step.

[0794] MS (ESI): C 24 H 29 Calculated value for F2N3O3 445.22, m / z measured value 446.2 [M+H] + .

[0795] Step 2

[0796] A mixture of tert-butyl 7-({1H,2H,3H-benzo[b]pyrrolizine-9-yl}carbonyl)-5,5-difluoro-2,7-diazaspiro[3.5]nonane-2-carboxylate (40 mg, 0.090 mmol) in HCl / EA (4N) (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-Bridge purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain (5,5-difluoro-2,7-diazaspiro[3.5]nonan-7-yl)(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)methanone formate (18.2 mg, 57%) as a yellow solid.

[0797] MS (ESI): C 19 H 21 Calculated value for F2N3O 345.17, m / z measured value 346.1 [M+H] + .

[0798] 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.16 - 7.08 (m, 2H), 4.13 (t, J = 8.0 Hz, 2H), 3.86 (t, J = 12.0 Hz, 4H), 3.56 - 3.47 (m, 4H), 3.01 (t, J = 7.2 Hz, 2H), 2.61 - 2.54 (m, 2H), 2.04 - 1.99 (m, 2H).

[0799] Example 52. Synthesis of I-67:

[0800]

[0801] Experimental Procedure:

[0802] Step 1

[0803] HATU (72 mg, 0.19 mmol) was added to a mixture of 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylic acid (40 mg, 0.20 mmol) and DIEA (117 mg, 0.90 mmol) in DMF (2 mL) at 25°C under N2. After stirring for 30 minutes, tert-butyl 8,8-difluoro-2,6-diazaspiro[3.4]octane-6-carboxylate (45 mg, 0.18 mmol) was added to the reaction mixture. The mixture was stirred at 25°C for 16 hours. The mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The organic layer was dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash chromatography (mobile phase A: PE, B: EA; 0 to 50% of A is B) to obtain tert-butyl 2-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carbonyl)-8,8-difluoro-2,6-diazaspiro[3.4]octane-6-carboxylate (78 mg, 89%) as a white solid.

[0804] MS (ESI): C 23 H 27 Calculated value for F2N3O3 431.20, m / z measured value 432.2 [M+H] + .

[0805] Step 2

[0806] 4 M HCl (2 mL) in EA was added to a mixture of tert-butyl 2-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carbonyl)-8,8-difluoro-2,6-diazaspiro[3.4]octane-6-carboxylate (73 mg, 0.17 mmol) in DCM (6 mL) at 0°C. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm; mobile phase A: water (0.1% TFA), B: acetonitrile, 15–45% B in 9 min; flow rate: 25 mL / min; wavelength: 214 / 254 nm) to obtain (8,8-difluoro-2,6-diazaspiro[3.4]octan-2-yl)(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)methanone trifluoroacetate (15.1 mg, 26%) as a white solid.

[0807] MS (ESI): C 18 H 19 Calculated value for F2N3O 331.15, m / z measured value 332.1 [M+H] + .

[0808] 1 H NMR (400 MHz, DMSO) δ 9.43 (s, 1.77H), 7.75 - 7.69 (m, 1H), 7.43 - 7.36 (m, 1H), 7.19 - 7.10 (m, 2H), 4.23 - 4.10 (m, 6H), 3.82 - 3.72 (m, 4H), 3.10 (t, J = 7.2 Hz, 2H), 2.63 - 2.55 (m, 2H).

[0809] Example 53. Synthesis of I-68:

[0810]

[0811] Experimental Procedure:

[0812] Step 1

[0813] HATU (68.0 mg, 0.18 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (30 mg, 0.15 mmol), tert-butyl 4,4-difluoro-2,7-diazaspiro[4.4]nonane-2-carboxylate (39.1 mg, 0.15 mmol) and DIEA (57.8 mg, 0.45 mmol) in DMF (5 mL). The reaction mixture was stirred at 50°C for 12 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain tert-butyl 7-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carbonyl)-4,4-difluoro-2,7-diazaspiro[4.4]nonane-2-carboxylate (40 mg, crude product) as a yellow solid, which was used directly in a subsequent step.

[0814] MS (ESI): C 24 H 29 Calculated value for F2N3O3 445.22, m / z measured value 446.2 [M+H] + .

[0815] Step 2

[0816] A mixture of tert-butyl 7-({1H,2H,3H-benzo[b]pyrrolizine-9-yl}carbonyl)-4,4-difluoro-2,7-diazaspiro[4.4]nonane-2-carboxylate (40 mg, 0.090 mmol) in HCl / EA (4N) (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (Xbridge purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% HCl) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain (9,9-difluoro-2,7-diazaspiro[4.4]nonan-2-yl)(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)methanone hydrochloride (8.5 mg, 27%) as a white solid.

[0817] MS (ESI): C 19 H 21 Calculated value for F2N3O 345.17, m / z measured value 346.2 [M+H] + .

[0818] 1 H NMR (400 MHz, DMSO-d6) δ 10.28 - 10.13 (m, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.14 - 7.06 (m, 2H), 4.12 (t, J = 7.2) Hz, 2H), 3.84 - 3.75 (m, 3H), 3.70 - 3.57 (m, 3H), 3.52 (s, 2H), 3.16 - 2.99 (m, 2H), 2.62 - 2.55 (m, 2H), 2.23 - 2.07 (m, 2H).

[0819] Example 54. Synthesis of I-69:

[0820]

[0821] Experimental Procedure:

[0822] Step 1

[0823] HATU (68.0 mg, 0.18 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (30 mg, 0.15 mmol), tert-butyl 9,9-difluoro-2,7-diazaspiro[4.4]nonane-2-carboxylate (39.1 mg, 0.15 mmol) and DIEA (57.8 mg, 0.45 mmol) in DMF (5 mL). The reaction mixture was stirred at 50°C for 12 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain tert-butyl 7-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carbonyl)-9,9-difluoro-2,7-diazaspiro[4.4]nonane-2-carboxylate (40 mg, crude material) as a yellow solid, which was used directly in a subsequent step.

[0824] MS (ESI): C 24 H 29 Calculated value for F2N3O3 445.22, m / z measured value 446.2 [M+H] + .

[0825] Step 2

[0826] A mixture of tert-butyl 7-({1H,2H,3H-benzo[b]pyrrolizine-9-yl}carbonyl)-9,9-difluoro-2,7-diazaspiro[4.4]nonane-2-carboxylate (40 mg, 0.090 mmol) in HCl / EA (4N) (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-Bridge purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 25 ml / min, wavelength: 214 / 254 nm) to obtain (4,4-difluoro-2,7-diazaspiro[4.4]nonan-2-yl)(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)methanone formate (19.1 mg, 61%) as a yellow solid.

[0827] MS (ESI): C 19 H 21 Calculated value for F2N3O 345.17, m / z measured value 346.3 [M+H] + .

[0828] 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 0.8H), 7.61 (d, J = 7.2 Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.16 - 7.09 (m, 2H), 4.13 (t, J = 7.2 Hz, 2H), 4.05 - 3.94 (m, 2H), 3.74 - 3.65 (m, 2H), 3.26 - 2.71 (m, 6H), 2.63 - 2.55 (m, 2H), 2.04 - 1.68 (m, 2H).

[0829] Example 55. Synthesis of I-70:

[0830]

[0831] Experimental Procedure:

[0832] Step 1

[0833] HATU (68.0 mg, 0.18 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (30 mg, 0.15 mmol), tert-butyl 4,4-difluoro-2,8-diazaspiro[4.5]decane-2-carboxylate (41.2 mg, 0.15 mmol) and DIEA (57.8 mg, 0.45 mmol) in DMF (5 mL). The reaction mixture was stirred at 50°C for 12 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain tert-butyl 8-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carbonyl)-4,4-difluoro-2,8-diazaspiro[4.5]decane-2-carboxylate (40 mg, crude material) as a yellow solid, which was used directly in a subsequent step.

[0834] MS (ESI): C 25 H 31 Calculated value for F2N3O3 459.23, m / z measured value 460.2 [M+H] + .

[0835] Step 2

[0836] A mixture of tert-butyl 8-({1H,2H,3H-benzo[b]pyrrolizine-9-yl}carbonyl)-4,4-difluoro-2,8-diazaspiro[4.5]decane-2-carboxylate (40 mg, 0.087 mmol) in HCl / EA (4N) (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-Bridge purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain (4,4-difluoro-2,8-diazaspiro[4.5]decane-8-yl)(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)methanone formate (22.8 mg, 73%) as a white solid.

[0837] MS (ESI): C 20 H 23 Calculated value for F2N3O 359.18, m / z measured value 360.1 [M+H] + .

[0838] 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 0.15H), 7.52 - 7.50 (m, 1H), 7.37 - 7.35 (m, 1H), 7.14 - 7.07 (m, 2H), 4.12 (t, J = 7.2 Hz, 2H), 4.00 - 3.97 (m, 2H), 3.16 - 3.09 (m, 4H), 3.04 (t, J = 7.2 Hz, 2H), 2.98 (s, 2H), 2.61 - 2.54 (m, 2H), 1.62 - 1.55 (m, 4H).

[0839] Example 56. Synthesis of I-71:

[0840]

[0841] Experimental Procedure:

[0842] Step 1

[0843] HATU (93 mg, 0.24 mmol) and DIEA (63 mg, 0.49 mmol) were added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (36 mg, 0.18 mmol) in dimethylformamide (3 mL) at 0°C under N2 protection. After stirring for 30 minutes, tert-butyl 6,6-difluoro-2,8-diazaspiro[4.5]decane-2-carboxylate (45 mg, 0.16 mmol) was added, and the reaction mixture was stirred at 50°C for 16 hours. LCMS indicated that the reaction was complete. The mixture was extracted with EA (10 ml x 3). The combined organic layer was washed with brine (10 mL x 2), dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by flash chromatography (PE / EA=1:1) on silica gel to obtain tert-butyl 8-({1H,2H,3H-benzo[b]pyrrolizine-9-yl}carbonyl)-6,6-difluoro-2,8-diazaspiro[4.5]decane-2-carboxylate (50.0 mg, 63%) as a pale yellow solid.

[0844] MS (ESI): C 25 H 31 Calculated value for F2N3O3 459.23, m / z measured value 460.3 [M+H] + .

[0845] Step 2

[0846] HCl (4 M, 2 ml) in EA was added dropwise to a solution of tert-butyl 8-({1H,2H,3H-benzo[b]pyrrolizine-9-yl}carbonyl)-6,6-difluoro-2,8-diazaspiro[4.5]decane-2-carboxylate (50 mg, 0.10 mmol) in DCM (2 mL) at 0°C under N2. The mixture was then stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (Welch 10u C18 250 x 21.2 mm, mobile phase A: water (0.05% NH3), B (acetonitrile), 37–47% of A, B, 9 min, flow rate: 25 ml / min, wavelength: 214 / 254 nm) to obtain 2-({1H,2H,3H-benzo[b]pyrrolizine-9-yl}carbonyl)-5,5-difluoro-2,7-diazaspiro[3.5]nonane (25.5 mg, 43.0%) as a pale yellow solid.

[0847] MS (ESI): C 20 H 23 Calculated value for F2N3O 359.18, m / z measured value 360.1 [M+H] + .

[0848] 1 H NMR (400 MHz, DMSO) δ 9.46 (s, 1H), 9.21 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.19 - 7.07 (m, 2H), 4.14 (t, J = 8.0 Hz, 2H), 4.09 - 3.87 (m, 2H), 3.78 - 3.65 (m, 1H), 3.60 - 3.50 (m, 1H), 3.33 - 3.30 (m, 1H), 3.22 (d, J = 1.6 Hz, 2H), 3.08 - 2.97 (m, 2H), 2.59 - 2.55 (m, 3H), 2.30 - 2.19 (m, 1H), 2.03 - 1.82 (m, 3H).

[0849] Example 57. Synthesis of I-72:

[0850]

[0851] Experimental Procedure:

[0852] Step 1

[0853] HATU (65 mg, 0.17 mmol) was added to a mixture of 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylic acid (36 mg, 0.18 mmol) and DIEA (105 mg, 0.81 mmol) in DMF (2 mL) at 25°C under N2. After stirring for 30 minutes, tert-butyl 4,4-difluoro-2,7-diazaspiro[4.5]decane-2-carboxylate (45 mg, 0.16 mmol) was added to the reaction mixture. The mixture was stirred at 25°C for 16 hours. The mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash chromatography (mobile phase A: PE, B: EA; 0 to 50% of A is B) to obtain tert-butyl 7-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carbonyl)-4,4-difluoro-2,7-diazaspiro[4.5]decane-2-carboxylate (75 mg, 95%) as a white solid.

[0854] MS (ESI): C 23 H 31 Calculated value for F2N3O3 459.23, m / z measured value 460.2 [M+H] + .

[0855] Step 2

[0856] 4 M HCl (2 mL) in EA was added to a mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carbonyl)-4,4-difluoro-2,7-diazaspiro[4.5]decane-2-carboxylate (70 mg, 0.15 mmol) in DCM (6 mL) at 0°C. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by flash reverse phase (mobile phase A: H2O (0.1% HCl), B: ACN; 0 to 35% of A is B) to obtain (4,4-difluoro-2,7-diazaspiro[4.5]decane-7-yl)(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)methanone hydrochloride (32.9 mg, 60%) as a white solid.

[0857] MS (ESI): C 20 H 23 Calculated value for F2N3O 359.18, m / z measured value 360.3 [M+H] + .

[0858] 1H NMR (400 MHz, DMSO) δ 9.83 (brs, 2H), 7.56 - 7.47 (m, 1H), 7.43 - 7.33 (m, 1H), 7.18 - 7.05 (m, 2H), 4.13 (t, J = 7.2 Hz, 2H), 4.05 (d, J = 13.2 Hz, 1H), 3.86 - 3.72 (m, 3H), 3.39 - 3.48 (m, 3H), 3.32 - 3.26 (m, 1H), 3.12 - 2.97 (m, 2H), 2.64 - 2.54 (m, 2H), 1.87 - 1.75 (m, 2H), 1.73 - 1.64 (m, 1H), 1.58 - 1.45 (m, 1H).

[0859] Example 58. Synthesis of I-73:

[0860]

[0861] Experimental Procedure:

[0862] Step 1

[0863] HATU (98 mg, 0.26 mmol) and DIEA (67 mg, 0.51 mmol) were added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (38 mg, 0.19 mmol) in dimethylformamide (3 mL) at 0°C under N2 protection. After stirring for 30 minutes, tert-butyl 5,5-difluoro-2,7-diazaspiro[3.5]nonane-7-carboxylate (45 mg, 0.17 mmol) was added to the reaction mixture. The mixture was stirred at 25°C for 2 hours. LCMS indicated that the reaction was complete. The mixture was extracted with EA (10 ml x 3). The combined organic layer was washed with brine (10 mL x 2), dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel flash chromatography (PE / EA=1:1) to obtain tert-butyl 2-({1H,2H,3H-benzo[b]pyrrolizine-9-yl}carbonyl)-5,5-difluoro-2,7-diazaspiro[3.5]nonane-7-carboxylate (50.0 mg, 62%) as a pale yellow solid.

[0864] MS (ESI): C 24 H 29 Calculated value for F2N3O3 445.22, m / z measured value 446.3 [M+H] + .

[0865] Step 2

[0866] HCl (4 M, 2 ml) in EA was added dropwise to a solution of tert-butyl 2-({1H,2H,3H-benzo[b]pyrrolizine-9-yl}carbonyl)-5,5-difluoro-2,7-diazaspiro[3.5]nonane-7-carboxylate (50 mg, 0.11 mmol) in DCM (2 mL) at 0°C under N2. The mixture was then stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain the crude product. The residue was purified by HPLC for purification (X-Bridge purification c18 10 µm OBD 19*150 mm / Welch's Xtimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA), B (acetonitrile), 15~45% of A, B, 10 min, flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain 2-({1H,2H,3H-benzo[b]pyrrolizine-9-yl}carbonyl)-5,5-difluoro-2,7-diazaspiro[3.5]nonane formate (30 mg, 77.3%) as a white solid.

[0867] MS (ESI): C 19 H 21 Calculated value for F2N3O 345.17, m / z measured value 346.2 [M+H] + .

[0868] 1 H NMR (400 MHz, DMSO) δ 8.20 (s, 0.35H), 7.76 - 7.69 (m, 1H), 7.40 - 7.33 (m, 1H), 7.17 - 7.07 (m, 2H), 4.14 - 4.10 (m, 4H), 3.81 (d, J = 8.0 Hz, 2H), 3.11 (t, J = 8.0 Hz, 2H), 2.84 (t, J = 12.0 Hz, 2H), 2.63 - 2.51 (m, 5H), 1.98 - 1.80 (m, 2H).

