Pyrazole derivatives as STING agonists

Abstract

The present invention provides a novel compound having the general formula: [Chemical Formula 1] TIFF2025516688000237.tif27170(wherein ring A, ring B, ring C, bond a, and R 1 ~R 7 are as defined herein), or a pharmaceutically acceptable salt thereof, a composition comprising the compound, and a method of using the compound.

Description

Technical Field

[0001] The present invention relates to organic compounds useful for the treatment of mammalian cancers, and particularly to STING agonists. In particular, the present invention relates to pyrazole derivatives having STING agonism activity, and to their production, pharmaceutical compositions containing them, and their potential use as medicaments.

Background Art

[0002] Cancer immunotherapy (CIT) represented by immune checkpoint inhibitors (ICI) has rapidly emerged in the past few years. The key to an effective CIT-mediated antitumor response is the priming and activation of T cells by antigen-presenting cells, followed by the directed transport and infiltration of T cells into the tumor mass so that the T cells recognize and kill cancer cells (Chen DS, et al. Immunity. 2013;39). Thus, blockade of immune checkpoints shows only a durable response in highly immunogenic "hot" tumors, but little efficacy in non-immunogenic "cold" tumors characterized by lack of T cell infiltration and impaired T cell priming. Therefore, the focus is on promoting the transformation from "cold tumors" to "hot tumors" using strategies to activate the innate immune system so as to re-engage non-immunogenic tumors by enhancing anti-cancer adaptive immunity. Antigen-presenting cells of the innate immune system, such as dendritic cells or macrophages, function as an important link between the innate and adaptive immune systems by phagocytosis, which processes foreign antigens and presents them to T cells on the cell surface, thereby activating the T cell response.

[0003] Interferon gene stimulator (STING) is a four-transmembrane endoplasmic reticulum adapter that promotes innate immune signaling. Activation of the STING protein by its natural ligand, cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), can activate the NF-kB and IRF3 transcriptional pathways, inducing the expression of type I interferons and pro-inflammatory cytokines / chemokines (Ishikawa.et al.Nature 2008, Quyang.et al.Immunity 2012, Chen.et al.Cell 2011).

[0004] STING activation enhances the immune response and suppresses tumor growth, which is achieved by strengthening cancer antigen presentation, contributing to T cell priming and activation, promoting the transport and infiltration of T cells into tumors, and promoting the recognition and killing of cancer cells by T cells. First-generation tumor-injected cyclic dinucleotides that have entered clinical development have shown limited single-agent activity mainly due to insufficient pharmacokinetic and physicochemical properties, i.e., low bioavailability, instability, and difficulty in bypassing the plasma membrane (Leila et al.J.Clin.Med.2020, Afsaneh et al.Cancers 2021).

Summary of the Invention

[0005] The object of the present invention is a novel compound of formula (I), its production, a medicament based on the compound according to the present invention and its production, and the use of the compound of formula (I) as a STING agonist for the treatment of a wide range of cancers that may enhance the response rate to current immunotherapies and overcome acquired resistance. The compounds of formula (I) exhibit excellent STING agonism activity. Furthermore, the compounds of formula (I) also exhibit good safety and a good PK profile, e.g., good solubility, microsomal stability, permeability, and safety margin.

[0006] One aspect of the present invention is formula (I),

Chemical formula

[0007] Another aspect of the present invention relates to a method for producing a compound of formula (I), and to a compound of formula (I) or a pharmaceutically acceptable salt thereof when produced according to this method.

[0008] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0009] Another aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a therapeutic active substance.

[0010] Another aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

[0011] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of cancer.

[0012] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the activation of STING.

[0013] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cancer.

[0014] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the activation of STING.

[0015] Another aspect of the present invention relates to a method for treating cancer, which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Mode for Carrying Out the Invention

[0016] Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, the following definitions are provided to illustrate and define the meaning and scope of the various terms used in the description of the present invention.

[0017] The nomenclature used in this application is based on the IUPAC systematic nomenclature unless otherwise indicated.

[0018] The terms "compound of this invention" and "compound of the present invention" refer to compounds of formula (I), formula (Ia), and formula (Ib) and their stereoisomers, solvates or salts (e.g., pharmaceutically acceptable salts).

[0019] The term "substituent" represents an atom or group of atoms that replaces a hydrogen atom of the parent molecule.

[0020] As used herein, "C 1~6 alkyl" alone or in combination means a saturated straight-chain or branched-chain alkyl group containing 1 to 6, particularly 2 to 6 or 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc. Specific "C 1~6 " alkyl groups are methyl and ethyl.

[0021] The term "halogen" represents fluoro, chloro, bromo or iodo.

[0022] "HaloC 1~6 The term "alkyl" means an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced by the same or different halogen atoms, especially fluorine atoms. HaloC 1~6 Examples of haloalkyl include monochloro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, for example, difluoromethyl.

[0023] The term "heteroaryl" represents a monovalent aromatic heterocyclic monocyclic or bicyclic ring system of 5 to 12 ring atoms containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Examples of heteroaryl moieties include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl. Heteroaryl can be further substituted by halogen, C 1~6 alkyl, haloC 1~6 alkyl, cyano, C 3~7 cycloalkyl, (C 1~6 alkyl) 2 amino or C 1~6 alkoxy.

[0024] The term "heterocyclyl" refers to a monocyclic or bicyclic ring system of 3 to 9 ring atoms, containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. In certain embodiments, heterocyclyl is a monovalent saturated monocyclic ring system consisting of 4 to 7 ring atoms, containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of monocyclic saturated heterocyclyls include aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, oxopiperidinyl, oxopiperazinyl, or oxopyrrolidinyl. Examples of bicyclic saturated heterocyclyls include azaspiro[3.3]heptanyl, 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocyclyls include dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl.

[0025] "Hydroxy-C 1~6 -alkyl" refers to a C 1~6 -alkyl group in which at least one of the hydrogen atoms of the C 1~6 -alkyl group is replaced by a hydroxy group.

[0026] The compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to conventional acid addition salts or base addition salts formed from pharmaceutically acceptable non-toxic organic or inorganic acids or organic or inorganic bases, which retain the biological effectiveness and properties of the compounds of formula (I). Acid addition salts include, for example, those obtained from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, and those obtained from organic acids such as p-toluenesulfonic acid, trifluoroacetic acid, formic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, etc. Base addition salts include those derived from ammonium, potassium, sodium, and quaternary ammonium hydroxides, for example, tetramethylammonium hydroxide. Chemical modification of pharmaceutical compounds to salts is a technique well-known to pharmacists in order to obtain improved physical and chemical stability, hygroscopicity, fluidity, and solubility of the compounds. This is described, for example, in Bastin R.J., et al., Organic Process Research & Development 2000, 4, 427-435. In particular, it is the sodium salt of the compound of formula (I).

