Novel compounds with GLP-1 receptor agonist activity

Abstract

Provided are compounds defined by chemical formulae 1A and 1B, or stereoisomers, tautomers, and pharmaceutically acceptable salts thereof. The compounds according to the present invention have GLP-1 receptor agonist activity. In chemical formulae 1A and 1B, R1 to R3, X1, Z1 to Z3, n, ring A, ring B, k, and m are as described in the present specification.

Description

Novel compound with GLP-1 receptor agonist activity

[0001] The present invention relates to small organic compounds. More specifically, the present invention relates to small organic compounds having a glucagon-like peptide-1 receptor activating effect.

[0002] Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by enterocrine L-cells that binds to the GLP-1 receptor, stimulating beta cells to secrete insulin in a glucose-concentration-dependent manner, inhibiting glucagon secretion, delaying the emptying of digested food from the stomach, and inhibiting appetite. Derivatives of GLP-1 that function as GLP-1 receptor agonists have already been commercialized as drugs for treating diabetes, and their weight-loss effects are also known.

[0003] However, since most of these GLP-1 receptor agonists are peptides or peptide derivatives that require injection for administration, they cause patient discomfort and pain and reduce compliance with treatment. In this field, the demand for GLP-1 receptor agonists in the form of small organic molecules that can be administered orally has not yet been sufficiently met.

[0004] The technical problem of the present invention is to provide a small organic molecule GLP-1 receptor agonist capable of activating the GLP-1 receptor like a GLP-1 peptide.

[0005] In order to solve the aforementioned technical problem, one aspect of the present invention provides a GLP-1 receptor agonist comprising a compound defined by Formula 1, its tautomer, its stereoisomer, and pharmaceutically acceptable salts thereof.

[0006] [Chemical Formula 1A]

[0007]

[0008] [Chemical Formula 1B]

[0009]

[0010] In chemical formulas 1A and 1B, m is an integer from 0 to 8;

[0011] Each R 1 C independently of each other 1~4 It is a substituent selected from the group consisting of alkyl, halogen, CN, NO2, and CF3, wherein when m is 2 or more, each R 1 Select m turns independently of each other;

[0012] R 2 is hydrogen, C 1~4 Alkyl and halo-C 1~4 It is a substituent selected from the group consisting of alkyls;

[0013] k is an integer from 0 to 5, and

[0014] R 3 Silver halogens, CN, CF3, OCF3, OH, NO2, NR A R B , C 1~4 Alkyl, C 3~8 Cycloalkyl, 5-9 member heterocycloalkyl, C 6~10 Aril, Halo C 1~4 Alkyl, hydroxy C 1~4 Alkyl and C 1~4 It is a substituent selected from the group consisting of alkyloxy groups, wherein when k is 2 or more, each R 3 Select k times independently, and R A and R B Each independently of hydrogen or C 1~3 It is alkyl;

[0015] Z 1 and Z 2 Among them, one is N and the other is C;

[0016] n is an integer from 0 to 3, and

[0017] Z 3 C 1~3 Alkyl, Halo C1~3 Alkyl, C(=O)C 1~3 Alkyl, halogen, OH, NH2, NH(C 1~3 alkyl) and (C 1~3 Alkyl)N(C 1~3 It is a substituent selected from the group consisting of alkyl groups, wherein when n is 2 or more, each Z 3 Select n times independently of each other.

[0018] X in chemical formulas 1A and 1B 1 is NH, NR 4 , NC(=O)-R 5 , O, S or C(=O), and in this case R 4 is C 1~4 Alkyl, (CH2) i C 3~6 Cycloalkyl, (CH2) i CH=CH2, (CH2) i CH=CH-(C 1~3 alkyl), (CH2) i C≡CH,(CH2) i C≡C(C 1~3 alkyl), (CH2) i 5~9-membered heterocycloalkyl, (CH2) i C 6~10 Aril, (CH2) i C 5~10 Heteroaryl or NR C R D and, where i is an integer from 0 to 3, and R C and R D Each independently of hydrogen or C 1~3 It is an alkyl, where R 5 is C 1~3 Alkyl, (CH2) j C 3~6 Cycloalkyl, (CH2) j CH=CH2, (CH2) j CH=CH-(C 1~3 alkyl), (CH2) j C≡CH, (CH2) j C≡C(C 1~3 alkyl), (CH2) j5~9-membered heterocycloalkyl, (CH2) j C 6~10 Aril, (CH2) j C 5~10 Heteroaryl or NR E R F and, where j is an integer from 0 to 3, and R E and R F Each independently of hydrogen or C 1~3 It is alkyl;

[0019] Is It is a substituted or unsubstituted 5- to 6-membered saturated or unsaturated hydrocarbon ring forming a triple fusion ring together with, or a substituted or unsubstituted 5- to 6-membered saturated or unsaturated heterocyclic ring comprising 1 to 3 cyclic heteroatoms, wherein the substituted 5- to 6-membered saturated or unsaturated hydrocarbon ring or the substituted 5- to 6-membered saturated or unsaturated heterocyclic ring has one or more hydrogens C 1~3 Alkyl, Halo C 1~3 Alkyl, C(=O)C 1~3 Alkyl, halogen, OH, NH2, NH(C 1~3 alkyl) and (C 1~3 Alkyl)N(C 1~3 It is a ring substituted with a substituent selected independently from each other in each case from the group consisting of alkyls, and

[0020] is a 5-6-membered fused bicyclic heteroaryl or a 6-membered fused bicyclic heteroaryl;

[0021] At this time, each of the above 5-6-membered fused bicyclic heteroaryls or 6-6-membered fused bicyclic heteroaryls optionally has one or more hydrogens C 1~3 Alkyl, Halo C 1~3 Alkyl, C 1~3 It may be a ring substituted with a functional group selected independently from each other in each case from the group consisting of alkoxy and halogen.

[0022] In another aspect of the present invention, a pharmaceutical composition for the treatment or prevention of GLP-1 receptor activity-related diseases is provided, comprising a pharmaceutically acceptable excipient and containing the aforementioned compound, its tautomer, its stereoisomer, or its pharmaceutically acceptable salt in a therapeutically effective amount.

[0023] In yet another aspect of the present invention, a method for treating a disease related to GLP-1 receptor activity is provided. The method comprises the step of administering a therapeutically effective amount of a compound of the present invention, such as a compound defined by Formula 1A or Formula 1B, or a pharmaceutical composition comprising such a compound of the present invention, to a subject requiring treatment for a disease related to GLP-1 receptor activity.

[0024] The compound according to the present invention, or a pharmaceutically acceptable salt thereof, can be usefully employed as a GLP-1 receptor agonist for the prevention or treatment of diseases related to GLP-1 receptor activity. In a preferred embodiment, the compound according to the present invention exhibits superior duration and absorption upon oral administration compared to small organic molecule GLP-1 receptor agonists of the prior art.

[0025] Figure 1 is a graph showing the average concentration of the compound in plasma and its standard deviation over time in mice (n=3) orally administered a positive control compound (danuglyfone and orpoglyfone) or the compound of the present invention.

[0026] Embodiments of the present invention will be described in detail below. Prior to this, terms and words used in this specification and claims should not be interpreted as being limited to their ordinary or dictionary meanings. Instead, based on the principle that the inventor can appropriately define the concepts of terms to best describe his invention, they should be interpreted in a meaning and concept consistent with the technical spirit of the present invention.

[0027] Therefore, the embodiments described in this specification are merely examples presented for the purpose of helping to understand the invention and do not represent all technical ideas of the invention; thus, it should be understood that various equivalents and modifications that can replace them may exist at the time of filing this application.

[0028] Unless otherwise defined, all technical terms used in this invention are used in the sense generally understood by a person skilled in the art related to this invention. While preferred methods or samples are described herein, similar or equivalents are also included within the scope of this invention. Numerical values ​​described herein are deemed to include the meaning of "approximately" unless explicitly stated otherwise. Numerical ranges indicated by the term "to" in this specification include ranges that include the values ​​described before and after the term "to" as lower and upper limits, respectively.

[0029] Definition of Terms

[0030] In this specification, the term "GLP-1 receptor" refers to a G protein-coupled receptor present on the surface of a cell that mediates intracellular signaling processes and has glucagon-like peptide-1 (GLP-1) as a ligand. Unless specifically defined herein, the term "GLP-1 receptor" may be derived from either humans or other mammals and encompasses all isoforms, precursor proteins, mutants, homologs, orthologs, derivatives, splice variants, alleles, protein processed forms, and active fragments in addition to the standard sequence of the receptor. For example, in this specification, the GLP-1 receptor may have the sequence of a human GLP-1 receptor, in particular, may have the amino acid sequence of primary accession number P43220 of the protein sequence database UniProt, and the precursor protein (in a form including a signal peptide) may be the sequence of U.S. NCBI standard sequence primary accession number NP_002053.3.

[0031] In this specification, the term "GLP-1 receptor agonist" refers to a substance having activity that binds to a GLP-1 receptor and stimulates signal transduction by the GLP-1 receptor—e.g., cAMP production or calcium ion release. Whether a substance is a GLP-1 receptor agonist can be determined by measuring the signal transduction activity of the GLP-1 receptor in various ways known in the art, for example, using a validated in vitro model of GLP-1 receptor signal transduction, and in particular, by evaluating the production of cAMP as described below in the embodiments of this specification. In this specification, having activity as a GLP-1 receptor agonist means that when the signal activity of the GLP-1 receptor is measured, the maximum value is in a numerical range of about 10% to about 200% (e.g., about 20%, 30%, 40%, 50%, 60%, 75%, 100%, 125%, 150%, or 175% of the natural signal activity) or greater than that of the natural signal activity value exhibited by the GLP-1 receptor when it binds to its natural ligand, GLP-1.

[0032] In this specification, the terms "selective agent" or "selective" mean that the agent has significantly greater activity toward a specific receptor(s) compared to other receptors, provided that this does not mean that the agent is completely inactive toward said other receptors.

[0033] In this specification, "GLP-1 receptor activity-related disease" refers to any disease, condition, or pathological state whose pathological state and / or symptoms and / or progression can be improved by regulating the signaling of GLP-1 receptors. Some examples of GLP-1 receptor activity-related diseases include diabetes and obesity.

[0034] In this specification, "subject requiring treatment" or "subject" refers to a person diagnosed by a physician with a certain disease, e.g., a GLP-1 receptor activity-related disease, or a mammal diagnosed by a veterinarian with a certain disease, e.g., a GLP-1 receptor activity-related disease. Furthermore, "subject requiring treatment" or "subject" includes a person or mammal who has suffered from such a disease but whose symptoms have improved, and a subject suspected of having or being suspected of having such a disease, such as a person or mammal exhibiting one or more symptoms related to the said disease.

[0035] In this specification, "treatment" refers to a measure or action that alleviates, to some extent, the symptoms, markers, and / or all adverse effects of a condition in a subject currently suffering from such condition. In order to reduce the risk of progression to the said disease, disorder, and / or condition, depending on the embodiment, such treatment may be performed on a subject exhibiting only early signs of the said condition.

[0036] In this specification, "prevention" refers to any method of wholly or partially delaying or preventing the manifestation of one or more symptoms or signs of a related disease, condition, and / or pathology. Prevention may be performed on subjects that do not exhibit signs of the disease, condition, and / or pathology.

[0037] The term "EC" as used in this specification 50 Or, half-effective concentration refers to the concentration of an agonist that produces 50% of the endpoint activity (e.g., cAMP activity) when an agonist activity test is performed in relation to a GLP-1 receptor agonist.

[0038] In this specification, the prefix "C x~y " or "C x ~C y"(Here, x and y are natural numbers) is placed before a functional group to indicate the number of carbon atoms that the group contains within its main framework. For example, C 1~4 The alkyl group has 1 to 4 carbon atoms, C 1~3 Each alkyl group indicates that it is an alkyl group having 1 to 3 carbon atoms. For example, C1 to C4 alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy, and tert-butoxy. For example, C3 to C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups. For example, C1 to 4 alkylenes include methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, and tert-butylene.

[0039] In addition, when the number of elements forming the ring is specified in the preceding cyclic functional group or compound (including both carbon rings and heterorings) in this specification, the ring is a ring composed of that number of elements, namely carbon and / or heteroatoms. For example, if a six-membered heteroaryl is used, it refers to a heteroaryl group in which the number of elements forming the ring is six, formed together with carbon and containing one or more heteroatoms.

[0040] Unless otherwise noted in this specification, when a functional group is connected to another part of a compound by a bond, it may be connected through any atom of the functional group if it is a suitable atom. For example, when referring to a propyl group, both prop-1-yl and prop-2-yl are included.

[0041] In this specification, the term "halogen" refers to an atom selected from fluorine, chlorine, bromine, and iodine when referred to in relation to a substituent of a chemical structural formula.

[0042] In this specification, "C 1~6 The term "alkyl" refers to the chemical formula C when n is a natural number from 1 to 6. n H2n+1 It refers to a monovalent saturated hydrocarbon atomic group. C 1~6 Alkyl groups include all leading or branched saturated hydrocarbons with 1 to 6 carbon atoms, such as n-propyl, i-propyl, 2-methyl-ethyl, 2-sec-butyl, 3-tert-butyl, etc.

[0043] In this specification, "C m~n The term "alkylene" refers to a chemical formula C when the number of carbon atoms is a natural number from m to n. m H 2m from C n H 2n It refers to a group of divalent saturated hydrocarbon atoms.

[0044] In this specification, the term “cycloalkyl” refers to a monovalent atomic group that is a saturated hydrocarbon forming a single or polycyclic ring. In the case of a single ring, cycloalkyl has the chemical formula C n H 2n-1 It is a monovalent atomic group. Single ring C 3~6 Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. An example of a dicyclic cycloalkyl is bicyclo[3.1.0]hexanyl.

[0045] In this specification, the term "bicyclic" compound refers to a carbon ring compound or heterocyclic compound comprising two rings, wherein one or more ring atoms are shared between the two constituent rings. In a bicyclic compound, the atom shared between the two rings is called a bridgehead atom. There are three types of bicyclic compounds based on the number of bridgehead atoms and whether they are directly connected. Fused bicyclic compounds have two bridgehead atoms that are directly connected by bonds. Examples of fused bicyclic compounds include decalin, naphthalene, anthracene, phenanthrene, indole, benzofuran, purine, and quinoline. A ring compound with only one bridgehead atom is a spirocyclic compound. Bridged ring compounds have two bridgehead carbon atoms, where these two bridgehead carbons are not immediately adjacent but one or more ring atoms are interposed between them. Examples of cross-linked ring compounds include norbornan, 7-oxabicyclo[2.2.1]heptane, and adamantane.

[0046] In this specification, fused bicyclic compounds may be indicated by specifying the number of constituent ring atoms in each of the two rings forming the compound. For example, thienopyridine, benzofuran, indole, etc., may be described as pentagonal-hexagonal fused bicyclic compounds. Likewise, naphthalene, chroman, tetrahydroquinoline, quinoline, quinoxaline, pteridine, etc., may be described as hexagonal-hexagonal fused bicyclic compounds.

[0047] In this specification, the term "aryl" refers to aromatic C6-C6 14 It refers to a monovalent hydrocarbon functional group that can have one to three aromatic rings as a functional group. For example, in aryls, C6, C 10 , C 13 and C 14Aromatic hydrocarbon ring groups are included, such as phenyl, naphthyl, anthracenyl, and fluorenyl.

[0048] In this specification, the term "heteroaryl" refers to an unsaturated ring comprising a carbon atom and one or more heteroatoms selected from nitrogen, oxygen, and sulfur, which is a monovalent aromatic ring. The ring system of a heteroaryl may be a single ring, or a double or triple ring in the form of a fused ring. Rings that include a direct link between oxygen and sulfur atoms, such as -OO-, -OS-, or -SS- among the ring constituent atoms, are excluded from the term heteroaryl. Some examples of heteroaryls include pyrroleyl, imidazoleyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, triazoleyl, quinazolinyl, 2-furyl, 3-furyl, benzofuryl, 2-thienyl, oxazoleyl, isothiazolyl, thiadiazoleyl, etc. Heteroaryls can also be limited by specifying the heteroatom. For example, if a heteroaryl is defined as having nitrogen as the heteroatom, it includes pyrroleyl, imidazoleyl, pyrazolyl, 2-pyridyl, etc., but excludes furyl, thienyl, etc.

[0049] The fused bicyclic heteroaryl groups include hexa-membered-pentagnostic bicyclic heteroaryl groups such as benzimidazoleyl, benzofuranyl, benzothiophenyl, isoindoleyl, indazoleyl, imidazopyridineyl, imidazopyrimidineyl, imidazopyridazineyl, indazoleyl, pyrazolopyridineyl, pyrrolopyrimidineyl, pyrrolopyrazineyl, triazolopyridineyl, triazolopyrimidineyl, purineyl, benzothiazoleyl, benzisothiazoleyl, benzothiadiaazoleyl, benzoxazoleyl, and benzothiadiaazoleyl, and as hexa-membered-hexa-membered bicyclic heteroaryl compounds, benzopyridineyl, benzopyrimidineyl, quinolineyl, isoquinolineyl, phthalazineyl, and quinazolinyl. There are quinoxalinyl, naftiridineyl, quinolininyl, cinnolinyl, etc.

[0050] In this specification, when a ring is referred to as "aromatic," it indicates that the ring possesses a delocalized π-electron system that is continuous and situated nearly in a plane. Typically, such an aromatic ring has a π-electron count of 4n+2, according to the Hückel model. It satisfies the law. Some examples of such aromatic rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, oxazole, thiazole, etc. When indicating an aromatic ring in this specification, the double and single bond connections between the ring constituent atoms may be briefly indicated by drawing a circle inside the ring. For example The ring represented as shown is Z 1 and Z 3 The definition of is C or N, and Z 2 When the definition is N or NH, it can be understood that it includes aromatic five-membered ring structures represented by the following structural formula:

[0051]

[0052] In this specification, the term "heterocycloalkyl" refers to a monovalent atomic group in which at least one of the ring-forming carbon atoms in the aforementioned cycloalkyl is independently substituted in each case with a heteroatom selected from nitrogen, oxygen, and sulfur. Examples of heterocycloalkyl include pyrrolidine, imidazolidine, piperidine, pyrroline, piperazine, morpholine, thiazolidine, etc. Heterocycloalkyl is not limited to a single ring as long as permitted by the number of ring atoms constituting the ring, and includes polycyclic rings such as double or triple rings. For example, when referring to 5- to 9-membered heterocycloalkyl, 3-azabicyclo[3.1.0]hexanyl is also included.

[0053] In this specification, the term "heterocyclyl" refers to a monovalent carbon ring group comprising at least one heteroatom as a ring atom, and such heterocyclyl includes not only heterocycloalkyl, which is a saturated functional group, but also unsaturated functional groups excluding heteroaryls, such as pyranyl, dihydropyranyl, and tetrahydropyridinyl.

[0054] In this specification, the terms "substituted" or "substituted" preceding any functional group refer to a structure in which one or more of the hydrogens of the functional group are replaced with functional groups other than the specified hydrogens, provided that the substituted functional group maintains normal valence and yields a chemically stable functional group. In typical cases, the substituents are halogens, CN, OH, and C 1~6 Alkyl, C 3~6 Cycloalkyl, C 3~14 Heteroaryl, C 1~6 Select from alkyloxy and CF3.

[0055] In this specification, to a specific atom of a substituent forming part of a compound, " " The presence of a mark indicates that the corresponding substituent is directly connected to the rest of the compound by chemical bonding through that atom.