[0869] Example 59. Synthesis of I-74:

[0870]

[0871] Experimental Procedure:

[0872] Step 1

[0873] HATU (68.0 mg, 0.18 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (30 mg, 0.15 mmol), tert-butyl 6,6-difluoro-2,8-diazaspiro[4.5]decane-8-carboxylate (41.2 mg, 0.15 mmol) and DIEA (57.8 mg, 0.45 mmol) in DMF (5 mL). The reaction mixture was stirred at 50°C for 12 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain tert-butyl 2-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carbonyl)-6,6-difluoro-2,8-diazaspiro[4.5]decane-8-carboxylate (40 mg, crude material) as a yellow solid, which was used directly in a subsequent step.

[0874] MS (ESI): C 25 H 31 Calculated value for F2N3O3 459.23, m / z measured value 460.2 [M+H] + .

[0875] Step 2

[0876] A mixture of tert-butyl 2-({1H,2H,3H-benzo[b]pyrrolizine-9-yl}carbonyl)-6,6-difluoro-2,8-diazaspiro[4.5]decane-8-carboxylate (40 mg, 0.087 mmol) in HCl / EA (4N) (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-Bridge Purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% TFA) B (acetonitrile), flow rate: 25 ml / min, wavelength: 214 / 254 nm) to obtain (6,6-difluoro-2,8-diazaspiro[4.5]decane-2-yl)(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)methanone trifluoroacetate (13.6 mg, 43%) as a white solid.

[0877] MS (ESI): C 20 H 23 Calculated value for F2N3O 359.18, m / z measured value 360.0 [M+H] + .

[0878] 1 H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.14 - 7.06 (m, 2H), 4.12 (t, J = 7.2 Hz, 2H), 3.86 - 3.83 (m, 1H), 3.69 - 3.62 (m, 4H), 3.52 - 3.49 (m, 1H), 3.20 - 3.16 (m, 2H), 3.05 (t, J = 7.2 Hz, 2H), 2.61 - 2.54 (m, 2H), 2.23 - 2.16 (m, 1H), 2.00 - 1.88 (m, 3H).

[0879] Example 60. Synthesis of I-75:

[0880]

[0881] Experimental Procedure:

[0882] Step 1

[0883] HATU (98 mg, 0.26 mmol) and DIEA (67 mg, 0.51 mmol) were added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (38 mg, 0.19 mmol) in dimethylformamide (3 mL) at 0°C under N2 protection. After stirring for 30 minutes, tert-butyl 9,9-difluoro-2,6-diazaspiro[3.5]nonane-6-carboxylate (45 mg, 0.17 mmol) was added, and the reaction mixture was stirred at 25°C for 2 hours. LCMS indicated that the reaction was complete. The mixture was extracted with EA (10 ml x 3). The combined organic layer was washed with brine (10 mL x 2), dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product, which was purified by flash chromatography (PE / EA=3:1) on silica gel to obtain tert-butyl 2-({1H,2H,3H-benzo[b]pyrrolizine-9-yl}carbonyl)-9,9-difluoro-2,6-diazaspiro[3.5]nonane-6-carboxylate (50.0 mg, 62%) as a pale yellow solid. MS (ESI): C 24 H 29 Calculated value for F2N3O3 445.22, m / z measured value 446.2 [M+H] + .

[0884] Step 2

[0885] HCl (4 M, 2 ml) in EA was added dropwise to a solution of tert-butyl 2-({1H,2H,3H-benzo[b]pyrrolizine-9-yl}carbonyl)-9,9-difluoro-2,6-diazaspiro[3.5]nonane-6-carboxylate (50 mg, 0.11 mmol) in DCM (2 mL) at 0°C under N2. The mixture was then stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain the residue, which was purified by HPLC for purification (X-Bridge Purification c18 10 µm OBD 19*150 mm / Welch's Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA), B (acetonitrile), 15–45% of A, 10 min, flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain 2-({1H,2H,3H-benzo[b]pyrrolizine-9-yl}carbonyl)-9,9-difluoro-2,6-diazaspiro[3.5]nonane formate (28 mg, 74%) as a white solid. MS (ESI): C 19 H 21 Calculated value for F2N3O 345.17, m / z measured value 346.3 [M+H] + .

[0886] 1 H NMR (400 MHz, DMSO) δ 8.14 (s, 0.51H), 7.73 -7.71 (m, 1H), 7.38 - 7.36 (m, 1H), 7.16 - 7.10 (m, 2H), 4.18 - 3.98 (m, 4H), 3.83 - 3.81 (m, 2H), 3.10 (t, J = 8.0 Hz, 2H), 3.01 - 2.97 (m, 2H), 2.79 - 2.75 (m, 2H), 2.63 - 2.52 (m, 3H), 1.91 - 1.82 (m, 2H).

[0887] Example 61. Synthesis of I-76:

[0888]

[0889] Experimental Procedure:

[0890] Step 1

[0891] HATU (51 mg, 0.13 mmol) was added to a mixture of 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylic acid (28 mg, 0.14 mmol) and DIEA (83 mg, 0.64 mmol) in DMF (2 mL) at 25°C under N2. After stirring for 30 minutes, tert-butyl 8,8-difluoro-2,6-diazaspiro[3.5]nonane-6-carboxylate oxalate (45 mg, 0.13 mmol) was added to the reaction mixture. The mixture was stirred at 25°C for 16 hours. The mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The organic layer was dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash chromatography (mobile phase A: PE, B: EA; 0–75% B in A) to obtain tert-butyl 2-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carbonyl)-8,8-difluoro-2,6-diazaspiro[3.5]nonane-6-carboxylate (57 mg, 90%) as a yellow solid.

[0892] MS (ESI): C 24 H 29 Calculated value for F2N3O3 445.22, m / z measured value 446.2 [M+H] + .

[0893] Step 2

[0894] 4 M HCl (2 mL) in EA was added to a mixture of tert-butyl 2-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carbonyl)-8,8-difluoro-2,6-diazaspiro[3.5]nonane-6-carboxylate (52 mg, 0.12 mmol) in DCM (6 mL) at 0°C. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by flash reverse phase (mobile phase A: H2O (0.1% HCl), B: ACN; 0–35% B in A) to obtain (8,8-difluoro-2,6-diazaspiro[3.5]nonan-2-yl)(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)methanone hydrochloride as a pale yellow solid.

[0895] MS (ESI): C 19 H 21 Calculated value for F2N3O 345.17, m / z measured value 346.1 [M+H] + .

[0896] 1 H NMR (400 MHz, DMSO) δ 9.84 (brs, 2H), 7.78 - 7.71 (m, 1H), 7.41 - 7.35 (m, 1H), 7.18 - 7.09 (m, 2H), 4.13 (t, 7.2 Hz, 2H), 4.05 (d, J = 9.2 Hz, 2H), 3.93 (d, J = 9.6 Hz, 2H), 3.54 (t, 11.6 Hz, 2H), 3.40 (s, 2H), 3.11 (t, J = 7.2 Hz, 2H), 2.63 - 2.56 (m, 2H), 2.55 - 2.52 (m, 1H), 2.48 - 2.44 (m, 1H).

[0897] Example 62. Synthesis of I-77:

[0898]

[0899] Experimental Procedure:

[0900] Step 1

[0901] HATU (68.0 mg, 0.18 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (30 mg, 0.15 mmol), tert-butyl 9,9-difluoro-2,7-diazaspiro[4.5]decane-7-carboxylate (41.2 mg, 0.15 mmol) and DIEA (57.8 mg, 0.45 mmol) in DMF (5 mL). The reaction mixture was stirred at 50°C for 12 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain tert-butyl 2-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carbonyl)-9,9-difluoro-2,7-diazaspiro[4.5]decane-7-carboxylate (40 mg, crude material) as a yellow solid, which was used directly in a subsequent step.

[0902] MS (ESI): C 25 H 31 Calculated value for F2N3O3 459.23, m / z measured value 460.1 [M+H] + .

[0903] Step 2

[0904] A mixture of tert-butyl 2-({1H,2H,3H-benzo[b]pyrrolizine-9-yl}carbonyl)-9,9-difluoro-2,7-diazaspiro[4.5]decane-7-carboxylate (40 mg, 0.087 mmol) in HCl / EA (4N) (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-Bridge purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain (9,9-difluoro-2,7-diazaspiro[4.5]decane-2-yl)(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)methanone formate (15.3 mg, 48%) as a white solid.

[0905] MS (ESI): C 20 H 23 Calculated value for F2N3O 359.18, m / z measured value 360.1 [M+H] + .

[0906] 1 H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 0.05H), 7.59 (d, J = 7.2 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.14 - 7.03 (m, 2H), 4.16 - 4.06 (m, 2H), 3.56 - 3.29 (m, 4H), 3.10 - 2.98 (m, 2H), 2.93 - 2.86 (m, 2H), 2.69 - 2.51 (m, 4H), 2.09 - 1.97 (m, 2H), 1.92 - 1.70 (m, 2H).

[0907] Example 63. Synthesis of I-78:

[0908]

[0909] Experimental Procedure:

[0910] Step 1

[0911] NMM (165 mg, 1.63 mmol) was added to a mixture of CDMT (114 mg, 0.65 mmol) in dioxane (5 mL) at 25°C. After stirring for 30 minutes, 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (125 mg, 0.54 mmol) was added to the reaction mixture. After stirring for 1 hour, N-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxymidamide (140 mg, 0.65 mmol) was added to the reaction mixture. The mixture was stirred under N2 at 50°C for 16 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by flash chromatography (mobile phase A: PE, B: EA; 0 to 35% of A is B) to obtain tert-butyl 4-(3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole-5-yl)piperidine-1-carboxylate (80 mg, 34%) as a pale yellow solid.

[0912] MS (ESI): C 23 H 28 Calculated value for N4O3 408.22, m / z measured value 431.0 [M+Na] + .

[0913] Step 2

[0914] 4 M HCl (2 mL) in EA was added to a mixture of tert-butyl 4-(3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole-5-yl)piperidine-1-carboxylate (80 mg, 0.19 mmol) in DCM (6 mL) at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by flash reverse phase (mobile phase A: H2O (0.1% FA), B: ACN; 0 to 35% B in A) to obtain 3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole formate (42.2 mg, 69%) as a white solid.

[0915] MS (ESI): C 18 H 20 Calculated value for N4O 308.16, m / z measured value 309.1 [M+H] + .

[0916] 1 H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 8.02 - 7.96 (m, 1H), 7.47 - 7.40 (m, 1H), 7.23 - 7.14 (m, 2H), 4.18 (t, J = 7.2 Hz, 2H), 3.50 - 3.22 (m, 3H), 3.21 - 3.12 (m, 2H), 2.89 - 2.76 (m, 2H), 2.69 - 2.59 (m, 2H), 2.17 - 2.05 (m, 2H), 1.91 - 1.75 (m, 2H).

[0917] Example 64. Synthesis of I-79:

[0918]

[0919] Experimental Procedure:

[0920] Step 1

[0921] HATU (312.2 mg, 0.82 mmol) was added to a mixture of 7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (150 mg, 0.68 mmol), {1-[(2-methoxyethyl)trimethyl-$l^{5}-silyl]-5-methylimidazole-4-yl}methaneamine (165.9 mg, 0.68 mmol) and DIEA (265.3 mg, 2.05 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 6 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 7-fluoro-N-((5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-yl)methyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide (100 mg, 26%) as a yellow solid, which was used directly in a subsequent step.

[0922] MS (ESI): C 23 H 31 Calculated value for FN4O2Si 442.22, m / z measured value 443.2 [M+H] + .

[0923] Step 2

[0924] A mixture of 7-fluoro-N-({1-[(2-methoxyethyl)trimethyl-$l^{5}-silyl]-5-methylimidazole-4-yl}methyl)-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (100 mg, 0.23 mmol) in DCM / TFA=3 / 1 (8 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (X-Bridge purification c18 10 µm OBD 19*150 mm / Welch Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain 7-fluoro-N-((5-methyl-1H-imidazole-4-yl)methyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate (5 mg, 7%) as a white solid.

[0925] MS (ESI): C 17 H 17 Calculated value for FN4O 312.14, m / z measured value 313.1 [M+H] + .

[0926] 1 H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.36 (s, 0.7H), 7.70 (dd, J = 10.4, 2.4 Hz, 1H), 7.42 (s, 1H), 7.37 (dd, J = 8.4, 4.4 Hz, 1H), 7.31 - 7.28 (m, 1H), 6.97 (td,J = 9.2, 2.4 Hz, 1H), 4.32 (d, J = 5.6 Hz, 2H), 4.11 (t, J = 7.2 Hz, 2H), 3.22 (t, J = 7.2 Hz, 2H), 2.61 - 2.55 (m, 2H), 2.16 (s, 3H).

[0927] Example 65. Synthesis of I-80:

[0928]

[0929] Experimental Procedure:

[0930] Step 1

[0931] Pd / C (60 mg) was added to a solution of (2R,7aS)-7a-(azidomethyl)-2-fluoro-hexahydropyrrolizine (300 mg, 1.63 mmol) in MeOH (15 mL). The mixture was then stirred at room temperature under H2 for 4 hours. Pd / C was removed by filtration, and the filtrate was concentrated under vacuum to obtain a crude product (250 mg, crude material), which was used directly in a subsequent step.

[0932] MS (ESI): C8H 15 Calculated value for FN2 158.12, m / z measured value 159.1 [M+H] + .

[0933] Step 2

[0934] Oxalyl chloride (174 mg, 1.37 mmol) and DMF (6.67 mg, 0.0912 mmol) were added dropwise under N2 at 0°C to a solution of 7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (100 mg, 0.456 mmol) in DCM (5 mL). The mixture was then stirred at room temperature for 0.5 hours. The mixture was concentrated. The crude product was used in the subsequent step without further purification. [(2R,7aS)-2-fluoro-hexahydropyrrolizine-7a-yl]methaneamine (144 mg, 0.912 mmol) and TEA (92 mg, 0.913 mmol) were added to the solution of the crude product in DCM (5 mL), and the mixture was then stirred under N2 at 25°C for 2 hours. The mixture was diluted with EA, the solid was removed by filtration, and the filtrate was washed with water. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product. The residue was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA), B (acetonitrile), 15–100% B in A, 10 min, flow rate: 25 ml / min, wavelength: 214 / 254 nm) to obtain N-{[(2R,7aS)-2-fluoro-hexahydropyrrolizine-7a-yl]methyl}-7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide formate (45 mg, 26.6%) as a white solid.

[0935] MS (ESI): C 20 H 23 Calculated value for F2N3O 359.18, m / z measured value 360.2 [M+H] + .

[0936] 1H NMR (400 MHz, DMSO) δ 8.21 (s, 0.15H), 7.57 (dd, J = 12.0, 4.0 Hz, 1H), 7.37 (dd, J = 8.0, 4.0 Hz, 1H), 6.96 (td,J = 8.0, 2.4 Hz, 1H), 6.42 (s, 1H), 4.93 - 4.62 (m, 1H), 4.11 (t, J = 8.0 Hz, 2H), 3.27 - 3.14 (m, 3H), 3.06 - 2.96 (m, 1H), 2.91 (m, 1H), 2.84 - 2.81 (m, 2H), 2.71 -2.66 (m, 1H), 2.61 -2.54 (m, 3H), 2.38 - 2.24 (m, 2H), 2.14 -2.11 (m, 1H), 1.91 - 1.83 (m, 1H), 1.37 - 1.34 (m, 1H).

[0937] Example 66. Synthesis of I-81:

[0938]

[0939] Experimental Procedure:

[0940] Step 1

[0941] NMM (123 mg, 1.21 mmol) was added to a mixture of CDMT (85 mg, 0.48 mmol) in dioxane (6 mL) at 25°C. After stirring for 30 minutes, (3R,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidine-4-carboxylic acid (100 mg, 0.40 mmol) was added to the reaction mixture. After stirring for 1 hour, N-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboximide (113 mg, 0.53 mmol) was added to the reaction mixture. The mixture was stirred under N2 at 50°C for 16 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by flash chromatography (mobile phase A: PE, B: EA; 0–20% B in A) to obtain tert-butyl (3R,4R)-4-(3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole-5-yl)-3-fluoropiperidine-1-carboxylate (78 mg, 42%) as a white solid. MS (ESI): C 23 H 27 Calculated value for FN4O3 426.21, m / z measured value 449.1 [M+Na] + .

