Indoline spiro derivative and preparation method and application thereof

Abstract

The present application provides a kind of indoline spiro derivative and its preparation method and application, the derivative structure is as shown in formula I, as GHSR agonist, for preparing the drug for diagnosing, preventing and / or treating growth hormone dependent disease. (I)

Description

Indole spiro derivative and preparation method and application thereof TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical compounds, and particularly relates to an indole spiro derivative, a preparation method thereof and application thereof in medicine. BACKGROUND

[0002] Growth Hormone (GH) is a single polypeptide chain protein hormone secreted by the acidophilic cells of the anterior pituitary, and mainly exists in two forms of relative molecular weight: 2.2 x 10 4 and 2.0 x 10 4 . The main form in serum is a large molecular weight GH monomer containing 191 amino acids in free form. The secretion of GH is regulated by various factors, among which growth hormone releasing hormone (GHRH) and ghrelin have a positive regulatory effect, while somatostatin (SST) and insulin-like growth factor-1 (IGF-1) have a negative regulatory effect. GH acts directly or indirectly on peripheral organs, and its core function is to promote the growth and development of the body, especially the proliferation of muscle and skin cells. Both in vivo and in vitro experiments have confirmed that ghrelin can significantly promote the secretion of GH, and this promoting effect is dose-dependent.

[0003] Growth hormone secretagogue receptor (GHSR) is a seven-transmembrane G protein-coupled receptor that is highly expressed in the anterior pituitary, islets, thyroid, heart and brain. It is currently believed that GHSR has two subtypes: GHSR1a and GHSR1b. Ghrelin, as an endogenous 28-amino-acid peptide, is the natural ligand of GHSR1a and is involved in the regulation of various physiological functions in the body.

[0004] Growth Hormone Deficiency (GHD) is an endocrine metabolic disease caused by insufficient secretion of GH from the anterior pituitary, and is mainly manifested as short stature. The occurrence of the disease may be related to congenital genetic variation, anterior pituitary disease, injury or surgical resection, etc. Persistent GHD without treatment can lead to complications such as metabolic disorders and cardiovascular diseases in adulthood, seriously affecting the quality of life and life span of patients. Therefore, early identification and timely treatment of GHD are crucial.

[0005] At present, a variety of compounds for stimulating the release of endogenous GH have been developed worldwide, such as growth hormone releasing factor (GRF) analogs and recombinant human GH. However, there is no oral small molecule growth hormone agonist on the market so far. SUMMARY

[0006] The purpose of this invention is to provide small molecule compounds that can effectively stimulate the release of natural or endogenous GH, which can be administered via parenteral, nasal, or oral routes, and are suitable for treating human patients with insufficient GH secretion or for increasing GH levels in food production animals, thereby increasing GH secretion in humans and animals.

[0007] In a first aspect, the present invention provides a compound of general formula (I), including its racemic, stereoisomer, tautomer, isotope-labeled, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof.

[0008] In the formula, * indicates racemic, S-configuration, or R-configuration;

[0009] X1, X2, X3, and X4 are each independently N or CR4;

[0010] Each R4 is independently selected from: H, halogen, cyano, NRaRb, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0011] X5 is selected from Each R1 is independently a C1-C4 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, 5-8 membered heterocyclic, or 5-8 membered heteroaryl; the above groups are optionally substituted by one or more substituents selected from the group consisting of: halogen, cyano, NRaRb, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy; or R1, X4 and the intercalary atom together form a 5-10 membered heterocycle;

[0012] n is 0, 1, 2, or 3; m is 0, 1, 2, or 3; X6 is N or CH;

[0013] R5, R6, R7, R8, R9, R 10 R 11 R 12 Each is independently selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy; or R5, R 11 The links together form a C1-C4 alkylene group, wherein the C1-C4 alkylene group is optionally substituted by one or more substituents selected from the group consisting of: halogen, NRaRb, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0014] L is NH; or L does not exist, and X6 is directly connected to CO.

[0015] L4 is absent, C3-C10 carbon ring, C1-C4 alkylene; the above group may be optionally substituted by one or more substituents selected from the group consisting of: NRaRb, =O, C1-C4 alkyl, cyano, halogen, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy.

[0016] R2 is NRaRb, cyano, 5-8 membered heterocyclic, C1-C4 alkyl, C3-C6 cycloalkyl, -CONH2, C6-C10 aryl or 5-8 membered heteroaryl; the above groups may be optionally substituted by one or more substituents selected from the group consisting of: C1-C4 alkyl, halogen, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy;

[0017] L1 is a C1-C4 alkylene group or is absent;

[0018] L2 can be O, S, CH, NH, -NHCO, -NHSO2-, or does not exist.

[0019] L3 is a C1-C4 alkylene group and does not exist;

[0020] R3 can be C6-C10 aryl, NH2, cyano, C3-C12 cycloalkyl, C1-C4 alkyl, 5-8 membered heterocyclic, or 5-12 membered heteroaryl.

[0021] L1, L2, L3, and R3 are each independently and optionally substituted by one or more substituents selected from the group consisting of: cyano, C1-C4 haloalkoxy, halogen, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkyl, C3-C6 cycloalkyl, and NRaRb.

[0022] Each Ra and each Rb is independently selected from: H, C1-C4 alkyl, C1-C4 deuterated alkyl, -C(=NH)NH2, -C(=NH)NH(C1-C4 alkyl);

[0023] The conditions are that n is 1, m is 1, L4 is a C1-C4 alkylene, L2 is O, R1 is a C1-C4 alkyl, R2 is NRaRb, and R3 is not a C6-C10 aryl.

[0024] In another preferred embodiment, the compound has a structure selected from the group consisting of:

[0025] In another preferred embodiment, the compound has the following structure:

[0026] In another preferred embodiment, n is 0, 11, or 2; m is 0, 1, or 2.

[0027] In another preferred embodiment, n and m are not both 0.

[0028] In another preferred embodiment, n is 0 or 1, and m is 1.

[0029] In another preferred embodiment, X1, X2, X3, and X4 are CR4; each R4 is independently selected from: H, halogen, and C1-C4 alkyl.

[0030] Each R1 is independently a C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, 5-7 membered heterocyclic or 5-7 membered heteroaryl; the above groups are optionally substituted by one or more substituents selected from the group consisting of: C1-C4 alkyl, C1-C4 haloalkyl, halogen;

[0031] Alternatively, R1, X4, and intercalary atoms can form 5-10 membered heterocycles.

[0032] In another preferred embodiment, R5, R6, R7, R8, R9, R 10 R 11 R 12 Each is independently selected from H, C1-C4 alkyl groups; or R5, R 11 They connect to form C1-C3 alkylene groups.

[0033] In another preferred embodiment, L1 is a C1-C2 alkylene group or is absent;

[0034] L2 can be O, CH, NH, -NHCO-, -NHSO2-, or not present.

[0035] L3 is a C1-C3 alkylene group and does not exist;

[0036] R3 is phenyl, NH2, C3-C12 cycloalkyl, C1-C4 alkyl, 5-7 membered heterocyclic group, or 6-10 membered heteroaryl group;

[0037] L1, L2, L3, and R3 are each independently and optionally substituted by one or more substituents selected from the group consisting of: cyano, C1-C4 haloalkoxy, halogen, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkyl, C3-C6 cycloalkyl, and NRaRb.

[0038] Each Ra and each Rb is independently selected from: H, C1-C4 alkyl, -C(=NH)NH2, -C(=NH)NH(C1-C4 alkyl).

[0039] In another preferred embodiment, the compound has the structure shown in Formula II:

[0040] X2 is a CH or C-halogen; *, R1, R2, R3, R4, L, L1, L2, L3, L4, and X6 are defined as before.

[0041] In another preferred embodiment, the compound has the structure shown in formula IIa or IIb:

[0042] R1, R2, R3, R4, L1, L2, L3, L4, and X2 are defined as before.

[0043] In another preferred embodiment, the compound has the following structure:

[0044] The definitions of each group are the same as before.

[0045] In another preferred embodiment, -L4- is absent or selected from the group below:

[0046] In another preferred embodiment, -L1-L2-L3- is a C1-C4 alkylene group or selected from the group consisting of:

[0047] In another preferred embodiment, R3 is phenyl, NH2, CN, C3-C10 cycloalkyl, C1-C4 alkyl, 5-7 heterocyclic, or 6-10 heteroaryl; optionally substituted by 1, 2, 3, or 4 substituents selected from the group consisting of: cyano, C1-C4 haloalkoxy, halogen, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 alkyl.

[0048] In another preferred embodiment, R3 is selected from the group consisting of: phenyl, amino, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, adamantyl, etc. The substituent may be selected from 1, 2, 3 or 4 substituents from the group consisting of: F, Cl, Br, cyano, methoxy, ethoxy, difluoromethyl, trifluoromethyl, methyl, ethyl, and difluoromethoxy.

[0049] In another preferred embodiment, the compound is the compound prepared in the example.

[0050] In another preferred embodiment, *, X1, X2, X3, X4, each of R4, Ra, Rb, X5, each of R1, n, m, X6, R5, R6, R7, R8, R9, R 10 R 11 R 12 L, L4, R2, L1, L2, L3, R3, etc. are independently and optionally the groups / configurations / values ​​corresponding to the specific compounds of the present invention (especially the compounds of the examples).

[0051] A second aspect of the present invention provides a pharmaceutical composition comprising:

[0052] The compounds of general formula (I) described in the first aspect, including racemic, stereoisomer, tautomer, isotope-labeled, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof; and pharmaceutically acceptable carriers.

[0053] A third aspect of the invention provides the use of a compound of general formula (I) as described in the first aspect, its racemic, stereoisomer, tautomer, isotope-labeled, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in the second aspect, for the preparation of a growth hormone secretagogue receptor agonist; or for the preparation of a medicament for the prevention and / or treatment of growth hormone-dependent diseases.

[0054] In another preferred embodiment, the growth hormone-dependent disease is growth hormone deficiency.

[0055] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0056] The inventors of this application, through extensive and in-depth research, have developed an indoline spirocyclic derivative that can effectively stimulate the release of natural or endogenous GH. It can be administered via parenteral, nasal, or oral routes and is suitable for treating human patients with insufficient GH secretion or for increasing GH levels in food production animals, thereby increasing GH secretion in humans and animals. Based on this, the present invention was completed.

[0057] the term

[0058] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0059] In this invention, the term "C1-C6" refers to having 1, 2, 3, 4, 5, or 6 carbon atoms, and so on. "3-8" refers to having 3, 4, 5, 6, 7, or 8 ring atoms, and so on.

[0060] In this invention, the term "alkyl" refers to a saturated linear or branched hydrocarbon group. For example, the term "C1-C6 alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and includes, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0061] "Alkylene" refers to a straight-chain or branched saturated aliphatic group, i.e., a divalent hydrocarbon group, having a specified number of carbon atoms and being attached to at least two other groups. The two groups attached to the alkylene can be the same or different atoms on the alkylene. For example, a straight-chain alkylene can be -(CH2). n - A divalent group, where n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene. Alkylenes may be substituted or unsubstituted.

[0062] In this invention, the term "alkoxy" refers to an -O-(alkyl) group. For example, the term "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, and includes, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, and butoxy groups.

[0063] In this invention, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon moiety, such as the term "C3-C". 10 "Cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms on a ring, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl. Cycloalkyl groups can be monocyclic, spirocyclic, fused, polycyclic, or bridged.

[0064] The term "carbon ring" refers to a non-aromatic ring with saturated or unsaturated carbon atoms, which can be a monocyclic, spirocyclic, fused, or bridged ring structure.

[0065] In this invention, the term "aryl" refers to a hydrocarbon moiety comprising one or more aromatic rings. For example, the term "C6-C..." 12 "Aryl" refers to an aromatic cyclic group with 6 to 12 carbon atoms that does not contain heteroatoms on the ring. Examples of aryl groups include, but are not limited to, phenyl (Ph), naphthyl, pyrene, anthracene, and phenanthryl.

[0066] In this invention, the terms "heterocycle" and "heterocyclic group" respectively refer to a saturated or unsaturated, non-aromatic cyclic or cyclic group containing at least one (e.g., 1, 2, 3, or 4) cyclic heteroatoms (e.g., N, O, or S), such as tetrahydropyridyl, pyrrolinyl, dihydropyridyl, dihydrofuranyl, dihydrothiophenyl, or morpholinyl. The heterocycle (group) can be a monoheterocyclic (group), spiroheterocyclic (group), fused heterocyclic (group), or bridged heterocyclic (group).

[0067] In this invention, the term "heteroaryl" refers to an aromatic cyclic group containing at least one (e.g., 1, 2, 3, or 4) cyclic heteroatoms (e.g., N, O, or S), and is a monocyclic or fused-ring structure. Examples include furanyl, pyrroleyl, thiopheneyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, quinolinyl, isoquinolinyl, indolyl, pyrimidinyl, pyranyl, benzimidazolyl, and benzofuranyl.

[0068] In this invention, the halogen is F, Cl, Br or I.