[0056] "---" or " When a dotted line is present as in ", it indicates that it is an optional element where a covalent bond may or may not exist between the two adjacent ring atoms. For example Notations like this represent X in this structural formula 3It indicates that the six-membered subring containing the ring atom is a completely unsaturated ring composed solely of double bonds, or that all ring bonds except for the side fused with the five-membered ring may be saturated bonds, and that one of them may be a double bond. However, "---" or " The maximum possible number of covalent bonds between two adjacent ring atoms, implied or contained per dotted line mark such as ", does not necessarily have to be one, and if otherwise specified in this specification for the relevant chemical structural formula, it follows the number specified therein, e.g., the number designated as no bond, single bond, or double bond.

[0057] In this specification, the term “active ingredient” refers to an active medicine having a therapeutic effect for curing, alleviating, treating, or preventing a disease, symptom, or condition (e.g., diabetes, obesity, etc.) suffered by a subject or patient. Preferably, the subject is a mammal, most preferably a human.

[0058] In this specification, the term “pharmaceuticalally acceptable salt” for any compound refers to a type of salt that does not cause toxicity, irritation, or allergic reactions, etc., unsuitable for contact with human or animal tissues without impairing the desirable biological activity of the compound. Pharmaceutically acceptable salts are well known in the art. For example, reference may be made to prior art such as the article published by Berge et al. (1977), *Pharmaceutical Sciences*, Vol. 66, pp. 1–19. To give just a few examples of pharmaceutically acceptable salts, acid addition salts include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, adipose, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, hydrosulfide, etc., and base addition salts include alkali metal salts, alkaline earth metal salts, ammonium salts, and quaternary ammonium (N+ (C 1~4 There are alkyls, and examples of alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc.

[0059] A person skilled in this field will be aware that some of the compounds of the present invention may exist in one or more tautomeric forms. Since a single chemical structural formula can only represent one tautomeric form, it will be well understood that when a compound is referred to by a single structural formula for convenience, that formula encompasses even the tautomeric variations of the compound. Depending on the compound, it may primarily exist in one of several tautomeric forms, exist as a mixture of multiple tautomerics at room temperature, or be able to isolate only a single tautomeric form. Examples of tautomeric forms include the pyridone form and the hydroxypyridine form, and the keto form and the enol form.

[0060] compound

[0061] In one aspect of the present invention, a compound defined by Formula 1A or Formula 1B, its tautomers, its stereoisomers, and pharmaceutically acceptable salts thereof are provided.

[0062] [Chemical Formula 1A]

[0063]

[0064] [Chemical Formula 1B]

[0065]

[0066] In chemical formulas 1A and 1B, m is an integer from 0 to 8;

[0067] Each R 1 C independently of each other 1~4 It is a substituent selected from the group consisting of alkyl, halogen, CN, NO2, and CF3, wherein when m is 2 or more, each R 1Select m turns independently of each other;

[0068] R 2 is hydrogen, C 1~4 Alkyl and halo-C 1~4 It is a substituent selected from the group consisting of alkyls;

[0069] k is an integer from 0 to 5, and

[0070] R 3 Silver halogens, CN, CF3, OCF3, OH, NO2, NR A R B , C 1~4 Alkyl, C 3~8 Cycloalkyl, 5-9 member heterocycloalkyl, C 6~10 Aril, Halo C 1~4 Alkyl, hydroxy C 1~4 Alkyl and C 1~4 It is a substituent selected from the group consisting of alkyloxy groups, wherein when k is 2 or more, each R 3 Select k times independently, and R A and R B Each independently of hydrogen or C 1~3 It is alkyl;

[0071] Z 1 and Z 2 Among them, one is N and the other is C;

[0072] n is an integer from 0 to 3.

[0073] Z 3 C 1~3 Alkyl, Halo C 1~3 Alkyl, C(=O)C 1~3 Alkyl, halogen, OH, NH2, NH(C 1~3 alkyl) and (C 1~3 Alkyl)N(C 1~3 It is a substituent selected from the group consisting of alkyl groups, wherein when n is 2 or more, each Z 3 Select n times independently of each other.

[0074] X in chemical formulas 1A and 1B 1 is NH, NR4 , NC(=O)-R 5 , O, S or C(=O), and in this case R 4 is C 1~4 Alkyl, (CH2) i C 3~6 Cycloalkyl, (CH2) i CH=CH2, (CH2) i CH=CH-(C 1~3 alkyl), (CH2) i C≡CH, (CH2) i C≡C 1~3 Alkyl, (CH2) i 5~9-membered heterocycloalkyl, (CH2) i C 6~10 Aril, (CH2) i C 5~10 Heteroaryl or NR C R D and, where i is an integer from 0 to 3, and R C and R D Each independently of hydrogen or C 1~3 It is an alkyl, where R 5 is C 1~3 Alkyl, (CH2) j C 3~6 Cycloalkyl, (CH2) j CH=CH2, (CH2) j CH=CH-(C 1~3 alkyl), (CH2) j C≡CH, (CH2) i C≡C(C 1~3 alkyl), (CH2) j 5~9-membered heterocycloalkyl, (CH2) j C 6~10 Aril, (CH2) j C 5~10 Heteroaryl or NR E R F and, where j is an integer from 0 to 3, and R E and R F Each independently of hydrogen or C 1~3 It is alkyl;

[0075] Is It is a substituted or unsubstituted 5- to 6-membered saturated or unsaturated hydrocarbon ring forming a triple fusion ring together with, or a substituted or unsubstituted 5- to 6-membered saturated or unsaturated heterocyclic ring comprising 1 to 3 cyclic heteroatoms, wherein the substituted 5- to 6-membered saturated or unsaturated hydrocarbon ring or the substituted 5- to 6-membered saturated or unsaturated heterocyclic ring has one or more hydrogens C 1~3 Alkyl, Halo C 1~3 Alkyl, C(=O)C 1~3 Alkyl, halogen, OH, NH2, NH(C 1~3 alkyl) and (C 1~3 Alkyl)N(C 1~3 It is a ring substituted with a substituent selected independently from each other in each case from the group consisting of alkyls, and

[0076] is a 5-6-membered fused bicyclic heteroaryl or a 6-membered fused bicyclic heteroaryl;

[0077] At this time, each of the above 5-6-membered fused bicyclic heteroaryls or 6-6-membered fused bicyclic heteroaryls optionally has one or more hydrogens C 1~3 Alkyl, Halo C 1~3 Alkyl, C 1~3 It may be a ring substituted with a functional group selected independently from each other in each case from the group consisting of alkoxy and halogen.

[0078] The compound of Formula 1A or Formula 1B according to the present invention has the activity of a GLP-1 receptor agonist.

[0079] In one specific embodiment, the compound of the present invention is Select from the group consisting of indole, benzimidazole, benzofuranyl, benzothiophen, pyrrolopyridine, pyrazolopyridine, pyrrolopyrimidine, oxazolopyridine, thiazolopyridine, thienopyridine, furopyridine, imidazopyridine, imidazopyrimidine, purine, and indolezine.

[0080] In one embodiment, the compound of the present invention described above is further a compound that satisfies the structure of Formula 2A or Formula 2B.

[0081] [Chemical Formula 2A]

[0082]

[0083] [Chemical Formula 2B]

[0084]

[0085] Q in Chemical Formulas 2A and 2B 1 to Q 7 silver

[0086] a) Q 2 ga is O, S or NH, and Q 1 , Q 3 and Q 4 While being C, Q 5 , Q 6 and Q 7 Each independently selects between CH and N, or

[0087] b) Q 1 , Q 3 and Q 4 One of them is N, and the rest are all C, and Q 2 , Q 5 , Q 6 and Q 7 Each is independently selected from CH and N.

[0088] In the above chemical formulas 2A and 2B, R 1 to R 3 , X 1 , Z 1 To Z 3 class The functional groups and coefficients k, n, and m are as previously defined in the compounds of Chemical Formula 1A and Chemical Formula 1B.

[0089] In one specific embodiment, the compound of formula 2A or formula 2B has m as an integer from 1 to 2 and k as an integer from 2 to 3.

[0090] In another embodiment of the compound of the present invention, the compound of Formula 2A of the present invention further takes the structure of Formula 3.

[0091] [Chemical Formula 3]

[0092]

[0093] X in Chemical Formula 3 2 is NH, NC 1~4 Alkyl, NC 3~6 Cycloalkyl, NCH2-C 3~6 Cycloalkyl, NC 6~10 Aryl, NCH2-C 6~10 Aril, NCH2CH=CH2, NC(=O)-R 6 It is any one selected from the group consisting of , O, S and C(=O), and in this case, R 6 C 1~3 Alkyl, (CH2) o C 3~6 Cycloalkyl, CH=CH2, CH=CH-(C 1~3 Alkyl), C≡CH, C≡C(C 1~3 alkyl), (CH2) o (3~6-membered heterocycloalkyl), (CH2) o C 6~10 Aryl or NHC 1~3 It is an alkyl, where o is an integer from 0 to 3.

[0094] X in Chemical Formula 3 3 is a functional group selected from the group consisting of CH, CH2 and N.

[0095] In chemical formula 3, p is an integer from 0 to 3.

[0096] Z in Chemical Formula 3 4 is C 1~3 Alkyl, Halo C 1~3 Alkyl, C(=O)C 1~3 Alkyl, halogen, OH, NH2, NH(C 1~3 alkyl) and (C 1~3 Alkyl)N(C 1~3 A substituent selected from the group consisting of alkyl groups, wherein when p is 2 or more, each Z4 Select p times independently of each other.

[0097] In the above chemical formula 3, R 1 to R 3 , Z 3 , Q 1 to Q 7 The substituents and coefficients m, n, and k are as previously defined for the compounds of Formula 2A and Formula 2B. In another embodiment of the compound of the present invention, the compound of Formula 3 of the present invention further takes the structure of Formula 3A.

[0098] [Chemical Formula 3A]

[0099]

[0100] In the above chemical formula 3A, R 1 to R 3 , X 2 , X 3 , Z 3 , Q 1 to Q 7 The substituents and coefficients m, n, and k are as previously defined in the compounds of Chemical Formula 3, Chemical Formula 2A, and Chemical Formula 2B.

[0101] In another embodiment of the compound of the present invention, the compound of Formula 3 of the present invention further takes the structure of Formula 4.

[0102] [Chemical Formula 4]

[0103]

[0104] R in Chemical Formula 4 6 and R 7 Silver is hydrogen, C 1~4 Alkyl, Halo C 1~4 It is a substituent selected independently from the group consisting of alkyl and halogens.

[0105] In the above chemical formula 4, R 2 to R 3 , X 2 , X 3 , Z 1 To Z 3 , Q 1, Q 2 , Q 5 to Q 7 The substituents and coefficients n and k are as previously defined in the compound of Chemical Formula 3.

[0106] In one specific embodiment of the compound of the present invention, the compound of the present invention takes the structure of Formula 5A or Formula 5B.

[0107] [Chemical Formula 5A]

[0108]

[0109] [Chemical Formula 5B]

[0110]

[0111] R in Chemical Formulas 5A and 5B 6 and R 7 Silver is hydrogen, C 1~4 Alkyl, Halo C 1~4 It is a substituent selected independently from the group consisting of alkyl and halogens.

[0112] R 8 is a substituent selected r times independently from the group consisting of methyl and halogens; where r is an integer from 0 to 3.

[0113] R 9 is hydrogen, methyl, isopropyl, and,

[0114] X 4 is CH or N.

[0115] R in Chemical Formulas 5A and 5B 2 is R defined earlier in Chemical Formulas 1A and 1B. 2 It is the same as.

[0116] In a more specific embodiment, the compound of Formula 5A or Formula 5B is X 4 When is N, R 9 It is hydrogen or methyl.

[0117] In the most specific embodiment, the compound of the present invention is the following compound, its stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt:

[0118] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0119] 3-((1S,2S)-1-(2-((S)-3-(3-(9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0120] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(9-ethyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0121] 3-((1S,2S)-1-(2-((S)-3-(3-(9-cyclopropyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0122] 3-((1S,2S)-1-(2-((S)-3-(3-(9-acetyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0123] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(9-isopropyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0124] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(5-methyl-5H-pyrido[4,3-b]indole-8-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0125] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-methyl-1,2,3,4-tetrahydrocyclopenta[b]indole-7-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0126] 3-((1S,2S)-1-(2-((S)-3-(3-(dibenzo[b,d]furan-2-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0127] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-2,3,4,9-tetrahydro-1H-carbazole-6-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0128] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-2-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0129] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(9-oxo-9H-fluorene-3-yl)-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0130] 3-((1S,2S)-1-(2-((S)-2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0131] 3-((1S,2S)-1-(2-((S)-3-(3-(6,9-dimethyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0132] 3-((1S,2S)-1-(2-((S)-2-(4-cyclopropyl-3-fluorophenyl)-3-(3-(9-isopropyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0133] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(4-hydroxy-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0134] 3-((1S,2S)-1-(2-((S)-3-(3-(5-chloro-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0135] 3-((1S,2S)-1-(2-((S)-3-(3-(6-acetyl-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0136] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0137] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(5-isopropyl-5H-pyrido[4,3-b]indole-8-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0138] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0139] 3-(1-(2-((S)-2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolezine-3-yl)cyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0140] 3-(1-(2-((S)-2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolezine-3-yl)cyclopropyl)-1,2,4-oxadiazole-5(4H)-one,

[0141] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-4-(methylamino)-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one and

[0142] 3-(1-(6-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)thieno[3,2-b]pyridine-3-yl)cyclopropyl)-1,2,4-oxadiazole-5(4H)-one.

[0143]

[0144] The compound of the present invention has agonist activity against GLP-1 receptors.

[0145] The compound represented by Formula 1 of the present invention comprises not only its pharmaceutically acceptable salts but also all possible solvates and hydrates that can be prepared therefrom, and also all possible stereoisomers. The solvates, hydrates, and stereoisomers of the compound represented by Formula 1 can be prepared from the compound represented by Formula 1 using conventional methods.

[0146] In addition, the compound represented by Formula 1 according to the present invention may be prepared in a crystalline or amorphous form, and if the compound represented by Formula 1 is prepared in a crystalline form, it may be optionally hydrated or solvated. The present invention may include not only the stoichiometric hydrate of the compound represented by Formula 1 but also compounds containing varying amounts of water. The solvates of the compound represented by Formula 1 according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.

[0147] Synthesis of the compound of the present invention

[0148] Compounds of the present invention, including Formula 1, can be synthesized by synthetic routes comprising methods well known in the field of chemistry and similar methods, particularly with reference to the descriptions provided herein. Starting materials are generally available from commercial sources, such as Aldrich Chemicals (Milwaukee, Wisconsin), or can be readily prepared using methods well known to those skilled in the art (e.g., can be prepared by methods generally described in the literature [Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, 1st to 19th editions, Wiley, NY (1967–1999)] or Beilsteins Handbuch der organischen Chemie, 4, Aufl (Springer-Verlag, Berlin, Germany)).

[0149] Pharmaceutical composition

[0150] In another aspect of the present invention, a pharmaceutical composition is disclosed that contains a therapeutically effective amount of the compound of the present invention or its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof, and further contains a pharmaceutically acceptable excipient. A pharmaceutical composition for the prevention or treatment of GLP-1 receptor activity-related diseases comprising a compound according to the present invention or its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient may be used to stimulate the activity of GLP-1 receptors in the body, for example, for the prevention or treatment of diabetes or obesity.

[0151] In yet another aspect of the present invention, a pharmaceutical composition for the treatment or prevention of type 2 diabetes, hyperglycemia, impaired glucose tolerance, type 1 diabetes, diabetic complications, obesity, hypertension, dyslipidemia, arteriosclerosis, myocardial infarction, coronary heart disease, cerebral infarction, or metabolic dysfunction-associated steatotic liver disease (MASLD) is provided, comprising as an active ingredient the compound of the present invention described above, or its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0152] In the pharmaceutical composition of the present invention, the aforementioned compound may exist as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include, for example, base addition salts and acid addition salts. Pharmaceutically acceptable base addition salts may be formed as addition salts of metals or amines, for example, alkali metal bases, alkaline earth metal bases, or organic amines. Pharmaceutically acceptable salts of the compound may also be prepared using pharmaceutically acceptable cations. Pharmaceutically acceptable acid addition salts include inorganic acid or organic acid salts.

[0153] In the present invention, a pharmaceutically acceptable excipient refers to an inactive ingredient approved by relevant administrative authorities (e.g., the Korea Food and Drug Administration, the U.S. Food and Drug Administration (FDA)) as suitable for use in combination with an active pharmaceutical ingredient for the manufacture of medicines for the treatment of diseases in humans or livestock. Such pharmaceutically acceptable excipients include, but are not limited to, carriers, lubricants, fluidizing agents, disintegrants, sweeteners, diluents, preservatives, coloring agents, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvent emulsifiers, and adjuvants.

[0154] The pharmaceutical composition of the present invention may be in a form suitable for oral administration, such as, for example, tablets, capsules, pills, powders, sustained-release formulations, solutions, and suspensions; in a form suitable for parenteral injection, such as sterile solutions, suspensions, or emulsions; in a form suitable for topical administration, such as ointments or creams; or in a form suitable for rectal administration, such as suppositories.

[0155] The pharmaceutical composition according to the present invention can be prepared in a conventional manner, for example by conventional mixing, dissolving, granulating, making a coated tablet, powdering, emulsifying, encapsulating, encapsulating, or freeze-drying processes. The appropriate formulation depends on the selected route of administration.

[0156] Pharmaceutical compositions suitable for oral administration can be easily formulated by combining the compounds disclosed herein with pharmaceutically acceptable excipients, such as carriers well known in the art. Using such excipients and carriers, the compounds disclosed herein can be formulated as tablets, pills, coated tablets, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral intake by patients to be treated. Oral pharmaceutical formulations can be obtained by adding the compounds of the present invention together with solid excipients, grinding the resulting mixture as needed, adding suitable adjuvants if necessary, and then processing the granulated mixture to form tablet or coated tablet cores. Suitable excipients include, for example, fillers and cellulose preparations. If necessary, disintegrants may be added.

[0157] In the case of a pharmaceutical composition for orally administering a therapeutically effective amount of the compound of the present specification, the composition is generally in the form of a solid (e.g., tablet, capsule, pill, powder, or troche) or a liquid formulation (e.g., aqueous suspension, solution, elixir, or syrup).

[0158] When administered in the form of tablets, the composition may additionally contain a functional solid and / or solid carrier, such as gelatin or an adjuvant. Compositions in the form of tablets, capsules, and powders may contain the compound of the present invention in an amount of about 1 to about 95 weight% based on the total weight of the composition, preferably in an amount of about 15 to about 90 weight%. Examples of tablet compositions include, for instance, about 80 weight% or less of an active pharmaceutical ingredient, about 10 weight% to about 90 weight% of a binder, about 0 weight% to about 85 weight% of a diluent, about 2 weight% to about 10 weight% of a disintegrant, and about 0.25 weight% to about 10 weight% of a lubricant.

[0159] When administered in liquid or suspension form, a functional liquid and / or liquid carrier, such as water, petroleum, or animal or vegetable oil, may be added. The composition in liquid form may further contain physiological saline, a sugar alcohol solution, dextrose or other sugar solutions, or glycol. When administered in liquid or suspension form, the composition may contain about 0.5 to about 90 weight percent of the compound of the present invention, preferably about 1 to about 50 percent of the compound of the present invention. In one embodiment considered, the liquid carrier is non-aqueous or substantially non-aqueous. For administration in liquid form, the composition may be supplied as a rapidly dissolving solid formulation for dissolution or suspension immediately before administration.