[0027] The term "therapeutically effective amount" refers to an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents a specific disease, condition, or disorder, (ii) attenuates, alleviates, or eliminates one or more symptoms of a specific disease, symptom, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The therapeutically effective amount can vary depending on the compound, the condition of the disease being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0028] The term "pharmaceutical composition" refers to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with a pharmaceutically acceptable excipient, which is administered to a mammal, for example, a human in need thereof.

[0029] STING agonist The present invention relates to (i) formula (I),

Chemical formula

[0030] A further embodiment of the present invention is (ii) a compound of formula (I) described in (i), or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from pyridyl, imidazo[1,5-a]pyrazinyl, imidazo[1,5-a]pyridinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-c]pyrimidinyl, pyrazolo[3,4-c]pyridinyl, and 1H-pyrazolo[4,3-c]pyridinyl, R 1 is carbamoyl, R 2 is C 1~6 Alkyl, halo C 1~6 Alkyl, halogen, acyl, and a 5- to 8-membered monocyclic heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, and preferably, R 2 is C 1~6 alkyl, R 3 is absent or is halogen, Ring B is

Chemical formula

[0031] A further embodiment of the present invention is a compound of formula (I) as described in (iii) (i) or (ii), or a pharmaceutically acceptable salt thereof, wherein, The substituted ring A is,

Chemical formula

[0032] A further embodiment of the present invention is a compound of formula (I) as described in any one of (iv) (i) to (iii) or a pharmaceutically acceptable salt thereof, wherein, The substituted ring A is,

Chemical formula

[0033] A further embodiment of the present invention is a compound of formula (I) as described in any one of (v) (i) to (iii) or a pharmaceutically acceptable salt thereof, wherein, R 1 is carbamoyl, R 2 is selected from methyl, difluoromethyl, acetyl, chloro and imidazolyl, R 3 is absent or is fluoro.

[0034] A further embodiment of the present invention is a compound of formula (I) as described in any one of (vi) (i) to (v) or a pharmaceutically acceptable salt thereof, wherein, R 1 is carbamoyl, R 2 is methyl, R 3 is absent or is fluoro.

[0035] A further embodiment of the present invention is a compound of formula (I) according to any one of (i) to (vi) or a pharmaceutically acceptable salt thereof, wherein ring B is selected from triazolyl, oxazolyl, oxadiazolyl and pyrimidinyl.

[0036] A further embodiment of the present invention is a compound of formula (I) according to any one of (i) to (vii) or a pharmaceutically acceptable salt thereof, wherein the substituted ring B is

Chemical formula

[0037] A further embodiment of the present invention is a compound of formula (I) according to any one of (i) to (viii) or a pharmaceutically acceptable salt thereof, wherein the substituted ring B is

Chemical formula

[0038] A further embodiment of the present invention is a compound of formula (I) according to any one of (i) to (viii) or a pharmaceutically acceptable salt thereof, wherein R 4 is absent or is selected from methyl, difluoromethyl, aminomethyl, hydroxymethyl and carbamoyl.

[0039] A further embodiment of the present invention is a compound of formula (I) according to any one of (i) to (x) or a pharmaceutically acceptable salt thereof, wherein R 4 is absent or is selected from methyl and hydroxymethyl.

[0040] A further embodiment of the present invention is a compound of formula (I) according to any one of (i) to (xi) or a pharmaceutically acceptable salt thereof, wherein the substituted ring C is [Chemical formula] as defined in (i) to (xi).

[0041] A further embodiment of the present invention is a compound of formula (I) according to any one of (i) to (xii) or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from ethyl, propyl, butyl, cyclopropyl, cyclopropylmethyl, 3,3-difluoropropyl, 3,3-difluoroallyl, 2-cyanoethyl, 3-cyanopropyl, 3-hydroxypropyl, 2-imidazol-1-ylethyl, 2-(triazol-2-yl)ethyl, 2-(triazol-1-yl)ethyl, 2-(1,2,4-triazol-4-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl, 3-fluoropropyl, 2-methoxyethyl, 3-methoxypropyl, 1-pent-3-ynyl, 5-methoxypent-3-ynyl, 2-phenylethyl, 2-(4-methoxyphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-[4-(methoxymethyl)phenyl]ethyl, 2-[3-(methoxymethyl)phenyl]ethyl, 2-(4-fluorophenyl)ethyl, 2-(3-fluorophenyl)ethyl, 2-(3-cyanophenyl)ethyl, 2-(4-cyanophenyl)ethyl, 2-(4-methoxycarbonylphenyl)ethyl, 2-[4-(hydroxymethyl)phenyl]ethyl, 2-pyridin-4-ylethyl, 2-(3-pyridyl)ethyl, 2-[4-(morpholinomethyl)phenyl]ethyl, and 2-thiazol-2-ylethyl; R 6 is absent or is methyl, R 7 is absent, fluoro, amino, or hydroxyl, or R 6 and R 7 together with the atom to which they are attached form a 5-membered ring. A further embodiment of the present invention is a compound of formula (I) according to any one of (xiv) (i) to (xiii), or a pharmaceutically acceptable salt thereof, wherein, R 5 is selected from propyl, butyl, cyclopropylmethyl, 3,3-difluoroallyl, 3-fluoropropyl, 3,3-difluoropropyl, 1-pent-3-ynyl, 2-(3-pyridyl)ethyl, 2-phenylethyl, 2-(4-methoxyphenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(3-fluorophenyl)ethyl, 2-[4-(methoxymethyl)phenyl]ethyl, 2-[3-(methoxymethyl)phenyl]ethyl, 2-[4-(hydroxymethyl)phenyl]ethyl, and 2-[4-(morpholinomethyl)phenyl]ethyl, R 6 is methyl, R 7 is hydroxyl. A further embodiment of the present invention is a compound of formula (I) according to any one of (xv) (i) or (ii) or a pharmaceutically acceptable salt thereof, wherein, the substituted ring A is

Chemical formula

Chemical formula

Chemical formula

[0042] A further embodiment of the present invention is a compound of formula (I) as described in (xvi)(xv), or a pharmaceutically acceptable salt thereof, wherein R 1 is carbamoyl, R 2 is methyl, R 3 is absent or is fluoro, R 4 is absent or is selected from methyl and hydroxymethyl, R 5is selected from propyl, butyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3-difluoroallyl, 1-pent-3-ynyl, cyclopropylmethyl, 2-(3-pyridyl)ethyl, 2-phenylethyl, 2-(4-methoxyphenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(3-fluorophenyl)ethyl, 2-[4-(methoxymethyl)phenyl]ethyl, 2-[3-(methoxymethyl)phenyl]ethyl, 2-[4-(hydroxymethyl)phenyl]ethyl, and 2-[4-(morpholinomethyl)phenyl]ethyl, R 6 is methyl, R 7 is hydroxyl.