[0069] Unless otherwise stated, the alkyl, alkoxy, cycloalkyl, heteroaryl, heterocyclic, and aryl groups mentioned herein are substituted and unsubstituted groups. Possible substituents on the alkyl, alkoxy, cycloalkyl, heterocyclic, and aryl groups include, but are not limited to: hydroxyl, amino, nitro, nitrile, halogen, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C1-C20 heterocyclic alkyl, C1-C20 heterocyclic alkenyl, C1-C6 alkoxy, C6-C10 aryl, heteroaryl, heteroaryloxy, C1-C10 alkylamino, C1-C20 dialkylamino, C6- C10 arylamino, diC6-C10 arylamino, C1-C10 alkylaminosulfonyl, C6-C10 arylaminosulfonyl, C1-C10 alkylimino, C1-C10 alkylsulfonylimino, C6-C10 arylsulfonylimino, mercapto, C1-C10 alkylthio, C1-C10 alkylsulfonyl, C6-C10 arylsulfonyl, acylamino, aminoacyl, aminothioacyl, guanidine, urea, cyano, acyl, thioacyl, acyloxy, carboxyl, and carboxylic acid ester groups. On the other hand, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl groups can also be fused together.

[0070] In this invention, the substitution can be monosubstituted or polysubstituted, and the polysubstituted can be disubstituted, trisubstituted, tetrasubstituted, or pentasubstituted. Disubstituted means having two substituents, and so on.

[0071] The pharmaceutically acceptable salts described in this invention can be salts formed by anion and a positively charged group on a compound of Formula I. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, toluenesulfonate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate, or maleate. Similarly, salts can be formed by cations and negatively charged groups on a compound of Formula I. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium ions, such as tetramethylammonium ions.

[0072] In another preferred embodiment, "pharmaceutically acceptable salt" refers to a salt formed by a compound of Formula I with an acid selected from the group consisting of: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, aminosulfonic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pyric acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, and hydroxyethanesulfonic acid; or a sodium, potassium, calcium, aluminum, or ammonium salt formed by a compound of Formula I with an inorganic base; or a methylamine, ethylamine, or ethanolamine salt formed by a compound of general Formula I with an organic base.

[0073] Pharmaceutical Composition

[0074] The present invention also provides a pharmaceutical composition comprising an active ingredient within a safe and effective range, and a pharmaceutically acceptable carrier.

[0075] The "active ingredient" mentioned in this invention refers to the compound of formula I described in this invention.

[0076] The "active ingredient" and pharmaceutical composition described in this invention are used to prepare remedies for the prevention and / or treatment of growth hormone-dependent diseases. The "active ingredient" and pharmaceutical composition described in this invention can be used as growth hormone secretagogue receptor (GHSR) agonists, effectively stimulating the release of natural or endogenous GH and increasing GH secretion in humans and animals.

[0077] "Safe and effective dose" refers to an amount of active ingredient sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of active ingredient per dose, more preferably 10-200 mg of active ingredient per dose. Preferably, "one dose" refers to one tablet.

[0078] "Pharmaceutically acceptable carriers" refer to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here refers to the ability of the components in the composition to interact with and incorporate the active ingredient of the invention without significantly reducing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0079] There are no particular limitations on the administration of the active ingredients or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

[0080] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0081] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. Besides these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0082] In addition to the active ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0083] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0084] The compounds of this invention can be administered alone or in combination with other therapeutic agents.

[0085] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 20–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0086] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions (such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989)) or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0087] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0088] The reagents used in this invention are commercially available reagents that are purchased directly or synthesized using common methods known in the art.

[0089] Example 1: 3-Amino-N-((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)bicyclo[1.1.1]pent-1-carboxamide

[0090] Step 1: Spiro[indole-3,3'-pyrrolidine]-1'-carboxylic acid benzyl ester

[0091] Phenylated hydrazine (5.10 g, 47.16 mmol) and trifluoroacetic acid (17.88 mL) were dissolved in a 49 / 1 toluene / acetonitrile mixture (200 mL), and the reaction mixture was heated to 35 °C. 3-Formylpyrrolidine-1-carboxylic acid benzyl ester (10.00 g, 42.87 mmol) was dissolved in a 49 / 1 toluene / acetonitrile mixture (50 mL), and added dropwise to the above reaction mixture. The mixture was stirred overnight at 35 °C. The reaction mixture was cooled to 0 °C, and methanol (20 mL) was added. Sodium borohydride (2.43 g, 64.30 mmol) was added in portions to the above reaction mixture, and the mixture was stirred for 1 hour. The reaction solution was quenched with 6% ammonia, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 60%-80% ethyl acetate) to give the title compound (2.10 g, 6.81 mmol, yield: 15.9%). LC / MS (ESI) M / Z: 309.2 [M+H] + .

[0092] Step 2: 1-(methylsulfonyl)spiro[indole-3,3'-pyrrolidine]-1'-carboxylic acid benzyl ester

[0093] 1.30 g (4.22 mmol) of spiro[indole-3,3'-pyrrolidine]-1'-carboxylic acid benzyl ester was dissolved in dichloromethane (20 mL). N,N-diisopropylethylamine (2.18 g, 16.86 mmol) and methanesulfonyl chloride (0.97 g, 8.43 mmol) were added at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture upon cooling, and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10%–30% ethyl acetate) to give the title compound (1.3 g, 3.36 mmol, yield: 79.8%). LC / MS (ESI) M / Z: 387.2 [MH] - .

[0094] Step 3: 1-(Methylsulfonyl)spiro[indole-3,3'-pyrrolidine]

[0095] 1-(methylsulfonyl)spiro[indole-3,3'-pyrrolidine]-1'-carboxylic acid benzyl ester (1.30 g, 3.36 mmol) was dissolved in methanol (20 mL), and 10% palladium on carbon (360 mg, 0.34 mmol) was added under hydrogen protection. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (800 mg, 3.17 mmol, yield: 94.3%). LC / MS (ESI) M / Z: 253.1 [M+H] + .

[0096] Step 4: ((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)tert-butyl carbamate

[0097] O-benzyl-N-(tert-Butoxycarbonyl)-D-serine (1.08 g, 3.66 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (1.18 g, 9.16 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.74 g, 4.58 mmol) were added. After stirring for 10 minutes, 1-(methylsulfonyl)spiro[indole-3,3'-pyrrolidine] (770 mg, 3.05 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 40%–90% ethyl acetate) to the title compound (1.40 g, 2.64 mmol, yield: 86.6%). LC / MS (ESI) M / Z: 530.3 [M+H] + .

[0098] Step 5: (2R)-2-amino-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)prop-1-one

[0099] ((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)carbamate tert-butyl ester (150 mg, 0.28 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, and the pH of the reaction system was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (120 mg, 0.28 mmol, yield: 98.7%). LC / MS (ESI) M / Z: 429.3 [M+H] + .

[0100] Step 6: (3-((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)carbamoyl)bicyclo[1.1.1]pent-1-yl)tert-butyl carbamate

[0101] 3-((tert-Butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (62.50 mg, 0.33 mmol) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (72.2 mg, 0.56 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (159 mg, 0.42 mmol) were added. After stirring for 10 minutes, (2R)-2-amino-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)prop-1-one (120 mg, 0.28 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (100 mg, 0.16 mmol, yield: 58.2%). LC / MS (ESI) M / Z: 638.2 [M+H] + .

[0102] Step 7: 3-Amino-N-((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)bicyclo[1.1.1]pentane-1-carboxamide

[0103] (3-((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)carbamoyl)bicyclo[1.1.1]pent-1-yl)carbamate tert-butyl ester (100 mg, 0.16 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-6% methanol) to give the title compound (white solid, 55 mg, 0.10 mmol, yield: 65.2%). LC / MS (ESI) M / Z: 538.4 [M+H] + .

[0104] 1H NMR (400MHz, Methanol-d4) δ7.42-7.19(m,16H),7.15-7.08(m,2H),5.10(dd,J=6.8,5.1Hz,1H ),4.77(t,J=6.1Hz,1H),4.69(dt,J=10.3,4.2Hz,1H),4.60-4.49(m,3H),4.42-4.33(m,1H),4 .30(d,J=1.8Hz,1H),4.16(dd,J=14.2,4.5Hz,1H),3.95(m,2H),3.81-3.58(m,7H),3.14(m,2H ),2.92(s,3H),2.79(s,2H),2.37(m,1H),2.23(m,1H),2.17-1.99(m,2H),2.06-2.07(m,12H).

[0105] Example 2: 2-Amino-N-((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0106] Step 1: (1-((2R)-3-(benzyloxy)-1-(1-(methylsulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)tert-butyl carbamate

[0107] 2-((tert-Butoxycarbonyl)amino)-2-methylpropionic acid (72.91 mg, 0.36 mmol) was dissolved in dichloromethane (4 mL), and N,N-diisopropylethylamine (84.3 mg, 0.65 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (186 mg, 0.49 mmol) were added. After stirring for 10 minutes, (2R)-2-amino-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)prop-1-one (140 mg, 0.33 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (120 mg, 0.20 mmol, yield: 59.9%). LC / MS (ESI) M / Z: 614.3 [M+H] + .

[0108] Step 2: 2-Amino-N-((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0109] (1-((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate tert-butyl ester (100 mg, 0.16 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-6% methanol) to give the title compound (white solid, 50 mg, 0.10 mmol, yield: 49.7%). LC / MS (ESI) M / Z: 514.2 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ7.42-7.19(m,16H),7.15-7.08(m,2H),5.10(dd,J=6.8,5.1Hz, 1H),4.77(t,J=6.1Hz,1H),4.69(dt,J=10.3,4.2Hz,1H),4.60-4.49(m,3H),4.42-4.33(m,1H ),4.30(d,J=1.8Hz,1H),4.16(dd,J=14.2,4.5Hz,1H),3.95(m,2H),3.81-3.58(m,7H),3.14( m,2H),2.92(s,3H),2.79(s,2H),2.37(m,1H),2.23(m,1H),2.17-1.99(m,2H),1.29(m,12H).

[0110] Example 3: 2,3-Diamino-N-((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)propionamide

[0111] Step 1: Di-tert-butyl(3-((2R)-3-(benzyloxy)-1-(1-(methylsulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)amino)-3-oxopropane-1,2-diyl)dicarbamate

[0112] 2,3-bis(tert-butoxycarbonyl)amino)propionic acid (119 mg, 0.39 mmol) was dissolved in dichloromethane (4 mL), and N,N-diisopropylethylamine (84.30 mg, 0.65 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (186 mg, 0.49 mmol) were added. After stirring for 10 minutes, (2R)-2-amino-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)prop-1-one (140 mg, 0.33 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (140 mg, 0.20 mmol, yield: 60.0%). LC / MS (ESI) M / Z: 715.4 [M+H] + .

[0113] Step 2: 2,3-Diamino-N-((2R)-3-(benzyloxy)-1-(1-(methylsulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)propionamide

[0114] Di-tert-butyl(3-((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)amino)-3-oxopropane-1,2-diyl)dicarbamate (140 mg, 0.20 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-6% methanol) to give the title compound (white solid, 60 mg, 0.12 mmol, yield: 59.5%). LC / MS (ESI) M / Z: 515.3 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ7.43-7.18(m,16H),7.16-7.07(m,2H),5.19-5.04(m,1H),4.82-4.76(m,1H),4.71( m,1H),4.62-4.57(m,1H),4.51(ddd,J=11.9,4.8,2.3Hz,2H),4.42(dddd,J=14.6,10.6,6.6,4.3Hz,1H),4.32-4. 28(m,1H),4.16(dt,J=14.2,4.2Hz,1H),3.99-3.87(m,3H),3.82(m,1H),3.76-3.63(m,5H),3.63-3.46(m,1H),3 .41-3.32(m,2H),3.28-3.21(m,1H),3.20-2.99(m,2H),2.96-2.88(m,4H),2.85-2.63(m,6H),2.43-1.97(m,4H).

[0115] Example 4: (R)-3-amino-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)bicyclo[1.1.1]pentane-1-carboxamide

[0116] Step 1: Spiro[indole-3,4'-piperidine]-1'-carboxylic acid benzyl ester

[0117] Phenylated hydrazine hydrochloride (4.81 g, 33.26 mmol) and trifluoroacetic acid (8.91 mL) were dissolved in a 4g / L toluene / acetonitrile mixture (200 mL), and the reaction mixture was heated to 35°C. 4-Formylpiperidin-1-carboxylic acid benzyl ester (7.40 g, 29.94 mmol) was dissolved in a 4g / L toluene / acetonitrile mixture (50 mL), and added dropwise to the above reaction mixture. The mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0°C, and methanol (25 mL) was added. Sodium borohydride (1.89 g, 49.90 mmol) was added in portions to the above reaction mixture, and the mixture was stirred for 1 hour. The reaction solution was quenched with 6% ammonia, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 60%-80% ethyl acetate) to give the title compound (6.70 g, 20.78 mmol, yield: 62.5%). LC / MS (ESI) M / Z: 323.2 [M+H] + .

[0118] Step 2: 1-(methylsulfonyl)spiro[indole-3,4'-piperidine]-1'-carboxylic acid benzyl ester

[0119] 1.70 g (5.27 mmol) of spiro[indoline-3,4'-piperidine]-1'-carboxylic acid benzyl ester was dissolved in dichloromethane (20 mL). N,N-diisopropylethylamine (1.02 g, 7.91 mmol) and methanesulfonyl chloride (0.72 g, 6.33 mmol) were added at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. Water (40 mL) was added to the reaction mixture upon cooling, and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10%–30% ethyl acetate) to give the title compound (1.80 g, 4.49 mmol, yield: 85.2%). LC / MS (ESI) M / Z: 401.2 [M+H] + .