[0160] When the pharmaceutical composition of the present invention is administered by intravenous, deslicating, or subcutaneous injection, it is in the form of a parenteral aqueous solution that does not contain a pyrogen. The preparation of such parenteral solutions, taking into account pH, isotonicity, stability, etc., falls within the art of the art. Preferred compositions for intravenous, deslicating, or subcutaneous injection generally contain an isotonic vehicle. Such compositions may be prepared for administration as a solution of a free base or a pharmacologically acceptable salt in water, suitably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions in glycerol, liquid polyethylene glycol, and mixtures thereof, as well as dispersions in oil, may also be prepared. Under normal storage and use conditions, such formulations may optionally contain a preservative to prevent microbial growth.

[0161] The injectable composition may comprise a sterile aqueous solution, suspension, or dispersion, and a sterile powder for the immediate preparation of the sterile injectable solution, suspension, or dispersion. The sterile injectable solution is prepared by mixing the required amount of the active compound, along with the various other components as needed, in a suitable solvent, and then filtering and sterilizing. Generally, the dispersion is prepared by mixing various sterile active ingredients in a sterile vehicle containing a base dispersion medium and other necessary components among those listed above. In an embodiment of the sterile powder for the preparation of the sterile injectable solution, a preferred manufacturing method is vacuum drying and freeze-drying techniques to produce a powder of the active ingredient and any additional necessary components from a pre-sterile filtered solution.

[0162] Sustained-release or sustained-release formulations may be prepared to achieve controlled release of an active compound in contact with body fluids in the gastrointestinal tract, and to provide substantially constant and effective levels of the active compound in plasma. For example, release may be controlled by one or more of dissolution, diffusion, and ion exchange. Additionally, sustained-release approaches may enhance absorption through saturation or restriction pathways within the gastrointestinal tract. For example, for this purpose, the compound may be embedded in a polymer matrix consisting of a biodegradable polymer, a water-soluble polymer, or a mixture thereof, and optionally a suitable surfactant. In this context, embedding may mean the incorporation of microparticles into a polymer matrix. Controlled-release formulations may also be obtained by encapsulating dispersed microparticles or emulsified microdroplets through known dispersion or emulsion coating techniques.

[0163] The pharmaceutical composition of the present invention may be formulated for parenteral administration by injection (e.g., bolus injection or continuous infusion). The injectable formulation may be provided in a unit dosage form (e.g., ampoule or multi-dose container) with added preservatives. The composition may take the form of a suspension, solution, or emulsion in an oil or aqueous vehicle and may contain formulation agents such as suspenders, stabilizers, and / or dispersants.

[0164] The pharmaceutical composition may exist in a unit dosage form suitable for a single administration of an accurate dosage.

[0165] A pharmaceutical composition containing the compound of the present invention can be used according to the method described below.

[0166] Treatment methods

[0167] In another aspect, the present invention provides a method for treating a disease related to GLP-1 receptor activity. The method comprises the step of administering a therapeutically effective amount of a compound of the present invention, such as a compound of Formula 1A or Formula 1B, to a subject requiring treatment for a disease related to GLP-1 receptor activity. Alternatively, the present invention comprises the step of administering a pharmaceutical composition to a patient, comprising the aforementioned compound of the present invention and a pharmaceutically acceptable excipient, in a therapeutically effective amount.

[0168] Diseases related to GLP-1 receptor activity include type 2 diabetes, hyperglycemia, impaired glucose tolerance, type 1 diabetes, diabetic complications, obesity, hypertension, dyslipidemia, atherosclerosis, myocardial infarction, coronary heart disease, cerebral infarction, and metabolic disorder-associated fatty liver disease (MASLD).

[0169] In a method for treating diseases related to GLP-1 receptor activity, the compound of the present invention may be administered alone or in combination with at least one other drug. The compound of the present invention and this other drug may be administered simultaneously or sequentially.

[0170] In this specification, unless specifically stated otherwise, the term “therapeutic effective dose” of any compound refers to an amount of the compound sufficient to delay or minimize one or more symptoms associated with any disease, condition, or state, or an amount of the compound sufficient to provide a therapeutic effect against any disease, condition, or state. The term “therapeutic effective dose” encompasses an amount that improves overall treatment, an amount that alleviates or avoids the cause of symptoms or the disease or state, and even an amount that enhances the therapeutic efficacy of other therapeutic agents.

[0171] The amount of compound administered may vary depending on the subject being treated, the subject's age, health, gender, and weight, the type of concurrent treatment (if any), the severity of pain, the nature of the desired effect, the mode and frequency of treatment, and the prescribing physician's judgment. The frequency of administration may also vary depending on the pharmacodynamic effect on arterial oxygen pressure. However, the most desirable dosage may be tailored to the individual subject as understood and determined by a person skilled in the art without excessive experimentation. This generally involves adjustments to the standard dosage (e.g., a reduction in dosage if the patient's weight is low).

[0172] Although demand may vary depending on the individual case, determining the optimal range of the therapeutically effective dose of the compound is common sense in the art. When administered to humans for the curative or prophylactic treatment of conditions and disorders using the compound of the present invention, for example, the dosage of the compound of the present invention may be about 0.01 mg / kg / day to about 50 mg / kg / day. For example, it may be about 0.5 mg / day to about 500 mg / day. These doses may be administered as a single dose or divided into multiple doses.

[0173] In another aspect of the present invention, a use of a compound according to Formula 1A or Formula 1B is provided for use as a medicinal agent. The medicinal agent may be a medicinal agent for the treatment of diabetes. The medicinal agent may be a medicinal agent for the treatment of obesity. In one embodiment, a use of a compound according to Formula 1A or Formula 1B is provided for use in the treatment or prevention of diabetes or obesity.

[0174] In another aspect of the present invention, a use is provided for a composition containing a compound according to Formula 1A or Formula 1B and a pharmaceutically acceptable excipient for use as a medicament. The medicament may be a medicament for the treatment of diabetes mellitus. The medicament may be a medicament for the treatment of obesity. In one embodiment, a use is provided for using the composition for the treatment or prevention of diabetes mellitus or obesity.

[0175] In yet another aspect of the present invention, a use is provided for the manufacture of a pharmaceutical agent using a compound or composition according to Formula 1A or Formula 1B, such as a pharmaceutically acceptable composition containing a therapeutically effective amount of a compound according to Formula 1A or Formula 1B. The pharmaceutical agent may be a pharmaceutical agent for the treatment of diabetes or obesity. In one embodiment, a use is provided for the manufacture of a pharmaceutical agent for the treatment or prevention of diabetes or obesity using a compound or composition according to Formula 1A or Formula 1B.

[0176] Another aspect of the present invention provides a method for stimulating intracellular GLP-1 receptor activity. This method comprises the step of contacting a cell to which GLP-1 receptor activity is to be inhibited with an effective amount of the compound of the present invention described above—e.g., a compound defined by Formula 1.

[0177] The present invention will be explained in more detail below through the following examples and experimental examples. However, these examples and experimental examples are intended only to aid in understanding the present invention and do not limit the scope of the present invention in any way. Various changes and modifications may be made to these examples, and such changes and modifications are also included within the scope of the appended claims.

[0178] As described below, the compounds of Examples 1 to 25 shown in Table 1 were synthesized.

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185] [Example 1]

[0186]

[0187] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0188] Step 1] Preparation of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0189] 3-Bromo-9-methyl-9H-carbazole (200 mg, 0.77 mmol), tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (328.7 mg, 0.77 mmol), (1S,2S)-N 1 ,N 2 Dimethylcyclohexane-1,2-diamine (109.4 mg, 0.77 mmol), CuI (146.4 mg, 0.77 mmol), and N-methyl-2-pyrrolidone (10 mL) were dissolved in the solvent, and potassium carbonate (159.4 mg, 1.15 mmol) was added to the solution and stirred at 130°C for 16 hours. Ethyl ester and water were added to the reaction solution for extraction to separate the organic layer. The aqueous layer was extracted two more times with ethyl ester, and the collected organic layer was washed with water. The organic layer was dried with magnesium sulfate, and the residue obtained by vacuum distillation was purified by column chromatography to obtain the title compound (100 mg, yield 21%).

[0190] LCMS (ESI): m / z 621.3 [M+H] + .

[0191] Step 2] Preparation of (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(9-methyl-9H-carbazole-3-yl)-1,3-dihydro-2H-imidazole-2-one

[0192] After adding the tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (100 mg, 0.16 mmol) obtained in Step 1 to a dioxane (10 mL) solvent, hydrochloric acid / dioxane (5 mL, 4 mol / L) was added, the solution was stirred at room temperature for 3 hours, and the solvent was concentrated under reduced pressure to obtain the title compound (90 mg, yield 100%).

[0193] LCMS (ESI): m / z 521.2 [M+H] + .

[0194] Step 3] Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0195] 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (50 mg, 0.12 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (69.31 mg, 0.18 mmol) and N,N-diisopropylethylamine (78.53 mg, 0.61 mmol) were dissolved in dimethylformamide (2 mL) as a solvent, and the solution obtained in Step 2 was added to this solution. (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(9-methyl-9H-carbazole-3-yl)-1,3-dihydro-2H-imidazole-2-one (63.26 mg, 0.12 mmol) was slowly added at 0°C and stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was purified by column chromatography to obtain the title compound (11.6 mg, yield 11%).

[0196] LCMS (ESI): m / z 914.3 [M+H] +

[0197] 1 H-NMR (400 MHz, DMSO-d6) δ 12.42~11.60 (m, 1H), 8.43~8.00 (m, 2H), 7.77~7.36 (m, 6H), 7.35~7.11 (m, 5H), 7.02~6.65 (m, 2H), 5.85~5.15(m, 1H), 4.87~4.29(m, 1H), 3.89(d, 3H), 3.77~3.43(m, 3H), 3.26~2.75(m, 3H), 2.24(s, 6H), 1.82~1.40(m, 9H), 1.35~1.04(m, 10H)

[0198] [Example 2]

[0199]

[0200] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0201] Step 1] Preparation of tert-butyl (S)-3-(3-(9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0202] 3-bromo-9H-carbazole (492 mg, 2.0 mmol) and tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (854.6 mg, 2.0 mmol) were reacted as in Step 1 of Example 1 to obtain the title compound (500 mg, yield 41%).

[0203] LCMS (ESI): m / z 607.2 [M+H] +

[0204] Step 2] Preparation of (S)-1-(9H-carbazole-3-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one

[0205] The tert-butyl (S)-3-(3-(9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (100 mg, 0.16 mmol) obtained in Step 1 was reacted as in Step 2 of Example 1 to obtain the title compound (90 mg, yield 100%).

[0206] LCMS (ESI): m / z 507.3 [M+H] +

[0207] Step 3] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0208] The (S)-1-(9H-carbazole-3-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one (30 mg, 0.07 mmol) obtained in Step 2 was reacted as in Step 3 of Example 1 to obtain the title compound (12.6 mg, yield 19%).

[0209] LCMS (ESI): m / z 900.4 [M+H] +

[0210] 1H-NMR (400 MHz, DMSO-d6) δ 11.99 - 11.29 (m, 2H), 8.37 - 7.94 (m, 2H), 7.62 - 6.69 (m, 13H), 5.81 - 5.16 (m, 1H), 4.89 - 4.30 (m, 1H), 3.76 - 3.64 (m, 2H), 3.25 - 2.78 (m, 3H), 2.25 (s, 6H), 2.08 - 0.96 (m, 20H).

[0211] [Example 3]

[0212]

[0213] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(9-ethyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0214] Step 1] Preparation of tert-butyl (S)-3-(3-(9-ethyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0215] In N,N-dimethylformamide (10 mL) solvent, tert-butyl (S)-3-(3-(9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (100 mg, 0.16 mmol) obtained in Step 1 of Example 2 and potassium hydroxide (46.2 mg, 0.82 mmol) were added, the temperature of the solution was lowered to 0˚C, ethane iodide (38.6 mg, 0.25 mmol) was slowly added, and the mixture was stirred at room temperature for 16 hours. Once the reaction was complete, the mixture was extracted with an ethyl ester, washed with water, and the organic layer was separated. The organic layer was dried with magnesium sulfate and vacuum-quenched to obtain the residue, which was then purified by column chromatography to obtain the title compound (100 mg, yield 98%).

[0216] LCMS (ESI): m / z 635.3 [M+H] +

[0217] Step 2] Preparation of (S)-1-(9-ethyl-9H-carbazole-3-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one

[0218] The tert-butyl (S)-3-(3-(9-ethyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (100 mg, 0.16 mmol) obtained in Step 1 was reacted as in Step 2 of Example 1 to obtain the title compound (90 mg, yield 100%).

[0219] LCMS (ESI): m / z 535.3 [M+H] +

[0220] Step 3] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(9-ethyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0221] The (S)-1-(9-ethyl-9H-carbazole-3-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one (30 mg, 0.07 mmol) obtained in Step 2 was reacted as in Step 3 of Example 1 to obtain the title compound (13.2 mg, yield 19%).

[0222] LCMS (ESI): m / z 928.5 [M+H] +

[0223] 1H-NMR (400 MHz, CDCl3) δ 11.33 (d, J = 16.7 Hz, 1H), 8.22 - 7.95 (m, 2H), 7.68 - 7.33 (m, 6H), 7.31 - 7.27 (m, 1H), 7.26 - 7.07 (m, 3H), 6.83 - 6.62 (m, 2H), 6.21 (dd, J = 95.5, 3.1 Hz, 1H), 5.88 - 5.25 (m, 1H), 4.92 - 4.33 (m, 3H), 3.92 - 3.75 (m, 2H), 3.67 - 3.36 (m, 1H), 3.22 - 2.94 (m, 3H), 2.27 (dd, J = 16.8, 1.3 Hz, 6H), 2.05 - 1.87 (m, 1H), 1.85 - 1.72 (m, 3H), 1.71 - 1.52 (m, 7H), 1.48 - 1.40 (m, 3H), 1.35 (s, 2H), 1.29 (s, 2H), 1.27 - 1.03 (m, 4H).

[0224] [Example 4]

[0225]

[0226] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(9-cyclopropyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0227] Step 1] Preparation of tert-butyl (S)-3-(3-(9-cyclopropyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0228] Under an oxygen atmosphere, tert-butyl (S)-3-(3-(9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (100 mg, 0.16 mmol), cyclopropylboronic acid (28.3 mg, 0.33 mmol), copper(II) acetate (3.3 mg, 0.02 mmol), and 4-dimethylaminopyridine (60.4 mg, 0.49 mmol) obtained in Step 1 of Example 2 were added to toluene (3 mL) solvent under an oxygen atmosphere, and bis(trimethylsilyl)amide sodium (1 M, 0.16 mL) was added to this solution. After slowly adding at room temperature, the temperature of the solution was raised to 100°C and stirred for 16 hours. Once the reaction was complete, water was added to the solution to stop the reaction, and the solution was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography to obtain the title compound (70 mg, yield 68%).

[0229] LCMS (ESI): m / z 647.2 [M+H] +

[0230] Step 2] Preparation of (S)-1-(9-cyclopropyl-9H-carbazole-3-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one

[0231] The tert-butyl (S)-3-(3-(9-cyclopropyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (70 mg, 0.11 mmol) obtained in Step 1 was reacted as in Step 2 of Example 1 to obtain the title compound (60 mg, yield 100%).

[0232] LCMS (ESI): m / z 547.3 [M+H]+

[0233] Step 3] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(9-cyclopropyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0234] The (S)-1-(9-cyclopropyl-9H-carbazole-3-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one (30 mg, 0.07 mmol) obtained in Step 2 was reacted as in Step 3 of Example 1 to obtain the title compound (10.2 mg, yield 19%).

[0235] LCMS (ESI): m / z 940.5 [M+H] +

[0236] 1 H-NMR (400 MHz, CDCl3) δ 11.33 (d, J = 17.6 Hz, 1H), 8.22 - 7.90 (m, 2H), 7.79 - 7.35 (m, 6H), 7.13 (dd, J = 40.7, 5.9 Hz, 2H), 6.84 - 6.61 (m, 2H), 6.21 (dd, J = 94.8, 2.5 Hz, 1H), 5.87 - 5.21 (m, 1H), 4.91 - 4.40 (m, 1H), 3.85 (d, J = 15.3 Hz, 2H), 3.69 - 2.95 (m, 5H), 2.26 (d, J = 17.1 Hz, 6H), 2.01 - 1.86 (m, 1H), 1.85 - 1.44 (m, 11H), 1.35 (s, 2H), 1.32 - 1.02 (m, 11H).

[0237] [Example 5]

[0238]

[0239] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(9-acetyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0240] Step 1] Preparation of tert-butyl (S)-3-(3-(9-acetyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0241] After adding ether-butyl (S)-3-(3-(9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (200 mg, 0.33 mmol) to acetic anhydride (5 mL), the solution is stirred at 140°C for 6 hours. The solution is concentrated under reduced pressure, an ethyl ester and a saturated sodium bicarbonate aqueous solution are added to it, and after washing, the organic layer is separated. The aqueous layer was extracted twice with ethyl ester, the resulting organic layer was washed twice with water, the organic layer was dried with sodium sulfate, and the residue obtained by vacuum drying was purified by column chromatography to obtain the title compound (50 mg, yield 23%).

[0242] LCMS (ESI): m / z 649.3 [M+H] +

[0243] Step 2] Preparation of (S)-1-(9-acetyl-9H-carbazole-3-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one

[0244] The tert-butyl (S)-3-(3-(9-acetyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (50 mg, 0.08 mmol) obtained in Step 1 was reacted as in Step 2 of Example 1 to obtain the title compound (45 mg, yield 100%).

[0245] LCMS (ESI): m / z 549.3 [M+H] +

[0246] Step 3]3-((1S,2S)-1-(2-((S)-3-(3-(9-acetyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one Preparation

[0247] The (S)-1-(9-acetyl-9H-carbazole-3-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one (30 mg, 0.07 mmol) obtained in Step 2 was reacted as in Step 3 of Example 1 to obtain the title compound (13.2 mg, yield 19%).

[0248] LCMS (ESI): m / z 942.3 [M+H] +

[0249] 1 H-NMR (400 MHz, DMSO-d6) δ 8.48 - 8.12 (m, 4H), 7.94 - 7.68 (m, 1H), 7.62 - 7.34 (m, 5H), 7.22 - 6.54 (m, 5H), 5.71 - 5.20 (m, 1H), 4.84 - 4.37 (m, 1H), 3.75 - 3.59 (m, 3H), 3.09 - 2.98 (m, 1H), 2.89 (d, J = 12.2 Hz, 3H), 2.21 (d, J = 11.7 Hz, 6H), 2.06 - 1.49 (m, 8H), 1.42 (s, 2H), 1.25 (d, J = 17.5 Hz, 7H), 1.18 (s, 4H), 1.09 - 0.76 (m, 1H).

[0250] [Example 6]

[0251]

[0252] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(9-isopropyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0253] Step 1] Preparation of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(9-isopropyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0254] tert-butyl (S)-3-(3-(9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (100 mg, 0.16 mmol), 2-bromopropane (30.4 mg, 0.25 mmol), and potassium hydroxide (13.9 mg, 0.25 mmol) were added to acetone (5 mL) solvent, and after lowering the temperature of the solution to 0°C, tetrabutylammonium fluoride (4.3 mg, 0.02 mmol) was slowly added. The solution was stirred at 50°C for 16 hours, and when the reaction was complete, it was washed with ethyl ester and water. The organic layer was separated, the aqueous layer was extracted twice with ethyl ester and washed with water, then the organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the title compound (40 mg, yield 39%).

[0255] LCMS (ESI): m / z 649.2 [M+H] +

[0256] Step 2] Preparation of (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(9-isopropyl-9H-carbazole-3-yl)-1,3-dihydro-2H-imidazole-2-one

[0257] The tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(9-isopropyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (40 mg, 0.06 mmol) obtained in Step 1 was reacted as in Step 2 of Example 1 to obtain the title compound (33 mg, yield 100%).