[0942] Step 2

[0943] 4 M HCl (2 mL) in EA was added to a mixture of tert-butyl (3R,4R)-4-(3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole-5-yl)-3-fluoropiperidine-1-carboxylate (78 mg, 0.18 mmol) in DCM (6 mL) at 25°C. The reaction mixture was stirred under N2 at 25°C for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by a reverse-phase column (Column: Welch's Extimate C18 21.2 × 250 mm 10 µm; Mobile phase A: H2O (0.1% FA), B: ACN; 20–50% B in A; Flow rate: 30 mL / min; Wavelength: 214 nm) to obtain 3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-5-((3R,4R)-3-fluoropiperidine-4-yl)-1,2,4-oxadiazole formate (30.2 mg, 50%) as a white solid. MS (ESI): C 18 H 19 Calculated value for FN4O 326.15, m / z measured value 327.1 [M+H] + .

[0944] 1 H NMR (400 MHz, DMSO) δ 8.43 (s, 0.18H), 8.05 - 7.93 (m, 1H), 7.49 - 7.38 (m, 1H), 7.24 - 7.14 (m, 2H), 4.91 - 4.66 (m, 1H), 4.19 (t, J = 6.8 Hz, 2H), 3.48 - 3.40 (m, 1H), 3.29 - 3.25 (m, 3H), 2.94 - 2.86 (m, 1H), 2.69 - 2.54 (m, 4H), 2.12 - 2.00 (m, 1H), 1.83 - 1.70 (m, 1H).

[0945] Example 67. Synthesis of I-82:

[0946]

[0947] Experimental Procedure:

[0948] Step 1

[0949] NMM (110 mg, 1.09 mmol) was added to a mixture of CDMT (77 mg, 0.44 mmol) in dioxane (6 mL) at 25°C. After stirring for 30 minutes, (3R,4S)-1-(tert-butoxycarbonyl)-3-fluoropiperidine-4-carboxylic acid (90 mg, 0.36 mmol) was added to the reaction mixture. After stirring for 1 hour, N-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboximide (102 mg, 0.47 mmol) was added to the reaction mixture. The mixture was stirred under N2 at 50°C for 16 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by flash chromatography (mobile phase A: PE, B: EA; 0 to 35% of A is B) to obtain tert-butyl (3R,4S)-4-(3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole-5-yl)-3-fluoropiperidine-1-carboxylate (58 mg, 37%) as a white solid.

[0950] MS (ESI): C 23 H 27 Calculated value for FN4O3 426.21, m / z measured value 449.2 [M+Na] + .

[0951] Step 2

[0952] 4 M HCl (1 mL) in EA was added to a mixture of tert-butyl (3R,4S)-4-(3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole-5-yl)-3-fluoropiperidine-1-carboxylate (58 mg, 0.14 mmol) in DCM (3 mL) at 25°C. The reaction mixture was stirred under N2 at 25°C for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by flash reverse phase (mobile phase A: H2O (0.1% HCl), B: ACN; 0 to 35% of A is B) to obtain 3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-5-((3R,4S)-3-fluoropiperidine-4-yl)-1,2,4-oxadiazole hydrochloride (32.3 mg, 72%) as a white solid.

[0953] MS (ESI): C 18 H 19 Calculated value for FN4O 326.15, m / z measured value 327.1 [M+H] + .

[0954] 1 H NMR (400 MHz, DMSO+DO) δ 8.03 - 7.96 (m, 1H), 7.52 - 7.43 (m, 1H), 7.29 - 7.18 (m, 2H), 5.66 - 5.47 (m, 1H), 4.19 (t, J = 7.2 Hz, 2H), 3.90 - 3.67 (m, 2H), 3.51 - 3.34 (m, 2H), 3.27 (t, J = 7.2 Hz, 2H), 3.16 (td, J = 12.4, 4.0 Hz, 1H), 2.70 - 2.60 (m, 2H), 2.43 - 2.32 (m, 2H).

[0955] Example 68. Synthesis of I-83:

[0956]

[0957] Experimental Procedure:

[0958] Step 1

[0959] NMM (110 mg, 1.09 mmol) was added to a mixture of CDMT (77 mg, 0.44 mmol) in dioxane (6 mL) at 25°C. After stirring for 30 minutes, (3S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidine-4-carboxylic acid (90 mg, 0.36 mmol) was added to the reaction mixture. After stirring for 1 hour, N-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboximide (102 mg, 0.47 mmol) was added to the reaction mixture. The mixture was stirred under N2 at 50°C for 16 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by flash chromatography (mobile phase A: PE, B: EA; 0 to 35% of A is B) to obtain tert-butyl (3S,4R)-4-(3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole-5-yl)-3-fluoropiperidine-1-carboxylate (57 mg, 36%) as a white solid.

[0960] MS (ESI): C 23 H 27 Calculated value for FN4O3 426.21, m / z measured value 449.2 [M+Na] + .

[0961] Step 2

[0962] 4 M HCl (1 mL) in EA was added to a mixture of tert-butyl (3S,4R)-4-(3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole-5-yl)-3-fluoropiperidine-1-carboxylate (57 mg, 0.13 mmol) in DCM (3 mL) at 25°C. The reaction mixture was stirred under N2 at 25°C for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by flash reverse phase (mobile phase A: H2O (0.1% HCl), B: ACN; 0 to 35% of A is B) to obtain 3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-5-((3S,4R)-3-fluoropiperidine-4-yl)-1,2,4-oxadiazole hydrochloride (37.6 mg, 86%) as a white solid.

[0963] MS (ESI): C 18 H 19 Calculated value for FN4O 326.15, m / z measured value 327.1 [M+H] + .

[0964] 1 H NMR (400 MHz, DMSO+DO) δ 8.03 - 7.96 (m, 1H), 7.50 - 7.44 (m, 1H), 7.27 - 7.19 (m, 2H), 5.64 - 5.47 (m, 1H), 4.19 (t, J = 7.2 Hz, 2H), 3.87 - 3.66 (m, 2H), 3.51 - 3.34 (m, 2H), 3.26 (t, J = 7.2 Hz, 2H), 3.16 (td, J = 12.4, 4.0 Hz, 1H), 2.70 - 2.61 (m, 2H), 2.42 - 2.31 (m, 2H).

[0965] Example 69. Synthesis of I-84:

[0966]

[0967] Experimental Procedure:

[0968] Step 1

[0969] MsCl (436 mg, 3.8 mmol) was added dropwise to a solution of (2,2-difluoro-tetrahydro-1H-pyrrolizine-7a-yl)methanol (450 mg, 2.5 mmol) and Et3N (771 mg, 7.6 mmol) in DCM (10 mL) at 0°C under N2. The mixture was then stirred at room temperature under N2 for 4 hours. The mixture was diluted with water (20 mL) and extracted with DCM (10 mL x 3). The organic layer was washed with water (50 mL x 2) and brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated. The crude product (450 mg, crude material) was used in subsequent steps without further purification.

[0970] MS (ESI): C8H 12 Calculated value for ClF2N 195.06, m / z measured value 196.1 [M+H] + .

[0971] Step 2

[0972] NaN3 (1.2 g, 18.4 mmol) was added to a solution of 7a-(chloromethyl)-2,2-difluoro-tetrahydro-1H-pyrrolizine (450 mg, 2.3 mmol) in DMF (8 mL) at room temperature under N2 protection. The reaction mixture was stirred at 80°C for 16 hours. After the reaction, the mixture was diluted with EA (50 mL), the solid was removed by filtration, and the filtrate was washed with water. The organic layer was washed with water (50 mL x 2) and brine (50 mL x 2) and dried over Na2SO4. The crude product was purified by silica gel column chromatography (PE / EA = 2:1) to obtain 7a-(azidomethyl)-2,2-difluoro-tetrahydro-1H-pyrrolizine (300 mg, 61.3%) as a yellow oil.

[0973] MS (ESI): C8H 12 Calculated value for F2N4 202.10, m / z Actual value 203.1 [M+H]+ .

[0974] Step 3

[0975] Pd / C (50 mg, wt%: 10%) was added to a solution of 7a-(azidomethyl)-2,2-difluoro-tetrahydro-1H-pyrrolizine (270 mg, 1.33 mmol) in CH3OH (10 mL). The mixture was then stirred under H2 at room temperature for 4 hours. Pd / C was removed by filtration, and the filtrate was concentrated under vacuum to obtain a crude product, which was used directly in a subsequent step.

[0976] MS (ESI): C8H 14 Calculated value for F2N2 176.11, m / z measured value 177.2 [M+H] + .

[0977] Step 4

[0978] Oxalyl chloride (174 mg, 1.4 mmol) and DMF (6.67 mg, 0.09 mmol) were added dropwise to a solution of 7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (100 mg, 0.46 mmol) in DCM (5 mL) at 0°C under N2. The mixture was then stirred at room temperature for 0.5 hours. The mixture was concentrated. The crude product was used in the subsequent step without further purification. (2,2-difluoro-tetrahydro-1H-pyrrolizine-7a-yl)methaneamine (161 mg, 0.912 mmol) and TEA (138 mg, 1.37 mmol) were added to the DCM (5 mL) solution of the crude product, and the mixture was then stirred at 50°C under N2 for 2 hours. The mixture was diluted with EA (50 mL). The organic layer was washed with water (50 mL x 2) and brine (50 mL x 2), dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product. The residue was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% TFA), B (acetonitrile), 35–100% B in A, 9.5 min, flow rate: 25 ml / min, wavelength: 214 / 254 nm) to obtain N-[(2,2-difluoro-tetrahydro-1H-pyrrolizine-7a-yl)methyl]-7-fluoro-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (80 mg, 46.5%) as a white solid.

[0979] MS (ESI): C 20 H 22 Calculated value for F3N3O 377.17, m / z measured value 378.2 [M+H] + .

[0980] 1H NMR (400 MHz, DMSO) δ 11.12 (s, 0.33H), 7.56 (dd, J = 8.0, 2.4 Hz, 1H), 7.41 (dd, J = 8.0, 4.0 Hz, 1H), 7.05 (s, 1H), 7.02 - 6.92 (m, 1H), 4.13 (t, J = 8.0 Hz, 2H), 3.86 - 3.76 (m, 3H), 3.31 - 3.15 (m, 5H), 3.06 - 2.92 (m, 1H), 2.75 -2.67 (m, 1H), 2.62 - 2.56 (m, 2H), 2.22 - 1.99 (m, 3H), 1.79 -1.72 (m, 1H).

[0981] Example 70. Synthesis of I-85:

[0982]

[0983] Experimental Procedure:

[0984] Step 1

[0985] Synthesis of tert-butyl (1R,5S,6S)-6-(3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. A mixture of CDMT (97.9 mg, 0.56 mmol) and NMM (141 mg, 1.39 mmol) in dioxane (10 mL) was stirred at room temperature for 0.5 hours. (1R,5S,6S)-3-(tert-butyl-$l^{3}-oxy)-3-azabicyclo[3.1.0]hexane-6-carboxylate (106 mg, 0.46 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. N-hydroxy-1H,2H,3H-benzo[b]pyrrolizine-9-carboximide (100 mg, 0.46 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and at 70°C for 16 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE:EA = 1:1) to obtain tert-butyl (1R,5S,6s)-6-(3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (40 mg, 17%) as a yellow solid.

[0986] MS (ESI): C 23 H 26 Calculated value for N4O3 406.20, m / z measured value 407.1 [M+H] + .

[0987] Step 2

[0988] Synthesis of 5-((1R,5S,6s)-3-azabicyclo[3.1.0]hexane-6-yl)-3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole. A mixture of (1R,5S,6S)-6-(3-{1H,2H,3H-benzo[b]pyrrolizine-9-yl}-1,2,4-oxadiazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl tert-butyl formate (40 mg, 0.098 mmol) in HCl / EA (4N) (5 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain 5-((1R,5S,6s)-3-azabicyclo[3.1.0]hexane-6-yl)-3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole formate (9.4 mg, 31%) as a white solid.

[0989] MS (ESI): C 18 H 18 Calculated value for N4O 306.15, m / z Actual value 307.1 [M+H] + .

[0990] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 0.3H), 8.01 - 7.89 (m, 1H), 7.50 - 7.39 (m, 1H), 7.25 - 7.10 (m, 2H), 4.17 (t, J = 7.2 Hz, 2H), 3.22 (t, J = 7.6 Hz, 2H), 3.10 (d, J = 10.8 Hz, 2H), 2.95 (d, J = 10.8 Hz, 2H), 2.70 - 2.57 (m, 2H), 2.26 - 2.19 (m, 1H), 2.15 - 2.07 (m, 2H).

[0991] Example 71. Synthesis of I-86

[0992]

[0993] Experimental Procedure:

[0994] Step 1

[0995] Synthesis of tert-butyl (1R,5S,6r)-6-(3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. A mixture of CDMT (97.9 mg, 0.56 mmol) and NMM (141.0 mg, 1.39 mmol) in dioxane (10 mL) was stirred at room temperature for 0.5 hours. (1R,5S,6R)-3-(tert-butyl-$l^{3}-oxy)-3-azabicyclo[3.1.0]hexane-6-carboxylate (106.1 mg, 0.46 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. N-hydroxy-1H,2H,3H-benzo[b]pyrrolizine-9-carboximide (100 mg, 0.46 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and at 70°C for 16 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 2). The organic layer was concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE:EA = 1:1) to obtain tert-butyl (1R,5S,6r)-6-(3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (80 mg, 38%) as a yellow solid.

[0996] MS (ESI): C 23 H 26 Calculated value for N4O3 406.20, m / z measured value 407.1 [M+H] + .

[0997] Step 2

[0998] Synthesis of 5-((1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-yl)-3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole. A mixture of (1R,5S,6R)-6-(3-{1H,2H,3H-benzo[b]pyrrolizine-9-yl}-1,2,4-oxadiazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl tert-butyl formate (40 mg, 0.098 mmol) in HCl / EA (4N, 5 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm) to obtain 5-((1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-yl)-3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-yl)-1,2,4-oxadiazole formate (22.8 mg, 73%) as a white solid.

[0999] MS (ESI): C 18 H 18 Calculated value for N4O 306.15, m / z Actual value 307.1 [M+H] + .

[1000] 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 0.8H), 7.97 - 7.95 (m, 1H), 7.43 - 7.41 (m, 1H), 7.22 - 7.12 (m, 2H), 4.17 (t, J = 7.2 Hz, 2H), 3.23 (t, J = 7.6 Hz, 2H), 3.07 (d, J = 11.6 Hz, 2H), 2.82 (d, J = 11.6 Hz, 2H), 2.67 - 2.59 (m, 2H), 2.35 - 2.32 (m, 1H), 2.20 - 2.18 (m, 2H).

[1001] Example 72. Synthesis of I-87:

[1002]

[1003] Experimental Procedure:

[1004] Step 1

[1005] Synthesis of ((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methyl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate. A mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (100 mg, 0.50 mmol), [(2S,7aR)-2-fluoro-hexahydropyrrolizine-7a-yl] methanol (79 mg, 0.50 mmol), EDCI (143 mg, 0.75 mmol), and 4-DMAP (121 mg, 0.99 mmol) in DCM (10 mL) was stirred at room temperature for 16 hours. The mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 2). The organic layer was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm, gradient: 23% of A to 33% of B) to obtain ((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methyl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate formate (32.8 mg, 19%)) as a white solid.

[1006] MS (ESI): C 20 H 23 Calculated value for FN2O2 342.17, m / z measured value 343.1 [M+H] + .

[1007] 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 0.2H), 7.98 - 7.90 (m, 1H), 7.46 - 7.38 (m, 1H), 7.25 - 7.13 (m, 2H), 5.36 - 5.21 (m, 1H), 4.17 (t, J = 7.2 Hz, 2H), 4.00 - 3.89 (m, 2H), 3.21 (t, J = 7.6 Hz, 2H), 3.15 - 3.10 (m, 2H), 3.04 - 3.02 (m, 1H), 2.88 - 2.80 (m, 1H), 2.69 - 2.56 (m, 2H), 2.15 - 2.06 (m, 2H), 2.02 - 1.72 (m, 4H).

[1008] Example 73. Synthesis of I-88:

[1009]

[1010] Experimental Procedure:

[1011] Step 1

[1012] Synthesis of ((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methyl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate. A mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (100 mg, 0.50 mmol), [(2S,7aS)-2-fluoro-hexahydropyrrolizine-7a-yl] methanol (79 mg, 0.50 mmol), EDCI (143 mg, 0.75 mmol), and 4-DMAP (121 mg, 0.99 mmol) in DCM (10 mL) was stirred at room temperature for 16 hours. The mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 2). The organic layer was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, wavelength: 214 / 254 nm, gradient: 20% to 50% of A B) to obtain ((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methyl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate formate (32.9 mg, 19%)) as a white solid.