[0120] Step 3: 1-(Methylsulfonyl)spiro[indoline-3,4'-piperidine]

[0121] 1-(methylsulfonyl)spiro[indole-3,4'-piperidine]-1'-carboxylic acid benzyl ester (1.80 g, 4.49 mmol) was dissolved in methanol (20 mL), and 10% palladium on carbon (180 mg, 0.17 mmol) was added under hydrogen protection. The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound (1.01 g, 3.79 mmol, yield: 84.4%). LC / MS (ESI) M / Z: 267.3 [M+H] + .

[0122] Step 4: (R)-(3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)tert-butyl carbamate

[0123] o-Benzyl-N-(tert-butoxycarbonyl)-D-serine (1.10 g, 3.72 mmol) was dissolved in dichloromethane (15 mL), and N,N-diisopropylethylamine (870 mg, 6.76 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.93 g, 5.07 mmol) were added. After stirring for 10 minutes, 1-(methylsulfonyl)spiro[indoline-3,4'-piperidine] (900 mg, 3.38 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 70%–90% ethyl acetate) to the title compound (1.02 g, 1.84 mmol, yield: 54.4%). LC / MS (ESI) M / Z: 544.3 [M+H] + 。

[0124] Step 5: (R)-2-amino-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)prop-1-one

[0125] (R)-(3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)tert-butyl carbamate (500 mg, 0.92 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction mixture, and the pH of the reaction system was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude title compound (350 mg, 0.79 mmol, yield: 85.8%). LC / MS (ESI) M / Z: 444.3 [M+H] + .

[0126] Step 6: (R)-(3-((3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)carbamoyl)bicyclo[1.1.1]pent-1-yl)tert-butyl carbamate

[0127] 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (184 mg, 0.81 mmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (218 mg, 1.69 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (385 mg, 1.02 mmol) were added. After stirring for 10 minutes, (R)-2-amino-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)prop-1-one (300 mg, 0.68 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (227 mg, 0.35 mmol, yield: 51.4%). LC / MS (ESI) M / Z: 653.4 [M+H] + .

[0128] Step 7: (R)-3-amino-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)bicyclo[1.1.1]pentane-1-carboxamide

[0129] (R)-(3-((3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)carbamoyl)bicyclo[1.1.1]pent-1-yl)carbamate tert-butyl ester (227 mg, 0.35 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-6% methanol) to give the title compound (white solid, 143 mg, 0.26 mmol, yield: 74.4%). LC / MS (ESI) M / Z: 552.3 [M+H] + .

[0130] 1H NMR(400MHz,Chloroform-d)δ7.40-7.27(m,11H),7.25-7.18(m,2H),7.13(d,J=7.4Hz,1H),7.06(t,J=7.4Hz,1H),6.95 (t,J=7.5Hz,1H),6.75(s,1H),6.61(d,J=7.5Hz,1H),5.25-5.11(m,2H),4.71-4.42(m,6H),4.11(d,J=13.6Hz,1H),3.96 (d,J=14.3Hz,1H),3.87(d,J=10.2Hz,1H),3.77(dd,J=18.5,8.3Hzm,4H),3.71-3.52(m,3H),3.15(t,J=13.0Hz,1H),3. 03(t,J=13.3Hz,1H),2.90(d,J=3.0Hz,6H),2.81(d,J=13.5Hz,2H),2.18-2.12(m,12H),1.84(m,2H),1.76-1.65(m,6H).

[0131] Example 5: N-((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)-2-cyano-2-methylpropionamide

[0132] Step 1: N-((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)-2-cyano-2-methylpropionamide

[0133] 2-Cyano-2-methylpropionic acid (47.4 mg, 0.42 mmol) was dissolved in dichloromethane (4 mL), and N,N-diisopropylethylamine (90 mg, 0.70 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (199 mg, 0.52 mmol) were added. After stirring for 10 minutes, (2R)-2-amino-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)prop-1-one (150 mg, 0.35 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%-10% methanol) to give a crude product (100 mg), which was further purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-6% methanol) to give the title compound (white solid, 50 mg, 0.10 mmol, yield: 27.3%). LC / MS (ESI) M / Z: 525.4 [M+H] + .1H NMR(400MHz, Methanol-d4)δ7.42-7.19(m,16H),7.15-7.08(m,2H),5.10(dd,J=6.8,5.1Hz, 1H),4.77(t,J=6.1Hz,1H),4.69(dt,J=10.3,4.2Hz,1H),4.60-4.49(m,3H),4.42-4.33(m,1H ),4.30(d,J=1.8Hz,1H),4.16(dd,J=14.2,4.5Hz,1H),3.95(m,2H),3.81-3.58(m,7H),3.14( m,2H),2.92(s,3H),2.79(s,2H),2.37(m,1H),2.23(m,1H),2.17-1.99(m,2H),1.58(m,12H).

[0134] Example 6: 3-Amino-N-((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)propionamide

[0135] Step 1: (3-(((2R)-3-(benzyloxy)-1-(1-(methylsulfonyl)spiro[indole-3,3'-pyrrolidine]-1′'-yl)-1-oxopropyl-2-yl)amino)-3-oxopropyl)tert-butyl carbamate

[0136] 3-((tert-Butoxycarbonyl)amino)propionic acid (74 mg, 0.39 mmol) was dissolved in dichloromethane (4 mL), and N,N-diisopropylethylamine (84 mg, 0.65 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (186 mg, 0.49 mmol) were added. After stirring for 10 minutes, (2R)-2-amino-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)prop-1-one (140 mg, 0.33 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (160 mg, 0.27 mmol, yield: 81.7%). LC / MS (ESI) M / Z: 601.3 [M+H] + .

[0137] Step 2: 3-Amino-N-((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)propionamide

[0138] (3-(((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)amino)-3-oxopropyl)carbamate tert-butyl ester (160 mg, 0.27 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-6% methanol) to give the title compound (white solid, 40 mg, 0.08 mmol, yield: 30.0%). LC / MS (ESI) M / Z: 501.2 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ7.43-7.29(m,9H),7.27-7.08(m,9H),5.26-5.19(m,1H),5.01(q,J=6.7Hz,1H),4.72(dt,J=1 0.1,5.1Hz,1H),4.64-4.50(m,3H),4.34(q,J=12.1Hz,2H),4.16(td,J=8.9,5.4Hz,1H),4.07(dd,J=13.8,5.6Hz,1H),3.97 -3.93(m,2H),3.89(dt,J=14.4,8.0Hz,2H),3.83-3.72(m,3H),3.66(m,1H),3.51(m,1H),3.47-3.38(m,1H),3.39-3.29(m, 3H),3.13(td,J=8.7,4.3Hz,1H),3.03(m,4H),2.96(s,2H),2.91(m,1H),2.68(s,3H),2.49-2.24(m,5H),2.22-2.01(m,4H).

[0139] Example 7: N-((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)piperazine-2-carboxamide

[0140] Step 1: 2-(((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)carbamoyl)piperazine-1,4-dicarboxylic acid di-tert-butyl ester

[0141] 1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (129 mg, 0.39 mmol) was dissolved in dichloromethane (4 mL), and N,N-diisopropylethylamine (84 mg, 0.65 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (186 mg, 0.49 mmol) were added. After stirring for 10 minutes, (2R)-2-amino-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)prop-1-one (140 mg, 0.33 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (220 mg, 0.30 mmol, yield: 90.1%). LC / MS (ESI) M / Z: 741.4 [M+H] + .

[0142] Step 2: N-((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)piperazine-2-carboxamide

[0143] 2-(((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)carbamoyl)piperazine-1,4-dicarboxylic acid di-tert-butyl ester (220 mg, 0.30 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-10% methanol) to give the title compound (white solid, 50 mg, 0.09 mmol, yield: 31.1%). LC / MS (ESI) M / Z: 541.2 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ7.42-7.17(m,16H),7.15-7.08(m,2H),5.20-5.07(m,1H),4.83-4.77(m,1H),4.70( m,1H),4.61-4.47(m,3H),4.45-4.35(m,1H),4.30(d,J=3.6Hz,1H),4.15(dt,J=14.2,4.4Hz,1H),3.92(td,J=13. 6,12.6,5.2Hz,3H),3.84-3.55(m,7H),3.54-3.47(m,1H),3.39-3.32(m,2H),3.29-3.20(m,1H),3.17-3.12(m,1 H),3.02(m,2H),2.92(m,6H),2.85-2.59(m,10H),2.31(dddd,J=36.6,15.1,10.4,5.6Hz,2H),2.15-1.98(m,2H).

[0144] Example 8: 3-amino-N-((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)bicyclo[1.1.1]pent-1-carboxamide

[0145] Step 1: Spiro[indole-3,4'-piperidine]-1'-carboxylic acid benzyl ester

[0146] Phenylated hydrazine (4.81 g, 44.48 mmol) and trifluoroacetic acid (12.39 mL) were dissolved in a 49 / 1 toluene / acetonitrile mixture (200 mL), and the reaction mixture was heated to 35 °C. 3-Formylpyrrolidine-1-carboxylic acid benzyl ester (10.00 g, 40.44 mmol) was dissolved in a 49 / 1 toluene / acetonitrile mixture (50 mL), and added dropwise to the above reaction mixture. The mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0 °C, and methanol (40 mL) and sodium borohydride (2.29 g, 60.66 mmol) were added in portions to the above reaction mixture, followed by stirring for 1 hour. The reaction solution was quenched with 6% ammonia, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 60%-80% ethyl acetate) to give the title compound (10.00 g, 31.02 mmol, yield: 76.7%). LC / MS (ESI) M / Z: 323.1 [M+H] + .

[0147] Step 2: 1-(methylsulfonyl)spiro[indole-3,4'-piperidine]-1'-carboxylic acid benzyl ester

[0148] Spiro[indole-3,4'-piperidine]-1'-carboxylic acid benzyl ester (1.00 g, 3.10 mmol) was dissolved in dichloromethane (20 mL), and N,N-diisopropylethylamine (1.20 g, 9.31 mmol) and methanesulfonyl chloride (0.53 g, 4.65 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. Water (40 mL) was added to the reaction mixture upon cooling, and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10%–30% ethyl acetate) to give the title compound (1.10 g, 2.75 mmol, yield: 88.6%). LC / MS (ESI) M / Z: 401.2 [M+H] + .

[0149] Step 3: 1-(Methylsulfonyl)spiro[indoline-3,4'-piperidine]

[0150] 1-(methylsulfonyl)spiro[indole-3,4'-piperidine]-1'-carboxylic acid benzyl ester (1.10 g, 2.75 mmol) was dissolved in methanol (20 mL), and 10% palladium on carbon (292 mg, 0.28 mmol) was added under hydrogen protection. The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound (580 mg, 2.18 mmol, yield: 79.3%). LC / MS (ESI) M / Z: 267.3 [M+H] + .

[0151] Step 4: (9H-fluorene-9-yl)methyl tert-butyl (3-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-3-oxopropane-1,2-diyl)(R)-dicarbamate

[0152] (R)-3-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino acid)propionic acid (1.02 g, 2.40 mmol) was dissolved in dichloromethane (15 mL), and N,N-diisopropylethylamine (563 mg, 4.36 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.24 g, 3.27 mmol) were added. After stirring for 10 minutes, 1-(methanesulfonyl)spiro[indoline-3,4'-piperidine] (580 mg, 2.18 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 70%–90% ethyl acetate) to the title compound (1.20 g, 1.78 mmol, yield: 81.7%). LC / MS (ESI) M / Z: 675.3 [M+H] + .

[0153] Step 5: (9H-fluorene-9-yl)methyl(R)-(2-amino-3-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-3-oxopropyl)carbamate

[0154] (9H-fluorene-9-yl)methyl tert-butyl(3-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-3-oxopropane-1,2-diyl)(R)-dicarbamate (1.10 g, 1.63 mmol) was dissolved in 10 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The reaction mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction mixture, and the pH of the reaction system was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude title compound (900 mg, 1.41 mmol, yield: 86.5%). LC / MS (ESI) M / Z: 575.4 [M+H] + .

[0155] Step 6: Tert-butyl(R)-(1-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate

[0156] 2-((tert-Butoxycarbonyl)amino)-2-methylpropionic acid (350 mg, 1.72 mmol) was dissolved in dichloromethane (15 mL), and N,N-diisopropylethylamine (405 mg, 3.13 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (893 mg, 2.35 mmol) were added. After stirring for 10 minutes, (9H-fluorene-9-yl)methyl(R)-(2-amino-3-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-3-oxopropyl)carbamate (900 mg, 1.57 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (1.10 g, 1.45 mmol, yield: 92.4%). LC / MS (ESI) M / Z: 759.4 [M+H] + .

[0157] Step 7: (R)-(1-(3-amino-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl) tert-butyl carbamate

[0158] 1.10 g (1.45 mmol) of tert-butyl(R)-(1-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate (10 mL) was dissolved in N,N-dimethylformamide (10 mL), and ammonia (2 mL) was added. The reaction mixture was stirred overnight at room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (450 mg, 0.84 mmol, yield: 57.8%). LC / MS(ESI)M / Z:538.4[M+H + ].