[0258] LCMS (ESI): m / z 549.2 [M+H] +

[0259] Step 3] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(9-isopropyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0260] The (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(9-isopropyl-9H-carbazole-3-yl)-1,3-dihydro-2H-imidazole-2-one (25 mg, 0.06 mmol) obtained in Step 2 was reacted as in Step 3 of Example 1 to obtain the title compound (12.5 mg, yield 22%).

[0261] LCMS (ESI): m / z 942.3 [M+H] +

[0262] 1 H-NMR (400 MHz, DMSO-d6) δ 12.40 - 11.61 (m, 1H), 8.40 - 8.01 (m, 2H), 7.86 - 6.72 (m, 13H), 5.84 - 5.08 (m, 2H), 4.89 - 4.34 (m, 1H), 3.81 - 3.46 (m, 3H), 3.27 - 2.73 (m, 3H), 2.24 (s, 6H), 2.10 - 1.41 (m, 15H), 1.34 - 1.06 (m, 10H).

[0263] [Example 7]

[0264]

[0265] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(5-methyl-5H-pyrido[4,3-b]indole-8-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0266] Step 1] Preparation of N-(4-bromophenyl)-N-methyl-3-nitropyridine-4-amine

[0267] 4-chloro-3-nitropyridine (1.7 g, 10.75 mmol) and sodium acetate (1.76 g, 21.50 mmol) were added to a solution in which 4-bromo-N-methylaniline (2.00 g, 10.75 mmol) was dissolved in acetic acid (20 mL) solvent, and the temperature of the solution was raised to 115°C and stirred for 1 hour. When the reaction was complete, the solution was concentrated under reduced pressure, washed with an ethyl ester and a saturated sodium bicarbonate aqueous solution, and the organic layer was separated. The aqueous layer was extracted twice with the ethyl ester, and the resulting organic layer was washed twice with water. The organic layer was then dried with sodium sulfate and the residue obtained by vacuum drying was purified by column chromatography to obtain the title compound (1.6 g, yield 48%).

[0268] LCMS (ESI): m / z 308.0 [M+H] +

[0269] Step 2]N 4 -(4-bromophenyl)-N 4 Preparation of -methylpyridine-3,4-diamine

[0270] N-(4-bromophenyl)-N-methyl-3-nitropyridine-4-amine (1.40 g, 4.54 mmol) obtained in Step 1 was dissolved in ethanol (20 mL) solvent, and then tin chloride dihydrate (7.16 g, 27.26 mmol) was added to the solution. The solution was stirred at 80°C for 24 hours, and once the reaction was complete, it was poured into 5 M sodium hydroxide (80 mL), extracted with ethyl acetate, and washed with salt water. The organic layer was dried with sodium sulfate, and the residue obtained by vacuum drying was purified by column chromatography to obtain the title compound (648 mg, yield: 51%).

[0271] LCMS (ESI): m / z 278.0 [M+H] +

[0272] Step 3] Preparation of 8-bromo-5-methyl-5H-pyrido[4,3-b]indole

[0273] N obtained in Step 2 4 -(4-bromophenyl)-N 4 A solution of methylpyridine-3,4-diamine (120 mg, 0.43 mmol) and 0.2 mL of concentrated sulfuric acid mixed with 2 mL of water was cooled to 0°C, and sodium nitrite (90 mg, 1.29 mmol) dissolved in 1 mL of water was added to the solution. After 30 minutes, urea (77 mg) was added to decompose the excess nitrite, and copper powder (28 mg, 0.73 mmol) was added. After stirring the solution at room temperature for 2 hours, ammonium hydroxide was added to the solution to make it basic, extracted with ethyl ester, and washed with salt water. The organic layer was dried with sodium sulfate, and the residue obtained by dark distillation of the solution was purified by column chromatography to obtain the title compound (60 mg, yield: 53%).

[0274] LCMS (ESI): m / z 261.0 [M+H] +

[0275] Step 4] Preparation of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(5-methyl-5H-pyrido[4,3-b]indole-8-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0276] 8-bromo-5-methyl-5H-pyrido[4,3-b]indole (30 mg, 0.114 mmol) obtained in Step 3 and tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (40 mg, 0.091 mmol) were reacted as in Step 1 of Example 1 to obtain the title compound (42 mg, yield 74%).

[0277] LCMS (ESI): m / z 622.3 [M+H] +

[0278] Step 5] Preparation of (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(5-methyl-5H-pyridodo[4,3-b]indole-8-yl)-1,3-dihydro-2H-imidazole-2-one

[0279] The tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(5-methyl-5H-pyrido[4,3-b]indole-8-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (42 mg, 0.068 mmol) obtained in Step 4 was reacted as in Step 2 of Example 1 to obtain the title compound (90 mg, yield 100%).

[0280] LCMS (ESI): m / z 522.3 [M+H] +

[0281] Step 6] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(5-methyl-5H-pyrido[4,3-b]indole-8-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0282] The (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(5-methyl-5H-pyridodo[4,3-b]indole-8-yl)-1,3-dihydro-2H-imidazole-2-one (27 mg, 0.07 mmol) obtained in Step 5 was reacted as in Step 3 of Example 1 to obtain the title compound (26.4 mg, yield 43%).

[0283] LCMS (ESI): m / z 915.4[M+H] +

[0284] 1 H-NMR (400 MHz, DMSO) δ 9.41 (s, 1H), 8.52 (d, J = 10.5 Hz, 2H), 7.81 (s, 2H), 7.68 (s, 1H), 7.53 (s,1H), 7.40 (d, J = 8.4 Hz, 2H), 7.25 (s, 1H), 7.20 (d, J = 6.0 Hz, 3H), 6.98 (m, 2H), 5.60 (s, 1H), 4.38 (s, 1H), 3.95 (s, 4H), 3.69 (m, 3H), 3.05 (d, J = 10.0 Hz, 1H), 2.89 (d, J = 13.5 Hz,1H), 2.67 (s, 1H), 2.33 (s, 1H), 2.24 (s, 9H), 1.67 - 1.63 (m, 2H), 1.43 (s, 2H), 1.28 (m, 4H), 1.24 (s, 1H),1.17 (m, 5H).

[0285] [Example 8]

[0286]

[0287] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-methyl-1,2,3,4-tetrahydrocyclopenta[b]indole-7-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0288] Step 1] Preparation of 7-bromo-4-methyl-1,2,3,4-tetrahydrocyclopenta[b]indole

[0289] 7-bromo-1,2,3,4-tetrahydrocyclopenta[b]indole (60 mg, 0.254 mmol) was dissolved in DMF (1.5 mL) at 0°C, and sodium hydride (60% dispersed in mineral oil, 21 mg, 0.51 mmol) was added to the solution. After 45 minutes, methyl iodide (44 mg, 0.30 mmol) was added. The solution was stirred at room temperature for 15 hours. Once the reaction was complete, the solution was poured into ice water (20 mL), extracted with ethyl ester, and washed with salt water. The organic layer was dried with sodium sulfate and concentrated under reduced pressure; the resulting residue was purified by column chromatography to obtain the title compound (30 mg, yield 47%).

[0290] LCMS (ESI): m / z 250.1 [M+H] +

[0291] Step 2] Preparation of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-methyl-1,2,3,4-tetrahydrocyclopenta[b]indole-7-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0292] 7-bromo-4-methyl-1,2,3,4-tetrahydrocyclopenta[b]indole (30 mg, 0.12 mmol) obtained in Step 1 and tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (40 mg, 0.09 mmol) were reacted as in Step 1 of Example 1 to obtain the title compound (52 mg, yield 93%).

[0293] LCMS (ESI): m / z 611.4[M+H] +

[0294] Step 3] Preparation of (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-methyl-1,2,3,4-tetrahydrocyclopenta[b]indole-7-yl)-1,3-dihydro-2H-imidazole-2-one

[0295] The tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-methyl-1,2,3,4-tetrahydrocyclopenta[b]indole-7-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (52 mg, 0.08 mmol) obtained in Step 2 was reacted as in Step 2 of Example 1 to obtain the title compound (45 mg, yield 96%).

[0296] LCMS (ESI): m / z 511.3 [M+H] +

[0297] Step 4] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-methyl-1,2,3,4-tetrahydrocyclopenta[b]indole-7-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0298] The (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-methyl-1,2,3,4-tetrahydrocyclopenta[b]indole-7-yl)-1,3-dihydro-2H-imidazole-2-one (34 mg, 0.08 mmol) obtained in Step 3 was reacted as in Step 3 of Example 1 to obtain the title compound (19.6 mg, yield 26%).

[0299] LCMS (ESI): m / z 904.4[M+H] + .

[0300] 1 H-NMR (400 MHz, DMSO) δ 11.76 (s, 1H), 7.33 (m, 10H), 6.94 (s, 2H), 4.39 (s, 1H), 3.69 (s, 7H), 2.90 (m, 8H), 2.23 (s, 6H), 1.68 (m, 7H), 1.42 (s, 2H), 1.28 (s, 5H), 1.18 (s, 5H).

[0301] [Example 9]

[0302]

[0303] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(dibenzo[b,d]furan-2-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0304] Step 1] Preparation of tert-butyl (S)-3-(3-(dibenzo[b,d]furan-2-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0305] 2-bromodibenzo[b,d]furan (39 mg, 0.16 mmol) and tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (70 mg, 0.16 mmol) were reacted as in Step 1 of Example 1 to obtain the title compound (85 mg, yield 88%).

[0306] LCMS (ESI): m / z 608.3[M+H] +

[0307] Step 2] Preparation of (S)-1-(dibenzo[b,d]furan-2-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one

[0308] The tert-butyl (S)-3-(3-(dibenzo[b,d]furan-2-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (85 mg, 0.14 mmol) obtained in Step 1 was reacted as in Step 2 of Example 1 to obtain the title compound (75 mg, yield 98%).

[0309] LCMS (ESI): m / z 508.2 [M+H] +

[0310] Step 3] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(dibenzo[b,d]furan-2-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0311] The (S)-1-(dibenzo[b,d]furan-2-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one (75 mg, 0.14 mmol) obtained in Step 2 was reacted as in Step 3 of Example 1 to obtain the title compound (48.8 mg, yield 39%).

[0312] LCMS (ESI): m / z 901.3[M+H] + .

[0313] 1H-NMR (400 MHz, DMSO) δ 11.75 (s, 1H), 8.41 (s, 1H), 8.21 (d, J = 7.9 Hz, 1H), 7.88 - 7.69 (m, 3H), 7.57 (m, 2H), 7.24 (m, 9H), 5.60 (s, 1H), 4.38 (s,1H), 3.69 (m, 3H), 2.98 (m, 2H), 2.24 (s, 7H), 1.69 - 1.53 (m, 5H), 1.43 (d, J = 5.9 Hz, 2H), 1.26 (m, 5H), 1.22 - 1.13 (m, 5H).

[0314] [Example 10]

[0315]

[0316] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-2,3,4,9-tetrahydro-1H-carbazole-6-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0317] Step 1] Preparation of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-2,3,4,9-tetrahydro-1H-carbazole-6-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0318] 6-bromo-9-methyl-2,3,4,9-tetrahydro-1H-carbazole (22 mg, 0.08 mmol) and tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (30 mg, 0.07 mmol) were reacted as in Step 1 of Example 1 to obtain the title compound (40 mg, yield 94%).

[0319] LCMS (ESI): m / z 625.3[M+H] +

[0320] Step 2] Preparation of (S)-1-(dibenzo[b,d]furan-2-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one

[0321] The tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-2,3,4,9-tetrahydro-1H-carbazole-6-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (40 mg, 0.06 mmol) obtained in Step 1 was reacted as in Step 2 of Example 1 to obtain the title compound (35 mg, yield 97%).

[0322] LCMS (ESI): m / z 525.3 [M+H] +

[0323] Step 3]3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-2,3,4,9-tetrahydro-1H-carbazole-6-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one preparation

[0324] The (S)-1-(dibenzo[b,d]furan-2-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one (34 mg, 0.06 mmol) obtained in Step 2 was reacted as in Step 3 of Example 1 to obtain the title compound (22.9 mg, yield 41%).

[0325] LCMS (ESI): m / z 918.4[M+H] + .

[0326] 1 H-NMR (400 MHz, DMSO) δ 11.75 (s, 1H), 7.57 - 7.33 (m, 5H), 7.27 - 7.12 (m, 6H), 6.93 (d, J = 13.0Hz, 2H), 5.59 (s, 1H), 4.38 (d, J = 9.3) Hz, 1H), 3.75 - 3.59 (m, 7H), 3.03 (s, 1H), 2.88 (d, J = 13.0 Hz,1H), 2.73 (s, 2H), 2.64 (s, 2H), 2.23 (s, 7H), 1.87 (s, 2H), 1.78 (s, 2H), 1.68 (s, 2H), 1.54 (m,2H), 1.42 (d, J = 5.8 Hz, 2H), 1.27 (m, 5H), 1.19 - 1.14 (m, 5H).

[0327] [Example 11]

[0328]

[0329] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-2-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0330] Step 1] Preparation of 2-Bromo-9-Methyl-9H-Carbazole

[0331] 2-Bromo-9H-carbazole (300 mg, 1.22 mmol) was reacted as in Step 1 of Example 8 to obtain the title compound (100 mg, yield 31%).

[0332] LCMS (ESI): m / z 260.1[M+H] +

[0333] Step 2] Preparation of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-2-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0334] 2-bromo-9-methyl-9H-carbazole (50 mg, 0.19 mmol) obtained in Step 1 and tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (84.9 mg, 0.19 mmol) were reacted as in Step 1 of Example 1 to obtain the title compound (50 mg, yield 39%).

[0335] LCMS (ESI): m / z 621.3[M+H] +

[0336] Step 3] Preparation of (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(9-methyl-9H-carbazole-2-yl)-1,3-dihydro-2H-imidazole-2-one

[0337] The tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-2-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (50 mg, 0.08 mmol) obtained in Step 2 was reacted as in Step 2 of Example 1 to obtain the title compound (44 mg, yield 100%).

[0338] LCMS (ESI): m / z 521.3 [M+H] +

[0339] Step 4] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-2-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0340] The (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(9-methyl-9H-carbazole-2-yl)-1,3-dihydro-2H-imidazole-2-one (44.3 mg, 0.09 mmol) obtained in Step 3 was reacted as in Step 3 of Example 1 to obtain the title compound (15.5 mg, yield 19%).

[0341] LCMS (ESI): 914.4 [M+H] +

[0342] 1 H-NMR (400 MHz, DMSO) δ12.03 - 11.53 (m, 1H), 8.28 - 6.66 (m, 15H), 5.83 - 5.17 (m, 1H), 4.87 - 4.34 (m, 1H), 3.96 - 3.48 (m, 6H), 3.26 - 2.73 (m, 3H), 2.22 (d, J = 10.9 Hz, 6H), 1.84 - 1.40 (m, 9H), 1.32 - 1.02 (m, 10H).

[0343] [Example 12]

[0344] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(9-oxo-9H-fluorene-3-yl)-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0345]

[0346] Step 1] Preparation of tert-butyl (R)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(9-oxo-9H-fluorene-3-yl)-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0347] 3-bromo-9H-fluoren-9-one (259 mg, 1.0 mmol) and tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (441.0 mg, 1.0 mmol) were reacted as in Step 1 of Example 1 to obtain the target compound (200 mg yield 35%).

[0348] LCMS (ESI): m / z 620.1 [M+H] +

[0349] Step 2] (R)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(9-oxo-9H-fluorene-3-yl)-1,3-dihydro-2H-imidazole-2-one

[0350] The tert-butyl (R)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(9-oxo-9H-fluorene-3-yl)-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (200 mg, 0.3 mmol) obtained in Step 1 was reacted as in Step 2 of Example 1 to obtain the target compound (160 mg, yield 100%).

[0351] LCMS (ESI): m / z 520.2 [M+H] +

[0352] Step 3] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(9-oxo-9H-fluorene-3-yl)-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0353] The (R)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(9-oxo-9H-fluorene-3-yl)-1,3-dihydro-2H-imidazole-2-one (26 mg, 0.05 mmol) obtained in Step 2 was reacted as in Step 3 of Example 1 to obtain the target compound (20.0 mg, yield 44%).

[0354] LCMS (ESI): 913.2 [M+H] +

[0355] 1 H-NMR (400 MHz, CDCl3) δ 11.29 (d, J = 21.0 Hz, 1H), 7.97 (s, 1H), 7.72 (dt, J = 17.5, 9.1 Hz, 2H), 7.63 - 7.49 (m, 4H), 7.47 - 7.33 (m, 2H), 7.24 - 6.98 (m, 3H), 6.91 - 6.62 (m, 2H), 6.51 - 5.69 (m, 2H), 5.39 - 4.16 (m, 3H), 4.02 - 3.55 (m, 3H), 3.21 - 2.99 (m, 3H), 2.25 (t, J = 7.9 Hz, 6H), 1.94 - 1.79 (m, 2H), 1.76 - 1.66 (m, 2H), 1.57 - 1.50 (m, 4H), 1.33 (d, J = 24.0 Hz, 6H), 1.24 - 1.15 (m, 3H).

[0356] [Example 13]

[0357] Preparation of 3-((1S,2S)-1-(2-((S)-2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0358]

[0359] Step 1] Preparation of 4-cyclopropyl-3-fluoroaniline

[0360] Palladium(II) acetate (1181.5 mg, 5.26 mmol) was added to a solution prepared by dissolving 4-bromo-3-fluoroaniline (20,000 mg, 105.25 mmol), cyclopropylboronic acid (11,753.5 mg, 136.83 mmol), tricyclohexylphosphane (2951.7 mg, 10.53 mmol), and potassium triphosphate (78192.8 mg, 368.38 mmol) in toluene (250 mL) and water (50 mL), and the mixture was stirred at 100°C for 16 hours. After the reaction was complete, the reaction product was extracted with an ethyl ester, and the organic phase was separated. The organic layer was dried with sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain the target compound (10,000 mg, yield 63%).

[0361] LCMS (ESI): m / z 152.1 [M+H] +

[0362] Step 2] Preparation of (4-cyclopropyl-3-fluorophenyl)hydrazine

[0363] Sodium nitrite (2373.3 mg, 34.40 mmol) was slowly added at 0°C to a solution of 4-cyclopropyl-3-fluoroaniline (4000 mg, 26.46 mmol) obtained in Step 1 dissolved in water (50 mL) and hydrochloric acid (40 mL), and the mixture was stirred at 0°C for 30 minutes. Tin dichloride (10033.6 mg, 52.92 mmol) was added and the mixture was stirred at room temperature for 2 hours. Once the reaction was complete, the reaction was stopped with an aqueous potassium carbonate solution, extracted with an ethyl ester, and the organic layer was washed with water. The organic layer was then dried with sodium sulfate and concentrated under reduced pressure to obtain the target compound (4000 mg, yield 91%).

[0364] LCMS (ESI): m / z 167.3 [M+H] +

[0365] Step 3] Preparation of tert-butyl (S)-3-amino-2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0366] Pyridine (2284.5 mg, 28.88 mmol) was added to a solution obtained in Step 2, in which (4-cyclopropyl-3-fluorophenyl)hydrazine (4000 mg, 24.07 mmol) and tert-butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylate (5735.0 mg, 24.07 mmol) were dissolved in ethanol (50 mL), and the mixture was stirred at 80°C for 2 hours. The mixture was concentrated, and the residue was purified by reverse-phase column chromatography to obtain the target compound (3000 mg, yield 32%).