[0043] A further embodiment of the present invention is a compound of formula (I) as described in (xvii)(xv), or a pharmaceutically acceptable salt thereof, wherein, R 1 is carbamoyl, R 2 is C 1~6 alkyl, R 3 is absent or is halogen, R 4 is absent or is hydroxy C 1~6 alkyl, R 5 is C 1~6 alkyl, halo C 1~6 alkyl, pyridinyl C 1~6 alkyl and phenyl C 1~6 alkyl (wherein phenyl C 1~6 alkyl is optionally substituted by halogen, C 1~6 alkoxy, C 1~6 alkoxy C 1~6 alkyl or hydroxy C 1~6 alkyl), and is preferably R 5 is C 1~6 alkyl, halo C 1~6 alkyl and phenyl C 1~6 alkyl (wherein phenyl C 1~6 alkyl is C1~6 is optionally substituted by an alkoxy group), and is selected from R 6 is a C 1~6 alkyl group, R 7 is hydroxyl.

[0044] A further embodiment of the present invention is a compound of formula (I) as described in (xviii)(xvii), or a pharmaceutically acceptable salt thereof, wherein R 1 is carbamoyl, R 2 is methyl, R 3 is absent or is fluoro, R 4 is absent or is hydroxymethyl, R 5 is selected from propyl, butyl, 3,3-difluoropropyl, 2-(3-pyridyl)ethyl, 2-phenylethyl, 2-(4-methoxyphenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(3-fluorophenyl)ethyl, 2-[4-(methoxymethyl)phenyl]ethyl and 2-[4-(hydroxymethyl)phenyl]ethyl, preferably R 5 is selected from propyl, butyl, 3,3-difluoropropyl, 2-phenylethyl and 2-(4-methoxyphenyl)ethyl, R 6 is methyl, R 7 is hydroxyl.

[0045] A further embodiment of the present invention is (xix) 1-[3-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-[5-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-2-methyl-1,2,4-triazol-3-yl]-6-[1,5-a]pyrazine-3-carboxamide, 8-[3-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, 8-[3-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, 4-Acetyl-6-[3-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]pyridine-2-carboxamide, 6-[3-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-4-imidazol-1-yl-pyridine-2-carboxamide, 4-[2-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)pyrimidin-4-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide, 1-[2-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)pyrimidin-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-[2-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 4-[5-(Difluoromethyl)-2-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide, 1-[5-(Aminomethyl)-2-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 4-(6-Carbamoyl-1-methyl-pyrazolo[4,3-c]pyridin-4-yl)-2-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazole-5-carboxamide, 4-[3-(2-Ethyl-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide, 1-[3-[2-(3-Hydroxypropyl)-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-[3-(2-Ethyl-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-[3-(2-Ethyl-4-fluoro-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-[3-(4-Amino-2-ethyl-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 6-Chloro-1-[3-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]imidazo[1,5-a]pyrazine-3-carboxamide, 1-[3-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyridine-3-carboxamide, 7-[3-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxamide, 1-[2-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 4-[3-[4-Hydroxy-2-(2-imidazol-1-ylethyl)-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide, 4-[3-[2-(3-Cyanopropyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide, 4-[3-[2-(2-Cyanoethyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide, 6-(Difluoromethyl)-1-[3-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]imidazo[1,5-a]pyrazine-3-carboxamide, 7-[3-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1,2,4-oxadiazol-5-yl]-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxamide, 8-[2-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, 1-[2-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-5-methyl-pyrrolo[2,3-c]pyridine-3-carboxamide, 8-[3-[2-(2-Cyanoethyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, 1-[3-(4-Hydroxy-5-methyl-2-propyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[2-(Cyclopropylmethyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-(2-Cyclopropyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 4-[3-[2-(3,3-Difluoroallyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide, 4-[3-[4-Hydroxy-5-methyl-2-[2-(triazol-2-yl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide, 4-[3-[4-Hydroxy-5-methyl-2-[2-(triazol-1-yl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide, 4-[3-[2-(3,3-Difluoropropyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide, 4-[3-[4-Hydroxy-5-methyl-2-[2-(1,2,4-triazol-4-yl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide, 4-[3-[4-Hydroxy-5-methyl-2-[2-(1,2,4-triazol-1-yl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide, 1-[3-[4-Hydroxy-5-methyl-2-(2-phenylethyl)pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[2-(3-Fluoropropyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[4-Hydroxy-2-(2-methoxyethyl)-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-(2-Butyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[4-Hydroxy-2-(3-methoxypropyl)-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 4-[3-(4-Hydroxy-5-methyl-2-pent-3-ynyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide, 1-[3-[4-Hydroxy-5-methyl-2-[2-(4-pyridyl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[4-Hydroxy-5-methyl-2-[2-(3-pyridyl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[5-[4-Hydroxy-5-methyl-2-(2-phenylethyl)pyrazol-3-yl]-2-methyl-1,2,4-triazol-3-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[5-(2-Butyl-4-hydroxy-5-methyl-pyrazol-3-yl)-2-methyl-1,2,4-triazol-3-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[4-Hydroxy-2-[2-(4-methoxyphenyl)ethyl]-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-(4-Hydroxy-5-methyl-2-pent-3-ynyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[2-[2-(4-Fluorophenyl)ethyl]-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[4-Hydroxy-5-methyl-2-(2-phenylethyl)pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-[3-[4-Hydroxy-2-[2-(3-methoxyphenyl)ethyl]-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-(3-(1-(3-Fluorophenethyl)-4-hydroxy-3-methyl-1H-pyrazol-5-yl)-1H-1,2,4-triazol-5-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[2-[2-(2-Fluorophenyl)ethyl]-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 7-Fluoro-8-[3-[4-hydroxy-5-methyl-2-(2-phenylethyl)pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, 1-(2-(4-Hydroxy-3-methyl-1-propyl-1H-pyrazol-5-yl)oxazol-4-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-(2-(1-Butyl-4-hydroxy-3-methyl-1H-pyrazol-5-yl)oxazol-4-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[2-[2-(3-Cyanophenyl)ethyl]-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[2-[2-(4-Cyanophenyl)ethyl]-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, Methyl 4-[2-[5-[5-(3-carbamoyl-5-methyl-pyrazolo[3,4-c]pyridin-1-yl)-1H-1,2,4-triazol-3-yl]-4-hydroxy-3-methyl-pyrazol-1-yl]ethyl]benzoate, 1-(3-(1-(3,3-difluoroallyl)-4-hydroxy-3-methyl-1H-pyrazol-5-yl)-1H-1,2,4-triazol-5-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[4-hydroxy-2-[2-[4-(methoxymethyl)phenyl]ethyl]-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[4-hydroxy-2-[2-[3-(methoxymethyl)phenyl]ethyl]-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-(3-(1-(3,3-difluoropropyl)-4-hydroxy-3-methyl-1H-pyrazol-5-yl)-1H-1,2,4-triazol-5-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-(2-(1-(3,3-difluoropropyl)-4-hydroxy-3-methyl-1H-pyrazol-5-yl)oxazol-4-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[4-hydroxy-2-[2-[4-(hydroxymethyl)phenyl]ethyl]-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 7-Fluoro-8-[3-[4-hydroxy-2-[2-(4-methoxyphenyl)ethyl]-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, 1-[3-[4-Hydroxy-2-[2-(4-methoxyphenyl)ethyl]-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-[3-[4-Hydroxy-2-[2-[4-(hydroxymethyl)phenyl]ethyl]-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-[3-[4-Hydroxy-5-methyl-2-[2-(3-pyridyl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 7-Fluoro-8-[3-[4-hydroxy-5-methyl-2-[2-(3-pyridyl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, 1-(2-(4-Hydroxy-3-methyl-1-(2-(pyridin-3-yl)ethyl)-1H-pyrazol-5-yl)oxazol-4-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-(2-(4-Hydroxy-1-(3-methoxyphenethyl)-3-methyl-1H-pyrazol-5-yl)oxazol-4-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, 8-[3-(2-Butyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, 1-[3-(2-Butyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-(2-(4-Hydroxy-1-(4-methoxyphenethyl)-3-methyl-1H-pyrazol-5-yl)oxazol-4-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, 7-Fluoro-8-[3-(4-hydroxy-5-methyl-2-propyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, 1-[3-(4-Hydroxy-5-methyl-2-propyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-[3-[4-Hydroxy-2-(5-methoxypent-3-ynyl)-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 4-(5-(4-Hydroxy-3-methyl-1-phenethyl-1H-pyrazol-5-yl)-2H-1,2,4-triazol-3-yl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-6-carboxamide, 1-[5-(Hydroxymethyl)-2-(4-hydroxy-5-methyl-2-propyl-pyrazol-3-yl)oxazol-4-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[5-(4-Hydroxy-5-methyl-2-propyl-pyrazol-3-yl)-2-methyl-1,2,4-triazol-3-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[2-(4-Hydroxy-5-methyl-2-propyl-pyrazol-3-yl)oxazol-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-[2-(2-Butyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-[3-[4-Hydroxy-5-methyl-2-[2-[4-(morpholinomethyl)phenyl]ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-[2-[4-Hydroxy-5-methyl-2-[2-[4-(morpholinomethyl)phenyl]ethyl]pyrazol-3-yl]oxazol-4-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[2-[4-Hydroxy-2-[2-[4-(methoxymethyl)phenyl]ethyl]-5-methyl-pyrazol-3-yl]oxazol-4-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[4-Hydroxy-5-methyl-2-(2-thiazol-2-ylethyl)pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 8-[3-(4-Hydroxy-5-methyl-2-propyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, 1-[5-(4-Hydroxy-5-methyl-2-propyl-pyrazol-3-yl)-2-methyl-1,2,4-triazol-3-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 7-Fluoro-8-[2-(4-Hydroxy-5-methyl-2-propyl-pyrazol-3-yl)oxazol-4-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, 8-[2-(4-Hydroxy-5-methyl-2-propyl-pyrazol-3-yl)oxazol-4-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, A compound selected from the above or a pharmaceutically acceptable salt thereof.