[0159] Step 8: (R)-(2,2,14-trimethyl-11-(1-(methanesulfonyl)spiro[indole-3,4'-piperidine]-1'-carbonyl)-4,8,13-trioxo-3-oxa-5,9,12-triazapentadecan-14-yl) tert-butyl carbamate

[0160] 3-((tert-Butoxycarbonyl)amino)propionic acid (58 mg, 0.31 mmol) was dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (72 mg, 0.56 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (159 mg, 0.42 mmol) were added. After stirring for 10 minutes, (R)-(1-(3-amino-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate tert-butyl ester (150 mg, 0.28 mmol) was added. The mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%-10% methanol) to give the title compound (130 mg, 0.18 mmol, yield: 65.7%). LC / MS (ESI) M / Z: 709.4 [M+H] + .

[0161] Step 9: (R)-2-amino-N-(3-(3-aminopropionamido)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0162] (R)-(2,2,14-trimethyl-11-(1-(methanesulfonyl)spiro[indole-3,4'-piperidine]-1'-carbonyl)-4,8,13-trioxo-3-oxa-5,9,12-triazapentadecan-14-yl)carbamate tert-butyl (130 mg, 0.18 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-6% methanol) to give the title compound (white solid, 50 mg, 0.10 mmol, yield: 53.6%). LC / MS (ESI) M / Z: 509.2 [M+H + ].

[0163] 1H NMR(400MHz,Chloroform-d)δ7.42(dd,J=8.0,2.4Hz,1H),7.15-7.36(m,2H),7.0 9(q,J=7.5Hz,1H),5.11(ddd,J=16.3,8.5,5.3Hz,1H),4.58(m,1H),4.22(t,J=15. 6Hz,1H),3.99-3.85(m,2H),3.62(m,1H),3.45-3.33(m,1H),3.10m,2H),2.95(s, 3H),2.81(m,1H),2.48(m,2H),2.04(s,2H),1.92-1.71(m,3H),1.41-1.33(m,6H).

[0164] Example 9: (R)-2-amino-N-(3-(benzylamino)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0165] Step 1: (R)-(1-((3-(benzylamino)-1-(1-(methylsulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate tert-butyl

[0166] (R)-(1-(3-amino-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate tert-butyl (170 mg, 0.32 mmol) was dissolved in methanol (4 mL), benzaldehyde (35 mg, 0.33 mmol) and one drop of acetic acid were added, and the mixture was stirred at 0 °C for 5 minutes. Sodium cyanoborohydride (40 mg, 0.63 mmol) was then added, and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (150 mg, 0.24 mmol, yield: 75.6%). LC / MS (ESI) M / Z: 628.3 [M+H] + .

[0167] Step 2: (R)-2-amino-N-(3-(benzylamino)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0168] (R)-(1-((3-(benzylamino)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate tert-butyl ester (150 mg, 0.24 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-6% methanol) to give the title compound (white solid, 40 mg, 0.08 mmol, yield: 31.7%). LC / MS (ESI) M / Z: 528.3 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ7.42-7.18(m,16H),7.16-7.00(m,2H),4.57-4.48( m,2H),4.15-3.99(m,2H),3.95m,4H),3.86(dd,J=7.4,4.3Hz,1H),3.84-3.67(m ,4H),3.58(d,J=12.9Hz,1H),3.52-3.41(m,2H),3.23(m,4H),2.97(d,J=3.0Hz, 6H),2.94-2.79(m,2H),2.05(td,J=13.1,4.4Hz,1H),1.78(m,7H),1.30(s,12H).

[0169] Example 10: (R)-2-amino-N-(3-((cyclopropylmethyl)amino)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0170] Step 1: (tert-butyl(R)-(1-((3-((cyclopropylmethyl)amino)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate

[0171] (R)-(1-(3-amino-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate tert-butyl ester (170 mg, 0.32 mmol) was dissolved in methanol (4 mL), cyclopropaneformaldehyde (23 mg, 0.33 mmol) and one drop of acetic acid were added, and the mixture was stirred at 0 °C for 5 minutes. Sodium cyanoborohydride (40 mg, 0.63 mmol) was then added, and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (140 mg, 0.24 mmol, yield: 74.8%). LC / MS (ESI) M / Z: 592.2 [M+H] + .

[0172] Step 2: ((R)-2-amino-N-(3-((cyclopropylmethyl)amino)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0173] Ethyl (tert-butyl(R)-(1-((3-((cyclopropylmethyl)amino)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate (140 mg, 0.24 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4 M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-6% methanol) to give the title compound (white solid, 60 mg, 0.12 mmol, yield: 51.6%). LC / MS (ESI) M / Z: 492.2 [M+H] + . 1H NMR (400 MHz, Methanol-d4) δ7.36(m,3H),7.30-7.14(m,3H),7.07(tt,J=7.5,1.2 Hz,2H),4.59-4.47(m,2H),4.22(t,J=14.4 Hz,2H),4.06-3.83(m,6H),3.52-3.33(m,4H),2.97(d,J=0.9 Hz,6H),2.95-2.81(m,2H),2.52(ddd,J=27.3,11.8,6.3Hz,2H),2.34-2.06(m,3H),1.96-1.72(m,7H),1.47-1.37(m,3H),1.31(dd,J=7.8,2.5 Hz,11H),1.01-0.84(m,2H),0.58-0.42(m,4H),0.25-0.07(m,4H).

[0174] Example 11: (R)-2-amino-N-(3-(cyclopropanesulfonamido)-1-(1-(methylsulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0175] Step 1: (R)-(1-((3-(cyclopropanesulfonamido)-1-(1-(methylsulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)tert-butyl carbamate

[0176] (R)-(1-(3-amino-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate tert-butyl ester (150 mg, 0.28 mmol) was dissolved in dichloromethane (4 mL), and N,N-diisopropylethylamine (72 mg, 0.56 mmol) was added. After stirring at 0 °C for 5 minutes, cyclopropanesulfonyl chloride (51 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (130 mg, 0.20 mmol, yield: 72.6%). LC / MS (ESI) M / Z: 642.3 [M+H] + .

[0177] Step 2: (R)-2-amino-N-(3-(cyclopropanesulfonamido)-1-(1-(methylsulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0178] (R)-(1-((3-(cyclopropanesulfonamide)-1-(1-(methylsulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate tert-butyl ester (130 mg, 0.20 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-6% methanol) to give the title compound (white solid, 65 mg, 0.12 mmol, yield: 59.2%). LC / MS (ESI) M / Z: 542.2 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ7.38(d,J=8.0Hz,2H),7.35-7.30(m,1H),7.26-7.19(m,3H),7.07(t,J=7.5Hz,2H),4.66(dd,J =8.0,4.4Hz,1H),4.60(dd,J=8.3,3.5Hz,1H),4.53(d,J=13.8Hz,2H),4.32(t,J=11.7Hz,2H),3.99(d,J=2.9Hz,4H),3.55(m 2H),3.46-3.36(m,2H),3.30-3.21(m,2H),2.98(s,6H),2.96-2.86(m,2H),2.54(m,1H),2.48- 2.38(m,1H),2.04(m,2H),1.93-1.75(m,6H),1.32(dd,J=5.5,2.0Hz,12H),1.10-0.94(m,8H).

[0179] Example 12: (R)-2-amino-2-methyl-N-(1-(1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxo-3-(benzenesulfonamido)propyl-2-yl)propionamide

[0180] Step 1: (R)-(2-methyl-1-(1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxo-3-(benzenesulfonamido)prop-2-yl)amino)-1-oxyprop-2-yl]amino)tert-butyl carbamate

[0181] (R)-(1-(3-amino-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate tert-butyl ester (150 mg, 0.28 mmol) was dissolved in dichloromethane (4 mL), and N,N-diisopropylethylamine (72 mg, 0.56 mmol) was added. After stirring at 0 °C for 5 minutes, benzenesulfonyl chloride (64 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (160 mg, 0.24 mmol, yield: 84.6%). LC / MS (ESI) M / Z: 678.4 [M+H] + .

[0182] Step 2: (R)-2-amino-2-methyl-N-(1-(1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxo-3-(benzenesulfonamido)prop-2-yl)propionamide

[0183] (R)-(2-methyl-1-(1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxo-3-(benzenesulfonamido)propyl-2-yl)amino)-1-oxypropyl-2-yl]amino)carbamate tert-butyl (160 mg, 0.24 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-6% methanol) to give the title compound (white solid, 70 mg, 0.12 mmol, yield: 51.3%). LC / MS (ESI) M / Z: 578.1 [M+H] + . 1H NMR(400MHz, Methanol-d4)δ7.91-7.79(m,4H),7.74-7.70(m,1H),7.66-7.54(m,5H),7.36(dd,J=8.1,3.9Hz,2H),7.2 4(m,3H),7.14(m,1H),7.05(m,2H),4.50-4.44(m,2H),4.30-4.23(m,1H),4.17-4.05(m,3H),3.94-3.80(m,4H),3.45(d dd,J=13.3,9.2,3.7Hz,2H),3.28-3.16(m,2H),3.12-3.02(m,2H),2.96(d,J=6.4Hz,6H),2.72(td,J=13.3,2.8Hz,1H) ,2.52(td,J=13.1,12.3,3.2Hz,1H),1.96(td,J=13.0,12.5,4.3Hz,1H),1.79-1.57(m,5H),1.40(m,2H),1.32(m,12H).

[0184] Example 13: (R)-2-amino-N-(3-(2-cyano-2-methylpropamido)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropylamine

[0185] Step 1: Tert-butyl(R)-(1-((3-(2-cyano-2-methylpropamido)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate

[0186] 2-Cyano-2-methylpropionic acid (35 mg, 0.31 mmol) was dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (72 mg, 0.56 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (159 mg, 0.42 mmol) were added. After stirring for 10 minutes, (R)-(1-(3-amino-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate tert-butyl ester (150 mg, 0.28 mmol) was added. The mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (130 mg, 0.21 mmol, yield: 73.6%). LC / MS (ESI) M / Z: 633.4 [M+H] + .

[0187] Step 2: (R)-2-amino-N-(3-(2-cyano-2-methylpropamido)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropylamine

[0188] 120 mg (0.19 mmol) of tert-butyl(R)-(1-((3-(2-cyano-2-methylpropamido)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate was dissolved in 3 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added. The reaction mixture was stirred at room temperature for 1 hour. The pH of the reaction mixture was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%–6% methanol) to give the title compound (white solid, 55 mg, 0.10 mmol, yield: 54.5%). LC / MS (ESI) M / Z: 533.2 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ8.23(dt,J=28.9,6.3Hz,2H),7.64(d,J=7.1Hz,2H),7.43(d,J=8.1Hz ,2H),7.34(d,J=7.5Hz,1H),7.27(m,3H),7.18-7.08(m,3H),5.10(m,2H),4.61(m,2H),4.21(d,J=1 4.3Hz,2H),3.98-3.87(m,4H),3.74-3.64(m,2H),3.55-3.46(m,1H),3.43-3.25(m,3H),2.95(s,6H ),2.84(m,2H),2.32-2.25(m,2H),1.93(ddd,J=25.4,12.8,7.6Hz,6H),1.65(m,12H),1.45(m,12H).

[0189] Example 14: N-((R)-2-(2-amino-2-methylpropamido)-3-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-3-oxopropyl)piperazin-2-carboxamide

[0190] Step 1: 2-(((R)-2-(2-((tert-butyloxycarbonyl)amino)-2-methylpropionamido)-3-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-3-oxopropyl)carbamoyl)piperazine-1,4-dicarboxylic acid ditert-butyl ester

[0191] 1,4-bis(tert-butyloxycarbonyl)piperazine-2-carboxylic acid (101 mg, 0.31 mmol) was dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (72 mg, 0.56 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (159 mg, 0.42 mmol) were added. After stirring for 10 minutes, (R)-(1-(3-amino-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate tert-butyl ester (150 mg, 0.28 mmol) was added. The mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%-10% methanol) to give the title compound (180 mg, 0.21 mmol, yield: 75.3%). LC / MS (ESI) M / Z: 850.3 [M+H]+ .

[0192] Step 2: N-((R)-2-(2-amino-2-methylpropamido)-3-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-3-oxopropyl)piperazine-2-carboxamide

[0193] Di-tert-butyl 2-(((R)-2-(2-((tert-butyloxycarbonyl)amino)-2-methylpropamido)-3-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-3-oxopropyl)carbamoyl)piperazine-1,4-dicarboxylate (180 mg, 0.21 mmol) was dissolved in 3 mL of 1,4-dioxane solution, and 3 mL of 4 M dioxane hydrochloride solution was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-10% methanol) to give the title compound (white solid, 35 mg, 0.06 mmol, yield: 30.1%). LC / MS (ESI) M / Z: 550.2 [M+H + ]. 1 H NMR(400MHz, Methanol-d4)δ7.38-7.33(m,3H),7.24(m,3H),7.07(td,J=7.3,4.3Hz,2H), 5.11(m,2H),4.49(d,J=13.8Hz,2H),4.20(d,J=13.7Hz,2H),3.98(d,J=6.6Hz,4H),3.53(m ,2H),3.45(m,1H),3.42-3.33(m,5H),3.07(m,2H),2.99(s,6H),2.95(m,2H),2.91-2.74(m ,6H),2.69(m,4H),2.15-2.06(m,1H),2.02-1.87(m,2H),1.86-1.72(m,6H),1.31(m,12H).