[0367] LCMS (ESI): m / z 387.1 [M+H] +

[0368] Step 4] Preparation of tert-butyl (S)-2-(4-cyclopropyl-3-fluorophenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0369] To a solution of tert-butyl (S)-3-amino-2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2000 mg, 5.18 mmol) obtained in Step 3 and N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (5154.6 mg, 25.88 mmol) obtained in Step 3 were slowly added at 0°C, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with an ethyl ester, the organic layer was washed with water, the organic layer was dried with magnesium sulfate, and then concentrated under reduced pressure to obtain the target compound (2000 mg, yield 75%).

[0370] LCMS (ESI): m / z 518.3 [M+H] +

[0371] Step 5] Preparation of tert-butyl (S)-2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0372] Methanesulfonic acid (371.4 mg, 3.86 mmol) was added to a solution in which tert-butyl (S)-2-(4-cyclopropyl-3-fluorophenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2000 mg, 3.86 mmol) obtained in Step 4 was dissolved in tetrahydrofuran (20 mL), and the mixture was stirred at 60°C for 4 hours. The mixture was concentrated under reduced pressure, washed and extracted with ethyl ester and a 1 M aqueous sodium bicarbonate solution, the organic layer was washed with water, dried with sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the target compound (700 mg, yield 40%).

[0373] LCMS (ESI): m / z 454.3 [M+H] +

[0374] Step 6] Preparation of tert-butyl (S)-2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0375] The tert-butyl (S)-2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (50 mg, 0.19 mmol) obtained in Step 5 was reacted with 3-bromo-9-methyl-9H-carbazole (87.1 mg, 0.19 mmol) as in Step 1 of Example 1 to obtain the target compound (60 mg, yield 49%).

[0376] LCMS (ESI): m / z 633.1 [M+H] +

[0377] Step 7] Preparation of (S)-1-(2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(9-methyl-9H-carbazole-3-yl)-1,3-dihydro-2H-imidazole-2-one

[0378] The tert-butyl (S)-2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (60 mg, 0.09 mmol) obtained in Step 6 was reacted as in Step 2 of Example 1 to obtain the target compound (50 mg, yield 100%).

[0379] LCMS (ESI): m / z 533.1 [M+H] +

[0380] Step 8] Preparation of 3-((1S,2S)-1-(2-((S)-2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0381] The (S)-1-(2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(9-methyl-9H-carbazole-3-yl)-1,3-dihydro-2H-imidazole-2-one (38.8 mg, 0.07 mmol) obtained in Step 7 was reacted as in Step 3 of Example 1 to obtain the target compound (10.2 mg, yield 16%).

[0382] LCMS (ESI): 926.3 [M+H] +

[0383] 1 H-NMR (400 MHz, DMSO-d6) δ 12.81 - 11.51 (m, 1H), 8.48 - 8.02 (m, 2H), 7.74 - 6.83 (m, 12H), 5.81 - 5.18 (m, 1H), 4.88 - 4.31 (m, 2H), 3.98 - 3.84 (m, 3H), 3.77 - 3.59 (m, 4H), 3.27 - 2.71 (m, 4H), 2.16 - 0.71 (m, 23H).

[0384] [Example 14]

[0385] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(6,9-dimethyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0386]

[0387] Step 1] Preparation of 3-Bromo-6-Methyl-9H-Carbazole

[0388] N-bromosuccinimide (196.4 mg, 1.1 mmol) was added to a solution of 3-methyl-9H-carbazole (200 mg, 1.1 mmol) dissolved in N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with ethyl ester and water, the organic layer was dried with magnesium sulfate, and the mixture was concentrated under reduced pressure to obtain the target compound (250 mg, yield 88%).

[0389] LCMS (ESI): m / z 260.0[M+H] +

[0390] Step 2] Preparation of 3-Bromo-6,9-Dimethyl-9H-Carbazole

[0391] To a solution of potassium hydroxide (285.0 mg, 5.08 mmol) in N,N-dimethylformamide (5 mL), 3-bromo-6-methyl-9H-carbazole (250 mg, 1.02 mmol) obtained in Step 1 and iodomethane (216.3 mg, 1.52 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was washed with water, extracted with ethyl ester, dried with magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the target compound (150 mg, yield 54%).

[0392] Step 3] Preparation of tert-butyl (S)-3-(3-(6,9-dimethyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0393] 3-bromo-6,9-dimethyl-9H-carbazole (50 mg, 0.18 mmol) obtained in Step 2 and tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (25.9 mg, 0.18 mmol) were reacted as in Step 1 of Example 1 to obtain the target compound (50 mg, yield 45%).

[0394] LCMS (ESI): m / z 635.1 [M+H] +

[0395] Step 4] Preparation of (S)-1-(6,9-dimethyl-9H-carbazole-3-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one

[0396] The tert-butyl (S)-3-(3-(6,9-dimethyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (50 mg, 0.08 mmol) obtained in Step 3 was reacted as in Step 2 of Example 1 to obtain the target compound (30 mg, yield 100%).

[0397] LCMS (ESI): m / z 535.3 [M+H] +

[0398] Step 5] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(6,9-dimethyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0399] The (S)-1-(6,9-dimethyl-9H-carbazole-3-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one (45.5 mg, 0.09 mmol) obtained in Step 4 was reacted as in Step 3 of Example 1 to obtain the target compound (10.6 mg, yield 13%).

[0400] LCMS (ESI): 928.4 [M+H] +

[0401] 1 H-NMR (400 MHz, DMSO-d6) δ 12.36 - 11.49 (m, 1H), 8.38 - 8.09 (m, 1H), 8.03 - 7.81 (m, 1H), 7.76 - 7.13 (m, 10H), 7.03 - 6.66 (m, 2H), 5.81 - 5.12 (m, 1H), 4.91 - 4.31 (m, 1H), 3.86 (d, J = 12.7 Hz, 3H), 3.78 - 3.58 (m, 3H), 3.25 - 2.86 (m, 3H), 2.48 (s, 3H), 2.24 (s, 6H), 1.80 - 1.42 (m, 9H), 1.33 - 1.05 (m, 10H).

[0402] [Example 15]

[0403] Preparation of 3-((1S,2S)-1-(2-((S)-2-(4-cyclopropyl-3-fluorophenyl)-3-(3-(9-isopropyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0404]

[0405] Step 1] Preparation of tert-butyl (S)-2-(4-cyclopropyl-3-fluorophenyl)-3-(3-(9-isopropyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0406] 3-bromo-9-isopropyl-9H-carbazole (70 mg, 0.24 mmol) and tert-butyl (S)-2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (34.6 mg, 0.24 mmol) obtained in Step 5 of Example 13 were reacted as in Step 1 of Example 1 to obtain the target compound (80 mg, yield 44%).

[0407] LCMS (ESI): m / z 661.3 [M+H] +

[0408] Step 2] Preparation of (S)-1-(2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(9-isopropyl-9H-carbazole-3-yl)-1,3-dihydro-2H-imidazole-2-one

[0409] The tert-butyl (S)-2-(4-cyclopropyl-3-fluorophenyl)-3-(3-(9-isopropyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (80 mg, 0.12 mmol) obtained in Step 1 was reacted as in Step 2 of Example 1 to obtain the target compound (70 mg, yield 100%).

[0410] LCMS (ESI): m / z 561.3 [M+H] +

[0411] Step 3] Preparation of 3-((1S,2S)-1-(2-((S)-2-(4-cyclopropyl-3-fluorophenyl)-3-(3-(9-isopropyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0412] The (S)-1-(2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(9-isopropyl-9H-carbazole-3-yl)-1,3-dihydro-2H-imidazole-2-one (68.1 mg, 0.12 mmol) obtained in Step 2 was reacted as in Step 3 of Example 1 to obtain the target compound (35.1 mg, yield 31%).

[0413] LCMS (ESI): m / z 954.4 [M+H] +

[0414] 1H-NMR (400 MHz, DMSO-d6) δ 12.36 - 11.39 (m, 1H), 8.49 - 7.96 (m, 2H), 7.89 - 6.60 (m, 13H), 5.84 - 4.96 (m, 2H), 4.90 - 4.10 (m, 1H), 3.95 - 3.37 (m, 3H), 3.25 - 2.67 (m, 3H), 2.15 - 1.37 (m, 16H), 1.34 - 0.69 (m, 15H).

[0415] [Example 16]

[0416] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(4-hydroxy-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0417]

[0418] Step 1] Preparation of 9-methyl-9H-carbazole-4-ol

[0419] 9H-carbazole-4-ol (200 mg, 1.09 mmol) and N,N-dimethylformamide (266.0 mg, 2.18 mmol) were added to a solution of tetrahydrofuran (10 mL) containing sodium hydride (100.4 mg, 2.51 mmol), and the mixture was stirred at 0°C for 10 minutes. Iodomethane (170.4 mg, 1.20 mmol) was slowly added at 0°C, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase chromatography to obtain the target compound (120 mg, yield 56%).

[0420] LCMS (ESI): m / z 198.2 [M+H] +

[0421] Step 2] Preparation of 3-Bromo-9-Methyl-9H-Carbazole-4-ol

[0422] The 9-methyl-9H-carbazole-4-ol (120 mg, 0.61 mmol) obtained in Step 1 was reacted as in Step 1 of Example 14 to obtain the target compound (100 mg, yield 57%).

[0423] LCMS (ESI): m / z 276.0 [M+H] +

[0424] Step 3] Preparation of 4-(benzyloxy)-3-bromo-9-methyl-9H-carbazole

[0425] To a solution of N,N-dimethylformamide (5 mL) containing potassium hydroxide (100.0 mg, 1.78 mmol), 3-bromo-9-methyl-9H-carbazole-4-ol (100 mg, 0.36 mmol) obtained in Step 2 and benzyl bromide (75.9 mg, 0.53 mmol) were added, and the mixture was stirred at 50 °C for 6 hours. Once the reaction was complete, the mixture was washed with water and extracted with ethyl ester; the organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the target compound (150 mg, yield 54%).

[0426] LCMS (ESI): m / z 280.4 [M+H] +

[0427] Step 4] Preparation of tert-butyl (S)-3-(3-(4-(benzyloxy)-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0428] The 4-(benzyloxy)-3-bromo-9-methyl-9H-carbazole (50 mg, 0.14 mmol) obtained in Step 3 and tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (60.3 mg, 0.14 mmol) were reacted as in Step 1 of Example 1 to obtain the target compound (50 mg, yield 48%).

[0429] LCMS (ESI): m / z 727.3 [M+H] +

[0430] Step 5] Preparation of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(4-hydroxy-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0431] After adding palladium / carbon (10 mg) to a solution in which tert-butyl (S)-3-(3-(4-(benzyloxy)-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (50 mg, 0.07 mmol) obtained in Step 4 was mixed with ethyl ester (5 mL), the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was filtered, washed with ethyl ester, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the target compound (35 mg, yield 78%).

[0432] LCMS (ESI): m / z 637.2 [M+H] +

[0433] Step 6] Preparation of (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-hydroxy-9-methyl-9H-carbazole-3-yl)-1,3-dihydro-2H-imidazole-2-one

[0434] The tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(4-hydroxy-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (35 mg, 0.05 mmol) obtained in Step 5 was reacted as in Step 2 of Example 1 to obtain the target compound (25 mg, yield 100%).

[0435] LCMS (ESI): m / z 537.3 [M+H] +

[0436] Step 7] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(4-hydroxy-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0437] The (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-hydroxy-9-methyl-9H-carbazole-3-yl)-1,3-dihydro-2H-imidazole-2-one (19.6 mg, 0.04 mmol) obtained in Step 6 was reacted as in Step 3 of Example 1 to obtain the target compound (4.5 mg, yield 12%).

[0438] LCMS (ESI): 926.3 [M+H] +

[0439] 1 H-NMR (400 MHz, CDCl3) δ 11.27 (s, 1H), 8.91 (d, J = 112.4 Hz, 1H), 8.41 (dd, J = 76.4, 7.7 Hz, 1H), 7.62 - 7.45 (m, 3H), 7.42 - 7.27 (m, 3H), 7.19 - 7.02 (m, 3H), 6.90 (dd, J = 50.5, 5.8 Hz, 1H), 6.73 - 6.46 (m, 2H), 6.24 - 5.76 (m, 1H), 4.93 - 4.43 (m, 1H), 3.92 - 3.38 (m, 6H), 3.22 - 2.96 (m, 3H), 2.26 (d, J = 16.7 Hz, 6H), 1.91 (t, J = 5.3 Hz, 1H), 1.84 - 1.55 (m, 11H), 1.27 (d, J = 12.5 Hz, 4H), 1.21 - 1.04 (m, 4H).

[0440] [Example 17]

[0441] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(5-chloro-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0442]

[0443] Step 1] Preparation of 5-Bromo-2'-Chloro-2-Nitro-1,1'-Biphenyl

[0444] Tetrakis(triphenylphosphine)palladium (352.4 mg, 0.3 mmol) was added to a solution prepared by dissolving 4-bromo-2-iodo-1-nitrobenzene (2000 mg, 6.10 mmol), (2-chlorophenyl)boronic acid (1001.5 mg, 6.4 mmol), and potassium carbonate (2529.0 mg, 18.3 mmol) in toluene (20 mL), ethanol (4 mL), and water (4 mL), and the mixture was stirred at 110°C for 16 hours. After the reaction was complete, the reaction product was extracted with water and ethyl ester, the organic layer was separated, dried with magnesium sulfate, and distilled under reduced pressure. The resulting residue was purified by column chromatography to obtain the target compound (1000 mg, yield 52%).

[0445] LCMS (ESI): m / z 312.1 [M+H] +

[0446] Step 2] Preparation of 3-Bromo-5-Chloro-9H-Carbazole

[0447] Triphenylphosphine (755.2 mg, 2.88 mmol) was added to a solution of 5-bromo-2'-chloro-2-nitro-1,1'-biphenyl (300 mg, 0.96 mmol) obtained in Step 1 dissolved in 1,4-dichlorobenzene (5 mL), and the mixture was stirred at 180 °C for 6 hours. Once the reaction was complete, the organic compounds were separated by extraction with water and ethyl ester, dried with magnesium sulfate, and distilled under reduced pressure. The resulting residue was purified by column chromatography to obtain the target compound (100 mg, yield 37%).

[0448] 1 H-NMR (400 MHz, CDCl3) δ 8.70 (d, J = 1.8 Hz, 1H), 8.22 (s, 1H), 7.56 (dd, J = 8.6, 1.9 Hz, 1H), 7.38 - 7.30 (m, 3H), 7.25 - 7.20 (m, 1H).

[0449] Step 3] Preparation of 3-Bromo-5-chloro-9-methyl-9H-carbazole

[0450] 3-bromo-5-chloro-9H-carbazole (100 mg, 0.36 mmol) obtained in Step 2 and iodomethane (75.9 mg, 0.53 mmol) were added to a mixed solution of N,N-dimethylformamide (5 mL) and potassium hydroxide (100.0 mg, 1.78 mmol), and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was extracted with water and ethyl ester, the organic layer was separated, dried with magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the target compound (60 mg, yield 54%).

[0451] LCMS (ESI): m / z 312.3 [M+Na] +

[0452] Step 4] Preparation of tert-butyl (S)-3-(3-(5-chloro-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0453] 3-bromo-5-chloro-9-methyl-9H-carbazole (60 mg, 0.20 mmol) obtained in Step 3 and tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (89.9 mg, 0.20 mmol) were reacted as in Step 1 of Example 1 to obtain the target compound (50 mg, yield 39%).

[0454] LCMS (ESI): m / z 655.3 [M+H] +

[0455] Step 5] Preparation of (S)-1-(5-chloro-9-methyl-9H-carbazole-3-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one

[0456] The tert-butyl (S)-3-(3-(5-chloro-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (50 mg, 0.08 mmol) obtained in Step 4 was reacted as in Step 2 of Example 1 to obtain the target compound (40 mg, yield 100%).

[0457] LCMS (ESI): m / z 555.3 [M+H] +

[0458] Step 6] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(5-chloro-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0459] The (S)-1-(5-chloro-9-methyl-9H-carbazole-3-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one (6.7 mg, 0.01 mmol) obtained in Step 5 was reacted as in Step 3 of Example 1 to obtain the target compound (10.1 mg, yield 88%).

[0460] LCMS (ESI): 948.3 [M+H] +

[0461] 1H-NMR (400 MHz, CDCl3) δ 11.32 (d, J = 11.0 Hz, 1H), 8.55 (dd, J = 56.3, 1.8 Hz, 1H), 7.82 - 7.30 (m, 6H), 7.25 - 6.80 (m, 4H), 6.73 - 6.31 (m, 2H), 6.11 - 5.78 (m, 1H), 4.94 - 4.41 (m, 1H), 3.96 - 3.32 (m, 6H), 3.21 - 2.94 (m, 3H), 2.37 - 2.19 (m, 6H), 1.90 (t, J = 5.6 Hz, 1H), 1.82 - 1.66 (m, 6H), 1.38 - 0.80 (m, 13H).

[0462] [Example 18]

[0463] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(6-acetyl-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0464]

[0465] Step 1] Preparation of 1-(6-bromo-9-methyl-9H-carbazole-3-yl)ethane-1-one

[0466] Acetic anhydride (94.2 mg, 0.92 mmol) was added to a solution of 3-bromo-9-methyl-9H-carbazole (200 mg, 0.77 mmol) and aluminum chloride (256.3 mg, 1.92 mmol) mixed with dichloromethane (5 mL), and the mixture was stirred at room temperature for 16 hours. When the reaction was complete, water was added to stop the reaction, the mixture was extracted with dichloromethane, the organic layer was dried with magnesium sulfate, and then distilled under reduced pressure. The resulting residue was purified by column chromatography to obtain the target compound (150 mg, yield 65%).

[0467] LCMS (ESI): m / z 302.0 [M+H] +

[0468] Step 2] Preparation of tert-butyl (S)-3-(3-(6-acetyl-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0469] 1-(6-bromo-9-methyl-9H-carbazole-3-yl)ethanol-1-one (60 mg, 0.20 mmol) obtained in Step 1 and tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (87.7 mg, 0.20 mmol) were reacted as in Step 1 of Example 1 to obtain the target compound (60 mg, yield 45%).

[0470] LCMS (ESI): m / z 663.3 [M+H] +

[0471] Step 3] Preparation of (S)-1-(6-acetyl-9-methyl-9H-carbazole-3-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one

[0472] The tert-butyl (S)-3-(3-(6-acetyl-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (60 mg, 0.09 mmol) obtained in Step 2 was reacted as in Step 2 of Example 1 to obtain the target compound (45 mg, yield 100%).

[0473] LCMS (ESI): m / z 563.3 [M+H] +

[0474] Step 4] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(6-acetyl-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0475] The (S)-1-(6-acetyl-9-methyl-9H-carbazole-3-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one (34.2 mg, 0.06 mmol) obtained in Step 3 was reacted as in Step 3 of Example 1 to obtain the target compound (4.5 mg, yield 8%).

[0476] LCMS (ESI): m / z 956.4 [M+H] +

[0477] 1H-NMR (400 MHz, CDCl3) δ 11.74 - 10.98 (m, 1H), 8.72 (d, J = 29.9 Hz, 1H), 8.31 - 7.34 (m, 7H), 7.25 - 6.28 (m, 5H), 6.19 - 5.74 (m, 1H), 4.92 - 4.42 (m, 2H), 3.97 - 3.37 (m, 6H), 3.23 - 2.96 (m, 3H), 2.72 (d, J = 10.3 Hz, 3H), 2.26 (d, J = 16.6 Hz, 6H), 1.91 (t, J = 5.3 Hz, 1H), 1.81 - 1.62 (m, 7H), 1.45 - 0.72 (m, 11H).