[1013] MS (ESI): C 20 H 23 Calculated value for FN2O2 342.17, m / z measured value 343.2 [M+H] + .

[1014] 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 0.2H), 7.95 - 7.93 (m, 1H), 7.42 - 7.40 (m, 1H), 7.18 - 7.16 (m, 2H), 5.42 - 5.29 (m, 1H), 4.16 (t, J = 7.2 Hz, 2H), 4.00 (q,J = 10.4 Hz, 2H), 3.33 - 3.26 (m, 1H), 3.21 (t, J = 7.6 Hz, 2H), 2.97 - 2.76 (m, 2H), 2.67 - 2.55 (m, 3H), 2.34 - 2.25 (m, 1H), 1.98 - 1.67 (m, 5H).

[1015] Example 74. Synthesis of I-89:

[1016]

[1017] Experimental Procedure:

[1018] Step 1

[1019] Synthesis of (2S,7aR)-7a-(chloromethyl)-2-fluorohexahydro-1H-pyrrolizine. MsCl (86.4 mg, 0.75 mmol) was added to a mixture of [(2S,7aR)-2-fluorohexahydropyrrolizine-7a-yl]methanol (100 mg, 0.63 mmol) and Et3N (190.7 mg, 1.88 mmol) in DCM (10 mL) at 0°C under N2. The reaction mixture was stirred at room temperature under N2 for 1 hour. The mixture was diluted with water (50 mL) and extracted with DCM (30 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain (2S,7aR)-7a-(chloromethyl)-2-fluorohexahydro-1H-pyrrolizine (100 mg, crude product) as a colorless oil, which was used directly in a subsequent step. MS (ESI): C8H 13 Calculated value for ClFN 177.07, m / z measured value 178.1 [M+H] + .

[1020] Step 2

[1021] Synthesis of (2S,7aR)-7a-(azidomethyl)-2-fluorohexahydro-1H-pyrrolizine. NaN3 (109.8 mg, 1.69 mmol) was added to a solution of (2S,7aR)-7a-(chloromethyl)-2-fluorohexahydropyrrolizine (100 mg, 0.56 mmol) in DMF (5 mL). The reaction mixture was stirred at 80°C under N2 for 16 hours. The mixture was diluted with EA (30 mL), the solid was removed by filtration, and the filtrate was washed with water. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE:EA = 3:1) to obtain (2S,7aR)-7a-(azidomethyl)-2-fluorohexahydro-1H-pyrrolizine (35 mg, 30%) as a colorless oil.

[1022] MS (ESI): C8H 13 Calculated value for FN4 184.11, m / z measured value 185.1 [M+H] + .

[1023] Step 3

[1024] Synthesis of ((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methaneamine. Pd / C (4.0 mg, 0.038 mmol) was added under nitrogen to a solution of (2S,7aR)-7a-(azidomethyl)-2-fluorohexahydropyrrolizine (35 mg, 0.19 mmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature under H2 for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain ((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methaneamine (30 mg, crude material) as a colorless oil, which was used directly in subsequent steps without further purification. MS (ESI): C8H 15Calculated value for FN2 158.12, m / z measured value 159.1 [M+H] + .

[1025] Step 4

[1026] Synthesis of N-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide. Oxalyl chloride (26.5 mg, 0.21 mmol) was added at 0°C to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (28 mg, 0.14 mmol) in DCM (10 mL) and DMF (0.5 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated. The crude product was used in a subsequent step without further purification. The crude product in DCM (2 mL) was added to a mixture of Et3N (41.5 mg, 0.42 mmol) and [(2S,7aR)-2-fluoro-hexahydropyrrolizine-7a-yl]methaneamine (21.6 mg, 0.14 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (50 mL) and extracted with DCM (30 mL x 2). The organic layer was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2*250 mm 10 µm, mobile phase A: water (0.1% NH3) B (acetonitrile), flow rate: 30 ml / min, gradient: 20% to 40% of A B, wavelength: 214 / 254 nm) to obtain N-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide (2 mg, 4%) as a white solid.

[1027] MS (ESI): C 20 H 24 Calculated value for FN3O 341.19, m / z measured value 342.2 [M+H] + .

[1028] 1 H NMR (400 MHz, MeOD) δ 7.85 - 7.78 (m, 1H), 7.34 - 7.27 (m, 1H), 7.19 - 7.08 (m, 2H), 4.89 - 4.74 (m, 1H), 4.12 (t, J = 7.2 Hz, 2H), 3.50 - 3.34 (m, 2H), 3.28 - 3.22 (m, 2H), 3.18 - 3.04 (m, 2H), 3.02 - 2.91 (m, 2H), 2.84 - 2.55 (m, 4H), 2.50 - 2.40 (m, 1H), 2.27 - 2.20 (m, 1H), 2.04 - 1.96 (m, 1H), 1.52 - 1.47 (m, 1H).

[1029] Example 75. Synthesis of I-90:

[1030]

[1031] Experimental Procedure:

[1032] Step 1

[1033] Synthesis of (2S,7aS)-7a-(chloromethyl)-2-fluorohexahydro-1H-pyrrolizine. MsCl (215.9 mg, 1.88 mmol) was added to a mixture of [(2S,7aS)-2-fluorohexahydropyrrolizine-7a-yl]methanol (250 mg, 1.57 mmol) and Et3N (476.7 mg, 4.71 mmol) in DCM (10 mL) at 0°C under N2. The reaction mixture was stirred at room temperature under N2 for 1 hour. The mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain (2S,7aS)-7a-(chloromethyl)-2-fluorohexahydro-1H-pyrrolizine (250 mg, crude product) as a colorless oil, which was used directly in a subsequent step. MS (ESI): C8H 13 Calculated value for ClFN 177.07, m / z measured value 178.1 [M+H]+ .

[1034] Step 2

[1035] Synthesis of (2S,7aS)-7a-(azidomethyl)-2-fluorohexahydro-1H-pyrrolizine. NaN3 (274.5 mg, 4.22 mmol) was added to a solution of (2S,7aS)-7a-(chloromethyl)-2-fluorohexahydropyrrolizine (250 mg, 1.41 mmol) in DMF (10 mL). The reaction mixture was stirred at 80°C under N2 for 16 hours. The mixture was diluted with EA (30 mL), the solid was removed by filtration, and the filtrate was washed with water. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE:EA = 3:1) to obtain (2S,7aS)-7a-(azidomethyl)-2-fluorohexahydro-1H-pyrrolizine (90 mg, 31%) as a colorless oil. MS (ESI): C8H 13 Calculated value for FN4 184.11, m / z measured value 185.1 [M+H] + .

[1036] Step 3

[1037] Synthesis of ((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methaneamine. Pd / C (10.4 mg, 0.10 mmol) was added under nitrogen protection to a solution of (2S,7aS)-7a-(azidomethyl)-2-fluorohexahydropyrrolizine (90 mg, 0.49 mmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature under H2 for 1 hour. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain ((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methaneamine (75 mg, crude material) as a colorless oil, which was used directly in a subsequent step. MS (ESI): C8H 15Calculated value for FN2 158.12, m / z measured value 159.1 [M+H] + .

[1038] Step 4

[1039] Synthesis of N-(2S,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide. Oxalyl chloride (87.0 mg, 0.69 mmol) was added at 0°C to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (92 mg, 0.46 mmol) in DCM (10 mL) and DMF (0.5 mL). The reaction mixture was stirred at room temperature for 1 hour, and the mixture was concentrated. The crude product was used in a subsequent step without further purification. The crude product in DCM (3 mL) was added to a mixture of Et3N (138.2 mg, 1.37 mmol) and [(2S,7aS)-2-fluoro-hexahydropyrrolizine-7a-yl]methaneamine (72.0 mg, 0.46 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 2). The organic layer was concentrated to obtain the crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm 10 µm, mobile phase A: water (0.1% FA) B (acetonitrile), flow rate: 30 ml / min, gradient: 17% to 47% B in A, wavelength: 214 / 254 nm) to obtain N-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate (39.3 mg, 25%) as a white solid. MS (ESI): C 20 H 24 Calculated value for FN3O 341.19, m / z measured value 342.2 [M+H] + .

[1040] 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 7.95 - 7.93 (m, 1H), 7.37 - 7.35 (m, 1H), 7.18 - 7.06 (m, 2H), 6.88 - 6.86 (m, 1H), 5.35 - 5.22 (m, 1H), 4.11 (t, J = 7.2 Hz, 2H), 3.32 - 3.18 (m, 4H), 3.02 - 2.84 (m, 2H), 2.82 - 2.54 (m, 4H), 2.33 - 2.17 (m, 1H), 2.03 - 1.89 (m, 1H), 1.87 - 1.55 (m, 4H).

[1041] Example 76. Synthesis of I-91 and I-92:

[1042]

[1043] Experimental Procedure:

[1044] Step 1

[1045] Synthesis of tert-butyl 3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate. HATU (226.8 mg, 0.60 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (100 mg, 0.50 mmol), tert-butyl 3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylate (119.5 mg, 0.50 mmol), and DIEA (192.7 mg, 1.49 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 6 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 3). The combined organic layer was concentrated to obtain the crude product, which was purified by column chromatography (PE:EA = 1:1) to obtain tert-butyl 3-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate (150 mg, 64%) as a yellow solid. MS (ESI): C 25 H 33 Calculated value for N3O3 423.25, m / z measured value 368.2 [M-55].

[1046] Step 2

[1047] Synthesis of N-(9-azabicyclo[3.3.1]nonan-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate. A mixture of tert-butyl 3-{1H,2H,3H-benzo[b]pyrrolizine-9-amido}-9-azabicyclo[3.3.1]nonan-9-carboxylate (50 mg, 0.12 mmol) in DCM / TFA=3 / 1 (8 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm × 10 µm, mobile phase A: water (0.1% FA), B: acetonitrile, flow rate: 30 ml / min, gradient: 20% to 40% of A in B, wavelength: 214 / 254 nm) to obtain N-(9-azabicyclo[3.3.1]nonane-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate (26.4 mg, 69%) as a white solid. MS (ESI): C 20 H 25 Calculated value for N3O 323.20, m / z measured value 324.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 0.75H), 7.93 - 7.91 (m, 1H), 7.37 - 7.35 (m, 1H), 7.17 - 7.06 (m, 2H), 6.95 (d, J = 8.4 Hz, 1H), 4.35 - 4.27 (m, 1H), 4.11 (t, J = 7.2 Hz, 2H), 3.64 - 3.61 (m, 2H), 3.23 (t, J = 7.6 Hz, 2H), 2.62 - 2.55 (m, 2H), 2.27 - 2.20 (m, 2H), 2.10 - 2.03 (m, 1H), 1.79 - 1.72 (m, 2H), 1.60 - 1.46 (m, 5H).

[1048] Step 3

[1049] Synthesis of N-(9-ethyl-9-azabicyclo[3.3.1]nonane-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate. HOAc (0.1 mL) was added to a mixture of N-{9-azabicyclo[3.3.1]nonane-3-yl}-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (80 mg, 0.25 mmol) and acetaldehyde (5.0 M solution in THF, 0.1 mL) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 4 hours. NaBH3CN (46.6 mg, 0.74 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm × 10 µm, mobile phase A: water (0.1% FA), B: acetonitrile, flow rate: 30 ml / min, gradient: 15% to 45% of A in B, wavelength: 214 / 254 nm) to obtain N-(9-ethyl-9-azabicyclo[3.3.1]nonane-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate (34.7 mg, 40%) as a white solid. MS (ESI): C 22 H 29 Calculated value for N3O 351.23, m / z measured value 352.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 0.55H), 7.93 - 7.91 (m, 1H), 7.37 - 7.35 (m, 1H), 7.16 - 7.05 (m, 2H), 6.92 (d, J = 8.4 Hz, 1H), 4.46 - 4.38 (m, 1H), 4.11 (t, J = 7.2 Hz, 2H), 3.41 - 3.38 (m, 2H), 3.23 (t, J = 8.0 Hz, 2H), 2.94 - 2.92 (m, 2H), 2.66 - 2.54 (m, 2H), 2.31 - 2.26 (m, 2H), 2.22 - 2.09 (m, 1H), 1.97 - 1.84 (m, 2H), 1.66 - 1.61 (m, 2H), 1.49 - 1.45 (m, 1H), 1.18 - 1.15 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H).

[1050] Example 77. Synthesis of I-93:

[1051]

[1052] Experimental Procedure:

[1053] Step 1

[1054] Synthesis of N-(9-propyl-9-azabicyclo[3.3.1]nonane-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate. HOAc (0.1 mL) was added to a mixture of N-{9-azabicyclo[3.3.1]nonane-3-yl}-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (80 mg, 0.25 mmol) and propionaldehyde (0.1 mL) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 4 hours. NaBH3CN (46.6 mg, 0.74 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm × 10 µm, mobile phase A: water (0.1% FA), B: acetonitrile, flow rate: 30 mL / min, gradient: 15% to 45% of A in B, wavelength: 214 / 254 nm) to obtain N-(9-propyl-9-azabicyclo[3.3.1]nonane-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate (46.5 mg, 51%) as a white solid. MS (ESI): C 23 H 31 Calculated value for N3O 365.25, m / z measured value 366.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 0.27H), 7.99 - 7.87 (m, 1H), 7.43 - 7.31 (m, 1H), 7.19 - 7.05 (m, 2H), 7.00 - 6.98 (m, 1H), 4.48 (s, 1H), 4.11 (t, J = 7.2 Hz, 2H), 3.51 (s, 2H), 3.24 (t, J = 7.2 Hz, 2H), 2.96 (s, 2H), 2.65 - 2.55 (m, 2H), 2.41 - 2.29 (m, 2H), 2.19 - 2.12 (m, 1H), 1.99 - 1.93 (m, 2H), 1.75 - 1.63 (m, 2H), 1.61 - 1.43 (m, 3H), 1.29 - 1.27 (m, 2H), 0.92 (t, J = 8.0 Hz, 3H).

[1055] Example 78. Synthesis of I-94:

[1056]

[1057] Experimental Procedure:

[1058] Step 1

[1059] Synthesis of N-(9-cyclopropyl-9-azabicyclo[3.3.1]nonan-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide. A mixture of N-{9-azabicyclo[3.3.1]nonan-3-yl}-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (70 mg, 0.22 mmol), (1-ethoxycyclopropoxy)trimethylsilane (377.2 mg, 2.16 mmol), HOAc (0.1 mL) and NaBH3CN (68.0 mg, 1.08 mmol) in THF (10 mL) was stirred at 60°C for 16 hours. The mixture was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm × 10 µm, mobile phase A: water (0.1% NH3), B: acetonitrile, flow rate: 30 ml / min, gradient: 65% to 95% of A in B, wavelength: 214 / 254 nm) to obtain N-(9-cyclopropyl-9-azabicyclo[3.3.1]nonane-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide (11.9 mg, 15%) as a white solid. MS (ESI): C 23 H 29 Calculated value for N3O 363.23, m / z measured value 364.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.91 - 7.89 (m, 1H), 7.35 - 7.33 (m, 1H), 7.16 - 7.02 (m, 2H), 6.76 (d, J = 8.8 Hz, 1H), 4.22 - 4.12 (m, 1H), 4.10 (t, J = 7.2 Hz, 2H), 3.22 (t, J = 7.6 Hz, 2H), 3.15 (d, J = 10.4 Hz, 2H), 2.60 - 2.55 (m, 2H), 2.37 - 2.32 (m, 1H), 2.19 - 2.12 (m, 2H), 1.94 - 1.88 (m, 2H), 1.48 - 1.43 (m, 3H), 1.23 (s, 1H), 1.03 (d, J = 12.4 Hz, 2H), 0.49 - 0.39 (m, 2H), 0.29 - 0.20 (m, 2H).