[0194] Example 15: 2-Amino-N-((2R)-3-(benzyloxy)-1-(1-(cyclopropylsulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0195] Step 1: 3-(2-isocyanoethyl)-1H-indole

[0196] Tryptophan (25 g, 156 mmol) was added to ethyl formate (125 mL), and the mixture was heated under reflux for 16 hours. The solution was then concentrated under reduced pressure to obtain crude N-(2-(1H-indol-3-yl)ethyl)formamide. N-(2-(1H-indol-3-yl)ethyl)formamide was dissolved in anhydrous dichloromethane (1000 mL), and triethylamine (108 mL, 780 mmol) was added. The reaction mixture was cooled to -78 °C, and phosphorus oxychloride (36 g, 234 mmol) was added dropwise. The mixture was then stirred at -78 °C for 4 hours. The reaction mixture was added to water (300 mL), extracted with dichloromethane (3 x 500 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (9.10 g, 53.46 mmol, yield: 34.3%). LC / MS (ESI) M / Z: 171.2 [M+H] + .

[0197] Step 2: Spiro[indole-3,3'-pyrrolidine]

[0198] 3-(2-isocyanoethyl)-1H-indole (8.60 g, 50.59 mmol) was dissolved in acetonitrile (80 mL), and N-iodosuccinimide (11.95 g, 53.12 mmol) was added. The mixture was stirred for 30 min. The reaction solution was diluted with acetonitrile (80 mL), and then a borane-ammonia complex (7.81 g, 252.90 mmol) was slowly added. The mixture was stirred at room temperature for 2 h. The reaction solution was quenched with 2 M sodium hydroxide aqueous solution and stirred for 30 min. The mixture was extracted with dichloromethane (3 x 500 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (eluent: ethyl acetate / 5% ammonia in methanol, gradient: 30%–50% methanol) to give the title compound (2.50 g, 14.35 mmol, yield: 28.4%). LC / MS (ESI) M / Z: 175.2 [M+H] + .

[0199] Step 3: ((2R)-3-(benzyloxy)-1-oxo-1-(spiro[indole-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)tert-butyl carbamate

[0200] O-benzyl-N-(tert-butoxycarbonyl)-D-serine (2.67 g, 9.04 mmol) was dissolved in dichloromethane (20 mL), and N,N-diisopropylethylamine (1.67 g, 12.91 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (3.60 g, 9.47 mmol) were added. After stirring for 10 minutes, spiro[indole-3,3'-pyrrolidine] (1.5 g, 8.61 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–5% methanol) to give the title compound (2.9 g, 6.42 mmol, yield: 74.6%). LC / MS (ESI) M / Z: 452.1 [M+H] + .

[0201] Step 4: (2R)-2-amino-3-(benzyloxy)-1-(spiro[indole-3,3'-pyrrolidine]-1'-yl)prop-1-one

[0202] ((2R)-3-(benzyloxy)-1-oxo-1-(spiro[indol-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)carbamate tert-butyl ester (2.90 g, 6.42 mmol) was dissolved in 1,4-dioxane (15 mL) solution, and 4M dioxane hydrochloride solution (15 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude title compound (2.30 g). LC / MS (ESI) M / Z: 352.2 [M+H] + .

[0203] Step 5: (1-((2R)-3-(benzyloxy)-1-oxo-1-(spiro[indoline-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)amino)-2-methyl-1-oxopropyl-2-ylcarbamate tert-butyl ester

[0204] 2-((tert-Butoxycarbonyl)amino)-2-methylpropionic acid (520 mg, 2.56 mmol) was dissolved in dichloromethane (15 mL), and N,N-diisopropylethylamine (496 mg, 3.84 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.07 g, 2.82 mmol) were added. After stirring for 10 minutes, (2R)-2-amino-3-(benzyloxy)-1-(spiro[indol-3,3'-pyrrolidine]-1'-yl)prop-1-one (900 mg, 2.56 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (600 mg, 1.12 mmol, yield: 43.7%). LC / MS (ESI) M / Z: 537.2 [M+H] + .

[0205] Step 6: (1-((2R)-3-(benzyloxy)-1-(1-(cyclopropylsulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)tert-butyl carbamate

[0206] (1-((2R)-3-(benzyloxy)-1-oxo-1-(spiro[indoline-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)amino)-2-methyl-1-oxopropyl-2-ylcarbamate tert-butyl ester (170 mg, 0.32 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (0.09 mL, 0.63 mmol) was added. The mixture was stirred at 0 °C for 5 minutes, and then cyclopropanesulfonyl chloride (58 mg, 0.41 mmol) was added. The mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%-10% methanol) to give the title compound (90 mg, 0.14 mmol, yield: 44.3%). LC / MS(ESI)M / Z: 641.3 [M+H] + .

[0207] Step 7: 2-Amino-N-((2R)-3-(benzyloxy)-1-(1-(cyclopropylsulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0208] (90 mg, 0.14 mmol) of tert-butyl carbamate (1-((2R)-3-(benzyloxy)-1-(1-(cyclopropylsulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate was dissolved in 3 mL of 1,4-dioxane solution, and 3 mL of 4 M dioxane hydrochloride solution was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-6% methanol) to give the title compound (white solid, 12 mg, 0.02 mmol, yield: 15.8%). LC / MS (ESI) M / Z: 541.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ7.48-7.17(m,15H),7.16-6.88(m,3H),4.92-4.86( m,2H),4.77(td,J=6.7,2.6Hz,1H),4.62-4.55(m,3H),4.55-4.47(m,1H),4.09- 3.98(m,1H),3.98-3.80(m,6H),3.80-3.65(m,6H),3.64-3.49(m,2H),2.78-2.5 9(m,2H),2.39-2.07(m,4H),1.33-1.26(m,12H),1.15(m,4H),1.05-0.92(m,4H).

[0209] Example 16: 2-Amino-N-((2R)-3-(benzyloxy)-1-oxo-1-(1-(benzenesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)-2-methylpropionamide

[0210] Step 1: (1-((2R)-3-(benzyloxy)-1-oxo-1-(1-(benzenesulfonyl)spiro[indole-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)amino)-2-methyl-1-oxopropyl-2-ylcarbamate tert-butyl

[0211] (1-((2R)-3-(benzyloxy)-1-oxo-1-(spiro[indoline-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)amino)-2-methyl-1-oxopropyl-2-ylcarbamate tert-butyl ester (170 mg, 0.32 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (0.09 mL, 0.63 mmol) was added. The mixture was stirred at 0 °C for 5 minutes, and then benzenesulfonyl chloride (73 mg, 0.41 mmol) was added. The mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%-10% methanol) to give the title compound (110 mg, 0.16 mmol, yield: 51.3%). LC / MS (ESI) M / Z: 677.2 [M+H] + .

[0212] Step 2: 2-Amino-N-((2R)-3-(benzyloxy)-1-oxo-1-(1-(benzenesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)-2-methylpropionamide

[0213] (1-((2R)-3-(benzyloxy)-1-oxo-1-(1-(benzenesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)amino)-2-methyl-1-oxopropyl-2-ylcarbamate tert-butyl ester (110 mg, 0.16 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-6% methanol) to give the title compound (white solid, 45 mg, 0.08 mmol, yield: 48.0%). LC / MS (ESI) M / Z: 577.2 [M+H] + . 1H NMR(400MHz,Methanol-d4)δ7.81(m,2H),7.78-7.73(m,2H),7.68-7.60(m,4H),7.50(m,4H),7.4 5-7.21(m,12H),7.16(m,1H),7.10-6.85(m,3H),4.83-4.78(m,2H),4.62-4.51(m,4H),4.49-4.39 (m,1H),3.98-3.87(m,1H),3.87-3.78(m,3H),3.77-3.69(m,4H),3.65(m,2H),3.61-3.56(m,1H) ,3.53-3.42(m,2H),3.40-3.33(m,1H),3.27-3.18(m,1H),2.04-1.65(m,4H),1.34-1.25(m,12H).

[0214] Example 17: N-((2R)-3-(1H-indol-3-yl)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)-2-amino-2-methylpropionamide

[0215] Step 1: ((2R)-3-(1H-indol-3-yl)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl) tert-butyl carbamate

[0216] (tert-Butoxycarbonyl)-D-tryptophan (531 mg, 1.74 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of N,N-diisopropylethylamine (410 mg, 3.17 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (904 mg, 2.38 mmol). After stirring for 10 minutes, 1-(methylsulfonyl)spiro[indole-3,3'-pyrrolidine] (400 mg, 1.59 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–5% methanol) to give the title compound (590 mg, 1.10 mmol, yield: 69.1%). LC / MS (ESI) M / Z: 539.3 [M+H] + .

[0217] Step 2: (2R)-2-amino-3-(1H-indol-3-yl)-1-(1-(methanesulfonyl)spiro[indololin-3,3'-pyrrolidine]-1'-yl)prop-1-one

[0218] ((2R)-3-(1H-indol-3-yl)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)carbamate tert-butyl ester (150 mg, 0.28 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude title compound (470 mg, 1.07 mmol, yield: 97.9%). LC / MS (ESI) M / Z: 439.2 [M+H] + .

[0219] Step 3: (1-((2R)-3-(1H-indol-3-yl)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)tert-butyl carbamate

[0220] 2-((tert-Butoxycarbonyl)amino)-2-methylpropionic acid (68.1 mg, 0.34 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of N,N-diisopropylethylamine (83 mg, 0.64 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (134 mg, 0.35 mmol). After stirring for 10 minutes, (2R)-2-amino-3-(1H-indol-3-yl)-1-(1-(methanesulfonyl)spiro[indololin-3,3'-pyrrolidine]-1'-yl)prop-1-one (140 mg, 0.32 mmol). The mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (110 mg, 0.18 mmol, yield: 55.2%). LC / MS (ESI) M / Z: 624.3 [M+H] + .

[0221] Step 4: N-((2R)-3-(1H-indol-3-yl)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)-2-amino-2-methylpropionamide

[0222] (1-((2R)-3-(1H-indol-3-yl)-1-(1-(methanesulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate tert-butyl (110 mg, 0.18 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-6% methanol) to give the title compound (white solid, 35 mg, 0.07 mmol, yield: 37.9%). LC / MS (ESI) M / Z: 524.1 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ7.80(m,2H),7.77-7.72(m,2H),7.69-7.61(m,4H),7.52-7.48(m,4H ),7.45-7.21(m,12H),7.19-7.14(m,1H),7.09-6.85(m,3H),4.82-4.78(m,2H),4.63-4.52(m,4H ),4.48-4.39(m,1H),3.97-3.86(m,1H),3.87-3.78(m,3H),3.68-3.64(m,2H),3.60-3.56(m,1H) ,3.52-3.42(m,2H),3.41-3.34(m,1H),3.27-3.18(m,1H),2.04-1.65(m,4H),1.34-1.25(m,12H).

[0223] Example 18: 2-Amino-N-((2R)-3-(benzyloxy)-1-((1'-(methanesulfonyl)spiro[cyclopentane-1,3'-dihydroindole]-3-yl)amino)-1-oxopropyl-2-yl)-2-methylpropionamide

[0224] Step 1: (1R,4S)-4-aminocyclopent-2-ene-1-carboxylic acid methyl ester

[0225] 2-azabicyclo[2.2.1]hepten-5-en-3-one (10.00 g, 91.64 mmol) was dissolved in anhydrous methanol (100 mL), and the mixture was cooled to 0 °C. Thionyl chloride (11.99 g, 100.80 mmol) was added dropwise to the reaction mixture. The reaction mixture was gradually heated to room temperature and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give a crude white solid (13.00 g). LC / MS (ESI) M / Z: 141.1 [M+H + ].

[0226] Step 2: (R)-4-(2,5-dimethyl-1H-pyrrolo-1-yl)cyclopent-1-ene-1-carboxylic acid methyl ester

[0227] Methyl (1R,4S)-4-aminocyclopentan-2-ene-1-carboxylic acid (13.00 g, 92.09 mmol) was dissolved in methanol (50 mL). N,N-diisopropylethylamine (11.90 g, 92.09 mmol) and 2,5-hexanedione (11.88 mL, 101.30 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3 x 500 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound. Under nitrogen protection, the crude compound was dissolved in anhydrous tetrahydrofuran, and the mixture was cooled to 0 °C. 1,8-diazabicyclo[5.4.0]undec-7-ene (42.06 g, 276.30 mmol) was added dropwise to the above mixture. The reaction mixture was gradually brought to room temperature and stirred overnight at room temperature. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 300 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10%–30% ethyl acetate) to give the title compound (11.00 g, 50.16 mmol, yield: 54.5%). LC / MS (ESI) M / Z: 220.2 [M+H] + .