[0478] [Example 19]

[0479] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0480]

[0481] Step 1] Preparation of ethyl 5-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

[0482] [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (816 mg, 1 mmol) was added to a mixture of ethyl 5-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (2680 mg, 10 mmol), 2-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2380 mg, 10 mmol), and potassium carbonate (3450 mg, 25 mmol) dissolved in dioxane (50 mL) and water (10 mL). The reaction mixture was stirred at 90°C for 3 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled, filtered, and the filtrate was distilled under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (2000 mg, yield 68.9%).

[0483] LCMS(ESI): m / z 301.2 [M+H] +

[0484] Step 2] Preparation of ethyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

[0485] 5% palladium / carbon (1.0 g) was added to a mixture in which ethyl 5-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (2.0 g, 6.67 mmol) obtained in Step 1 was dissolved in dichloromethane (20 mL) and methanol (20 mL), and the mixture was stirred for 6 hours under a hydrogen atmosphere. After the reaction was complete, the solution was filtered and vacuum distilled to obtain the target compound (2.0 g, yield 100%).

[0486] LCMS(ESI): m / z 303.1 [M+H] +

[0487] Step 3] Preparation of ethyl 1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

[0488] Chloroacetonitrile (1004 mg, 13.3 mmol) was added at 0 °C to a mixture of N,N-dimethylformamide (30 mL), ethyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (2000 mg, 6.67 mmol) obtained in Step 2, and potassium carbonate (1835 mg, 13.33 mmol). The solution was stirred at room temperature for 4 hours, and upon completion of the reaction, it was extracted with water and ethyl ester, and the organic layer was washed with salt water. The organic layer was separated, dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the target compound (1364 mg, yield: 60%).

[0489] LCMS(ESI): m / z 342.2 [M+H] +

[0490] Step 4] Preparation of 1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

[0491] Ethyl 1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (1364 mg, 4 mmol) obtained in Step 3 was mixed with lithium hydroxide (96 mg, 4 mmol) at 0 °C in a tetrahydrofuran / water (20 ml:4 ml) mixture and stirred at room temperature for 4 hours. Once the reaction was complete, water was added and the pH was adjusted to 6 using a 1N aqueous hydrochloric acid solution. The reaction mixture was extracted with an ethyl ester, the resulting organic layer was washed with brine, dried with sodium sulfate, and subjected to vacuum distillation to obtain the target compound (475 mg, yield: 38%).

[0492] LCMS(ESI): m / z 314.2 [M+H] +

[0493] Step 5] Preparation of 1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[0494] To the mixed solution of 1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-c]pyridin-2-carboxylate (100 mg, 0.32 mmol) and N,N-dimethylacetamide (5 mL) obtained in Step 4, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 1-oxide hexafluorophosphate (182 mg, 0.48 mmol) and diisopropylethylamine (124 mg, 0.96 mmol) were added, followed by the addition of N-methylaniline (34 mg, 0.32 mmol), and the mixture was stirred at room temperature for 8 hours. Once the reaction was complete, the mixture was extracted with water and ethyl ester, the organic layer was dried with magnesium sulfate, and then distilled under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (101 mg, yield: 77.7%).

[0495] LCMS(ESI): m / z 403.3 [M+H] +

[0496] Step 6] Preparation of 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[0497] 1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (101 mg, 0.25 mmol) obtained in Step 5, (R)-4-methyl-1,3,2-dioxathiolan 2,2-dioxate (69 mg, 0.5 mmol), and N,N'-dimethylpropylene urea (64 mg, 0.5 mmol) were dissolved in tetrahydrofuran (6 mL), then potassium hexamethyldisilazane (0.6 mL, 2.5 mmol) was added at 0°C and stirred for 30 minutes. When the reaction was complete, the reaction was stopped with an aqueous ammonium chloride solution and extracted with an ethyl ester. The organic layer was separated, dried with ammonium sulfate, and then subjected to vacuum distillation to obtain the target compound (18 mg, 16% yield).

[0498] LCMS(ESI): m / z 443.2[M+H] +

[0499] Step 7] Preparation of 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-1-((Z)-N'-hydroxycarbamimidoy)-2-methylcyclopropyl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[0500] Hydroxylamine (3.96 mg, 0.12 mmol) was added to a mixed solution of 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (18 mg, 0.04 mmol) obtained in Step 6 and isopropyl alcohol (3 mL), and the mixture was stirred at 65°C for 8 hours. After the reaction was complete, the solid was filtered to obtain the target compound (10 mg, yield 50%).

[0501] LCMS(ESI): m / z 476.2 [M+H] +

[0502] Step 8] Preparation of 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)cyclopropyl)-N-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[0503] 1,1'-carbonyldiimidazole (6.45 mg, 0.04 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (7.6 mg, 0.05 mmol) were added to a solution of 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-1-((Z)-N'-hydroxycarbamidyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (10 mg, 0.02 mmol) obtained in Step 7 mixed with tetrahydrofuran (3 mL), and the mixture was stirred at 80°C for 8 hours. When the reaction was completed, the organic layer was extracted with water and ethyl ester, dried with sodium sulfate, and then subjected to vacuum distillation to obtain the target compound (5 mg, yield 50%).

[0504] LCMS(ESI): m / z 502.0 [M+H] +

[0505] Step 9] Preparation of 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)cyclopropyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

[0506] Potassium ethert-butoxylide (2.24 mg, 0.02 mmol) and water (0.18 mg, 0.01 mmol) were added to a solution in which 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)cyclopropyl)-N-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (5 mg, 0.01 mmol) obtained in Step 8 was dissolved in 1,3-dimethyl-2-imidazolidinone (1 mL). The solution was stirred at 110°C for 8 hours, and once the reaction was complete, the pH of the solution was adjusted to 6 with an aqueous 1N hydrochloric acid solution and extracted with an ethyl ester. The organic layer was dried with sodium sulfate and vacuum distilled to obtain the target compound (4 mg, 100%).

[0507] LCMS(ESI): m / z 413.2 [M+H] +

[0508] [Step 10] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0509] 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)cyclopropyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (4 mg, 0.01 mmol) obtained in Step 9 and (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-3-yl)-3-(9-methyl-9H-carbazole-3-yl)-1,3-dihydro-2H-imidazole-2-one (5 mg, 0.01 mmol) were reacted as in Step 3 of Example 1 to produce the target compound (2 mg, A yield of 22% was obtained.

[0510] LCMS(ESI): m / z 915.3 [M+H] +

[0511] 1 H-NMR (400 MHz, CDCl3) δ 9.00 (d, J = 11.3 Hz, 1H), 8.26 - 7.87 (m, 2H), 7.69 - 7.40 (m, 4H), 7.32 - 7.29 (m, 1H), 7.18 (d, J = 6.1 Hz, 2H), 7.10 - 6.97 (m, 1H), 6.84 - 6.56 (m, 2H), 6.46 - 5.71 (m, 2H), 5.54 - 4.72 (m, 1H), 4.44 - 3.74 (m, 6H), 3.62 (s, 1H), 3.39 - 2.81 (m, 4H), 2.36 - 2.13 (m, 7H), 1.90 (dd, J = 30.2, 23.9 Hz, 3H), 1.36 - 1.20 (m, 12H), 1.05 (d, J = 6.2 Hz, 2H).

[0512] [Example 20]

[0513] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(5-isopropyl-5H-pyrido[4,3-b]indole-8-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0514]

[0515] Step 1] Preparation of 5-isopropyl-5H-pyrido[4,3-b]indole

[0516] 5H-pyrido[4,3-b]indole (1680 mg, 10 mmol) was reacted as in Step 1 of Example 6 to obtain the target compound (1700 mg, yield 82%).

[0517] LCMS (ESI): m / z 211.2 [M+H] +

[0518] Step 2] Preparation of 8-Bromo-5-isopropyl-5H-pyrido[4,3-b]indole

[0519] The 5-isopropyl-5H-pyrido[4,3-b]indole (1050 mg, 5 mmol) obtained in Step 1 was reacted as in Step 1 of Example 14 to obtain the target compound (600 mg, yield 40%).

[0520] LCMS (ESI): m / z 291.2 [M+H] +

[0521] Step 3] Preparation of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(5-isopropyl-5H-pyrido[4,3-b]indole-8-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0522] 8-bromo-5-isopropyl-5H-pyrido[4,3-b]indole (230 mg, 0.8 mmol) obtained in Step 2 and tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (352.8 mg, 0.8 mmol) were reacted as in Step 1 of Example 1 to obtain the target compound (500 mg yield 76%).

[0523] LCMS (ESI): m / z 650.2 [M+H] +

[0524] Step 4] Preparation of (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(5-isopropyl-5H-pyridodo[4,3-b]indole-8-yl)-1,3-dihydro-2H-imidazole-2-one

[0525] The tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(5-isopropyl-5H-pyrido[4,3-b]indole-8-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (428 mg, 0.66 mmol) obtained in Step 3 was reacted as in Step 2 of Example 1 to obtain the target compound (362 mg, yield 100%).

[0526] LCMS (ESI): m / z 551.1 [M+H] +

[0527] Step 5] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(5-isopropyl-5H-pyrido[4,3-b]indole-8-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0528] The (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(5-isopropyl-5H-pyridodo[4,3-b]indole-8-yl)-1,3-dihydro-2H-imidazole-2-one (329 mg, 0.6 mmol) obtained in Step 4 was reacted as in Step 3 of Example 1 to obtain the target compound (303 mg, yield 33%).

[0529] LCMS (ESI): m / z 943.4[M+H] +

[0530] 1 H-NMR (400 MHz, DMSO) δ 9.41 (s, 1H), 8.48 (d, J = 6.0 Hz, 2H), 7.94 (d, J = 9.2 Hz, 1H), 7.76 (s, 2H), 7.42 (dd, J = 41.5, 33.1 Hz, 3H), 7.09 (dd, J = 86.6, 16.6 Hz, 5H), 6.75 - 5.56 (m, 1H), 5.34 - 4.90 (m, 1H), 3.72 (d, J = 9.1 Hz, 3H), 3.12 - 2.82 (m, 2H), 2.23 (d, J = 13.1 Hz, 6H), 1.89 - 1.40 (m, 16H), 1.34 - 1.06 (m, 11H).

[0531] [Example 21]

[0532] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0533]

[0534] Step 1] Preparation of 5-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid

[0535] Methyl 5-bromo-3,4-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (2.54 g, 10 mmol) was reacted as in Step 1 of Example 19 to obtain the target compound (1.0 g, yield 36%).

[0536] LCMS(ESI): m / z 273.1 [M+H] +

[0537] Step 2] Preparation of 5-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0538] The 5-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (544 mg, 2 mmol) obtained in Step 1 was reacted as in Step 5 of Example 19 to obtain the target compound (361 mg, yield 50%).

[0539] LCMS(ESI): m / z 362.3 [M+H] +

[0540] Step 3] Preparation of 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0541] The 5-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (361 mg, 1 mmol) obtained in Step 2 was reacted as in Step 2 of Example 19 to obtain the target compound (363 mg, yield 100%).

[0542] LCMS(ESI): m / z 364.2 [M+H] +

[0543] Step 4] Preparation of 1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0544] The 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (363 mg, 1.0 mmol) obtained in Step 3 was reacted as in Step 3 of Example 19 to obtain the target compound (201 mg, yield 50%).

[0545] LCMS(ESI): m / z 403.4 [M+H] +

[0546]

[0547] Step 5] Preparation of 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0548] The 1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (101 mg, 0.25 mmol) obtained in Step 4 was reacted as in Step 6 of Example 19 to obtain the target compound (18 mg, yield 16%).

[0549] LCMS(ESI): m / z 443.2 [M+H] +

[0550] Step 6] Preparation of 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-1-((Z)-N'-hydroxycarbamimidoy)-2-methylcyclopropyl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0551] The 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (18 mg, 0.04 mmol) obtained in Step 5 was reacted as in Step 7 of Example 19 to obtain the target compound (10 mg, yield 50%).

[0552] LCMS(ESI): m / z 476.3 [M+H] +

[0553] Step 7] Preparation of 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)cyclopropyl)-N-phenyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0554] The 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-1-((Z)-N'-hydroxycarbamimidoy)-2-methylcyclopropyl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (10 mg, 0.02 mmol) obtained in Step 6 was reacted as in Step 8 of Example 19 to obtain the target compound (5 mg, yield 50%).

[0555] LCMS(ESI): m / z 502.3 [M+H] +

[0556] Step 8] Preparation of 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid

[0557] The 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)cyclopropyl)-N-phenyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (5 mg, 0.01 mmol) obtained in Step 7 was reacted as in Step 9 of Example 19 to obtain the target compound (4 mg, yield 100%).

[0558] LCMS(ESI): m / z 413.3 [M+H] +

[0559] Step 9] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0560] The 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (4 mg, 0.01 mmol) obtained in Step 8 was reacted as in Step 10 of Example 19 to obtain the target compound (2 mg, yield 22%).

[0561] LCMS(ESI): m / z 915.3 [M+H] +

[0562] 1H-NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.14 (dd, J = 29.4, 4.8 Hz, 2H), 7.80 (d, J = 20.7 Hz, 1H), 7.67 - 7.38 (m, 4H), 7.14 (dd, J = 37.3, 6.1 Hz, 3H), 6.79 (d, J = 3.1 Hz, 1H), 6.66 (s, 1H), 6.33 (d, J = 3.1 Hz, 1H), 5.82 (d, J = 6.8 Hz, 1H), 5.35 (t, J = 6.1 Hz, 2H), 4.57 - 4.30 (m, 1H), 3.98 - 3.66 (m, 6H), 3.09 (dt, J = 36.3, 10.6 Hz, 3H), 2.54 (d, J = 8.6 Hz, 1H), 2.25 - 2.17 (m, 2H), 1.37 - 1.20 (m, 16H), 0.97 (d, J = 5.7 Hz, 3H), 0.89 (dd, J = 12.9, 6.6 Hz, 2H).

[0563] [Example 22]

[0564] Preparation of 3-(1-(2-((S)-2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indoleizine-3-yl)cyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0565]

[0566] Step 1] Preparation of Ethyl 7-Bromoindolizine-2-Carboxylate

[0567] Sodium bicarbonate (146 g, 1.74 mol) and ethyl 3-bromo-2-oxo-propanoate (255 g, 1.30 mol) were added to a solution of 4-bromo-2-methylpyridine (150 g, 872 mmol) dissolved in acetonitrile (1.2 L). The mixture was stirred at 90 °C for 16 hours. Once the reaction was complete, the solution was filtered and extracted with water and ethyl ester; the organic layer was dried with magnesium sulfate and distilled under reduced pressure. The resulting residue was purified by column chromatography to obtain the target compound (14 g, yield 6%).

[0568] LCMS(ESI): m / z 267.9 [M+H] +

[0569] Step 2] Preparation of Ethyl 7-(4,4,5,5-Tetramethyl-1,3,2-Dioxaborolan-2-yl)Indolezine-2-Carboxylate

[0570] Ethyl 7-bromoindolezine-2-carboxylate (12 g, 44.9 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (14.7 g, 58.2 mmol), potassium acetate (8.78 g, 89.6 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (1.64 g, 2.2 mmol) obtained in Step 1 were dissolved in dioxane (120 mL) and stirred at 90°C for 16 hours. After the reaction was complete, the solution was filtered and vacuum distilled to obtain the target compound (15 g, 100%).

[0571] LCMS(ESI): m / z 316.2 [M+H] +

[0572] Step 3] Preparation of Ethyl 7-(2,2-Dimethyl-3,6-Dihydro-2H-pyran-4-yl)indolezine-2-carboxylate

[0573] Potassium carbonate (6.6 g, 47.6 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (1.74 g, 2.38 mmol), and 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (12.4 g, 47.6 mmol) were added to a mixture in which ethyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoleizine-2-carboxylate (7.5 g, 23.7 mmol) obtained in Step 2 was dissolved in dioxane (200 mL) and water (15 mL), and the mixture was stirred at 90°C under nitrogen for 1 hour. Once the reaction was complete, the solution was subjected to vacuum distillation, the residue was extracted with water and ethyl acetate, the organic layer was dried with sodium sulfate, and then vacuum distilled. The obtained residue was purified by column chromatography to obtain the target compound (6.23g, yield 88%).

[0574] LCMS(ESI): m / z 300.3 [M+H] +

[0575] Step 4] Preparation of Ethyl 7-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)indoleizine-2-carboxylate

[0576] The ethyl 7-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)indolezine-2-carboxylate (6.23 g, 20.8 mmol) obtained in Step 3 was reacted as in Step 2 of Example 19 to obtain the target compound (3.5 g, yield 56.2%).

[0577] LCMS(ESI): m / z 302.1 [M+H] +

[0578] Step 5] Preparation of Ethyl 3-(cyanomethyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indoleizine-2-carboxylate

[0579] Ethyl 7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolezine-2-carboxylate (3.01 g, 10 mmol), 2-bromoacetonitrile (1.3 g, 11 mmol), ferrous sulfate heptahydrate (1.33 g, 5 mmol), and sodium iodide (1.49 g, 10 mmol) obtained in Step 4 were dissolved in dimethyl sulfoxide (70 mL), and then hydrogen peroxide (12 mL, 30%) was added at 0–15°C. The solution was stirred for 1 hour and extracted with water and ethyl ester. The organic layer was dried with sodium sulfate and then subjected to vacuum distillation. The resulting residue was purified by column chromatography to obtain the target compound (1.7 g, yield 50%).

[0580] LCMS(ESI): m / z 341.1 [M+H] +

[0581] Step 6] Preparation of Ethyl (S)-3-(1-cyanocyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indoleizine-2-carboxylic acid

[0582] 3-(cyanomethyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolezin-2-carboxylate (1.7 g, 5 mmol) and 1,3,2-dioxathiolan 2,2-dioxide (930 mg, 7.5 mmol) obtained in Step 5 were reacted as in Step 6 of Example 19 to obtain the racemic target compound (1.5 g, yield 91%).

[0583] The obtained 3-(1-cyanocyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolezine-2-carboxylate (250 mg, 0.74 mmol) was separated by chiral HPLC to obtain two single enantiomers (S isomer 111 mg; R isomer 115 mg).

[0584] LCMS(ESI): m / z 367.1 [M+H] +

[0585] Step 7] Preparation of (S)-3-(1-cyanocyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenylindoleizine-2-carboxamide

[0586] The (S)-3-(1-cyanocyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolezine-2-carboxylic acid (101 mg, 0.298 mmol) obtained in Step 6 was reacted as in Step 5 of Example 19 to obtain the target compound (90 mg, yield 70.8%).

[0587] LCMS(ESI): m / z 428.1 [M+H] +

[0588] Step 8] Preparation of (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(N-hydroxycarbamimidoy)cyclopropyl)-N-methyl-N-phenylindoleizine-2-carboxamide

[0589] The (S)-3-(1-cyanocyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenylindolezine-2-carboxamide (90 mg, 0.211 mmol) obtained in Step 7 was reacted as in Step 7 of Example 19 to obtain the target compound (97 mg, yield 100%).

[0590] LCMS(ESI): m / z 461.1 [M+H] +

[0591] Step 9] Preparation of (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-3-(1-(5-oxo-2,5-dihydro-1,2,4-oxadiazole-3-yl)cyclopropyl)-N-phenylindolezine-2-carboxamide

[0592] The (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(N-hydroxycarbamimidoy)cyclopropyl)-N-methyl-N-phenylindolezine-2-carboxamide (97 mg, 0.211 mmol) obtained in Step 8 was reacted as in Step 8 of Example 19 to obtain the target compound (100 mg, yield 99%).