[0046] A further embodiment of the present invention is (xx) formula (Ia) [Chemical formula] A method for the preparation of a compound having the structure of, comprising the following steps, namely, (a) A compound of formula (IIa) [Chemical formula] is reacted with a compound of formula (III) [Chemical formula] in the presence of a catalyst and a base to obtain a compound of formula (Ia), wherein the catalyst is preferably Pd(OAc) 2 , CuI, and Pd(dppf)Cl 2 selected from, and the base is preferably K 2 CO 3 , Cs 2 CO 3 , and Li 2 CO 3 selected from, step, (b) A compound of formula (V) [Chemical formula] is reacted with a compound of formula (VI) [Chemical formula] in the presence of a catalyst and a base to obtain a compound of formula (Ia), wherein the catalyst is preferably Pd(OAc) 2 , and the base is preferably K 2 CO 3 , Na 2 CO 3 , Cs 2 CO 3 and KOAc selected from, step, (c) A compound of formula (VII), [Chemical formula] is reacted with a compound of formula (VIII) [Chemical formula] Reacting a compound with a catalyst to obtain a compound of formula (Ia), wherein the catalyst is preferably AgOTf and AgBF 4 Selected from the process (d) A compound of formula (X)

Chemical formula

Chemical formula

[0047] A further embodiment of the present invention is (xxi) a method for the preparation of a compound having the structure of formula (Ib)

Chemical formula

Chemical formula

Chemical formula

[0048] A further embodiment of the present invention is a compound of formula (I), formula (Ia), formula (Ib) or a pharmaceutically acceptable salt thereof when manufactured according to the process of (xx) or (xxi).

[0049] A further embodiment of the present invention is a pharmaceutical composition comprising a compound according to any one of (i) to (xix) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0050] Pharmaceutical Compositions and Administration The present invention also provides a pharmaceutical composition or medicament containing a compound of the present invention and a therapeutically inert carrier, diluent or additive, and a method of using a compound of the present invention for preparing such a composition and medicament. In one example, a compound of formula (I) is formulated into a galenical dosage form by mixing it with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the dosage and concentration used, at ambient temperature, appropriate pH, and desired degree of purity. The pH of the formulation mainly depends on the particular use and the concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, a compound of formula (I) is formulated in an acetate buffer at pH 5. In another embodiment, a compound of formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0051] The composition is formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the dosing schedule, and other factors known to the medical practitioner. The "effective amount" of the compound administered is governed by such considerations and is the minimum amount necessary to activate the type I IRF response and the STING-mediated production of pro-inflammatory cytokines. For example, such an amount may be less than an amount that is toxic to normal cells or to the mammal as a whole.