[0228] Step 3: (R)-4-(2,5-dimethyl-1H-pyrrolo-1-yl)-N-(2-iodophenyl)cyclopent-1-ene-1-carboxamide

[0229] In a flame-dried flask, 2M trimethylaluminum (30.10 mL, 60.20 mmol) was added to anhydrous toluene (80 mL). Under nitrogen protection, the mixture was cooled to 0°C, and 12.09 g (55.18 mmol) of 2-iodoaniline dissolved in anhydrous toluene (80 mL) was added. The mixture was stirred at 0°C for 5 minutes, removed from the ice bath, and stirred at room temperature for 20 minutes. The mixture was cooled again to 0°C, and methyl (R)-4-(2,5-dimethyl-1H-pyrrolo-1-yl)cyclopent-1-ene-1-carboxylic acid (11.00 g, 50.16 mmol) dissolved in anhydrous toluene (80 mL) was added dropwise to the mixture, which was stirred at 0°C for 10 minutes. The mixture was heated to 60°C and stirred for 16 hours. After cooling to room temperature, 200 mL of 1M hydrochloric acid solution was added, and the mixture was stirred for 30 minutes. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 400 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 20%-50% ethyl acetate) to give the title compound (14.60 g, 35.94 mmol, yield: 71.6%). LC / MS (ESI) M / Z: 407.2 [M+H] + .

[0230] Step 4: (1R,4S)-4-(2,5-dimethyl-1H-pyrrolo-1-yl)spiro[cyclopentan-1,3'-indoline]-2-en-2'-one

[0231] (R)-4-(2,5-dimethyl-1H-pyrrolo-1-yl)-N-(2-iodophenyl)cyclopent-1-ene-1-carboxamide (8.00 g, 19.69 mmol) was dissolved in N,N-dimethylformamide (80 mL), and palladium acetate (0.22 g, 0.99 mmol), triphenylphosphine (0.52 g, 1.97 mmol), and triethylamine (5.47 mL, 39.38 mmol) were added. The reaction mixture was stirred overnight at 80 °C under nitrogen protection. Water (80 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 160 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-50% ethyl acetate) to give the title compound (4.80 g, 17.24 mmol, yield: 87.6%). LC / MS (ESI) M / Z: 279.1 [M+H] + .

[0232] Step 5: (1R,4S)-4-aminospiro[cyclopentane-1,3'-indoline]-2-en-2'-one

[0233] (1R,4S)-4-(2,5-dimethyl-1H-pyrrolo-1-yl)spiro[cyclopentan-1,3'-indoline]-2-en-2'-one (8 g, 19.69 mmol) was dissolved in methanol / water (30 / 10 mL), and hydroxylamine hydrochloride (0.22 g, 0.99 mmol) and potassium hydroxide (5.47 mL, 39.38 mmol) were added. The reaction mixture was stirred overnight at 90 °C under nitrogen protection. The reaction mixture was cooled to room temperature, and the pH was adjusted to 8 with 1 M hydrochloric acid. Extraction was performed with ethyl acetate (3 x 50 mL). The combined organic phases were purified by C18 reversed-phase chromatography to give the title compound (1.5 g, 7.49 mmol, yield: 90.7%). LC / MS (ESI) M / Z: 201.2 [M+H] + .

[0234] Step 6: (1S,3R)-3-aminospiro[cyclopentane-1,3'-indoline]-2'-one

[0235] (1R,4S)-4-aminospiro[cyclopentan-1,3'-indoline]-2-en-2'-one (1.50 g, 7.49 mmol) was dissolved in methanol (30 mL), and 10% palladium on carbon (0.40 g, 0.38 mmol) was added. The mixture was stirred overnight at room temperature. The reaction solution was filtered and concentrated under reduced pressure to give the title compound (1.40 g, 6.99 mmol, yield: 92.4%). LC / MS (ESI) M / Z: 203.2 [M+H] + .

[0236] Step 7: ((1S,3R)-2'-oxospiro[cyclopentane-1,3'-dihydroindole]-3-yl)tert-butyl carbamate

[0237] (1S,3R)-3-aminospiro[cyclopentane-1,3'-indoline]-2'-one (1.40 g, 6.99 mmol) was dissolved in dichloromethane (30 mL), and N,N-diisopropylethylamine (2.68 g, 20.77 mmol) and di-tert-butyl dicarbonate (2.27 g, 10.38 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. Water (80 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 160 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10%-30% ethyl acetate) to give the title compound (1.80 g, 5.95 mmol, yield: 86.0%). LC / MS (ESI) M / Z: 303.1 [M+H] + .

[0238] Step 8: ((1S,3R)-spiro[cyclopentane-1,3'-dihydroindole]-3-yl)tert-butyl carbamate

[0239] ((1S,3R)-2'-oxospiro[cyclopentane-1,3'-dihydroindole]-3-yl)tert-butyl carbamate (500 mg, 1.65 mmol) was added to THF (25 mL), followed by the boranetetrahydrofuran complex (426 mg, 4.96 mmol). The reaction was carried out overnight at room temperature, and the reaction was monitored by LC-MS. When half of the reactants had reacted, 5 equivalents of sodium borohydride were added, and the mixture was stirred for another 4 hours. LC-MS analysis indicated that the reactants were not completely reacted; the reaction was then stopped, the mixture was poured into water, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound (240 mg, 0.83 mmol, yield 50.3%). LC / MS (ESI) M / Z: 289.2 [M+H] + .

[0240] Step 9: ((1S,3R)-1'-(methanesulfonyl)spiro[cyclopentane-1,3'-dihydroindole]-3-yl)tert-butyl carbamate

[0241] Under nitrogen protection, tert-butyl carbamate ((1S,3R)-spiro[cyclopentane-1,3'-dihydroindole]-3-yl)carbamate (240 mg, 0.83 mmol) was dissolved in dichloromethane (5 mL), followed by N,N-diisopropylethylamine (161.34 mg, 1.248 mmol), and then methanesulfonyl chloride (114 mg, 0.10 mmol). The reaction was carried out at room temperature for 3 hours, and the reaction was stopped by LCMS. The reaction solution was poured into water (20 mL), extracted with ethyl acetate (3 x 30 mL), washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10%-30% ethyl acetate) to give the target compound (100 mg, 0.27 mmol, yield 32.8%). LC / MS (ESI) M / Z: 367.1 [M+H] + .

[0242] Step 10: (1S,3R)-1'-(methanesulfonyl)spiro[cyclopentane-1,3'-indoline]-3-amine

[0243] Under nitrogen protection, tert-butyl carbamate ((1S,3R)-1'-(methanesulfonyl)spiro[cyclopentane-1,3'-dihydroindole]-3-yl)carbamate (230 mg, 0.63 mmol) was added to dichloromethane (5 mL), followed by the addition of 4M hydrogen chloride / 1,4-dioxane (2 mL). The reaction was carried out at room temperature for 3 hours. The reaction was stopped by LCMS. The crude target compound (167 mg, 0.63 mmol, yield 99.90%) was obtained by concentration under reduced pressure and used directly in the next step without purification.

[0244] Step 11: ((R)-3-(benzyloxy)-1-(((1R,3S)-1'-(methanesulfonyl)spiro[cyclopentane-1,3'-dihydroindole]-3-yl)amino)-1-oxopropyl-2-yl)tert-butyl carbamate

[0245] o-Benzyl-N-(tert-butoxycarbonyl)-D-serine (230 mg, 0.78 mmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (402.6 mg, 3.12 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (355.4 mg, 0.94 mmol) were added. After stirring for 10 minutes, (1S,3R)-1'-(methanesulfonyl)spiro[cyclopentane-1,3'-indoline]-3-amine (166.0 mg, 0.62 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-90% ethyl acetate) to give the title compound (250 mg, 0.46 mmol, yield 59.1%). LC / MS (ESI) M / Z: 544.2 [M+H] + .

[0246] Step 12: (R)-2-amino-3-(benzyloxy)-N-((1R,3S)-1'-(methanesulfonyl)spiro[cyclopentane-1,3'-dihydroindole]-3-yl)propionamide

[0247] Under nitrogen protection, tert-butyl carbamate ((R)-3-(benzyloxy)-1-(((1R,3S)-1'-(methanesulfonyl)spiro[cyclopentane-1,3'-dihydroindole]-3-yl)amino)-1-oxopropyl-2-yl)carbamate (265 mg, 0.49 mmol) was added to dichloromethane (5 mL), followed by the addition of 4M hydrogen chloride / 1,4-dioxane (2 mL). The reaction was carried out at room temperature for 3 hours. LC / MS analysis indicated the reaction was complete. The crude target compound (216 mg, 0.49 mmol, yield 99.95%) was concentrated under reduced pressure and used directly in the next reaction without purification. LC / MS (ESI) M / Z: 444.2 [M+H] + .

[0248] Step 13: (1-(((R)-3-(benzyloxy)-1-(((1R,3S)-1'-(methanesulfonyl)spiro[cyclopentane-1,3'-dihydroindole]-3-yl)amino)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropyl-2-yl)carbamate tert-butyl

[0249] 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (110 mg, 0.54 mmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (280 mg, 2.17 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (247 mg, 0.65 mmol) were added. After stirring for 10 minutes, (R)-2-amino-3-(benzyloxy)-N-((1R,3S)-1'-(methanesulfonyl)spiro[cyclopentane-1,3'-dihydroindole]-3-yl)propionamide (216 mg, 0.49 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-90% ethyl acetate) to give the title compound (250 mg, 0.40 mmol, yield 73.5%). LC / MS (ESI) M / Z: 628.2 [M+H] + .

[0250] Step 14: 2-Amino-N-((R)-3-(benzyloxy)-1-(((1R,3S)-1'-(methanesulfonyl)spiro[cyclopentane-1,3'-indoline]-3-yl)amino)-1-oxopropyl-2-yl)-2-methylpropionamide

[0251] Under nitrogen protection, tert-butyl carbamate (240 mg, 0.38 mmol) was added to dichloromethane (5 mL), followed by the addition of 4M hydrogen chloride / 1,4-dioxane (2 mL). The reaction was carried out at room temperature for 3 hours. The reaction was confirmed by LC-MS. The mixture was then concentrated under reduced pressure and purified by reversed-phase column chromatography to give the title compound (150 mg, 0.28 mmol, yield 74.3%). LC / MS (ESI) M / Z: 528.2 [M+H] + .

[0252] H NMR (400MHz, Methanol-d4) δ7.37-7.17(m,8H),7.11-7.05(m,1H),4.59-4.52(m,2H),4.49(q,J=5.1Hz,1H),4.44-4.36(m,1H),3.88-3.73(m,3H) ,3.68(ddd,J=9.5,5.5,1.2Hz,1H),2.89(m,3H),2.35(m,1H),2.24(m,1H ),2.07-1.97(m,1H),1.89-1.77(m,2H),1.70(m,1H),1.35-1.28(m,6H).

[0253] Example 19: 2-Amino-N-((2R)-3-(benzyloxy)-1-(1-((4-(tert-butyl)phenyl)sulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0254] Step 1: (1-((2R)-3-(benzyloxy)-1-(1-(4-(tert-butyl)phenyl)sulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxoprop-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate tert-butyl

[0255] (1-((2R)-3-(benzyloxy)-1-oxo-1-(spiro[indoline-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)amino)-2-methyl-1-oxopropyl-2-ylcarbamate tert-butyl ester (150 mg, 0.28 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (0.08 mL, 0.56 mmol) was added. The mixture was stirred at 0 °C for 5 minutes, and then 4-(tert-butyl)benzenesulfonyl chloride (78 mg, 0.34 mmol) was added. The mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (100 mg, 0.14 mmol, yield: 48.8%). LC / MS (ESI) M / Z: 733.4 [M+H] + .

[0256] Step 2: 2-Amino-N-((2R)-3-(benzyloxy)-1-(1-((4-(tert-butyl)phenyl)sulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0257] (1-((2R)-3-(benzyloxy)-1-(1-(4-(tert-butyl)phenyl)sulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate tert-butyl ester (100 mg, 0.14 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-6% methanol) to give the title compound (white solid, 22 mg, 0.04 mmol, yield: 25.5%). LC / MS (ESI) M / Z: 633.3 [M+H] + . 1H NMR(400MHz,Methanol-d4)δ7.76-7.71(m,2H),7.69-7.62(m,4H),7.57-7.51(m,4H),7.43-7.22 (m,12H),7.19-7.15(m,1H),7.06-6.86(m,3H),4.83-4.78(m,2H),4.62-4.51(m,4H),4.49-4.39 (m,1H),3.98-3.87(m,1H),3.87-3.78(m,3H),3.77-3.69(m,4H),3.65(m,2H),3.61-3.56(m,1H) ,3.53-3.42(m,2H),3.40-3.33(m,1H),3.27-3.18(m,1H),2.04-1.65(m,4H),1.34-1.25(m,36H).

[0258] Example 20: 2-Amino-N-((2R)-3-(benzyloxy)-1-oxo-1-(1-(4-(trifluoromethyl)phenyl)sulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)-2-methylpropionamide

[0259] Step 1: (1-((2R)-3-(benzyloxy)-1-oxo-1-(1-(4-(trifluoromethyl)phenyl)sulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)amino)-2-methyl-1-oxopropyl-2-ylcarbamate tert-butyl

[0260] (1-((2R)-3-(benzyloxy)-1-oxo-1-(spiro[indoline-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)amino)-2-methyl-1-oxopropyl-2-ylcarbamate tert-butyl ester (150 mg, 0.28 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (0.08 mL, 0.56 mmol) was added. After stirring at 0 °C for 5 minutes, 4-(trifluoromethyl)benzenesulfonyl chloride (82 mg, 0.34 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (120 mg, 0.16 mmol, yield: 57.6%). LC / MS (ESI) M / Z: 745.3 [M+H] + .