[1060] Example 79. Synthesis of I-95:

[1061]

[1062] Experimental Procedure:

[1063] Step 1

[1064] Synthesis of N-(9-(2-fluoroethyl)-9-azabicyclo[3.3.1]nonane-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide. DIEA (60.0 mg, 0.46 mmol) was added to a mixture of N-{9-azabicyclo[3.3.1]nonane-3-yl}-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (50 mg, 0.15 mmol) and 1-fluoro-2-iodoethane (53.8 mg, 0.31 mmol) in ACN (10 mL). The reaction mixture was stirred at 80°C for 16 hours. The mixture was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm 10 µm, mobile phase A: water (0.1% NH3), B: acetonitrile, flow rate: 30 mL / min, gradient: 55% to 85% of A in B, wavelength: 214 / 254 nm) to obtain N-(9-(2-fluoroethyl)-9-azabicyclo[3.3.1]nonane-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide (18.5 mg, 31%) as a white solid. MS (ESI): C 22 H 28 Calculated value for FN3O 369.22, m / z measured value 370.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.93 - 7.91 (m, 1H), 7.36 - 7.34 (m, 1H), 7.15 - 7.04 (m, 2H), 6.77 (d, J = 8.8 Hz, 1H), 4.50 - 4.36 (m, 2H), 4.33 - 4.23 (m, 1H), 4.10 (t, J = 7.2 Hz, 2H), 3.23 (t, J = 7.6 Hz, 2H), 3.10 (d, J = 10.8 Hz, 2H), 2.95 - 2.86 (m, 2H), 2.61 - 2.54 (m, 2H), 2.25 - 2.06 (m, 3H), 1.85 - 1.75 (m, 2H), 1.54 - 1.39 (m, 3H), 1.00 (d, J = 13.2 Hz, 2H).

[1065] Example 80. Synthesis of I-96:

[1066]

[1067] Experimental Procedure:

[1068] Step 1

[1069] Synthesis of N-(9-((1-fluorocyclopropyl)methyl)-9-azabicyclo[3.3.1]nonane-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide trifluoroacetate. HOAc (0.1 mL) was added to a mixture of N-{9-azabicyclo[3.3.1]nonane-3-yl}-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (80 mg, 0.25 mmol) and 1-fluorocyclopropane-1-carbaldehyde (43.6 mg, 0.50 mmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 4 hours. NaBH3CN (46.6 mg, 0.74 mmol) was subsequently added, and the reaction mixture was stirred at 60°C for 12 hours. The mixture was concentrated to obtain the crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm 10 µm, mobile phase A: water (0.1% TFA), B: acetonitrile, flow rate: 30 mL / min, gradient: 22% to 40% B in A, wavelength: 214 / 254 nm) to obtain N-(9-((1-fluorocyclopropyl)methyl)-9-azabicyclo[3.3.1]nonane-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide trifluoroacetate (11.4 mg, 12%) as a white solid. MS (ESI): C 24 H 30 Calculated value for FN3O 395.24, m / z measured value 396.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 0.77H), 7.94 - 7.92 (m, 1H), 7.39 - 7.37 (m, 1H), 7.25 - 7.07 (m, 3H), 4.72 - 4.35 (m, 1H), 4.13 (t, J = 7.2 Hz, 2H), 3.92 - 3.80 (m, 4H), 3.25 (t, J = 7.6 Hz, 2H), 2.67 - 2.54 (m, 4H), 2.28 - 2.06 (m, 3H), 1.92 - 1.75 (m, 2H), 1.57 - 1.47 (m, 3H), 1.25 - 1.19 (m, 2H), 1.08 - 1.02 (m, 2H).

[1070] Example 81. Synthesis of I-97:

[1071]

[1072] Experimental Procedure:

[1073] Step 1

[1074] Synthesis of N-(9-(cyclobutylmethyl)-9-azabicyclo[3.3.1]nonane-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate. HOAc (0.1 mL) was added to a mixture of N-{9-azabicyclo[3.3.1]nonane-3-yl}-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (80 mg, 0.25 mmol) and cyclobutanecarboxaldehyde (41.6 mg, 0.50 mmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 4 hours. Subsequently, NaBH3CN (46.6 mg, 0.74 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm 10 µm, mobile phase A: water (0.1% FA), B: acetonitrile, flow rate: 30 mL / min, gradient: 20% to 60% of A in B, wavelength: 214 / 254 nm) to obtain N-(9-(cyclobutylmethyl)-9-azabicyclo[3.3.1]nonane-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate (43.2 mg, 45%) as a white solid. MS (ESI): C 25 H 33 Calculated value for N3O 391.26, m / z measured value 392.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 0.5H), 7.93 - 7.91 (m, 1H), 7.37 - 7.35 (m, 1H), 7.17 - 7.05 (m, 2H), 6.89 (d, J = 8.0 Hz, 1H), 4.46 - 4.41 (m, 1H), 4.11 (t, J = 7.2 Hz, 2H), 3.23 (t, J = 8.0 Hz, 2H), 2.93 (s, 2H), 2.62 - 2.54 (m, 3H), 2.32 - 2.25 (m, 2H), 2.20 - 2.08 (m, 1H), 2.02 - 1.97 (m, 3H), 1.94 - 1.69 (m, 7H), 1.63 - 1.57 (m, 2H), 1.48 - 1.45 (m, 1H), 1.19 - 1.16 (m, 2H).

[1075] Example 82. Synthesis of I-98:

[1076]

[1077] Experimental Procedure:

[1078] Step 1

[1079] Synthesis of N-(9-(oxetane-3-ylmethyl)-9-azabicyclo[3.3.1]nonane-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide. HOAc (0.1 mL) was added to a mixture of N-{9-azabicyclo[3.3.1]nonane-3-yl}-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (80 mg, 0.25 mmol) and oxetane-3-carbaldehyde (42.6 mg, 0.50 mmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 4 hours. After adding NaBH3CN (46.6 mg, 0.74 mmol), the reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm × 10 µm, mobile phase A: water (0.1% NH3), B: acetonitrile, flow rate: 30 mL / min, gradient: 45% to 75% of A in B, wavelength: 214 / 254 nm) to obtain N-(9-(oxetane-3-ylmethyl)-9-azabicyclo[3.3.1]nonane-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide (43.5 mg, 45%) as a white solid. MS (ESI): C 24 H 31 Calculated value for N3O2 393.24, m / z measured value 394.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.92 - 7.90 (m, 1H), 7.36 - 7.33 (m, 1H), 7.17 - 7.04 (m, 2H), 6.75 (d, J = 8.8 Hz, 1H), 4.65 - 4.61 (m, 2H), 4.31 - 4.18 (m, 3H), 4.10 (t, J = 7.2 Hz, 2H), 3.22 (t, J = 7.6 Hz, 2H), 3.10 - 2.95 (m, 3H), 2.92 - 2.90 (m, 2H), 2.62 - 2.53 (m, 2H), 2.24 - 2.03 (m, 3H), 1.84 - 1.77 (m, 2H), 1.53 - 1.37 (m, 3H), 0.99 - 0.96 (m, 2H).

[1080] Example 83. Synthesis of I-99 and I-100:

[1081]

[1082] Experimental Procedure:

[1083] Step 1

[1084] Synthesis of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamido)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate. HATU (907.0 mg, 2.39 mmol) was added to a mixture of 1H,2H,3H-benzo[b]pyrrolizine-9-carboxylic acid (400 mg, 1.99 mmol), tert-butyl 7-amino-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (481.7 mg, 1.99 mmol), and DIEA (770.8 mg, 5.96 mmol) in DMF (20 mL). The reaction mixture was stirred at room temperature for 6 hours. The mixture was diluted with water (200 mL) and extracted with EA (100 mL x 3). The combined organic layer was concentrated to obtain the crude product, which was purified by column chromatography (PE:EA = 1:1) to obtain tert-butyl 7-(2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamido)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (500 mg, 47%) as a yellow solid. MS (ESI): C 24 H 31 Calculated value for N3O4 425.23, m / z measured value 426.2 [M+H] + .

[1085] Step 2

[1086] Synthesis of N-(3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide. A mixture of tert-butyl 7-{1H,2H,3H-benzo[b]pyrrolizine-9-amido}-3-oxa-9-azabicyclo[3.3.1]nonan-9-carboxylate (50 mg, 0.12 mmol) in DCM / TFA=3 / 1 (8 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm × 10 µm, mobile phase A: water (0.1% NH3), B: acetonitrile, flow rate: 30 mL / min, gradient: 33% to 43% of A in B, wavelength: 214 / 254 nm) to obtain N-(3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide (10.6 mg, 28%) as a white solid. MS (ESI): C 19 H 23 Calculated value for N3O2 325.18, m / z measured value 326.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 10.4 Hz, 1H), 8.01 - 7.99 (m, 1H), 7.36 - 7.34 (m, 1H), 7.15 - 7.04 (m, 2H), 4.59 - 4.53 (m, 1H), 4.10 (t, J = 7.2 Hz, 2H), 3.90 - 3.69 (m, 4H), 3.19 (t, J = 7.6 Hz, 2H), 2.84 - 2.83 (m, 2H), 2.63 - 2.55 (m, 2H), 2.26 - 2.14 (m, 2H), 1.60 (d, J = 14.4 Hz, 2H).

[1087] Step 3

[1088] Synthesis of N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate. HOAc (0.1 mL) was added to a mixture of N-{3-oxa-9-azabicyclo[3.3.1]nonane-7-yl}-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (80 mg, 0.25 mmol) in MeOH (10 mL) and CH2O (30%, 73.8 mg, 0.74 mmol) in H2O. The reaction mixture was stirred at room temperature for 4 hours. Subsequently, NaBH3CN (46.3 mg, 0.74 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm × 10 µm, mobile phase A: water (0.1% FA), B: acetonitrile, flow rate: 30 ml / min, gradient: 10% to 40% B in A, wavelength: 214 / 254 nm) to obtain N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate (49 mg, 59%) as a white solid. MS (ESI): C 20 H 25 Calculated value for N3O2 339.19, m / z measured value 340.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 0.4H), 8.06 (d, J = 10.4 Hz, 1H), 8.01 - 7.99 (m, 1H), 7.37 - 7.34 (m, 1H), 7.16 - 7.05 (m, 2H), 4.56 (dd, J = 17.2, 7.2 Hz, 1H), 4.11 (t, J = 7.2 Hz, 2H), 3.94 - 3.80 (m, 4H), 3.20 (t, J = 7.6 Hz, 2H), 2.78 (s, 2H), 2.63 - 2.56 (m, 2H), 2.54 (s, 3H), 2.46 - 2.41 (m, 2H), 1.45 (d, J = 15.2 Hz, 2H).

[1089] Example 84. Synthesis of I-101:

[1090]

[1091] Experimental Procedure:

[1092] Step 1

[1093] Synthesis of N-(9-ethyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide. HOAc (0.1 mL) was added to a mixture of N-{3-oxa-9-azabicyclo[3.3.1]nonane-7-yl}-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (80 mg, 0.25 mmol) and acetaldehyde (5.0 M solution in THF, 0.1 mL) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 4 hours. Subsequently, NaBH3CN (46.3 mg, 0.74 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm × 10 µm, mobile phase A: water (0.1% NH3), B: acetonitrile, flow rate: 30 mL / min, gradient: 38% to 48% of A in B, wavelength: 214 / 254 nm) to obtain N-(9-ethyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide (33.5 mg, 38%) as a white solid. MS (ESI): C 21 H 27 Calculated value for N3O2 353.21, m / z measured value 354.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 10.4 Hz, 1H), 8.02 - 8.00 (m, 1H), 7.36 - 7.34 (m, 1H), 7.16 - 7.04 (m, 2H), 4.55 (dd, J = 17.2, 7.2 Hz, 1H), 4.10 (t, J = 7.2 Hz, 2H), 3.85 - 3.76 (m, 4H), 3.20 (t, J = 7.6 Hz, 2H), 2.73 (s, 2H), 2.70 - 2.64 (m, 2H), 2.63 - 2.56 (m, 2H), 2.39 - 2.30 (m, 2H), 1.33 (d, J = 14.8 Hz, 2H), 0.99 (t, J = 7.2 Hz, 3H).

[1094] Example 85. Synthesis of I-102:

[1095]

[1096] Experimental Procedure:

[1097] Step 1

[1098] Synthesis of N-(9-propyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate. HOAc (0.1 mL) was added to a mixture of N-{3-oxa-9-azabicyclo[3.3.1]nonane-7-yl}-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (80 mg, 0.25 mmol) and propionaldehyde (0.1 mL) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 4 hours. NaBH3CN (46.3 mg, 0.74 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm × 10 µm, mobile phase A: water (0.1% FA), B: acetonitrile, flow rate: 30 mL / min, gradient: 17% to 47% of A in B, wavelength: 214 / 254 nm) to obtain N-(9-propyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide formate (42 mg, 47%) as a white solid. MS (ESI): C 22 H 29 Calculated value for N3O2 367.20, m / z measured value 368.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 0.25H), 8.01 - 7.99 (m, 2H), 7.37 - 7.35 (m, 1H), 7.18 - 7.06 (m, 2H), 4.59 - 4.57 (m, 1H), 4.11 (t, J = 7.2 Hz, 2H), 3.92 (s, 4H), 3.20 (t, J = 7.6 Hz, 2H), 3.01 - 2.52 (m, 7H), 2.47 - 2.35 (m, 1H), 1.49 (s, 4H), 0.91 (t, J = 7.2 Hz, 3H).

[1099] Example 86. Synthesis of I-103:

[1100]

[1101] Experimental Procedure:

[1102] Step 1

[1103] Synthesis of N-(9-cyclopropyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide. A mixture of N-{3-oxa-9-azabicyclo[3.3.1]nonane-7-yl}-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (70 mg, 0.21 mmol), (1-ethoxycyclopropoxy)trimethylsilane (374.9 mg, 2.15 mmol), HOAc (0.1 mL) and NaBH3CN (67.6 mg, 1.08 mmol) in THF (10 mL) was stirred at 60°C for 16 hours. The mixture was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm × 10 µm, mobile phase A: water (0.1% NH3), B: acetonitrile, flow rate: 30 ml / min, gradient: 52% to 62% of A in B, wavelength: 214 / 254 nm) to obtain N-(9-cyclopropyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide (7.2 mg, 9%) as a white solid. MS (ESI): C 22 H 27 Calculated value for N3O2 365.21, m / z measured value 366.2 [M+H] + . 1H NMR (400 MHz, MeOD) δ 8.65 (d, J = 10.4 Hz, 1H), 8.00 - 7.98 (m, 1H), 7.32 - 7.30 (m, 1H), 7.19 - 7.07 (m, 2H), 4.73 - 4.67 (m, 1H), 4.13 (t, J = 7.2 Hz, 2H), 3.95 - 3.83 (m, 4H), 3.29 - 3.26 (m, 2H), 2.88 - 2.86 (m, 2H), 2.71 - 2.66 (m, 2H), 2.64 - 2.56 (m, 2H), 2.55 - 2.50 (m, 1H), 1.57 (d, J = 15.2 Hz, 2H), 0.58 - 0.49 (m, 2H), 0.42 - 0.34 (m, 2H).

[1104] Example 87. Synthesis of I-104:

[1105]

[1106] Experimental Procedure:

[1107] Step 1

[1108] Synthesis of N-(9-(2-fluoroethyl)-3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide. DIEA (83.4 mg, 0.65 mmol) was added to a mixture of N-{3-oxa-9-azabicyclo[3.3.1]nonane-7-yl}-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (70 mg, 0.22 mmol) and 1-fluoro-2-iodoethane (74.8 mg, 0.43 mmol) in ACN (10 mL). The reaction mixture was stirred at 80°C for 16 hours. The mixture was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm × 10 µm, mobile phase A: water (0.1% FA), B: acetonitrile, flow rate: 30 ml / min, gradient: 10% to 40% B in A, wavelength: 214 / 254 nm) to obtain N-(9-(2-fluoroethyl)-3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide (16.2 mg, 20%) as a white solid. MS (ESI): C 21 H 26 Calculated value for FN3O2 371.20, m / z measured value 372.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.16 - 8.13 (m, 1H), 8.02 - 7.99 (m, 1H), 7.36 - 7.34 (m, 1H), 7.16 - 7.06 (m, 2H), 4.59 - 4.55 (m, 2H), 4.44 - 4.42 (m, 1H), 4.10 (t, J = 7.2 Hz, 2H), 3.88 - 3.78 (m, 4H), 3.20 (t, J = 7.6 Hz, 2H), 2.99 - 2.92 (m, 2H), 2.76 (s, 2H), 2.64 - 2.55 (m, 2H), 2.45 - 2.28 (m, 2H), 1.37 (d, J = 14.8 Hz, 2H).