[0052] In one example, the pharmaceutically effective amount of the compound of the invention administered parenterally per single dose ranges from about 0.01 to 1000 (e.g., 0.01 to 100) mg / kg of the patient's body weight per day, or from about 0.01 to 1000 (e.g., 0.1 to 20) mg / kg of the patient's body weight per day, and a typical initial range for the compound used is 0.3 to 15 mg / kg / day. In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain from about 1 to about 1000 (e.g., 25 to 100) mg of the compound of the invention.

[0053] The compounds of the invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intralung, intradermal, intrathecal, epidural, and intranasal, and, if desired in local treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0054] The compounds of the invention can be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions can contain standard ingredients in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, bulking agents, and additional active agents.

[0055] Typical formulations are prepared by mixing the compounds of the present invention with carriers or additives. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004, Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000, and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, flow promoters, processing aids, colorants, sweeteners, flavors, fragrances, diluents, and other known additives for presenting the drug (i.e., the compound of the present invention or its pharmaceutical composition) well or for assisting in the manufacture of a pharmaceutical product (i.e., a medicament).

[0056] Examples of suitable oral dosage forms include tablets formulated with about 1 to 1000 mg (e.g., 25 mg, 50 mg, 100 mg, 250 mg, or 500 mg) of the compound of the present invention, about 1 to 1000 (e.g., 90 to 30) mg of anhydrous lactose, about 1 to 1000 (e.g., 5 to 40) mg of croscarmellose sodium, about 1 to 1000 (e.g., 5 to 30 mg) mg of polyvinylpyrrolidone (PVP) K30, and about 1 to 1000 (e.g., 1 to 10 mg) mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablets using conventional equipment. Examples of aerosol formulations can be prepared, for example, by dissolving 1 to 500 mg (e.g., 5 to 400 mg) of the compound of the present invention in a suitable buffer solution, such as a phosphate buffer, and adding, if desired, an isotonic agent, such as a salt like sodium chloride. The solution can be filtered, for example, using a 0.2 micron filter to remove impurities and contaminants.

[0057] Accordingly, one embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. Further embodiments include a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or additive.

[0058] Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of cancer.

[0059] The following embodiments illustrate typical compositions of the present invention but serve merely as representatives thereof.

[0060] Composition A The compounds of the present invention can be used in a manner known per se as an active ingredient to produce tablets of the following composition. Per 425 mg tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg

[0061] Composition B The compound of the present invention can be used in a method known per se for producing a capsule preparation having the following composition as an active ingredient. Per 220.0 mg of the capsule preparation Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg

[0062] Indications and treatment methods The compound of the present invention binds to STING and initiates a signaling cascade that induces type I interferon and other pro-inflammatory cytokines and / or costimulatory factors. Therefore, the compound of the present invention is useful for enhancing cancer antigen presentation, contributing to T cell priming, trafficking and infiltration, and promoting the death of cancer, particularly cancer cells. The compound of the present invention is useful for enhancing the innate immune response in myeloid cells expressing STING. Alternatively, the compound of the present invention is useful for activating T cells in tumors where T cells are present but are suppressed, for example, by upregulation of costimulatory molecules and production of pro-inflammatory cytokines. More broadly, the present compound can be used for the treatment of immune deserts or immunity that are not inflamed but are eliminated by enhancing antigen presentation, T cell priming, mobilization / infiltration, and tumor death.

[0063] Another embodiment includes a method of treating or preventing cancer in a mammal in need of treatment, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt thereof. Cancers include sarcomas, adenocarcinomas, blastomas and carcinomas of various organ systems, such as those affecting the pancreas, liver, lung, breast, lymphatic system, stomach, biliary tract / intestine (e.g., large intestine), urogenital tract (e.g., renal urothelial cells), prostate and pharynx, but are not limited thereto.

[0064] A further embodiment of the invention is a compound of the invention for use as a therapeutic active substance.

[0065] A further embodiment of the invention is a compound of the invention for use in the treatment of cancer.

[0066] A further embodiment of the invention is the use of a compound of the invention for treating cancer.

[0067] A further embodiment of the invention is the use of a compound of the invention for the activation of STING.

[0068] A further embodiment of the invention is the use of a compound of the invention for the preparation of a medicament for treating cancer.

[0069] A further embodiment of the invention is the use of a compound of the invention for the preparation of a medicament for the activation of STING.

[0070] A further embodiment of the invention is a method of treating cancer, the method comprising administering an effective amount of a compound of the invention.

[0071] A further embodiment of the present invention is the use according to (xxxi), wherein the cancer is a cancer of the pancreas, liver, lung, breast, lymphatic system, stomach, biliary tract / intestine, urogenital tract, prostate or pharynx, or the method according to (xxvi) or (xxviii).

[0072] Synthesis The compounds of the present invention can be prepared by any conventional means. Suitable methods for synthesizing these compounds and their starting materials are shown in the following schemes and examples. All substituents, especially ring A, X 1 ~X 3 and R 1 ~R 7 are as defined above, unless otherwise indicated. Further, unless otherwise specified, all reactions, reaction conditions, abbreviations and symbols have meanings well-known to those skilled in the art of organic chemistry.

[0073] A general synthetic route for preparing the compounds of the present invention is shown in Scheme 1. Scheme 1

Chemical formula

[0074] As shown in Scheme 1, the compound having the structure of formula (Ia) can be prepared by a method including one of the following steps.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0075] Also, as shown in Scheme 1, a compound having a structure of formula (Ib) can be prepared by a method including the following steps. [Chemical formula] The bromide compound of formula (IIa) is [Chemical formula] A Pd catalyst (e.g., Pd(PPh 3 ), 4 Pd(PPh 3 ), 2 Cl 2 Pd(dppf)Cl 2 Pd(dppp)Cl 2 ), and a Sonogashira coupling reaction with tert-butyldimethyl(2-propynyloxy)silane in the presence of a Cu(I) cocatalyst (such as CuI or CuBr), followed by deprotection under NH 4 F and oxidation in the presence of an oxidizing agent (such as DMP) can convert it into an α,β-unsaturated carbonyl compound. Then, a reaction of the compound of formula (XII) with a compound of formula (XIII) [Chemical formula] in the presence of a catalyst (such as PPh 3 AuCl 3 etc.) and a base (e.g., K 2 CO 3 , Cs 2 CO 3 , or DBU) gives a compound of formula (Ib) through cyclization of the pyrimidine ring. [Examples]

[0076] The present invention will be more fully understood by reference to the following examples. However, these examples should not be construed as limiting the scope of the present invention.