[0261] Step 2: 2-Amino-N-((2R)-3-(benzyloxy)-1-oxo-1-(1-(4-(trifluoromethyl)phenyl)sulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)-2-methylpropionamide

[0262] (1-((2R)-3-(benzyloxy)-1-oxo-1-(1-(4-(trifluoromethyl)phenyl)sulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)amino)-2-methyl-1-oxopropyl-2-ylcarbamate tert-butyl ester (120 mg, 0.16 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-6% methanol) to give the title compound (white solid, 25 mg, 0.04 mmol, yield: 24.1%). LC / MS (ESI) M / Z: 645.1 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ8.06-8.02(m,2H),7.99-7.95(m,2H),7.87-7.81(m,4H),7.67-7.63 (m,2H),7.43-7.18(m,13H),7.11-6.89(m,3H),4.83-4.78(m,2H),4.62-4.51(m,4H),4.49-4.39 (m,1H),3.98-3.87(m,1H),3.87-3.78(m,3H),3.77-3.69(m,4H),3.65(m,2H),3.61-3.56(m,1H) ,3.53-3.42(m,2H),3.40-3.33(m,1H),3.27-3.18(m,1H),2.04-1.65(m,4H),1.34-1.26(m,12H).

[0263] Example 21: 2-Amino-N-((2R)-3-(benzyloxy)-1-oxo-1-(1-(2,4,6-trifluorophenyl)sulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)-2-methylpropionamide

[0264] Step 1: (1-((2R)-3-(benzyloxy)-1-oxo-1-(1-(2,4,6-trifluorophenyl)sulfonyl)spiro[indole-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)amino)-2-methyl-1-oxopropyl-2-ylcarbamate tert-butyl

[0265] (1-((2R)-3-(benzyloxy)-1-oxo-1-(spiro[indoline-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)amino)-2-methyl-1-oxopropyl-2-ylcarbamate tert-butyl ester (150 mg, 0.28 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (0.08 mL, 0.56 mmol) was added. The mixture was stirred at 0 °C for 5 minutes, and then 2,4,6-trifluorobenzenesulfonyl chloride (77 mg, 0.34 mmol) was added. The mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (110 mg, 0.15 mmol, yield: 53.9%). LC / MS (ESI) M / Z: 731.1 [M+H] + .

[0266] Step 2: 2-Amino-N-((2R)-3-(benzyloxy)-1-oxo-1-(1-(2,4,6-trifluorophenyl)sulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)-2-methylpropionamide

[0267] (1-((2R)-3-(benzyloxy)-1-oxo-1-(1-(2,4,6-trifluorophenyl)sulfonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)amino)-2-methyl-1-oxopropyl-2-ylcarbamate tert-butyl ester (110 mg, 0.15 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-6% methanol) to give the title compound (white solid, 18 mg, 0.03 mmol, yield: 19.0%). LC / MS (ESI) M / Z: 631.2 [M+H] + . 1H NMR(400MHz,Methanol-d4)δ8.05-8.02(m,2H),7.98-7.94(m,2H),7.83-7.80(m,4H),7.66-7.62 (m,2H),7.41-7.15(m,8H),7.11-6.89(m,3H),4.83-4.78(m,2H),4.62-4.51(m,4H),4.49-4.39( m,1H),3.98-3.87(m,1H),3.87-3.78(m,3H),3.78-3.69(m,4H),3.65(m,2H),3.62-3.56(m,1H), 3.52-3.42(m,2H),3.40-3.32(m,1H),3.27-3.18(m,1H),2.03-1.65(m,4H),1.34-1.27(m,12H).

[0268] Example 22: (R)-2-amino-N-(3-(4-cyanobenzyl)oxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0269] Step 1: N-(tert-Butoxycarbonyl)-O-(4-cyanobenzyl)-D-serine

[0270] (tert-Butoxycarbonyl)-D-serine (1.00 g, 4.87 mmol) was dissolved in N,N-dimethylformamide (10 mL). The reaction mixture was cooled to 0 °C in an ice bath, and sodium hydride (60% in mineral oil, 0.49 g, 12.20 mmol) was added. The mixture was stirred at 0 °C for 30 minutes. 4-(bromomethyl)benzonitrile (1.00 g, 5.12 mmol) was added to the above mixture, and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (20 mL), extracted with tert-butyl methyl ether (3 x 30 mL), acidified with 10% citric acid, separated, and the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by C18 reversed-phase chromatography to give the title compound (770 mg, 2.40 mmol, yield: 49.3%). LC / MS (ESI) M / Z: 321.2 [M+H] + .

[0271] Step 2: (R)-(3-((4-cyanobenzyl)oxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)tert-butyl carbamate

[0272] N-(tert-butoxycarbonyl)-O-(4-cyanobenzyl)-D-serine (577 mg, 1.80 mmol) was dissolved in dichloromethane (8 mL), and N,N-diisopropylethylamine (388 mg, 3.00 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (856 mg, 2.25 mmol) were added. After stirring for 10 minutes, 1-(methanesulfonyl)spiro[indoline-3,4'-piperidine] (400 mg, 1.50 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 70%–90% ethyl acetate) to the title compound (750 mg, 1.32 mmol, yield: 97.8%). LC / MS (ESI) M / Z: 569.2 [M+H] + .

[0273] Step 3: (R)-4-(2-amino-3-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-3-oxopropoxy)methyl)benzonitrile

[0274] (R)-(3-((4-cyanobenzyl)oxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)carbamate tert-butyl ester (250 mg, 0.44 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude title compound (210 mg). LC / MS (ESI) M / Z: 469.3 [M+H] + .

[0275] Step 4: Tert-butyl(R)-(1-((3-((4-cyanobenzyl)oxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate

[0276] 2-((tert-Butoxycarbonyl)amino)-2-methylpropionic acid (109 mg, 0.54 mmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (174 mg, 1.35 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (256 mg, 0.67 mmol) were added. After stirring for 10 minutes, (R)-4-(2-amino-3-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-3-oxopropoxy)methyl)benzonitrile (210 mg, 0.45 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (150 mg, 0.23 mmol, yield: 51.2%). LC / MS (ESI) M / Z: 654.1 [M+H] + .

[0277] Step 5: (R)-2-amino-N-(3-(4-cyanobenzyl)oxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0278] 150 mg (0.23 mmol) of tert-butyl(R)-(1-((3-((4-cyanobenzyl)oxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate was dissolved in 4 mL of 1,4-dioxane solution, and 4 mL of 4 M dioxane hydrochloride solution was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%–6% methanol) to give the title compound (white solid, 80 mg, 0.14 mmol, yield: 63.0%). LC / MS (ESI) M / Z: 554.2 [M+H] + . 1H NMR(400MHz, Methanol-d4)δ7.79-7.68(m,4H),7.57(d,J=7.9Hz,2H),7.52(d,J=7.9Hz,2H),7.36 (t,J=7.8Hz,2H),7.29-7.17(m,3H),7.03(dt,J=19.5,7.5Hz,2H),6.77(d,J=7.5Hz,1H),5.16(t,J =5.6Hz,2H),4.71-4.61(m,4H),4.59-4.50(m,2H),4.12(d,J=13.7Hz,2H),3.93(d,J=5.0Hz,4H), 3.76(m,4H),2.96(d,J=6.8Hz,6H),2.90(d,J=12.3Hz,2H),1.99-1.65(m,8H),1.38-1.30(m,12H).

[0279] Example 23: (R)-2-amino-N-(3-((4-(difluoromethoxy)benzyl)oxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0280] Step 1: N-(tert-Butoxycarbonyl)-O-(4-(difluoromethoxy)benzyl)-D-serine

[0281] (tert-Butoxycarbonyl)-D-serine (1.00 g, 4.87 mmol) was dissolved in N,N-dimethylformamide (10 mL). The reaction mixture was cooled to 0 °C in an ice bath, and sodium hydride (60% in mineral oil, 0.49 g, 12.20 mmol) was added. The mixture was stirred at 0 °C for 30 minutes. 1-(bromomethyl)-4-(difluoromethoxy)benzene (1.14 g, 5.12 mmol) was added to the above mixture, and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (20 mL), extracted with tert-butyl methyl ether (50 mL), acidified with 10% citric acid, and extracted with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase chromatography to give the title compound (950 mg, 2.63 mmol, yield: 54.0%). LC / MS (ESI) M / Z: 362.1 [M+H] + .

[0282] Step 2: (R)-(3-((4-(difluoromethoxy)benzyl)oxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)tert-butyl carbamate

[0283] N-(tert-butoxycarbonyl)-O-(4-(difluoromethoxy)benzyl)-D-serine (407 mg, 1.13 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (243 mg, 1.88 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (464 mg, 1.22 mmol) were added. After stirring for 10 minutes, 1-(methylsulfonyl)spiro[indoline-3,4'-piperidine] (250 mg, 0.94 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–5% methanol) to give the title compound (450 mg, 1.32 mmol, yield: 97.8%). LC / MS (ESI) M / Z: 610.3 [M+H] + .

[0284] Step 3: (R)-2-amino-3-((4-(difluoromethoxy)benzyl)oxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)prop-1-one

[0285] (R)-(3-((4-(difluoromethoxy)benzyl)oxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)carbamate tert-butyl ester (250 mg, 0.44 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude title compound (180 mg). LC / MS (ESI) M / Z: 510.2 [M+H] + .

[0286] Step 4: Tert-butyl(R)-(1-((3-((4-(difluoromethoxy)benzyl)oxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate

[0287] 2-((tert-Butoxycarbonyl)amino)-2-methylpropionic acid (86 mg, 0.42 mmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (137 mg, 1.06 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (175 mg, 0.35 mmol) were added. After stirring for 10 minutes, (R)-2-amino-3-((4-(difluoromethoxy)benzyl)oxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)prop-1-one (180 mg, 0.45 mmol) was added. The mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (120 mg, 0.17 mmol, yield: 48.9%). LC / MS (ESI) M / Z: 695.2 [M+H] + .

[0288] Step 5: (R)-2-amino-N-(3-((4-(difluoromethoxy)benzyl)oxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0289] 120 mg (0.17 mmol) of tert-butyl(R)-(1-((3-((4-(difluoromethoxy)benzyl)oxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate was dissolved in 1,4-dioxane (4 mL) solution, and 4 M dioxane hydrochloride solution (4 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-6% methanol) to give the title compound (white solid, 45 mg, 0.08 mmol, yield: 43.8%). LC / MS (ESI) M / Z: 595.2 [M+H] + .

[0290] 1H NMR(400MHz,Methanol-d4)δ7.46-7.30(m,6H),7.28-7.17(m,3H),7.17-7.09(m,4 H),7.09-6.96(m,2H),6.94-6.52(m,3H),5.12(q,J=6.4Hz,2H),4.61-4.44(m,6H) ,4.09(m,2H),3.92(m,4H),3.71(dd,J=10.5,6.2Hz,4H),3.24(m,2H),2.96(d,J=6 .3Hz,6H),2.93-2.83(m,2H),2.02-1.80(m,2H),1.72(m,6H),1.38-1.27(m,12H).

[0291] Example 24: 2-Amino-N-((2R)-1-(1-(cyclopropylsulfonyl)spiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-((4-fluorobenzyl)oxy)-1-oxopropyl-2-yl)-2-methylpropionamide

[0292] Step 1: N-(tert-Butoxycarbonyl)-O-(4-Fluorobenzyl)-D-Serine

[0293] (tert-Butoxycarbonyl)-D-serine (1.00 g, 4.87 mmol) was dissolved in N,N-dimethylformamide (10 mL). The reaction mixture was cooled to 0 °C in an ice bath, and sodium hydride (60% in mineral oil, 0.49 g, 12.20 mmol) was added. The mixture was stirred at 0 °C for 30 minutes. 4-Fluorobenzyl bromide (0.97 g, 5.12 mmol) was added to the above mixture, and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (20 mL), extracted with tert-butyl methyl ether (3 x 30 mL), acidified with 10% citric acid, separated, and the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by C18 reversed-phase chromatography to give the title compound (785 mg, 2.51 mmol, yield: 51.54%). LC / MS (ESI) M / Z: 314.2 [M+H] + .

[0294] Step 2: ((2R)-3-((4-fluorobenzyl)oxy)-1-oxo-1-(spiro[indoline-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)tert-butyl carbamate

[0295] N-(tert-butoxycarbonyl)-O-(4-fluorobenzyl)-D-serine (785 mg, 2.51 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (648 mg, 5.02 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1037 mg, 2.73 mmol) were added. After stirring for 10 minutes, spiro[indoline-3,3'-pyrrolidine] (437 mg, 2.51 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 70%–90% ethyl acetate) to give the title compound (929 mg, 1.98 mmol, yield: 78.9%). LC / MS (ESI) M / Z: 470.2 [M+H] + .

[0296] Step 3: (2R)-2-amino-3-((4-fluorobenzyl)oxy)-1-(spiro[indoline-3,3'-pyrrolidine]-1'-yl)prop-1-one

[0297] (2R)-3-((4-fluorobenzyl)oxy)-1-oxo-1-(spiro[indoline-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)carbamate tert-butyl ester (929 mg, 1.98 mmol) was dissolved in 1,4-dioxane (3 mL) solution, and 4M dioxane hydrochloride solution (3 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude title compound (730 mg). LC / MS (ESI) M / Z: 370.3 [M+H] + .