[1109] Example 88. Synthesis of I-105:

[1110]

[1111] Experimental Procedure:

[1112] Step 1

[1113] Synthesis of N-(9-((1-fluorocyclopropyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide. HOAc (0.1 mL) was added to a mixture of N-{3-oxa-9-azabicyclo[3.3.1]nonane-7-yl}-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (80 mg, 0.25 mmol) and 1-fluorocyclopropane-1-carbaldehyde (43.3 mg, 0.49 mmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 4 hours. NaBH3CN (46.3 mg, 0.74 mmol) was added. The reaction mixture was stirred at 60°C for 12 hours. The mixture was concentrated to obtain the crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm 10 µm, mobile phase A: water (0.1% FA), B: acetonitrile, flow rate: 30 mL / min, gradient: 20% to 30% B in A, wavelength: 214 / 254 nm) to obtain N-(9-((1-fluorocyclopropyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide (18.4 mg, 19%) as a white solid. MS (ESI): C 23 H 28 Calculated value for FN3O2 397.22, m / z measured value 398.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.01 - 7.99 (m, 1H), 7.82 - 7.80 (m, 1H), 7.38 - 7.36 (m, 1H), 7.18 - 7.06 (m, 2H), 4.64 - 4.62 (m, 1H), 4.47 - 4.14 (m, 4H), 4.12 (t, J = 7.2 Hz, 2H), 4.06 - 3.89 (m, 2H), 3.69 (s, 2H), 3.21 (t, J = 7.6 Hz, 2H), 2.79 - 2.67 (m, 2H), 2.64 - 2.58 (m, 2H), 2.08 - 1.81 (m, 2H), 1.29 - 1.24 (m, 2H), 1.03 - 1.00 (m, 2H).

[1114] Example 89. Synthesis of I-106:

[1115]

[1116] Experimental Procedure:

[1117] Step 1

[1118] Synthesis of N-(9-(cyclobutylmethyl)-3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide. HOAc (0.1 mL) was added to a 10 mL MeOH mixture of N-{3-oxa-9-azabicyclo[3.3.1]nonane-7-yl}-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (80 mg, 0.25 mmol) and cyclobutanecarboxaldehyde (62.0 mg, 0.74 mmol). The reaction mixture was stirred at room temperature for 4 hours. NaBH3CN (46.3 mg, 0.74 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm 10 µm, mobile phase A: water (0.1% FA), B: acetonitrile, flow rate: 30 mL / min, gradient: 20% to 50% of A in B, wavelength: 214 / 254 nm) to obtain N-(9-(cyclobutylmethyl)-3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide (17.7 mg, 18%) as a white solid. MS (ESI): C 24 H 31 Calculated value for N3O2 393.24, m / z measured value 394.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.18 - 8.08 (m, 1H), 8.05 - 7.95 (m, 1H), 7.40 - 7.30 (m, 1H), 7.17 - 6.99 (m, 2H), 4.55 (dd, J = 16.8, 7.2 Hz, 1H), 4.12 (t, J = 7.2 Hz, 2H), 3.90 - 3.75 (m, 4H), 3.19 (t, J = 7.2 Hz, 2H), 2.68 - 2.67 (m, 2H), 2.62 - 2.56 (m, 2H), 2.41 - 2.33 (m, 2H), 2.00 - 1.96 (m, 3H), 1.90 - 1.77 (m, 4H), 1.72 - 1.65 (m, 2H), 1.35 (d, J = 14.8 Hz, 2H).

[1119] Example 90. Synthesis of I-107:

[1120]

[1121] Experimental Procedure:

[1122] Step 1

[1123] Synthesis of N-(9-(oxetane-3-ylmethyl)-3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide. HOAc (0.1 mL) was added to a mixture of N-{3-oxa-9-azabicyclo[3.3.1]nonane-7-yl}-1H,2H,3H-benzo[b]pyrrolizine-9-carboxamide (80 mg, 0.25 mmol) and oxetane-3-carbaldehyde (63.5 mg, 0.74 mmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 4 hours. NaBH3CN (46.3 mg, 0.74 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm 10 µm, mobile phase A: water (0.1% NH3), B: acetonitrile, flow rate: 30 mL / min, gradient: 30% to 60% B in A, wavelength: 214 / 254 nm) to obtain N-(9-(oxetane-3-ylmethyl)-3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide (10.1 mg, 10%) as a white solid. MS (ESI): C 23 H 29 Calculated value for N3O3 395.22, m / z measured value 396.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 10.4 Hz, 1H), 8.01 - 7.99 (m, 1H), 7.36 - 7.34 (m, 1H), 7.16 - 7.03 (m, 2H), 4.63 - 4.60 (m, 2H), 4.55 (dd, J = 17.2, 7.2 Hz, 1H), 4.28 (t, J = 6.0 Hz, 2H), 4.10 (t, J = 7.2 Hz, 2H), 3.83 - 3.75 (m, 4H), 3.19 (t, J = 7.6 Hz, 2H), 3.13 - 3.02 (m, 1H), 2.95 - 2.94 (m, 2H), 2.67 - 2.54 (m, 4H), 2.40 - 2.30 (m, 2H), 1.35 (d, J = 14.8 Hz, 2H).

[1124] Example 91. Synthesis of I-108:

[1125]

[1126] Step 1

[1127] Synthesis of N-(9-cyclopropyl-9-azabicyclo[3.3.1]nonane-3-yl)-7-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide. NaBH3CN (88 mg, 1.4 mmol) was added to a mixture of N-(9-azabicyclo[3.3.1]nonane-3-yl)-7-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide (80 mg, 0.2 mmol), CH3COOH (36 mg, 0.6 mmol), and (1-ethoxycyclopropyl)trimethylsilane (245 mg, 1.4 mmol) in THF (5 mL), and the mixture was stirred at 60°C for 6 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was dried over Na2SO4 and concentrated under vacuum to obtain the residue. The residue was purified by HPLC for purification (Column: Welch C18 21.2 × 250 mm 10 µm, Mobile phase A: water (0.1% NH3), B (acetonitrile), Flow rate: 25 ml / min, Gradient: 60% to 90% of A in B, Wavelength: 214 / 254 nm) to obtain N-(9-cyclopropyl-9-azabicyclo[3.3.1]nonane-3-yl)-7-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxamide (16.6 mg, 18%) as a white solid. MS (ESI): C 23 H 28 Calculated value for FN3O 381.22, m / z measured value 382.2 [M+H] + . 1H NMR (400 MHz, DMSO) δ 7.63 (dd, J = 12.0 Hz, 4.0 Hz, 1H), 7.36 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 6.98-6.93 (m, 1H), 6.74 (d, J = 8.0 Hz, 1H), 4.21-4.09 (m, 3H), 3.23 - 3.14 (m, 4H), 2.58-2.50 (m, 2H), 2.37-2.33 (m, 1H), 2.18-2.07 (m, 3H), 1.94-1.88 (m, 2H), 1.49 - 1.42 (m, 3H), 1.03 (d, J = 12.0 Hz, 2H), 0.46 - 0.41 (m, 2H), 0.26 - 0.22 (m, 2H).

[1128] Example 92. Synthesis of I-109:

[1129]

[1130] Experimental Procedure:

[1131] Step 1

[1132] Synthesis of N-(9-methyl-9-azabicyclo[3.3.1]nonane-3-yl)-6,7,8,9-tetrahydropyrido[1,2-a]indole-10-carboxyamide formate. HATU (159.0 mg, 0.42 mmol) was added to a mixture of 1H,2H,3H,4H-pyrido[1,2-a]indole-10-carboxylic acid (see Example 5) (75 mg, 0.35 mmol), 9-methyl-9-azabicyclo[3.3.1]nonane-3-amine (53.7 mg, 0.35 mmol), and DIEA (135.1 mg, 1.05 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 6 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 3). The combined organic layer was concentrated to obtain the crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm 10 µm, mobile phase A: water (0.1% FA), B: acetonitrile, flow rate: 30 ml / min, gradient: 23% to 53% of A in B, wavelength: 214 / 254 nm) to obtain N-(9-methyl-9-azabicyclo[3.3.1]nonane-3-yl)-6,7,8,9-tetrahydropyrido[1,2-a]indole-10-carboxamide formate (42 mg, 34%) as a yellow solid. MS (ESI): C 22 H 29 Calculated value for N3O 351.23, m / z measured value 352.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 0.8H), 7.83 - 7.73 (m, 1H), 7.45 - 7.36 (m, 1H), 7.17 - 7.11 (m, 3H), 4.44 - 4.36 (m, 1H), 4.07 (t, J = 6.0 Hz, 2H), 3.18 - 3.14 (m, 4H), 2.54 (s, 3H), 2.32 - 2.24 (m, 2H), 2.17 - 1.89 (m, 5H), 1.88 - 1.77 (m, 2H), 1.63 - 1.50 (m, 2H), 1.46 - 1.43 (m, 1H), 1.09 - 1.05 (m, 2H).

[1133] Example 93. Synthesis of I-110:

[1134]

[1135] Experimental Procedure:

[1136] Step 1

[1137] Synthesis of N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-carboxamide formate. HATU (147.1 mg, 0.39 mmol) was added to a mixture of 1H,3H,4H-[1,4]oxazino[4,3-a]indole-10-carboxylic acid (see Example 3) (70 mg, 0.32 mmol), 9-methyl-9-azabicyclo[3.3.1]nonan-3-amine (49.7 mg, 0.32 mmol), and DIEA (125.0 mg, 0.97 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 6 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 3). The combined organic layer was concentrated to obtain the crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm × 10 µm, mobile phase A: water (0.1% FA), B: acetonitrile, flow rate: 30 mL / min, gradient: 20% to 50% of A in B, wavelength: 214 / 254 nm) to obtain N-(9-methyl-9-azabicyclo[3.3.1]nonane-3-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-carboxamide formate (47 mg, 41%) as a white solid. MS (ESI): C 21 H 27 Calculated value for N3O2 353.21, m / z measured value 354.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.87 - 7.84 (m, 1H), 7.52 - 7.45 (m, 1H), 7.26 - 7.14 (m, 3H), 5.13 (s, 2H), 4.43 - 4.35 (m, 1H), 4.13 (s, 4H), 3.15 - 3.12 (m, 2H), 2.51 (s, 3H), 2.27 - 2.22 (m, 2H), 2.18 - 2.07 (m, 1H), 1.98 - 1.90 (m, 2H), 1.66 - 1.55 (m, 2H), 1.46 - 1.43 (m, 1H), 1.07 - 1.03 (m, 2H).

[1138] Example 94. Synthesis of I-111 and I-112:

[1139]

[1140] Step 1

[1141] Synthesis of tert-butyl 3-(8,8-difluoro-6,7,8,9-tetrahydropyrido[1,2-a]indole-10-carboxylate)-9-azabicyclo[3.3.1]nonane-9-carboxylate. HATU (345 mg, 0.90 mmol) was added to a mixture of 2,2-difluoro-1H,3H,4H-pyrido[1,2-a]indole-10-carboxylic acid (190 mg, 0.76 mmol), tert-butyl 3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylate (181 mg, 0.76 mmol), and DIEA (293 mg, 2.27 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 6 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 3). The combined organic layer was concentrated to obtain the crude product, which was purified by column chromatography (PE:EA = 1:1) to obtain tert-butyl 3-(8,8-difluoro-6,7,8,9-tetrahydropyrido[1,2-a]indole-10-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate (240 mg, 54%) as a yellow solid. MS (ESI): C 26 H 33 Calculated value for F2N3O3 473.25, m / z measured value 474.2 [M+H] + .

[1142] Step 2

[1143] Synthesis of N-(9-azabicyclo[3.3.1]nonan-3-yl)-8,8-difluoro-6,7,8,9-tetrahydropyrido[1,2-a]indole-10-carboxamide. A mixture of tert-butyl 3-{2,2-difluoro-1H,3H,4H-pyrido[1,2-a]indole-10-amido}-9-azabicyclo[3.3.1]nonan-9-carboxylate (240 mg, 0.51 mmol) in DCM / TFA=3 / 1 (12 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm 10 µm, mobile phase A: water (0.1% FA), B (acetonitrile), flow rate: 30 ml / min, gradient: 22% to 32% B in A, wavelength: 214 / 254 nm) to obtain N-(9-azabicyclo[3.3.1]nonane-3-yl)-8,8-difluoro-6,7,8,9-tetrahydropyrido[1,2-a]indole-10-carboxamide (110 mg, 58%) as a white solid. MS (ESI): C 21 H 25 Calculated value for F2N3O 373.20, m / z measured value 374.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.30 (s, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.50 (m, 2H), 7.31 - 7.16 (m, 2H), 4.47 - 4.36 (m, 1H), 4.31 (t, J = 6.4 Hz, 2H), 3.84 - 3.77 (m, 4H), 2.75 - 2.60 (m, 2H), 2.37 - 2.25 (m, 2H), 2.13 - 2.01 (m, 1H), 1.86 - 1.61 (m, 4H), 1.58 - 1.52 (m, 3H).

[1144] Step 3

[1145] Synthesis of 8,8-difluoro-N-(9-methyl-9-azabicyclo[3.3.1]nonane-3-yl)-6,7,8,9-tetrahydropyridodo[1,2-a]indole-10-carboxamide. AcOH (12.9 mg, 0.21 mmol) was added to a solution of N-{9-azabicyclo[3.3.1]nonane-3-yl}-2,2-difluoro-1H,3H,4H-pyridodo[1,2-a]indole-10-carboxamide (80 mg, 0.21 mmol) in MeOH (10 mL) and CH2O (30%, 64 mg, 0.64 mmol) in H2O. The reaction mixture was stirred at room temperature for 4 hours. NaBH3CN (40.4 mg, 0.64 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated to obtain the crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm 10 µm, mobile phase A: water (0.1% TFA), B (acetonitrile), flow rate: 30 mL / min, gradient: 25% to 35% B in A, wavelength: 214 / 254 nm) to obtain 8,8-difluoro-N-(9-methyl-9-azabicyclo[3.3.1]nonane-3-yl)-6,7,8,9-tetrahydropyrido[1,2-a]indole-10-carboxamide (22.5 mg, 27%) as a white solid. MS (ESI): C 22 H 27 Calculated value for F2N3O 387.21, m / z measured value 388.2 [M+H] + . 1H NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 7.84 - 7.81 (m, 1H), 7.54 - 7.51 (m, 2H), 7.27 - 7.20 (m, 2H), 4.66 - 4.57 (m, 1H), 4.32 (t, J = 6.4 Hz, 2H), 3.81 (t, J = 14.8 Hz, 2H), 3.67 - 3.65 (m, 2H), 2.91 - 2.83 (m, 3H), 2.71 - 2.62 (m, 2H), 2.44 - 2.38 (m, 2H), 2.20 - 2.00 (m, 3H), 1.89 - 1.78 (m, 2H), 1.54 - 1.42 (m, 3H).

[1146] Example 95. Synthesis of I-113 and I-114:

[1147]

[1148] Experimental Procedure:

[1149] Step 1

[1150] Synthesis of 2-(4,4-difluoropiperidin-1-yl)-5-fluorobenzaldehyde. K2CO3 (97.27 g, 0.71 mol) was added to a solution of 2,5-difluorobenzaldehyde (40 g, 0.2815 mol) and 4,4-difluoropiperidin hydrochloride (53.23 g, 0.34 mol) in DMSO (400 mL). The reaction mixture was stirred at 95°C for 16 hours. The mixture was diluted with water (1000 mL) and extracted with EA (500 mL x 3). The combined organic layer was concentrated to obtain a crude product, which was purified by column chromatography (PE:EA = 10:1) to obtain 2-(4,4-difluoropiperidin-1-yl)-5-fluorobenzaldehyde (4 g, 7%) as a yellow solid. MS (ESI): C 12 H 12 Calculated value for F3NO 243.09, m / z measured value 244.1 [M+H] + .

[1151] Step 2

[1152] Synthesis of (Z)-N'-(2-(4,4-difluoropiperidin-1-yl)-5-fluorobenzylidene)-4-methylbenzenesulfonohydrazide. 4-methylbenzenesulfonohydrazide (3.67 g, 0.020 mol) was added to a mixture of 2-(4,4-difluoropiperidin-1-yl)-5-fluorobenzaldehyde (4 g, 0.016 mol) in toluene (50 mL). The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain (Z)-N'-(2-(4,4-difluoropiperidin-1-yl)-5-fluorobenzylidene)-4-methylbenzenesulfonohydrazide (6.77 g, crude product) as a yellow solid, which was used directly in a subsequent step. MS (ESI): C 19 H 20 Calculated value for F3N3O2S 411.12, m / z measured value 412.1 [M+H] + .