[0077] The abbreviations used in this specification are as follows. ACN: Acetonitrile Ac 2 O: Acetic anhydride AcOH: Acetic acid AIBN: Azobisisobutyronitrile Boc 2 O: Di-tert-butyl dicarbonate BnBr: Benzyl bromide BzCl: Benzoyl chloride B 2 pin 2 : Bis(pinacolato)diboron cataCXium A: Di(1-adamantyl)-n-butylphosphine CMBP: Cyanomethylene tributylphosphorane DAST: Diethylaminosulfur trifluoride DCM: Dichloromethane DCE: Dichloroethane DIPEA or DIEA: N,N-Diisopropylethylamine DMAP: 4-Dimethylaminopyridine DMBNH 2 : 2,4-Dimethoxybenzylamine DMF: N,N-Dimethylformamide DMP: Dess-Martin periodinane DMSO: Dimethyl sulfoxide DPPF: 1,1'-Bis(diphenylphosphino)ferrocene EA or EtOAc: Ethyl acetate HATU: 1-[Bis(dimethylamino)methylene]1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate h(s) or hr(s): time HFIP: 1,1,1,3,3,3 - hexafluoro - 2 - propanol LCMS: liquid chromatography - mass spectrometry LDA: lithium diisopropylamide LiHMDS: lithium bis(trimethylsilyl)amide mCPBA: meta - chloroperoxybenzoic acid min(s): minute(s) MeOH: methanol MsOH: methanesulfonic acid MTBE: methyl tert - butyl ether n - BuLi: n - butyllithium NBS: N - bromosuccinimide NIS: N - iodosuccinimide PCy 3 HBF 4 : tris(cyclohexyl)phosphine tetrafluoroborate PE: petroleum ether PivOH: 2,2 - dimethylpropanoic acid PMBBr: 4 - methoxybenzyl bromide PMBNCS: 4 - methoxybenzyl isothiocyanate PMBNH 2 : 4 - methoxybenzylamine prep - HPLC: preparative high - performance liquid chromatography prep - TLC: preparative thin - layer chromatography PPh 3 : triphenylphosphine Pd(dppf)Cl 2 : (1,1’ - bis(diphenylphosphino)ferrocene)palladium(II) dichloride Pd(OAc) 2 : palladium(II) acetate Py: pyridine r.t.: room temperature sat.: saturated Selectfluor 1 - chloromethyl - 4 - fluoro - 1,4 - diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) SEMCl: 2-(Trimethylsilyl)ethoxymethyl chloride TBAF: Tetra-n-butylammonium fluoride TBSCl: tert-Butyldimethylsilyl chloride TEA: Triethylamine TFA: Trifluoroacetic acid TFAA: Trifluoroacetic anhydride TFE: 2,2,2-Trifluoroethanol Tf 2 O: Trifluoromethanesulfonic anhydride THF: Tetrahydrofuran TLC: Thin layer chromatography TMSCN: Trimethylsilyl cyanide Tol: Toluene v / v volume ratio

[0078] General experimental conditions The intermediates and final compounds were purified by flash chromatography using one of the following equipment: i) Biotage SP1 system and Quad 12 / 25 cartridge module, ii) ISCO combi-flash chromatography equipment, silica gel brand and pore size: i) KP-SIL 60Å, particle size: 40 - 60μm, ii) CAS registration number: silica gel: 63231 - 67-4, particle size: 47 - 60 micron silica gel, iii) ZCX manufactured by Qingdao Haiyang Chemical Co., Ltd., pore: 200 - 300 or 300 - 400.

[0079] The intermediate and final compounds were purified by Prep-HPLC on a reverse-phase column using an XBridge™ Prep-C18 (5 μm, OBD™ 30×100 mm) column, a SunFire™ Prep-C18 (5 μm, OBD™ 30×100 mm) column, a Phenomenex Synergi-C18 (10 μm, 25×150 mm) or a Phenomenex Gemini-C18 (10 μm, 25×150 mm), a Waters AutoP purification system (sample manager 2767, pump 2525, detector: Micromass ZQ and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water or acetonitrile and 0.1% TFA in water), or a Gilson-281 purification system (pump 322, detector: UV 156, solvent system: acetonitrile and 0.05% ammonium hydroxide in water; acetonitrile and 0.225% FA in water; acetonitrile and 0.05% HCl in water; acetonitrile and 0.075% TFA in water; or acetonitrile and water).

[0080] The LC / MS spectra of the compounds were obtained using an LC / MS (Waters™ Alliance 2795-Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ). The LC / MS conditions were as follows (run time 3 minutes or 1.5 minutes): Acidic condition I: A: H 2 O with 0.1% TFA, B: acetonitrile with 0.1% TFA, Acidic condition II: A: H 2 O with 0.0375% TFA, B: acetonitrile with 0.01875% TFA, Basic condition I: A: H 2 O with 0.1% NH 3 ·H 2 O, B: acetonitrile, Basic condition II: A: H 2 O with 0.025% NH 3 ·H 2 O, B: acetonitrile, Neutral condition: A:H 2 O, B: Acetonitrile.

[0081] Mass spectra (MS): Generally, only the ions showing the parent mass are reported, and unless otherwise specified, the cited mass ions are positive mass ions (MH). + are.

[0082] The NMR spectra were obtained using a Bruker Avance 400 MHz or 500 MHz.

[0083] The microwave-assisted reactions were carried out in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under an argon or nitrogen atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise described.

[0084] Preparation Example Intermediate A1 1-Bromo-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

Chemical Structure

[0085] The title compound was prepared according to the following scheme.

Chemical Structure

[0086] Step 1: Preparation of ethyl 2-[(5-methylpyrazin-2-yl)methylamino]-2-oxo-acetate (Compound A1-b) A solution of 2-(aminomethyl)-5-methylpyrazine (A1-a, 7.0 g, 56.84 mmol) in THF (250 mL) was added with TEA (12.63 g, 125.04 mmol), and the mixture was stirred at room temperature for 1 hour. Then, ethyl 2-chloro-2-oxo-acetate (0.22 g, 1.62 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was poured into water (100 mL) and extracted with DCM (200 mL × 4). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 and concentrated to obtain compound A1-b (10 g). LCMS (M+H) + : 224

[0087] Step 2: Preparation of ethyl 6-methylimidazo[1,5-a]pyrazine-3-carboxylate (Compound A1-c) POCl 3 (100 mL) was added with P 2 O 5 (31.79 g, 224 mmol), and a solution of ethyl 2-[(5-methylpyrazin-2-yl)methylamino]-2-oxo-acetate (A1-b, 10 g, 44.8 mmol) was added thereto. The mixture was stirred at 110 °C for 12 hours. Then, the mixture was concentrated, and the residue was quenched with saturated NaHCO 3 solution and extracted with EA (300 mL × 3). The combined organic phases were washed with saturated NaHCO 3 solution and brine, dried over anhydrous Na 2 SO 4 and concentrated to obtain compound A1-c (8 g). LCMS (M+H) + : 206.