[0593] LCMS(ESI): m / z 487.1 [M+H] +

[0594] Step 10] Preparation of (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-2,5-dihydro-1,2,4-oxadiazole-3-yl)cyclopropyl)indolizine-2-carboxylic acid

[0595] The (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-3-(1-(5-oxo-2,5-dihydro-1,2,4-oxadiazole-3-yl)cyclopropyl)-N-phenylindolezine-2-carboxamide (100 mg, 0.21 mmol) obtained in Step 9 was reacted as in Step 9 of Example 19 to obtain the target compound (80 mg, yield 96%).

[0596] LCMS(ESI): m / z 398.0 [M+H] +

[0597] Step 11] Preparation of 3-(1-(2-((S)-2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indoleizine-3-yl)cyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0598] (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-2,5-dihydro-1,2,4-oxadiazole-3-yl)cyclopropyl)indolizine-2-carboxylic acid (20 mg, 0.05 mmol) obtained in Step 10 and (S)-1-(2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(9-isopropyl-9H-carbazole-3-yl)-1,3-dihydro-2H-imidazole-2-one (26.8 mg, 0.08 mmol) were reacted as in Step 3 of Example 1 to obtain the target compound (11.6 mg, yield 25%).

[0599] LCMS (ESI): m / z= 912.4 [M+H] +

[0600] 1 H-NMR (400 MHz, CDCl3) δ 11.72 - 11.41 (m, 1H), 8.24 - 7.99 (m, 3H), 7.69 - 7.33 (m, 4H), 7.26 - 7.04 (m, 3H), 6.97 - 5.78 (m, 6H), 4.97 - 4.29 (m, 1H), 3.95 - 3.44 (m, 6H), 3.17 - 2.76 (m, 3H), 1.82 - 1.51 (m, 9H), 1.35 - 1.26 (m, 6H), 1.21 - 0.96 (m, 5H), 0.89 - 0.70 (m, 3H).

[0601] [Example 23]

[0602] Preparation of 3-(1-(2-((S)-2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indoleizine-3-yl)cyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0603]

[0604] Step 1] Preparation of (R)-3-(1-cyanocyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenylindoleizine-2-carboxamide

[0605] (R)-3-(1-cyanocyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolezine-2-carboxylic acid (101 mg, 0.298 mmol) obtained in Step 6 of Example 22 was reacted as in Step 5 of Example 19 to obtain the target compound (89 mg, yield 70%).

[0606] LCMS(ESI): m / z 428.1 [M+H] +

[0607] Step 2] Preparation of (R)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(N-hydroxycarbamimidoy)cyclopropyl)-N-methyl-N-phenylindoleizine-2-carboxamide

[0608] The (R)-3-(1-cyanocyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenylindolezine-2-carboxamide (89 mg, 0.20 mmol) obtained in Step 1 was reacted as in Step 7 of Example 19 to obtain the target compound (95 mg, yield 100%).

[0609] LCMS(ESI): m / z 461.1 [M+H] +

[0610]

[0611] Step 3] Preparation of (R)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-3-(1-(5-oxo-2,5-dihydro-1,2,4-oxadiazole-3-yl)cyclopropyl)-N-phenylindolezine-2-carboxamide

[0612] The (R)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(N-hydroxycarbamimidoy)cyclopropyl)-N-methyl-N-phenylindolezine-2-carboxamide (95 mg, 0.20 mmol) obtained in Step 2 was reacted as in Step 8 of Example 19 to obtain the target compound (99 mg, yield 99%).

[0613] LCMS(ESI): m / z 487.1 [M+H] +

[0614] Step 4] Step 10] Preparation of (R)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-2,5-dihydro-1,2,4-oxadiazole-3-yl)cyclopropyl)indolizine-2-carboxylic acid

[0615] The (R)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-3-(1-(5-oxo-2,5-dihydro-1,2,4-oxadiazole-3-yl)cyclopropyl)-N-phenylindolezine-2-carboxamide (100 mg, 0.21 mmol) obtained in Step 3 was reacted as in Step 9 of Example 19 to obtain the target compound (75 mg, yield 90%).

[0616] LCMS(ESI): m / z 398.0 [M+H] +

[0617] Step 5] Preparation of 3-(1-(2-((S)-2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indoleizine-3-yl)cyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0618] (R)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-2,5-dihydro-1,2,4-oxadiazole-3-yl)cyclopropyl)indolizine-2-carboxylic acid (20 mg, 0.05 mmol) obtained in Step 4 and (S)-1-(2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(9-isopropyl-9H-carbazole-3-yl)-1,3-dihydro-2H-imidazole-2-one (26.8 mg, 0.08 mmol) were reacted as in Step 3 of Example 1 to obtain the target compound (11.7 mg, yield 26%).

[0619] LCMS (ESI): m / z= 912.4 [M+H] +

[0620] 1 H-NMR (400 MHz, CDCl3) δ 11.72 - 11.41 (m, 1H), 8.24 - 7.99 (m, 3H), 7.69 - 7.33 (m, 4H), 7.26 - 7.04 (m, 3H), 6.97 - 5.78 (m, 6H), 4.97 - 4.29 (m, 1H), 3.95 - 3.44 (m, 6H), 3.17 - 2.76 (m, 3H), 1.82 - 1.51 (m, 9H), 1.35 - 1.26 (m, 6H), 1.21 - 0.96 (m, 5H), 0.89 - 0.70 (m, 3H).

[0621] [Example 24]

[0622] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-4-(methylamino)-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0623]

[0624] Step 1] Preparation of 4-Bromo-9-Methyl-9H-Carbazole

[0625] Iodomethane (1730 mg, 12.2 mmol) was added to a solution of 4-bromo-9H-carbazole (2000 mg, 8.1 mmol) and potassium hydroxide (2280 mg, 40.6 mmol) dissolved in N,N-dimethylformamide (50 mL), and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was extracted with water and ethyl ester, the organic layer was dried with magnesium sulfate, and then subjected to vacuum distillation. The resulting residue was purified by column chromatography to obtain the target compound (1500 mg, yield 74%).

[0626] LCMS (ESI): m / z 260.0 [M+H] +

[0627] Step 2] Preparation of tert-butyl(9-methyl-9H-carbazole-4-yl)carbamate

[0628] After adding xanthos (476.5 mg, 1.0 mmol) and palladium acetate (224.4 mg, 1.0 mmol) to a solution obtained in Step 1, in which 4-bromo-9-methyl-9H-carbazole (300 mg, 5.0 mmol), tert-butyl carbamate (702.5 mg, 6.0 mmol), and cesium carbonate (3256.6 mg, 10.0 mmol) were dissolved in toluene (30 mL), the mixture was stirred at 90°C for 6 hours. The solution was filtered and subjected to vacuum distillation, and the resulting residue was purified by column chromatography to obtain the target compound (1000 mg, yield 67%).

[0629] LCMS (ESI): m / z 241.2 [M-56+H] +

[0630] Step 3] Preparation of 9-Methyl-9H-Carbazole-4-Amine

[0631] After adding hydrochloric acid / dioxane (10 mL) to a solution in which tert-butyl(9-methyl-9H-carbazole-4-yl)carbamate (500 mg, 1.69 mmol) obtained in Step 2 was dissolved in dioxane (3 mL), the mixture was stirred at room temperature for 3 hours. Once the reaction was complete, the solution was concentrated under reduced pressure to obtain the target compound (300 mg, yield 90%).

[0632] LCMS (ESI): m / z 197.2 [M-56+H] +

[0633] Step 4] Preparation of 3-Bromo-9-Methyl-9H-Carbazole-4-Amine

[0634] Hydrogen peroxide (33%, 157.5 mg, 1.53 mmol) was slowly added at -20°C to a solution in which 9-methyl-9H-carbazole-4-amine (300 mg, 1.53 mmol) and hydrogen bromide (40%, 309.2 mg, 1.53 mmol) obtained in Step 3 were dissolved in acetonitrile (5 mL), and the solution was stirred at room temperature for 16 hours. When the reaction was complete, a 1 M aqueous sodium bisulfate solution was added to stop the reaction, and the residue obtained by vacuum distillation of the solution was purified by reverse-phase chromatography to obtain the target compound (150 mg, yield 36%).

[0635] LCMS (ESI): m / z 275.0 [M-56+H] +

[0636] Step 5] Preparation of 3-Bromo-N,9-Dimethyl-9H-Carbazole-4-Amine

[0637] The 3-bromo-9-methyl-9H-carbazole-4-amine (100 mg, 0.36 mmol) obtained in Step 4 was reacted as in Step 1 to obtain the target compound (50 mg, yield 48%).

[0638] LCMS (ESI): m / z 289.0 [M-56+H] +

[0639] Step 6] Preparation of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-4-(methylamino)-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0640] 3-bromo-N,9-dimethyl-9H-carbazole-4-amine (25 mg, 0.09 mmol) obtained in Step 5 and tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (38.2 mg, 0.09 mmol) were reacted as in Step 1 of Example 1 to obtain the target compound (20 mg, yield 24%).

[0641] LCMS (ESI): m / z 650.3 [M+H] +

[0642] Step 7] Preparation of (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(9-methyl-4-(methylamino)-9H-carbazole-3-yl)-1,3-dihydro-2H-imidazole-2-one

[0643] The tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-4-(methylamino)-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (20 mg, 0.03 mmol) obtained in Step 6 was reacted as in Step 2 of Example 1 to obtain the target compound (17 mg, yield 100%).

[0644] LCMS (ESI): m / z 550.2 [M+H] +

[0645] Step 8] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-4-(methylamino)-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0646] The (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(9-methyl-4-(methylamino)-9H-carbazole-3-yl)-1,3-dihydro-2H-imidazole-2-one (16.0 mg, 0.03 mmol) obtained in Step 7 was reacted as in Step 3 of Example 1 to obtain the target compound (6.5 mg, yield 23%).

[0647] LCMS (ESI): m / z 943.4 [M+H] +

[0648] 1 H-NMR (400 MHz, CDCl3) δ 11.47 - 11.17 (m, 1H), 8.03 (dd, J = 55.0, 7.9 Hz, 1H), 7.63 - 7.38 (m, 4H), 7.32 - 7.27 (m, 1H), 7.25 - 5.75 (m, 8H), 4.93 - 4.42 (m, 1H), 3.93 - 3.54 (m, 6H), 3.19 - 2.97 (m, 3H), 2.70 (d, J = 168.8 Hz, 3H), 2.30 (d, J = 13.6 Hz, 6H), 1.96 - 1.37 (m, 14H), 1.31 - 1.19 (m, 6H), 1.09 - 0.83 (m, 1H).

[0649] [Example 25]

[0650] Preparation of 3-(1-(6-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)thieno[3,2-b]pyridin-3-yl)cyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0651]

[0652] Step 1] Preparation of methyl 3-amino-6-bromothieno[3,2-b]pyridine-2-carboxylate

[0653] Sodium ether-butoxyoxide (2.88 g, 30 mmol) was added in portions at 0°C to a solution of 5-bromo-3-nitropicolinonitrile (4.52 g, 20 mmol) and methyl 2-mercaptoacetate (2.54 g, 24 mmol) in N,N-dimethylformamide (60 mL), and the mixture was stirred for 2 hours. Once the reaction was complete, ice water was poured to terminate the reaction, and the mixture was extracted with ethyl ester. The organic layer was dried with anhydrous sodium sulfate, filtered, and subjected to vacuum distillation. The residue was then purified by column chromatography to obtain the target compound (4.00 g, 70%) as a brown solid.

[0654] LCMS(ESI): m / z 287.0 [M+H] +

[0655] Step 2] Preparation of methyl 3-amino-6-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)thieno[3,2-b]pyridine-2-carboxylate

[0656] The methyl 3-amino-6-bromothieno[3,2-b]pyridine-2-carboxylate (3432 mg, 12 mmol) obtained in Step 1 was reacted as in Step 2 of Example 22 to obtain the target compound (2400 mg, yield 68.9%).

[0657] LCMS(ESI): m / z 319.2 [M+H] +

[0658] Step 3] Preparation of methyl 3-amino-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)thieno[3,2-b]pyridine-2-carboxylate

[0659] The methyl 3-amino-6-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)thieno[3,2-b]pyridine-2-carboxylate (1.0 g, 3.1 mmol) obtained in Step 2 was reacted as in Step 3 of Example 22 to obtain the target compound (1.0 g, 100%).

[0660] LCMS(ESI): m / z 321.1 [M+H] +

[0661] Step 4] Preparation of methyl 3-bromo-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)thieno[3,2-b]pyridine-2-carboxylate

[0662] Isopentyl nitrite (544 mg, 4.65 mmol) was added at 0°C to a solution prepared in acetonitrile (20 mL) containing methyl 3-amino-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)thieno[3,2-b]pyridine-2-carboxylate (1000 mg, 3.1 mmol) and copper bromide (669.6 mg, 4.65 mmol) obtained in Step 3. The reaction solution was stirred at room temperature under a nitrogen atmosphere for 16 hours, and the solution was filtered. This solution was extracted with water and ethyl acetate, the organic layer was dried with anhydrous sodium sulfate, and then subjected to vacuum distillation. The residue was purified by column chromatography to obtain the target compound (382 mg, yield 32.2%).

[0663] LCMS(ESI): m / z 384.0 [M+H] +

[0664] Step 5] Preparation of methyl 6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(isooxazole-4-yl)thieno[3,2-b]pyridine-2-carboxylate

[0665] Methyl 3-bromo-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)thieno[3,2-b]pyridine-2-carboxylate (382 mg, 1.0 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isooxazole (390 mg, 2.0 mmol) obtained in Step 4 were dissolved in a solvent of dioxane (5 mL) and water (0.5 mL). Potassium fluoride (204 mg, 4 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane (81.6 mg, 0.2 mmol) were added to this solution. The solution was stirred at 90°C for 3 hours under a nitrogen atmosphere. When the reaction was complete, the solution was distilled under reduced pressure, and the resulting residue was purified by column chromatography to obtain the target compound (200 mg, yield 54%).

[0666] LCMS(ESI): m / z 373.2 [M+H] +

[0667] Step 6] Preparation of methyl 3-(cyanomethyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)thieno[3,2-b]pyridine-2-carboxylate

[0668] Methyl 6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(isooxazole-4-yl)thieno[3,2-b]pyridine-2-carboxylate (200 mg, 0.54 mmol) obtained in Step 5 and potassium fluoride (94 mg, 1.6 mmol) were dissolved in a mixed solvent of methanol (5 mL) and water (1 mL). This solution was reacted in a microwave reactor at 100°C for 2 hours. After the reaction was complete, the solution was distilled under reduced pressure, and the resulting residue was purified by column chromatography to obtain the target compound (100 mg, yield 54%).

[0669] LCMS(ESI): m / z 345.2 [M+H] +

[0670] Step 7] Preparation of 3-(1-cyanocyclopropyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)thieno[3,2-b]pyridine-2-carboxylic acid

[0671] Methyl 3-(cyanomethyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)thieno[3,2-b]pyridine-2-carboxylate (68.8 mg, 0.2 mmol) and 1,3,2-dioxathiolan 2,2-dioxide (49.6 mg, 0.4 mmol) obtained in Step 6 were reacted as in Step 6 of Example 19 to obtain a racemic target compound (8 mg, yield 22%).

[0672] LCMS(ESI): m / z 357.2 [M+H] + ,

[0673] Step 8] Preparation of Methyl 3-Bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylate

[0674] Diethyl azodicarboxylate (31855.2 mg, 182.92 mmol) was slowly added at 0°C to a solution prepared by dissolving methyl 5-bromo-1H-pyrazole-3-carboxylate (25000 mg, 121.95 mmol), tert-butyl(2-hydroxyethyl)carbamate (19657.6 mg, 121.95 mmol), and triphenylphosphine (63970.1 mg, 243.89 mmol) in tetrahydrofuran (300 mL), and then stirred at room temperature for 16 hours. After the reaction was complete, the solution was concentrated and extracted with water and ethyl ester. The resulting organic layer was dried with sodium sulfate, and the residue obtained by vacuum distillation was purified by column chromatography to obtain the target compound (35000 mg, yield 83%).

[0675] LCMS(ESI): m / z=292.0 [M-56+H] +

[0676] Step 9] Preparation of 3-Bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylic acid

[0677] Lithium hydroxide (4411.26 mg, 183.80 mmol) was added to a solution in which methyl 3-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylate (32000 mg, 91.90 mmol) obtained in Step 8 was dissolved in tetrahydrofuran (400 mL) and water (100 mL) solvents, and the mixture was stirred at room temperature for 3 hours. The solution was neutralized with 1N hydrochloric acid and filtered, and then the solution was subjected to vacuum distillation to obtain the target compound (25000 mg, yield 82%).

[0678] LCMS (ESI): m / z=278.0 [M-55+H] +

[0679] Step 10] Preparation of tert-butyl(2-(3-bromo-5-(methoxy(methyl)carbamoyl)-1H-pyrazole-1-yl)ethyl)carbamate

[0680] Diisopropylethylamine (29008 mg, 224.44 mmol) was slowly added at 0°C to a solution obtained in Step 9, in which 3-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylic acid (25000 mg, 74.81 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (42670 mg, 112.22 mmol), and N,N-dimethylhydroxylamine hydrochloride (10946 mg, 112.22 mmol) were dissolved in N,N-dimethylformamide (300 mL), and then stirred at room temperature for 16 hours. Once the reaction was complete, the mixture was extracted with water and ethyl ester. The organic layer was separated and dried with sodium sulfate, and the solution was distilled under reduced pressure. The resulting residue was purified by column chromatography to obtain the target compound (25 g, yield 89%).

[0681] LCMS(ESI): m / z=321.1 [M-55+H] +

[0682] Step 11] Preparation of tert-butyl(2-(5-acetyl-3-bromo-1H-pyrazole-1-yl)ethyl)carbamate

[0683] To a solution in which tert-butyl(2-(3-bromo-5-(methoxy(methyl)carbamoyl)-1H-pyrazole-1-yl)ethyl)carbamate (25,000 mg, 66.27 mmol) obtained in Step 10 was dissolved in tetrahydrofuran (300 mL), 1 M methyl magnesium bromide solution (270 mL) was slowly added at 0°C, and the mixture was stirred at room temperature for 16 hours. Once the reaction was complete, a saturated ammonium chloride solution was added to the solution to stop the reaction, and the mixture was extracted with water and ethyl ester. The organic layer was separated, dried with sodium sulfate, and subjected to vacuum distillation to obtain the target compound (20 g, yield 90%).

[0684] LCMS(ESI): m / z=276.1 [M-55+H] +

[0685] Step 12] Preparation of 2-Bromo-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine

[0686] After adding hydrochloric acid / dioxane (300 mL) to a solution in which tert-butyl(2-(5-acetyl-3-bromo-1H-pyrazole-1-yl)ethyl)carbamate (20,000 mg, 60.2 mmol) obtained in Step 11 was dissolved in dioxane (500 mL), the mixture was stirred at room temperature for 3 hours. The solution was subjected to vacuum distillation to obtain the target compound (10,000 mg, yield 78%).

[0687] LCMS: MS(ESI): m / z 214.1 [M+H] +

[0688] Step 13] Preparation of 2-Bromo-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

[0689] Sodium borohydride (7068.72 mg, 186.85 mmol) was slowly added at 0°C to a solution of 2-bromo-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine (10000 mg, 46.71 mmol) obtained in Step 12 dissolved in methanol (100 mL), and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was extracted with water and ethyl ester, the organic layer was separated, and the solution was dried with sodium sulfate. The target compound (8000 mg, yield 80%) was obtained by vacuum distillation.