[1153] Step 3

[1154] Synthesis of 2,8,8-trifluoro-6,7,8,9,9a,10-hexahydropyrido[1,2-a]indole. NaH (0.44 g, 0.018 mol) was added to a mixture of N'-[(1Z)-[2-(4,4-difluoropiperidin-1-yl)-5-fluorophenyl]methylidene]-4-methylbenzenesulfonohydrazide (6.77 g, 0.017 mol) in toluene (100 mL). The reaction mixture was stirred at 135°C for 0.5 hours. The mixture was diluted with water (500 mL) and extracted with EA (200 mL x 3). The combined organic layer was concentrated to obtain a crude product, which was purified by column chromatography (PE:EA = 10:1) to obtain 2,8,8-trifluoro-6,7,8,9,9a,10-hexahydropyrido[1,2-a]indole (1.6 g, 37%) as a yellow solid. MS (ESI): C 12 H 12Calculated value for F3N 227.09, m / z measured value 228.1 [M+H] + .

[1155] Step 4

[1156] Synthesis of 2,8,8-trifluoro-6,7,8,9-tetrahydropyridodo[1,2-a]indole. MnO2 (3.04 g, 0.035 mol) was added to a mixture of 2,2,8-trifluoro-1H,3H,4H,10H,10aH-pyridodo[1,2-a]indole (1.6 g, 0.007 mol) in chloroform (50 mL). The reaction mixture was stirred at 80°C for 24 hours. The mixture was filtered through Celite, and the filtrate was concentrated to obtain the crude product. This was purified by column chromatography (PE:EA = 3:1) to obtain 2,8,8-trifluoro-6,7,8,9-tetrahydropyridodo[1,2-a]indole (0.7 g, 44%) as a yellow solid. MS (ESI): C 12 H 10 Calculated value for F3N 225.08, m / z measured value 226.1 [M+H] + .

[1157] Step 5

[1158] Synthesis of 2,8,8-trifluoro-6,7,8,9-tetrahydropyrido[1,2-a]indole-10-carbaldehyde. POCl3 (1.39 g, 9.06 mmol) was added to a mixture of 2,2,8-trifluoro-1H,3H,4H-pyrido[1,2-a]indole (680 mg, 3.02 mmol) in DMF (20 mL). The reaction mixture was stirred at 90°C for 2 hours. The reaction mixture was quenched with ice water and the pH was adjusted to 8 with saturated NaHCO3. The mixture was extracted with EA (100 mL x 2). The combined organic layer was concentrated to obtain the crude product, which was purified by column chromatography (PE:EA = 3:1) to obtain 2,8,8-trifluoro-6,7,8,9-tetrahydropyrido[1,2-a]indole-10-carbaldehyde (520 mg, 63%) as a yellow solid. MS (ESI): Calculated value for C13H10F3NO 253.07, m / z found value 254.1 [M+H] + .

[1159] Step 6

[1160] Synthesis of 2,8,8-trifluoro-6,7,8,9-tetrahydropyrido[1,2-a]indole-10-carboxylic acid. To a mixture of NaClO2 (536 mg, 5.92 mmol) and NaH2PO4 (2369 mg, 19.75 mmol) in H2O (5 mL), 2,2,8-trifluoro-1H,3H,4H-pyrido[1,2-a]indole-10-carbaldehyde (500 mg, 1.97 mmol) and 2-methyl-2-butene (1385 mg, 19.75 mmol) were added in t-BuOH (15 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 3). The combined organic layer was concentrated under reduced pressure to obtain 2,8,8-trifluoro-6,7,8,9-tetrahydropyrido[1,2-a]indole-10-carboxylic acid (370 mg, crude product) as a yellow solid, which was used directly in a subsequent step. MS (ESI): C13 H 10 Calculated value for F3NO2 269.07, m / z measured value 270.0 [M+H] + .

[1161] Step 7

[1162] Synthesis of tert-butyl 7-(2,8,8-trifluoro-6,7,8,9-tetrahydropyrido[1,2-a]indole-10-carboxylamido)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate. HATU (305 mg, 0.80 mmol) was added to a mixture of 2,2,8-trifluoro-1H,3H,4H-pyrido[1,2-a]indole-10-carboxylic acid (180 mg, 0.67 mmol), tert-butyl 7-amino-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (162 mg, 0.67 mmol) and DIEA (259 mg, 2.01 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 6 hours. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 3). The combined organic layer was concentrated to obtain the crude product, which was purified by column chromatography (PE:EA = 1:1) to obtain tert-butyl 7-(2,8,8-trifluoro-6,7,8,9-tetrahydropyrido[1,2-a]indole-10-carboxamido)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (250 mg, 66%) as a yellow solid. MS (ESI): C 25 H 30 Calculated value for F3N3O4 493.22, m / z measured value 494.2 [M+H] + .

[1163] Step 8

[1164] Synthesis of N-(3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-2,8,8-trifluoro-6,7,8,9-tetrahydropyrido[1,2-a]indole-10-carboxamide. A mixture of tert-butyl 7-{2,2,8-trifluoro-1H,3H,4H-pyrido[1,2-a]indole-10-amido}-3-oxa-9-azabicyclo[3.3.1]nonan-9-carboxylate (250 mg, 0.51 mmol) in DCM / TFA = 3 / 1 (12 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to obtain a crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm 10 µm, mobile phase A: water (0.1% FA), B (acetonitrile), flow rate: 30 ml / min, gradient: 18% to 48% of A in B, wavelength: 214 / 254 nm) to obtain N-(3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-2,8,8-trifluoro-6,7,8,9-tetrahydropyrido[1,2-a]indole-10-carboxamide (100 mg, 49%) as a white solid. MS (ESI): C 20 H 22 Calculated value for F3N3O2 393.17, m / z measured value 394.2 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.43 (s, 1H), 8.28 (s, 0.25 H), 7.56 - 7.53 (m, 1H), 7.45 (dd, J = 8.8 Hz, 4.4 Hz, 1H), 7.03 (td,J = 9.2 Hz, 2.4 Hz, 1H), 4.77 - 4.74 (m, 1H), 4.33 (t, J = 6.4 Hz, 2H), 4.18 - 4.07 (m, 4H), 3.80 (t, J = 14.4 Hz, 2H), 3.54 - 3.52 (m, 2H), 2.69 - 2.49 (m, 4H), 2.10 (d, J = 15.6 Hz, 2H).

[1165] Step 9

[1166] Synthesis of 2,8,8-trifluoro-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-6,7,8,9-tetrahydropyridodo[1,2-a]indole-10-carboxamide. AcOH (13.7 mg, 0.23 mmol) was added to a solution of 2,2,8-trifluoro-N-{3-oxa-9-azabicyclo[3.3.1]nonane-7-yl}-1H,3H,4H-pyridodo[1,2-a]indole-10-carboxamide (90 mg, 0.23 mmol) in MeOH (10 mL) and CH2O (30%, 68 mg, 0.69 mmol) in H2O. The reaction mixture was stirred at room temperature for 4 hours. NaBH3CN (43.1 mg, 0.69 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated to obtain the crude product, which was purified by HPLC for purification (Welch's Extimate C18 21.2 × 250 mm 10 µm, mobile phase A: water (0.1% FA), B: acetonitrile, flow rate: 30 mL / min, gradient: 18% to 48% of A in B, wavelength: 214 / 254 nm) to obtain 2,8,8-trifluoro-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-6,7,8,9-tetrahydropyridodo[1,2-a]indole-10-carboxamide (31.4 mg, 33%) as a white solid. MS (ESI): C 21 H 24 Calculated value for F3N3O2 407.18, m / z measured value 408.2 [M+H] + . 1H NMR (400 MHz, DMSO) δ 8.14 (s, 0.4H), 8.12 - 8.10 (m, 1H), 7.62 - 7.50 (m, 2H), 7.10 (td,J = 9.2, 2.4 Hz, 1H), 4.60 - 4.54 (m, 1H), 4.31 (t, J = 6.4 Hz, 2H), 3.98 - 3.78 (m, 6H), 2.89 (s, 2H), 2.72 - 2.55 (m, 5H), 2.46 - 2.44 (m, 2H), 1.58 (d, J = 13.2 Hz, 2H).

[1167] Example 96. Synthesis of I-115 and I-116:

[1168]

[1169] Experimental Procedure:

[1170] Step 1

[1171] Synthesis of ethyl 2-(2-(6-chlorohexaneamido)phenyl)acetate. 6-chlorohexanoyl chloride (8.01 g, 0.047 mol) was added to a mixture of ethyl 2-(2-aminophenyl)acetate (8.5 g, 0.047 mol) and DIEA (12.25 g, 0.095 mol) in THF (100 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (300 mL) and extracted with EA (200 mL x 3). The combined organic layer was concentrated to obtain the crude product, which was purified by column chromatography (PE:EA = 10:1) to obtain ethyl 2-(2-(6-chlorohexaneamido)phenyl)acetate (11.5 g, 74%) as a yellow solid. MS (ESI): C 16 H 22 Calculated value for ClNO3 311.13, m / z measured value 312.1 [M+H] + .

[1172] Step 2

[1173] Synthesis of ethyl 7,8,9,10-tetrahydro-6H-azefino[1,2-a]indole-11-carboxylate. t-BuOK (10.35 g, 0.092 mol) was added to a mixture of ethyl 2-[2-(6-chlorohexanamido)phenyl]acetate (11.5 g, 0.037 mol) in THF (200 mL). The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with water (300 mL) and extracted with EA (200 mL x 3). The combined organic layer was concentrated to obtain a crude product, which was purified by column chromatography (PE:EA = 3:1) to obtain ethyl 7,8,9,10-tetrahydro-6H-azefino[1,2-a]indole-11-carboxylate (0.9 g, 7%) as a yellow solid.

[1174] MS (ESI): C 16 H 19 Calculated value for NO2 257.14, m / z measured value 258.1 [M+H] + .

[1175] Step 3

[1176] Synthesis of 7,8,9,10-tetrahydro-6H-azefino[1,2-a]indole-11-carboxylic acid. KOH (180 mg, 3.21 mmol) was added to a solution of ethyl 7,8,9,10-tetrahydro-6H-azefino[1,2-a]indole-11-carboxylate (230 mg, 0.89 mmol) in EtOH (20 mL) and H2O (5 mL). The reaction solution was stirred at 80°C for 16 hours. The reaction solution was diluted with water (50 mL) and extracted with EtOAc (20 mL x 2). The aqueous phase was acidified with HCl (1N) to a pH of 2–3 and extracted with EtOAc (30 mL x 2). The combined organic layer was concentrated under reduced pressure to obtain 7,8,9,10-tetrahydro-6H-azefino[1,2-a]indole-11-carboxylic acid (140 mg, crude material) as a white solid.

[1177] MS (ESI): C14 H 15 Calculated value for NO2 229.11, m / z measured value 230.2 [M+H] + .

[1178] Step 4

[1179] Synthesis of tert-butyl 7-(7,8,9,10-tetrahydro-6H-azefino[1,2-a]indole-11-carboxylate)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate. DIEA (310 mg, 2.56 mmol) and HATU (304 mg, 0.80 mmol) were added to a solution of 7,8,9,10-tetrahydro-6H-azefino[1,2-a]indole-11-carboxylic acid (120 mg, 0.52 mmol) and tert-butyl 7-amino-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (120 mg, 0.49 mmol) in DMF (10 mL), and the reaction mixture was stirred at room temperature for 4 hours. LCMS showed that the reaction was complete. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain the residue, which was purified by silica gel chromatography eluted with 50% EA in PE to obtain tert-butyl 7-(7,8,9,10-tetrahydro-6H-azefino[1,2-a]indole-11-carboxamido)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (140 mg, 59%) as a yellow solid.

[1180] MS (ESI): C 26 H 35 Calculated value for N3O4 453.26, m / z measured value 454.2 [M+H] + .

[1181] Step 5

[1182] Synthesis of N-(3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-7,8,9,10-tetrahydro-6H-azefino[1,2-a]indole-11-carboxamide formate. TFA (2 mL) was added at 0°C to a solution of tert-butyl 7-(7,8,9,10-tetrahydro-6H-azefino[1,2-a]indole-11-carboxamide)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (140 mg, 0.31 mmol) in DCM (20 mL), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to obtain a crude product, which was purified by HPLC for purification (Column: Welch's Extimate C18 21.2 × 250 mm × 10 µm, Mobile phase A: Water (0.1% FA), B: Acetonitrile, Flow rate: 30 mL / min, Gradient: 15% to 45% of A in B, Wavelength: 214 / 254 nm) to obtain N-(3-oxa-9-azabicyclo[3.3.1]nonane-7-yl)-7,8,9,10-tetrahydro-6H-azefino[1,2-a]indole-11-carboxamide formate (80 mg, 73%) as a yellow solid. MS (ESI): C 21 H 27 Calculated value for N3O2 353.21, m / z measured value 354.2 [M+H] +...