[0088] Step 3: Preparation of ethyl 1-bromo-6-methyl-imidazo[1,5-a]pyrazine-3-carboxylate (Compound A1-d) A solution of ethyl 6-methylimidazo[1,5-a]pyrazine-3-carboxylate (A1-c, 3.0 g, 14.62 mmol) in DMF (30 mL) was added with NBS (2.6 g, 14.62 mmol), and the mixture was stirred at 20 °C for 3 h. Then, the mixture was poured into water (80 mL) and extracted with EA (100 mL×2). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The residue was purified by column chromatography to obtain compound A1-d (2.9 g). LCMS (M+H) + : 284

[0089] Step 4: Preparation of 1-bromo-6-methyl-imidazo[1,5-a]pyrazine-3-carboxylic acid (Compound A1-e) To a solution of ethyl 1-bromo-6-methyl-imidazo[1,5-a]pyrazine-3-carboxylate (A1-d, 2.5 g, 8.8 mmol) in THF (30 mL) were added NaOH (1.41 g, 35.2 mmol) and water (6 mL), and the mixture was stirred at 20 °C for 12 h. Then, the mixture was adjusted to pH about 3 with HCl (12N), filtered, and the filter cake was dried to obtain compound A1-e (2.3 g). LCMS (M+H) + : 256

[0090] Step 5: Preparation of 1-bromo-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Intermediate A1) To a solution of 1-bromo-6-methyl-imidazo[1,5-a]pyrazine-3-carboxylic acid (A1-e, 2.2 g, 8.59 mmol) in DMF (25 mL) were added DIPEA (3.33 g, 25.78 mmol), HATU (3.26 g, 8.59 mmol), and 2,4-dimethoxybenzylamine (1.55 mL, 10.31 mmol), and the mixture was stirred at 20 °C for 3 h. Then, the mixture was poured into water (200 mL), filtered, and the filter cake was dried to obtain intermediate A1 (2.2 g). LCMS (M+H) + : 405

[0091] Intermediate A2 4-Bromo-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide

Chemical formula

[0092] The title compound was prepared according to the following scheme. TIFF2025516688000046.tif84170

[0093] Step 1: Preparation of ethyl 5-formyl-1-methyl-pyrazole-4-carboxylate (Compound A2-b) To a solution of diisopropylamine (43.89 mL, 311.34 mmol) in THF (200 mL), n-BuLi (2.5 M in hexane solution, 116.75 mL, 291.89 mmol) was added dropwise at -78 °C. The mixture was stirred at -78 °C for 1 hour. Then, a solution of ethyl 1-methylpyrazole-4-carboxylate (A2-a, 30.0 g, 194.59 mmol) in THF (50 mL) was added dropwise at -78 °C, and the mixture was stirred for 1 hour. Next, a solution of DMF (33.07 mL, 428.1 mmol) in THF (30 mL) was added dropwise, and the mixture was stirred at -78 °C for 2 hours. The mixture was poured into HCl (1 N, 400 mL) and extracted with EA (400 mL × 3). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography to obtain Compound A2-b (23.5 g). LCMS (M+H) + : 183

[0094] Step 2: Preparation of ethyl 1-methyl-5-[(Z)-(2-methyl-5-oxo-oxazol-4-ylidene)methyl]pyrazole-4-carboxylate (Compound A2-c) To a solution of ethyl 5-formyl-1-methyl-pyrazole-4-carboxylate (A2-b, 30.0 g, 164.67 mmol) and 2-acetamidoacetic acid (28.92 g, 247.01 mmol) dissolved in acetic anhydride (60 mL), KOAc (24.21 g, 247.01 mmol) was added, and the mixture was stirred at 100 °C for 2 hours. Then, the mixture was quenched with saturated NaHCO 3 solution (500 mL) and extracted with EA (200 mL × 3). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 and concentrated to obtain compound A2-c (32.0 g). LCMS (M+H) + : 264

[0095] Step 3: Preparation of 1-methyl-4-oxo-5H-pyrazolo[4,3-c]pyridine-6-carboxylic acid (Compound A2-d) To a suspension of ethyl 1-methyl-5-[(Z)-(2-methyl-5-oxo-oxazol-4-ylidene)methyl]pyrazole-4-carboxylate (A2-c, 32.0 g, 121.56 mmol) in MeOH (200 mL), K 2 CO 3 (33.6 g, 243.11 mmol) was added, and the suspension was stirred at 70 °C for 12 hours. The mixture was diluted with MTBE (500 mL), filtered, and the filter cake was washed with MTBE and then suspended in H 2 O (200 mL). Concentrated HCl was added to adjust the pH to about 1. Then, the mixture was filtered, and the filter cake was dried to obtain compound A2-d (20.0 g). LCMS (M+H) + : 194

[0096] Step 4: Preparation of methyl 1-methyl-4-oxo-5H-pyrazolo[4,3-c]pyridine-6-carboxylate (Compound A2-e) SOCl 2(112.74 mL, 1.55 mol) was added to MeOH (400 mL) at 0 °C, then 1-methyl-4-oxo-5H-pyrazolo[4,3-c]pyridine-6-carboxylic acid (A2-d, 20.0 g, 103.54 mmol) was added, and the mixture was stirred at 60 °C for 16 hours and then concentrated to obtain compound A2-e (18.9 g). LCMS (M+H) + : 208 Step 5: Preparation of methyl 1-methyl-4-(trifluoromethylsulfonyloxy)pyrazolo[4,3-c]pyridine-6-carboxylate (Compound A2-f) To a suspension of methyl 1-methyl-4-oxo-5H-pyrazolo[4,3-c]pyridine-6-carboxylate (A2-e, 18.9 g, 91.22 mmol) in ACN (200 mL), Py (22.07 mL, 273.66 mmol) and Tf 2 O (46.07 mL, 273.66 mmol) were added dropwise at 0 °C, and the mixture was stirred at 20 °C for 1 hour and then used in the next step to obtain compound A2-f (30.9 g). LCMS (M+H) + : 340