[0298] Step 4: (1-(((2R)-3-((4-fluorobenzyl)oxy)-1-oxo-1-(spiro[indoline-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)amino)-2-methyl-1-oxopropyl-2-yl)carbamate tert-butyl

[0299] 2-((tert-Butoxycarbonyl)amino)-2-methylpropionic acid (402 mg, 1.98 mmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (516 mg, 4.00 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (836 mg, 2.20 mmol) were added. After stirring for 30 minutes, (2R)-2-amino-3-((4-fluorobenzyl)oxy)-1-(spiro[indoline-3,3'-pyrrolidine]-1'-yl)prop-1-one (730 mg, 1.98 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (452 ​​mg, 0.82 mmol, yield: 41.2%). LC / MS (ESI) M / Z: 555.1 [M+H] + .

[0300] Step 5: (1-(((2R)-1-(1-(cyclopropylsulfonyl)spiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-((4-fluorobenzyl)oxy)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropyl-2-yl)tert-butyl carbamate

[0301] (1-(((2R)-3-((4-fluorobenzyl)oxy)-1-oxo-1-(spiro[indoline-3,3'-pyrrolidine]-1'-yl)propyl-2-yl)amino)-2-methyl-1-oxopropyl-2-yl)carbamate tert-butyl ester (452 ​​mg, 0.82 mmol) was dissolved in dry dichloromethane (5 mL), and N,N-diisopropylethylamine (258 mg, 2.00 mmol) was added. The mixture was cooled to 0 °C, and cyclopropylsulfonyl chloride (126 mg, 0.90 mmol) was added. The mixture was stirred at 0 °C for 30 minutes and then at room temperature for 2 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (330 mg, 0.50 mmol, yield: 61.2%). LC / MS (ESI) M / Z: 659.2 [M+H] + .

[0302] Step 6: 2-Amino-N-((2R)-1-(1-(cyclopropylsulfonyl)spiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-((4-fluorobenzyl)oxy)-1-oxopropyl-2-yl)-2-methylpropionamide

[0303] (1-(((2R)-1-(1-(cyclopropylsulfonyl)spiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-((4-fluorobenzyl)oxy)-1-oxopropyl-2-yl)amino)-2-methyl-1-oxopropyl-2-yl)carbamate tert-butyl (330 mg, 0.50 mmol) was dissolved in dichloromethane (4 mL), and 4 M dioxane hydrochloride solution (4 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 0.5% ammonia in dichloromethane / 0.5% ammonia in methanol, gradient: 1%-6% methanol) to give the title compound (white solid, 159 mg, 0.29 mmol, yield: 57.0%). LC / MS (ESI) M / Z: 559.2 [M+H] + .

[0304] Example 25: N-((2R)-3-(benzyloxy)-1-(1-(cyclopropylsulfonyl)spiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)-2-guanidinyl-2-methylpropionamide

[0305] Step 1: N-((2R)-3-(benzyloxy)-1-(1-(cyclopropylsulfonyl)spiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)-2-(2,3-bis(tert-butoxycarbonyl)guanidinyl)-2-methylpropionamide

[0306] 2-Amino-N-((2R)-3-(benzyloxy)-1-(1-(cyclopropylsulfonyl)spiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide (270 mg, 0.50 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (101 mg, 0.10 mmol) and (((tert-butoxycarbonyl)imino)(1H-pyrazol-1-yl)methyl)tert-butyl carbamate (186 mg, 0.6 mmol) were added. The reaction mixture was stirred at 60 °C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 50%-90%) to give the title compound (white solid, 227 mg, 0.29 mmol, yield: 57.0%). LC / MS (ESI) M / Z: 783.3 [M+H] + .

[0307] Step 2: N-((2R)-3-(benzyloxy)-1-(1-(cyclopropylsulfonyl)spiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)-2-guanidino-2-methylpropionamide

[0308] N-((2R)-3-(benzyloxy)-1-(1-(cyclopropylsulfonyl)spiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxopropyl-2-yl)-2-(2,3-bis(tert-butoxycarbonyl)guanidinyl)-2-methylpropionamide (227 mg, 0.29 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by high pressure to give the title compound (white solid, 64 mg, 0.11 mmol, yield: 37.9%). LC / MS (ESI) M / Z: 583.3 [M+H] + .

[0309] The compounds of Examples 26-57 were prepared using a similar method:

[0310] Bioactivity testing:

[0311] Example A: Activity test of the compound of the present invention against human GHSR

[0312] In this embodiment, HEK293 cells overexpressing human GHSR-1α were used, and the agonistic activity of the compound was characterized by detecting changes in the intracellular signaling pathway factor IP-1.

[0313] The cells and reagents used in this experiment included: HEK293-GHSR-1α stable transgenic cells, culture medium (DMEM + 10% fetal bovine serum + 1% penicillin-streptomycin + 100 μg / mL hygromycin), and IP-One-Gq HTRF detection kit.

[0314] The compound was prepared into working solutions of different concentrations by serially diluting it 3-fold with DMSO. 10 nL / well was added to 384-well plates (replicas, 11 concentration points, with a maximum final concentration of 1 μM). Cultured HEK293-GHSR-1α cells were dissociated at 37°C for 3 minutes with 0.05% trypsin-EDTA, and the process was terminated by adding fresh culture medium. Cells were resuspended and counted, centrifuged at 1000 rpm for 5 minutes, and the supernatant was removed. Cells were resuspended in 1×stimulation buffer until a cell density of 2×10⁶ cells / well was reached. 6Cells / mL. Cells were added at a rate of 10 μL / well to a 384-well plate, sealed, and incubated at 37°C for 2 hours. After incubation, 5 μL / well of 1×IP-1 d2 reagent and then 5 μL / well of 1×anti-IP-1 antibody were added. The plate was sealed and incubated at room temperature for 60 minutes. After incubation, the cells were detected using a microplate reader. Data were analyzed using a ratio assay (665 nm / 615 nm), and activation curves were fitted using a four-parameter logistic curve. The activation activity of the compounds on GHSR is shown in Table 1.

[0315] The Ibutamoren structure is as follows:

[0316] Synthesis method reference: ZL93112858.7

[0317] Ghrelin was purchased from Good Laboratory Practice Bioscience; catalog number: GC16346.

[0318] Table 1. Agonistaltic activity of compounds against human GHSR (EC) 50 value Note: * indicates EC 50 ≥1000nM; ** indicates 1000nM > EC 50 ≥500nM; *** indicates 500nM > EC 50 ≥100nM; **** indicates 100nM > EC 50 ≥10nM; ***** indicates 10nM > EC 50 ≥2nM; ****** indicates 2nM>EC 50 ≥0.5nM; ******* indicates 0.5nM > EC 50

[0319] The experimental results show that most of the compounds provided by this invention have good agonistic activity against GHSR.

[0320] Example B: Pharmacokinetic Characteristics of Compounds in Rats

[0321] Six- to eight-week-old male SD rats were housed in an SPF-barrier environment. Throughout the experiment, the temperature and relative humidity in the animal room were controlled at 23±2℃ and 50±10%, respectively, with a constant 12-hour light / dark cycle. All rats were acclimatized for 3 days before the start of the experiment. Rats were randomly divided into groups of three according to body weight. The gavage group was fasted overnight before administration and fed 4 hours after administration. The intravenous group had free access to food. A single administration of the compound (PO 3 mg / kg, IV 1 mg / kg, solvent: 5% DMSO + 95% (0.5% CMC-Na)) was administered. Plasma samples were collected at specific time points after administration, and the compound was detected using chromatography-tandem triple quadrupole mass spectrometry. Pharmacokinetic parameters were calculated using a non-compartmental model analysis method. The experimental results are shown in Table 2.

[0322] Table 2. Drug metabolism data in rats Note: NA indicates that parameters cannot be calculated below the detection limit.

[0323] The above experimental data show that, in the drug metabolism experiment of rats administered the drug via gavage in Example 15 of this invention, C max Its AUC was significantly better than that of the positive control ibutamoren, indicating better drug-like properties.

Claims

1. A compound of general formula (I), including its racemic, stereoisomer, tautomer, isotopic label, nitride, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof. In the formula, * indicates racemic, S-configuration, or R-configuration; X1, X2, X3, and X4 are each independently N or CR4; Each R4 is independently selected from: H, halogen, cyano, NRaRb, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 haloalkyl, and C1-C4 haloalkoxy. X5 is selected from in, Each R1 is independently a C1-C4 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, 5-8 membered heterocyclic, or 5-8 membered heteroaryl; the above groups are optionally substituted by one or more substituents selected from the group consisting of: halogen, cyano, NRaRb, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy; or R1, X4 and the intercalary atom together form a 5-10 membered heterocycle; n is 0, 1, 2, or 3; m is 0, 1, 2, or 3; X6 is N or CH; R5, R6, R7, R8, R9, R 10 R 11 R 12 Each is independently selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy; or R5, R 11 The links together form a C1-C4 alkylene group, wherein the C1-C4 alkylene group is optionally substituted by one or more substituents selected from the group consisting of: halogen, NRaRb, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 haloalkyl, and C1-C4 haloalkoxy. L is NH; or L does not exist, and X6 is directly connected to CO. L4 is absent, C3-C10 carbon ring, C1-C4 alkylene; the above group may be optionally substituted by one or more substituents selected from the group consisting of: NRaRb, =O, C1-C4 alkyl, cyano, halogen, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy. R2 is NRaRb, cyano, 5-8 membered heterocyclic, C1-C4 alkyl, C3-C6 cycloalkyl, -CONH2, C6-C10 aryl or 5-8 membered heteroaryl; the above groups may be optionally substituted by one or more substituents selected from the group consisting of: C1-C4 alkyl, halogen, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy; L1 is a C1-C4 alkylene group or is absent; L2 can be O, S, CH, NH, -NHCO, -NHSO2-, or does not exist. L3 is a C1-C4 alkylene group and does not exist; R3 can be C6-C10 aryl, NH2, cyano, C3-C12 cycloalkyl, C1-C4 alkyl, 5-8 membered heterocyclic, or 5-12 membered heteroaryl. L1, L2, L3, and R3 are each independently and optionally substituted by one or more substituents selected from the group consisting of: cyano, C1-C4 haloalkoxy, halogen, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkyl, C3-C6 cycloalkyl, and NRaRb. Each Ra and each Rb is independently selected from: H, C1-C4 alkyl, C1-C4 deuterated alkyl, -C(=NH)NH2, -C(=NH)NH(C1-C4 alkyl); The conditions are that n is 1, m is 1, L4 is a C1-C4 alkylene, L2 is O, R1 is a C1-C4 alkyl, R2 is NRaRb, and R3 is not a C6-C10 aryl.

2. The compound according to claim 1, characterized in that, X1, X2, X3, and X4 are CR4; Each R4 is independently selected from: H, halogens, and C1-C4 alkyl groups; Each R1 is independently a C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, 5-7 membered heterocyclic or 5-7 membered heteroaryl; the above groups are optionally substituted by one or more substituents selected from the group consisting of: C1-C4 alkyl, C1-C4 haloalkyl, halogen; Alternatively, R1, X4, and intercalary atoms can form 5-10 membered heterocycles.

3. The compound according to claim 1, characterized in that, R5, R6, R7, R8, R9, R 10 R 11 R 12 Each is independently selected from H, C1-C4 alkyl; or R5, R 11 They connect to form C1-C3 alkylene groups.

4. The compound according to claim 1, characterized in that, L1 is a C1-C2 alkylene group or is absent; L2 can be O, CH, NH, -NHCO-, -NHSO2-, or does not exist; L3 is a C1-C3 alkylene group and does not exist; R3 is phenyl, NH2, C3-C12 cycloalkyl, C1-C4 alkyl, 5-7 membered heterocyclic group, or 6-10 membered heteroaryl group; L1, L2, L3, and R3 are each independently and optionally substituted by one or more substituents selected from the group consisting of: cyano, C1-C4 haloalkoxy, halogen, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkyl, C3-C6 cycloalkyl, and NRaRb. Each Ra and each Rb is independently selected from: H, C1-C4 alkyl, -C(=NH)NH2, -C(=NH)NH(C1-C4 alkyl).

5. The compound according to claim 1, characterized in that, The compound has the structure shown in Formula II: X2 is a CH or C-halogen; The definitions of *, R1, R2, R3, R4, L, L1, L2, L3, L4, and X6 are the same as before.

6. The compound according to claim 5, characterized in that, The compound has the structure shown in formula IIa or IIb: R1, R2, R3, R4, L1, L2, L3, L4, and X2 are defined as before.

7. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of:

8. A pharmaceutical composition, characterized in that, Include: The compound of general formula (I) as described in claim 1, including its racemic, stereoisomer, tautomer, isotope label, nitride, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof. And pharmaceutically acceptable carriers.

9. Use of the compound of formula (I) as claimed in claim 1 or the pharmaceutical composition as claimed in claim 8, characterized in that, Used for the preparation of growth hormone secretagogue receptor (GHSR) agonists; or for the preparation of drugs for the prevention and / or treatment of growth hormone-dependent diseases.

10. The use as described in claim 9, characterized in that, The growth hormone-dependent disease is growth hormone deficiency.

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