Claims

Claim 1 Compound of formula (II) or its pharmaceutically permissible salt: Here, ring A is selected from the group consisting of a 4-7 member monocyclic heterocyclil ring having 1-3 cyclic heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, a 7-10 member cyclic heterocyclil ring having 1-3 cyclic heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, or a 5-6 member heteroaryl ring, wherein ring A has 1, 2, or 3 R 3 It can be substituted by; ring B is a 5-7-membered heterocyclil ring containing 1-3 cyclic heteroatoms, including the cyclic nitrogen to which it is attached, wherein additional cyclic heteroatoms can each be independently selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein ring B is 1 or 2 R 2 It can be substituted by; W is selected from the group consisting of -C(O)-, -C(O)O-, -C(O)N(H)-, -C(O)OCH2-, -C(O)N(H)CH2-, and 5-membered heteroaryls having 1-3 cyclic heteroatoms; and Z is CR 1 or N and;R 1 In each case, independently hydrogen, halogen, -OH, C1-C3 alkyl (optionally substituted with 1, 2, or 3 halogens), C 3-7 Selected from the group consisting of cycloalkyl; and a 3-7-membered heterocyclyl ring containing 1-3 nitrogen atoms; R 2 is independently selected from hydrogen, halogen, C1-C3 alkyl (optionally substituted with 1, 2, or 3 halogens), -C(O)-(C1-C3 alkyl (optionally substituted with 1, 2, or 3 halogens)), and -C(O)O-(C1-C3 alkyl (optionally substituted with 1, 2, or 3 halogens)) in each case; R 3 In each case, independently are halogens, C1-C3 alkyls (optionally substituted with 1, 2, or 3 halogens), C 3-7 Selected from the group consisting of 4-6 monocyclic heterocyclyl rings having 1-3 cyclic heteroatoms each independently selected from the group consisting of cycloalkyl, nitrogen, oxygen, and sulfur (optionally substituted with 1, 2, or 3 halogens); m is 1, 2, or 3. Claim 2 In claim 1, a compound of the formula (Ia), (Ib), (Ic), or (Id) or a salt thereof that is pharmaceutically permissible: . Claim 3 A compound according to claim 1 or 2, wherein ring A is a 7-9 cyclic heterocyclyl ring comprising 1-3 cyclic heteroatoms each independently selected from the group consisting of nitrogen, oxygen, and sulfur. Claim 4 A compound according to any one of claims 1 to 3, wherein ring A is a bicyclo[2.2.2]heterocyclyl ring. Claim 5 A compound according to any one of claims 1 to 3, wherein ring A is a bicyclo[4.4.0]heterocyclyl ring. Claim 6 A compound according to any one of claims 1 to 3, wherein ring A is a bicyclo[3.3.1]heterocyclyl ring. Claim 7 A compound according to any one of claims 1 to 3, wherein ring A is a bicyclo[2.2.1]heterocyclyl ring. Claim 8 A compound according to any one of claims 1 to 3, wherein ring A is a bicyclo[3.2.1]heterocyclyl ring. Claim 9 A compound in which ring A is quinuclidinyl in any one of paragraphs 1 to 3. Claim 10 A compound in which ring A is nortropanyl in any one of paragraphs 1 to 3. Claim 11 A compound according to any one of claims 1 to 3, wherein ring A is 3-oxa-9-azabicyclo[3.3.1]nonanyl. Claim 12 A compound according to any one of claims 1 to 3, wherein ring A is a 4-7-membered monocyclic heterocyclyl ring having 1-3 cyclic heteroatoms each independently selected from the group consisting of nitrogen, oxygen, and sulfur. Claim 13 In any one of paragraphs 1, 2 and 12, ring A is selected from the group consisting of azetidinyl, pyrrolidinyl, and piperidinyl, and ring A has 1, 2, or 3 R 3 A compound that can be substituted by. Claim 14 A compound according to any one of paragraphs 1, 2 and 12, wherein ring A is selected from the group consisting of: . Claim 15 A compound according to any one of paragraphs 1, 2 and 12, wherein ring A is selected from the group consisting of: . Claim 16 A compound in which W is -C(O)- in any one of claims 1 to 15. Claim 17 A compound in which W is -C(O)O- in any one of claims 1 to 15. Claim 18 A compound in which W is -C(O)N(H)- in any one of claims 1 to 15. Claim 19 A compound according to any one of claims 1 to 15, wherein W is -C(O)OCH2-. Claim 20 A compound according to any one of claims 1 to 15, wherein W is -C(O)N(H)CH2-. Claim 21 A compound according to any one of claims 1 to 15, wherein W is a 5-membered heteroaryl ring having 1 to 3 cyclic heteroatoms. Claim 22 In paragraph 21, a compound in which W is oxadiazole. Claim 23 Compound of formula (II) or its pharmaceutically permissible salt: Here, X is selected from the group consisting of -C(R")2-, -O-, and -N(H)-; W is selected from the group consisting of -C(O)O-, -C(O)N(H)-, and 5-membered heteroaryls having 1-3 cyclic heteroatoms; R 1 is independently hydrogen or halogen in each case; R 2 is hydrogen or C1-C3 alkyl; R" is independently selected from hydrogen, halogen, and methyl in each case; m is 1, 2, or 3; n is 0, 1, 2, or 3; and p is 0, 1, 2, 3. Claim 24 A compound in which m is 1, in any one of paragraphs 1 to 23. Claim 25 A compound in which m is 2, in any one of paragraphs 1 to 23. Claim 26 In any one of claims 1 to 23, a compound of formula (II-a) or a salt thereof that is pharmaceutically permissible: . Claim 27 In any one of claims 1 to 23, a compound of formula (II-a') or a pharmaceutically permissible salt thereof: Here, each R 1 It may be the same or different. Claim 28 In any one of paragraphs 1 through 27, R 1 This halogen compound. Claim 29 In paragraph 28, R 1 This fluorochemical compound. Claim 30 In any one of paragraphs 1 through 27, R 1 This hydrogen compound. Claim 31 In any one of paragraphs 1 through 27, R 1 This C1-C3 alkyl compound. Claim 32 In Paragraph 31, R 1 This methyl compound. Claim 33 In paragraph 23, a compound of formula (II-a) or a pharmaceutically permissible salt thereof: . Claim 34 A compound in which W is -C(O)O- in any one of claims 1 to 33. Claim 35 A compound in which W is -C(O)N(H)- in any one of claims 1 to 33. Claim 36 A compound according to any one of claims 1 to 35, wherein W is a 5-membered heteroaryl ring having 1 to 3 cyclic heteroatoms. Claim 37 A compound according to claim 36, wherein W is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, and thiadiazolyl. Claim 38 In any one of claims 1 to 32, a compound of formula (II-b) or a salt thereof that is pharmaceutically permissible: . Claim 39 In any one of paragraphs 1 through 38, R 2 A compound in which hydrogen is present. Claim 40 In any one of paragraphs 1 through 38, R 2 A compound in which α is a C1-C3 alkyl. Claim 41 In Paragraph 40, R 2 A compound that is methyl. Claim 42 A compound in which X is -CH2- in any one of paragraphs 23 to 41. Claim 43 A compound in which X is -O- in any one of paragraphs 23 to 41. Claim 44 A compound in which X is -N(H)- in any one of paragraphs 23 to 41. Claim 45 A compound in which n is 0, in any one of paragraphs 23 to 44. Claim 46 A compound in which n is 1, in any one of paragraphs 23 to 44. Claim 47 A compound in which p is 1, in any one of paragraphs 23 to 46. Claim 48 A compound in which p is 2, in any one of paragraphs 23 to 46. Claim 49 In any one of paragraphs 1 through 48, R 3 This halogen compound. Claim 50 In Paragraph 49, R 3 This fluorochemical compound. Claim 51 Compound of formula (III) or its pharmaceutically permissible salt: Here, X is selected from the group consisting of -C(R")2-, -O-, and -N(H)-; W is selected from the group consisting of -C(O)O-, -C(O)N(H)-, and 5-membered heteroaryls having 1-3 cyclic heteroatoms; R 1 is independently hydrogen or halogen in each case; R 2 is hydrogen or C1-C3 alkyl and R 3 is selected from the group consisting of hydrogen, halogen, and C1-C3 alkyl (optionally substituted with 1, 2 or 3 halogens); m is 1, 2, or 3; n is 0, 1, 2, or 3; and p is 0, 1, 2, 3. Claim 52 In paragraph 51, a compound in which m is 1. Claim 53 A compound in which m is 2, in paragraph 51 or 52. Claim 54 In paragraph 51, a compound of formula (III-a) or formula (III-b) or a salt thereof that is permitted by the law: . Claim 55 In paragraph 51, a compound of formula (III-a') or formula (III-b') or a salt thereof that is permitted by the law: Here, each R 1 It may be the same or different. Claim 56 In any one of paragraphs 51 through 55, R 1 This halogen compound. Claim 57 In Paragraph 56, R 1 This fluorochemical compound. Claim 58 In any one of paragraphs 51 through 57, R 1 This hydrogen compound. Claim 59 In any one of paragraphs 51 through 58, R 1 This C1-C3 alkyl compound. Claim 60 In paragraph 59, R 1 This methyl compound. Claim 61 A compound in which W is -C(O)O- in any one of claims 51 to 60. Claim 62 A compound in which W is -C(O)N(H)- in any one of claims 51 to 60. Claim 63 A compound according to any one of claims 51 to 60, wherein W is a 5-membered heteroaryl ring having 1 to 3 cyclic heteroatoms. Claim 64 A compound according to paragraph 63, wherein W is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, and thiadiazolyl. Claim 65 In any one of paragraphs 51 through 64, R 2 A compound in which hydrogen is present. Claim 66 In any one of paragraphs 51 through 64, R 2 A compound in which α is a C1-C3 alkyl. Claim 67 In Paragraph 66, R 2 A compound that is methyl. Claim 68 A compound in which X is -CH2- in any one of paragraphs 51 to 67. Claim 69 A compound in which X is -O- in any one of paragraphs 51 to 67. Claim 70 A compound in which X is -N(H)- in any one of claims 51 to 67. Claim 71 A compound in which n is 0, in any one of claims 51 to 70. Claim 72 A compound in which n is 1, in any one of claims 51 to 70. Claim 73 A compound in which p is 1, in any one of paragraphs 51 to 72. Claim 74 A compound in which p is 2, in any one of paragraphs 51 to 72. Claim 75 In any one of paragraphs 51 through 74, R 3 This halogen compound. Claim 76 In paragraph 75, R 3 This fluorochemical compound. Claim 77 Compounds selected from the group consisting of those identified in Table 1. Claim 78 A pharmaceutical composition comprising a compound of any one of claims 1 to 77 and a pharmaceutically acceptable adjuvant. Claim 79 A method for treating, improving, or preventing a disease, disability, or injury, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 77 or a pharmaceutical composition of claim 78 to a subject in need thereof. Claim 80 A method according to claim 79, wherein the disease, disorder, or injury is selected from the group consisting of pulmonary arterial hypertension PAH, asthma, chronic obstructive pulmonary disease COPD, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis IPF, cystic fibrosis), coronavirus infection (e.g., SARS-COV2 infection), acute lung injury, respiratory distress syndrome, respiratory failure, small cell lung cancer, interstitial lung disease, chronic obstructive pulmonary disease, and chronic thromboembolic pulmonary hypertension. Claim 81 In paragraph 79, the method in which the disease, disability, or injury is pulmonary arterial hypertension. Claim 82 A method for treating, improving, or preventing cardiovascular disease, cardiovascular disorder, or heart damage, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 77 or a pharmaceutical composition of claim 78 to a subject in need thereof. Claim 83 In paragraph 82, a method in which ischemia-reperfusion injury is the result of myocardial infarction or ischemic stroke. Claim 84 In paragraph 82 or 83, a method in which the subject is at high risk of developing a disease or condition. Claim 85 A method according to paragraph 82, wherein the cardiovascular disease or cardiovascular disorder is selected from the group consisting of arrhythmia, aortic disease, cardiomyopathy, congenital heart disease, coronary artery disease, deep vein thrombosis, heart valve disease, hypertension, Marfan syndrome, pericardial disease, pulmonary embolism, rheumatic heart disease, vascular disease, and drug-induced cardiotoxicity. Claim 86 A method in which, in any one of paragraphs 82 through 85, the subject is expected to undergo coronary artery bypass graft (CABG) surgery. Claim 87 A method in which, in any one of paragraphs 82 through 85, the subject has undergone CABG surgery. Claim 88 A method according to any one of claims 82 to 87, wherein the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 is administered to a subject by a route selected from the group consisting of intravenous administration, intracardiac administration, and administration into a cardiac arrest solution. Claim 89 A method according to any one of claims 82 to 88, wherein, after administering the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 to a subject in need thereof, the subject has a reduced symptom selected from the group consisting of arrhythmia, microvascular dysfunction, myocardial fainting, and myocardial cell death. Claim 90 A method according to any one of claims 82 to 88, wherein the myocardial cells of the subject exhibit reduced reactive oxygen species generation after administration of the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 compared to the myocardial cells before administration of the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78, or compared to a control sample of the myocardial cells. Claim 91 A method according to any one of claims 79 to 90, wherein the cardiomyocytes from a subject exhibit reduced troponin I release after administration of the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78, compared to the cardiomyocytes or heart tissue before administration of the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78, or compared to a control sample of cardiomyocytes or heart tissue from a subject to which the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 was not administered. Claim 92 A method according to any one of claims 79 to 91, wherein the cardiomyocytes from a subject exhibit a cellular response selected from the group consisting of reduced apoptosis, increased cell viability, reduced cell damage, and reduced oxidative stress after administration of the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78, compared to the cardiomyocytes before administration of the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78, or compared to a control sample of cardiomyocytes or heart tissue from a subject to which the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 was not administered. Claim 93 A method according to any one of claims 79 to 92, wherein the administration of the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 results in an increased aortic velocity in a subject compared to before the administration of the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78, or compared to a subject to whom the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 was not administered. Claim 94 A method according to any one of claims 79 to 93, wherein the administration of the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 results in an improved cardiac output in a subject compared to before the administration of the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78, or compared to a subject to whom the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 has not been administered. Claim 95 A method according to any one of claims 79 to 94, wherein the administration of the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 results in a reduction of an indicator of cardiovascular disease selected from the group consisting of reduced collagen deposition, reduced differentiation of fibroblasts into myofibroblasts, increased or reduced expression of Smad binding factor (SBE), increased cardiac contractility generation or contractility, increased or enhanced maintenance of calcium processing, reduced hypertrophy (cell size), and reduced expression of cardiac hypertrophy marker genes. Claim 96 A method for treating a subject who has suffered a myocardial infarction or cardiac arrest and requires treatment, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 77 or a pharmaceutical composition of claim 78 to the subject after the myocardial infarction or cardiac arrest. Claim 97 A method according to claim 96, wherein the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 results in a reduced infarct size in the heart tissue of a subject compared to a subject to whom the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 was not administered after myocardial infarction or cardiac arrest. Claim 98 A method according to claim 96 or 97, wherein the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 causes reduced thinning of the heart tissue wall after myocardial infarction or cardiac arrest. Claim 99 A method according to any one of claims 96 to 98, wherein the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 causes reduced cardiac tissue granulation tissue formation after myocardial infarction or cardiac arrest. Claim 100 A method according to any one of claims 96 to 99, wherein the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 causes neovascularization in reduced heart tissue after myocardial infarction or cardiac arrest. Claim 101 A method according to any one of claims 96 to 100, wherein the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 causes neovascularization in reduced heart tissue after myocardial infarction or cardiac arrest. Claim 102 A method in which, in any one of claims 79 to 101, the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 is administered in more than one dose. Claim 103 A method in which, in any one of claims 79 to 102, the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 is administered in combination with at least one additional therapeutic agent. Claim 104 A method for preventing or minimizing cardiac damage in subjects at risk of myocardial infarction or cardiac arrest, comprising administering an effective amount of a compound of any one of claims 1 to 77 or a pharmaceutical composition of claim 78 to a subject prior to myocardial infarction or cardiac arrest, thereby preventing or improving cardiovascular damage. Claim 105 A method according to paragraph 104 in which a subject at risk of myocardial infarction or cardiac arrest has a cardiovascular disease or condition selected from the group consisting of arrhythmia, aortic disease, cardiomyopathy, congenital heart disease, coronary artery disease, deep vein thrombosis, heart valve disease, hypertension, Marfan syndrome, pericardial disease, pulmonary embolism, rheumatic heart disease, and vascular disease. Claim 106 A method according to claim 104 or 105 in which the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 is administered in more than one dose. Claim 107 A method for reducing heart damage in a subject resulting from coronary artery bypass graft (CABG) surgery, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 before, after, and / or during surgery. Claim 108 A method for reducing heart damage in a subject due to cardiopulmonary bypass surgery, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 77 or a pharmaceutical composition of claim 78 before, after, and / or during surgery. Claim 109 A method according to claim 108 in which the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 is administered in more than one dose. Claim 110 A method according to claim 108 or 109, wherein the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 is administered before surgery, after surgery, or both before and after surgery. Claim 111 A method for treating a subject having heart tissue damage and requiring treatment, comprising administering a sufficient amount of the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 to the subject, thereby improving the heart tissue damage. Claim 112 A method according to claim 111 in which a compound of any one of claims 1 to 77 or a pharmaceutical composition of claim 78 causes neovascularization in reduced damaged heart tissue. Claim 113 A method in which, in any one of claims 79 to 112, the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 is administered in combination with at least one additional therapeutic agent. Claim 114 A method according to paragraph 113, wherein at least one additional therapeutic agent is an agent selected from the group consisting of an agent that reduces cholesterol, an agent that reduces low-density lipoprotein, an agent that reduces systemic blood pressure, and an agent that reduces blood glucose levels. Claim 115 A method of increasing the overall survival rate of a subject compared to a subject to which the compound of any one of claims 1 to 77 or the pharmaceutical composition of claim 78 has not been administered, in any one of claims 79 to 114. Claim 116 In paragraph 79, the method of a disease or disability is a lung disease or lung disability. Claim 117 In paragraph 116, the method in which the disease or disorder is an obstructive lung disease or a restrictive lung disease. Claim 118 In paragraph 116, a method in which the disease or disorder is selected from the group consisting of asthma, bronchiolitis obstructive organizing pneumonia (BOOP), chronic obstructive pulmonary disease (COPD), emphysema, pulmonary fibrosis, and sarcoidosis. Claim 119 In paragraph 116, a disease or disorder of acute chest syndrome, acute respiratory distress syndrome, alpha-1 antitrypsin deficiency, asbestosis, aspergillosis, asthma, bronchiectasis, bronchiolitis, obstructive bronchiolitis, bronchitis, bronchopulmonary dysplasia, chronic cough, chronic obstructive pulmonary disease (COPD), coccidioidomycosis, latent organizing pneumonia, cystic fibrosis, lung injury associated with electronic cigarette or vaping product use (EVALI), emphysema, eosinophilic granulomatosis with polyangiitis (EGPA), common cold, hantavirus pulmonary syndrome (HPS), histoplasmosis, human metapneumovirus (hMPV), hypersensitivity pneumonitis, idiopathic pulmonary fibrosis (IPF), infectious lung disease, influenza, interstitial lung disease (ILD), Legionellosis, lung cancer, LAM, MAC lung disease, mesothelioma, NTM lung disease, occupational lung disease, A method selected from the group consisting of pertussis, pneumonia, pneumothorax, primary ciliary dyskinesia (PCD), pulmonary arterial hypertension (PAH), pulmonary embolism, pulmonary fibrosis, pulmonary hypertension, respiratory syncytial virus, sarcoidosis, silicosis, sleep apnea, coronavirus-related disease, and tuberculosis. Claim 120 In paragraph 119, the method in which the bronchitis is acute bronchitis or chronic bronchitis. Claim 121 A method according to paragraph 116 in which the disease or disorder is selected from the group consisting of aspergillosis, asthma, bronchiectasis, bronchitis, chronic cough, chronic obstructive pulmonary disease (COPD), common cold, croup, cystic fibrosis, hantavirus pulmonary syndrome (HPS), idiopathic pulmonary fibrosis (IPF), influenza, lung cancer, LAM, MAC lung disease, pertussis, pleuritis, pneumonia, pulmonary embolism, pulmonary hypertension, respiratory syncytial virus, sarcoidosis, sleep apnea, spirometry, sudden infant death syndrome, tobacco termination, and tuberculosis.

Images