[0690] LCMS (ESI): m / z= 216.1 [M+H] +

[0691] Step 14] Preparation of 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

[0692] [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (2030.09 mg, 2.77 mmol) was added to a solution obtained in Step 13 in which 2-bromo-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (8000 mg, 46.24 mmol), 2-(4-fluoro-3,5-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (100084.97 mg, 46.24 mmol), and potassium carbonate (19171.15 mg, 138.72 mmol) were dissolved in dioxane (100 mL) and water (20 mL), and the mixture was stirred at 100°C for 2 hours. When the reaction was complete, the solution was concentrated, extracted with water and ethyl ester, the organic layer was dried with sodium sulfate, and then subjected to vacuum distillation to obtain the target compound (10 g, yield 83%).

[0693] LCMS (ESI): m / z= 260.1 [M+H] +

[0694] Step 15] Preparation of tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

[0695] Di-tert-butyl dicarbonate (26015.5 mg, 77.12 mmol) was slowly added at 0°C to a solution obtained in Step 14, in which 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (10000 mg, 38.56 mmol) and diisopropylethylamine (210.25 mg, 1.63 mmol) were dissolved in dichloromethane (200 mL), and then the mixture was stirred at room temperature for 3 hours. Once the reaction was complete, the mixture was concentrated and the residue was purified by column chromatography to obtain the target compound (10.7 g, yield 78%).

[0696] LCMS (ESI): m / z= 360.2 [M+H] +

[0697] Step 16] Preparation of tert-butyl 3-bromo-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

[0698] N-bromosuccinimide (4951.5 mg, 27.82 mmol) was added to a solution obtained in Step 15, in which tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (10000 mg, 27.82 mmol) was dissolved in acetonitrile (100 mL), and the mixture was stirred at 0 °C for 6 hours. After the reaction was complete, the solution was distilled under reduced pressure, and the resulting residue was purified by column chromatography to obtain the target compound (10 g, yield 82%).

[0699] LCMS (ESI): m / z= 438.1 [M+H] +

[0700] Step 17] Preparation of tert-butyl 3-((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

[0701] After adding Zanphos (2112.0 mg, 3.65 mmol) and Tris(dibenzylideneacetone)dipalladium (3133.6 mg, 3.42 mmol) to a solution obtained in Step 16 in which tert-butyl 3-bromo-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (10000 mg, 22.81 mmol), diphenylmethaneimine (6202.0 mg, 34.22 mmol), and tert-sodium butoxyoxide (8769.4 mg, 91.25 mmol) were dissolved in toluene (100 mL), the solution was stirred at 110°C for 16 hours. After the reaction was complete, the organic layer was extracted with water and ethyl acetate, dried with magnesium sulfate, and distilled under reduced pressure. The resulting residue was purified by column chromatography to obtain the target compound (9 g, yield 73%).

[0702] LCMS (ESI): m / z= 539.3 [M+H] +

[0703] Step 18] Preparation of tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

[0704] Sodium acetate (6478.5 mg, 50.12 mmol) was slowly added at 0°C to a solution obtained in Step 17, in which tert-butyl 3-((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (9000 mg, 16.71 mmol) and hydroxylamine hydrochloride (2322.1 mg, 33.42 mmol) were dissolved in methanol (180 mL), and then the mixture was stirred at room temperature for 48 hours. The mixture was concentrated and purified by reverse-phase chromatography to obtain the target compound (3900 mg, yield 62%).

[0705] LCMS (ESI): m / z= 375.2 [M+H] +

[0706] Step 19] Preparation of tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

[0707] N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (8299.1 mg, 41.66 mmol) was added to a solution obtained in Step 18, in which tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (3900 mg, 10.41 mmol) was dissolved in dioxane (50 mL), and the mixture was stirred at 100°C for 2 hours. After the reaction was complete, the solution was concentrated and the residue was purified by column chromatography to obtain the target compound (4 g, yield 76%).

[0708] LCMS(ESI): m / z= 506.3 [M+H] +

[0709] Step 20] Preparation of tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazole-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

[0710] Methanesulfonic acid (703.4 mg, 7.32 mmol) was added to a solution in which tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (3700 mg, 7.32 mmol) obtained in Step 19 was dissolved in tetrahydrofuran (50 mL), and the mixture was stirred at 60°C for 4 hours. After the reaction was complete, the mixture was extracted with an aqueous 1N sodium bicarbonate solution and an ethyl ester, the organic layer was dried with sodium sulfate, and the residue was distilled under reduced pressure. The resulting residue was purified by column chromatography to obtain the target compound (2800 mg, yield 87%).

[0711] LCMS(ESI): m / z= 442.1 [M+H] +

[0712] Step 21] Preparation of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

[0713] The tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazole-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (385.5 mg, 0.87 mmol) obtained in Step 20 was reacted as in Step 1 of Example 1 to obtain the target compound (118 mg, yield 22%).

[0714] LC-MS: m / z 621.3 [M+H] + .

[0715] Step 22] Preparation of (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-yl)-3-(9-methyl-9H-carbazole-3-yl)-1,3-dihydro-2H-imidazole-2-one

[0716] The tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (118 mg, 0.19 mmol) obtained in Step 21 was reacted as in Step 2 of Example 1 to obtain the target compound (98.9 mg, 100%).

[0717] MS(ESI): m / z 521.2 [M+H] +

[0718] Step 23] Preparation of 1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)thieno[3,2-b]pyridine-3-yl)cyclopropane-1-carbonitrile

[0719] The 3-(1-cyanocyclopropyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)thieno[3,2-b]pyridine-2-carboxylic acid (7 mg, 0.02 mmol) obtained in Step 7 and the (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-yl)-3-(9-methyl-9H-carbazole-3-yl)-1,3-dihydro-2H-imidazole-2-one (10.4 mg, 0.02 mmol) obtained in Step 22 were reacted as in Step 3 of Example 1 to obtain the target compound (5 mg, yield 29%).

[0720] LCMS(ESI): m / z 859.1 [M+H] +

[0721] Step 24] Preparation of (Z)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)thieno[3,2-b]pyridine-3-yl)-N'-hydroxycyclopropane-1-carboxyimideamide

[0722] The 1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)thieno[3,2-b]pyridine-3-yl)cyclopropane-1-carbonitrile (5 mg, 0.025 mmol) obtained in Step 23 was reacted as in Step 7 of Example 19 to obtain the target compound (3 mg, yield 80%).

[0723] LCMS(ESI): m / z 892.3 [M+H] +

[0724] [Step 25] Preparation of 3-(1-(6-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)thieno[3,2-b]pyridine-3-yl)cyclopropyl)-1,2,4-oxadiazole-5(4H)-one

[0725] The (Z)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)thieno[3,2-b]pyridine-3-yl)-N'-hydroxycyclopropane-1-carboxyimideamide (3 mg, 0.003 mmol) obtained in Step 24 was reacted as in Step 8 of Example 19 to obtain the target compound (1 mg, yield 36%).

[0726] LCMS(ESI): m / z 918.3 [M+H] +

[0727]

[0728] [Experimental Example 1] Measurement of In Vitro cAMP Signaling Activation of Human GLP-1 Receptor

[0729] To evaluate whether the compounds of the aforementioned examples possess GLP-1 receptor stimulating activity, the cAMP increase response in cells was measured.

[0730] Human GLP-1 receptor agonist activity was detected in HEK293 cells transformed to stably express the human GLP-1 receptor using the cAMP Gs dynamic kit (Cisbio, USA, catalog number 62AM4PEC).

[0731] Specifically, GLP-1 cells are thawed in 37°C water, and the suspension is placed in HBSS solution in a conical tube. The cells are pelleted by centrifuging at 1000 rpm for 5 minutes at room temperature, the supernatant is removed, and the cells are resuspended in HBSS solution to check cell viability. Cells are placed in assay buffer containing 0.1% BSA and 0.5 mM IBMX at a rate of 2.5 x 10⁶ 5The cells were resuspended at a concentration of cells / mL. The compound solution and cell suspension were added to each well of a 384 white black plate and incubated at 37°C for 30 minutes. Afterward, 10 μL of HTRF cAMP detection solution was added, a sealing film was attached, and the plate was incubated at room temperature for 1 hour. As positive control ligands, the GLP-1 receptor agonist peptide exendin-4 or the GLP-1 receptor agonist small organic molecule orforglyphorone were used. HTRF signals were read at 665 and 615 nm using an EnVision plate reader, and cAMP concentrations were calculated by interpolating standard curves.

[0732] Thus, the half-effective concentration (EC) of the evaluation compound and the positive control for GLP-1 receptor activation according to the in vitro cAMP signaling activation experiment 50 Find ) and EC 50 The values ​​were classified into grades A if they were less than 10 nM, B if they were 10 nM or more and less than 100 nM, and C if they were greater than 100 nM, as shown in Table 2.

[0733]

[0734]

[0735] [Experimental Example 2] Pharmacokinetics experiment after oral administration in mice

[0736] The pharmacokinetic properties of the compounds of the aforementioned examples upon oral administration were evaluated.

[0737] Pharmacokinetic studies were conducted on male C57BL / 6J mice (n=3) following oral administration of the drug. The test substance was prepared by dissolving the free base form of the positive control compound (danuglyfone or orforglyfone, which are small organic molecules of GLP-1 receptor agonists) or the example compound in a solvent of 10% DMSO, 10% Cremophore EL, 10% PEG400, and 70% glycine-sodium hydroxide buffer solution (0.08 M, pH 10). The dosage was 3 mg / kg and was administered as a single oral dose.

[0738] Blood samples were collected at a total of eight time points after administration: 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Plasma samples at each time point were analyzed using LC-MS / MS. Changes in blood drug concentration over time were measured and are shown in Figure 1, with the values ​​summarized in Table 3.

[0739]

[0740] As shown in Fig. 1, Examples 1 and 6 exhibit higher area under the curve (AUC) values ​​compared to the positive control compound, demonstrating pharmacokinetic characteristics of superior in vivo exposure at the same dose. Furthermore, compared to the positive control, these compounds T max The absorption is delayed and exhibits a relatively slow pattern, which can be interpreted as a characteristic favorable for maintaining the drug's sustained effect. In particular, these compounds have a half-life (T 1 / 2 Since the length is significantly longer compared to danuglyfone and orforglyfone, it suggests the possibility of application as a once-daily oral formulation.

[0741] Although the present invention has been described above by limited embodiments, the technical concept and scope of the present invention are not limited to these embodiments. Various modifications or variations of the invention described in the claims below, which are obvious to those skilled in the art to which this invention belongs, are also included within the scope of the present invention within the equivalent scope of the invention described in the claims.

Claims

1. Compounds of Formula 1A or Formula 1B, or their tautomeric isomers, stereoisomers, or pharmaceutically acceptable salts thereof: [Chemical Formula 1A] [Chemical Formula 1B] In chemical formulas 1A and 1B, m is an integer from 0 to 8; Each R 1 C independently of each other 1~4 It is a substituent selected from the group consisting of alkyl, halogen, CN, NO2, and CF3, wherein when m is 2 or more, each R 1 Select m turns independently of each other; R 2 is hydrogen, C 1~4 Alkyl and halo-C 1~4 It is a substituent selected from the group consisting of alkyls; k is an integer from 0 to 5, and R 3 Silver halogens, CN, CF3, OCF3, OH, NO2, NR A R B , C 1~4 Alkyl, C 3~8 Cycloalkyl, 5-9 member heterocycloalkyl, C 6~10 Aril, Halo C 1~4 Alkyl, hydroxy C 1~4 Alkyl and C 1~4 It is a substituent selected from the group consisting of alkyloxy groups, wherein when k is 2 or more, each R 3 Select k times independently, and R A and R B Each independently of hydrogen or C 1~3 It is alkyl; Z 1 and Z 2 Among them, one is N and the other is C; n is an integer from 0 to 3, and Z 3 C 1~3 Alkyl, Halo C 1~3 Alkyl, C(=O)C 1~3 Alkyl, halogen, OH, NH2, NH(C 1~3 alkyl) and (C 1~3 Alkyl)N(C 1~3 It is a substituent selected from the group consisting of alkyl groups, wherein when n is 2 or more, each Z 3 Select n times independently of each other, X 1 is NH, NR 4 , NC(=O)-R 5 , O, S or C(=O), and in this case R 4 is C 1~4 Alkyl, (CH2) i C 3~6 Cycloalkyl, (CH2) i CH=CH2, (CH2) i CH=CH-(C 1~3 alkyl), (CH2) i C≡CH, (CH2) i C≡C 1~3 alkyl), (CH2) i 5~9-membered heterocycloalkyl, (CH2) i C 6~10 Aril, (CH2) i C 5~10 Heteroaryl or NR C R D and, where i is an integer from 0 to 3, and R C and R D Each independently of hydrogen or C 1~3 It is an alkyl, where R 5 is C 1~3 Alkyl, (CH2) j C 3~6 Cycloalkyl, (CH2) j CH=CH2, (CH2) j CH=CH-(C 1~3 alkyl), (CH2) j C≡CH, (CH2) i C≡C(C 1~3 alkyl), (CH2) j 5~9-membered heterocycloalkyl, (CH2) j C 6~10 Aril, (CH2) j C 5~10 Heteroaryl or NR E R F and, where j is an integer from 0 to 3, and R E and R F Each independently of hydrogen or C 1~3 It is alkyl; Is It is a substituted or unsubstituted 5- to 6-membered saturated or unsaturated hydrocarbon ring forming a triple fusion ring together with, or a substituted or unsubstituted 5- to 6-membered saturated or unsaturated heterocyclic ring comprising 1 to 3 cyclic heteroatoms, wherein the substituted 5- to 6-membered saturated or unsaturated hydrocarbon ring or the substituted 5- to 6-membered saturated or unsaturated heterocyclic ring has one or more hydrogens C 1~3 Alkyl, Halo C 1~3 Alkyl, C(=O)C 1~3 Alkyl, halogen, OH, NH2, NH(C 1~3 alkyl) and (C 1~3 Alkyl)N(C 1~3 It is a ring substituted with a substituent selected independently from each other in each case from the group consisting of alkyls, and is a 5-6-membered fused bicyclic heteroaryl or a 6-membered fused bicyclic heteroaryl; At this time, each of the above 5-6-membered fused bicyclic heteroaryls or 6-6-membered fused bicyclic heteroaryls optionally has one or more hydrogens C 1~3 Alkyl, Halo C 1~3 Alkyl, C 1~3 It may be a ring substituted with a functional group selected independently from each other in each case from the group consisting of alkoxy and halogen.

2. In Paragraph 1, A compound characterized by being selected from the group consisting of indole, benzimidazole, benzofuranyl, benzothiophen, pyrrolopyridine, pyrazolopyridine, pyrrolopyrimidine, oxazolopyridine, thiazolopyridine, thienopyridine, furopyridine, imidazopyridine, imidazopyrimidine, purine, and indolizine.

3. A compound according to claim 1, characterized in that the compound or its tautomer or stereoisomer has the structure of Formula 2A or Formula 2B: [Chemical Formula 2A] [Chemical Formula 2B] Q in Chemical Formulas 2A and 2B 1 to Q 7 silver a) Q 2 ga is O, S or NH, and Q 1 , Q 3 and Q 4 While being C, Q 5 , Q 6 and Q 7 Each independently selects between CH and N, or b) Q 1 , Q 3 and Q 4 One of them is N, and the rest are all C, and Q 2 , Q 5 , Q 6 and Q 7 Each is independently selected from CH and N.

4. A compound according to paragraph 3, characterized in that m is an integer from 1 to 2 and k is an integer from 1 to 2.

5. A compound according to claim 3, characterized in that the compound or its tautomer and its stereoisomer have the structure of Formula 3: [Chemical Formula 3] X in Chemical Formula 3 2 is NH, NC 1~4 Alkyl, NC 3~6 Cycloalkyl, NCH2-C 3~6 Cycloalkyl, NC 6~10 Aryl, NCH2-C 6~10 Aril, NCH2CH=CH2, NC(=O)-R 6 It is any one selected from the group consisting of , O, S and C(=O), and in this case, R 6 C 1~3 Alkyl, (CH2) o C 3~6 Cycloalkyl, CH=CH2, CH=CH-(C 1~3 Alkyl), C≡CH, C≡C(C 1~3 alkyl), (CH2) o (3~6-membered heterocycloalkyl), (CH2) o C 6~10 Aryl or NHC 1~3 It is alkyl, where j is an integer from 0 to 3; X 3 is a functional group selected from the group consisting of CH, CH2 and N; p is an integer from 0 to 3; Z 4 is C 1~3 Alkyl, Halo C 1~3 Alkyl, C(=O)C 1~3 Alkyl, halogen, OH, NH2, NH(C 1~3 alkyl) and (C 1~3 Alkyl)N(C 1~3 It is a substituent selected from the group consisting of alkyl groups, wherein when p is 2 or more, each Z 4 Select p times independently of each other.

6. A compound according to claim 5, characterized in that the compound or its tautomer and its stereoisomer have the structure of Formula 4: [Chemical Formula 4] R in Chemical Formula 4 6 and R 7 Silver is hydrogen, C 1~4 Alkyl, Halo C 1~4 It is a substituent selected independently from the group consisting of alkyl and halogens.

7. The compound according to claim 1, characterized in that the compound or its tautomer or its stereoisomer has the structure of Formula 5 or Formula 6: [Chemical Formula 5A] [Chemical Formula 5B] R in Chemical Formulas 5A and 5B 6 and R 7 Silver is hydrogen, C 1~4 Alkyl, Halo C 1~4 Substituents independently selected from the group consisting of alkyl and halogens; R 8 is a substituent selected r times independently from the group consisting of methyl and halogen; where r is an integer from 0 to 3; R 9 is hydrogen, methyl, and isopropyl. X 4 is CH or N.

8. Any compound selected from the group consisting of the following compounds, its stereoisomers, tautomers, solvates, or pharmaceutically acceptable salts thereof: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(2-((S)-3-(3-(9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(9-ethyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(2-((S)-3-(3-(9-cyclopropyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(2-((S)-3-(3-(9-acetyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(9-isopropyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(5-methyl-5H-pyrido[4,3-b]indole-8-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-methyl-1,2,3,4-tetrahydrocyclopenta[b]indole-7-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(2-((S)-3-(3-(dibenzo[b,d]furan-2-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-2,3,4,9-tetrahydro-1H-carbazole-6-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-2-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(9-oxo-9H-fluorene-3-yl)-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(2-((S)-2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(2-((S)-3-(3-(6,9-dimethyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(2-((S)-2-(4-cyclopropyl-3-fluorophenyl)-3-(3-(9-isopropyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(4-hydroxy-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(2-((S)-3-(3-(5-chloro-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(2-((S)-3-(3-(6-acetyl-9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(5-isopropyl-5H-pyrido[4,3-b]indole-8-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-(1-(2-((S)-2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolezine-3-yl)cyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-(1-(2-((S)-2-(4-cyclopropyl-3-fluorophenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolezine-3-yl)cyclopropyl)-1,2,4-oxadiazole-5(4H)-one, 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-4-(methylamino)-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one and 3-(1-(6-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-9H-carbazole-3-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)thieno[3,2-b]pyridine-3-yl)cyclopropyl)-1,2,4-oxadiazole-5(4H)-one.

9. A pharmaceutical composition comprising a therapeutically effective amount of one compound according to claim 1 and a pharmaceutically acceptable excipient.

10. A pharmaceutical composition for the treatment or prevention of type 2 diabetes, hyperglycemia, impaired glucose tolerance, type 1 diabetes, diabetic complications, obesity, hypertension, dyslipidemia, arteriosclerosis, myocardial infarction, coronary heart disease, cerebral infarction, or metabolic disorder-associated fatty liver disease (MASLD), comprising as an active ingredient a compound according to claim 1 or its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof.

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