[0097] Step 6: Preparation of methyl 4-bromo-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxylate (Compound A2-g) To a solution of methyl 1-methyl-4-(trifluoromethylsulfonyloxy)pyrazolo[4,3-c]pyridine-6-carboxylate (A2-f, 30.9 g, 91.08 mmol) in ACN (200 mL), LiBr (79.11 g, 910.83 mmol) was added, then TFA (30.44 mL, 409.87 mmol) was added slowly, and the mixture was stirred at 20 °C for 16 hours. Then the mixture was quenched with saturated NaHCO 3 solution to make pH > 7, and the mixture was extracted with EA (500 mL × 4). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by Prep-HPLC to obtain compound A2-g (11.5 g). LCMS (M+H) + : 270

[0098] Step 7: Preparation of 4-Bromo-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxylic acid (Compound A2-h) To a suspension of methyl 4-bromo-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxylate (A2-g, 11.5 g, 42.58 mmol) in THF (50 mL) and water (20 mL), LiOH.H 2 O (2.66 g, 63.87 mmol) was added and the mixture was stirred at 20 °C for 1 hour. Then, the mixture was adjusted to pH about 1 using aqueous concentrated HCl, and the mixture was filtered. The filter cake was washed with water to obtain Compound A2-h (10.55 g). LCMS (M+H) + : 256

[0099] Step 8: Preparation of 4-Bromo-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Intermediate A2) To a suspension of 4-bromo-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxylic acid (A2-h, 10.55 g, 41.2 mmol) in DMF (40 mL), DIPEA (15.97 g, 123.6 mmol), 2,4-dimethoxybenzylamine (7.43 mL, 49.44 mmol) and HATU (23.5 g, 61.8 mmol) were added and the mixture was stirred at 20 °C for 1 hour. Then, the mixture was diluted with H 2 O (400 mL), filtered, and the filter cake was washed with H 2 O and EA. The solid was concentrated to obtain Intermediate A2 (15.5 g). LCMS (M+H) + : 405

[0100] Intermediate B1 3-(4-Benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole

Chemical Structure

[0101] The title compound was prepared according to the following scheme. [Chemical formula]

[0102] Step 1: Preparation of N-(isopropylideneamino)ethanamine (Compound B1-b) To a solution of ethylhydrazine dihydrochloride (B1-a, 40.0 g, 303.03 mmol) dissolved in DCM (750 mL), acetone (24.54 mL, 333.33 mmol) and K 2 CO 3 (105.3 g, 757.58 mmol) were added, and the mixture was stirred at 20 °C for 12 h. The mixture was then filtered, the filter cake was washed with DCM, and the filtrate was concentrated to obtain Compound B1-b (25.0 g).

[0103] Step 2: Preparation of 1-ethyl-3-methyl-pyrazole-4-carbaldehyde (Compound B1-c) POCl 3 (81.68 mL, 873.6 mmol) was added dropwise to DMF (100 mL) at 0 °C, the mixture was stirred for 1 h, then cooled to -20 °C, and then a solution of N-(isopropylideneamino)ethanamine (B1-b, 35.0 g, 349.44 mmol) dissolved in DMF (50 mL) was added dropwise at -20 °C. The mixture was stirred at -20 °C for 3 h. Then the mixture was further stirred at 80 °C for 2 h. The mixture was slowly poured into ice, the pH was adjusted to about 9 - 10 with 30% aqueous NaOH solution, and then extracted with EA (1.5 L × 3). The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography to obtain Compound B1-c (26.0 g). LCMS (M+H) + : 139

[0104] Step 3: Preparation of (1-ethyl-3-methyl-pyrazol-4-yl) formate (Compound B1-d) A solution of 1-ethyl-3-methyl-pyrazole-4-carbaldehyde (B1-c, 12.0 g, 86.85 mmol) in DCM (120 mL) was added with mCPBA (35.15 g, 173.7 mmol), and the mixture was stirred at 40 °C for 1 hour. Then, the mixture was poured into saturated Na 2 SO 3 solution (800 mL) and extracted with EA (400 mL × 3). The combined organic phases were washed with saturated NaHCO 3 solution and brine, then dried over anhydrous Na 2 SO 4 and concentrated to obtain compound B1-d (12.0 g). LCMS (M+H) + : 155

[0105] Step 4: Preparation of 1-ethyl-3-methyl-pyrazol-4-ol (Compound B1-e) To a solution of (1-ethyl-3-methyl-pyrazol-4-yl) formate (B1-d, 10.0 g, 64.86 mmol) in MeOH (100 mL) was added TEA (18.13 mL, 129.73 mmol), and the mixture was stirred at room temperature for 0.5 hour, then concentrated to obtain compound B1-e (12.0 g). LCMS (M+H) + : 127

[0106] Step 5: Preparation of 4-benzyloxy-1-ethyl-3-methyl-pyrazole (Compound B1-f) To a solution of 1-ethyl-3-methyl-pyrazol-4-ol (B1-e, 8.0 g, 63.41 mmol) in ACN (100 mL) were added Cs 2 CO 3 (41.34 g, 126.82 mmol) and BnBr (11.31 mL, 95.12 mmol), and the mixture was stirred at room temperature for 0.5 hour. Then, the mixture was filtered, and the filtrate was poured into water (500 mL) and extracted with EA (800 mL × 3). The combined organic phases were washed with saturated NaHCO 3 solution and brine, and dried over anhydrous Na 2 SO 4It was dried, concentrated, and the residue was purified by column chromatography to obtain Compound B1-f (12.0 g). LCMS (M+H) + : 217

[0107] Step 6: Preparation of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxylic acid (Compound B1-g) To a solution of 4-benzyloxy-1-ethyl-3-methyl-pyrazole (B1-f, 1.5 g, 6.94 mmol) dissolved in THF (160 mL), n-BuLi (2.5 M in hexane solution, 4.16 mL, 10.4 mmol) was added at -78 °C and stirred for 1 hour. Then, CO 2 (3.05 g, 69.35 mmol) was added, the mixture was stirred at room temperature for 1 hour, then the pH was adjusted to about 7 using concentrated HCl, and then concentrated to obtain Compound B1-g (1.8 g). LCMS (M+H) + : 261

[0108] Step 7: Preparation of isobutoxycarbonyl 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxylate (Compound B1-h) To a solution of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxylic acid (B1-g, 1.8 g, 6.92 mmol) dissolved in DCM (20 mL), DIPEA (3.63 mL, 20.75 mmol) and isobutyl chloroformate (1.75 mL, 13.83 mmol) were added, the mixture was stirred at room temperature for 2 hours, and then concentrated to obtain Compound B1-h (3.0 g). LCMS (M+H) + : 361

[0109] Step 8: Preparation of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carbohydrazide (Compound B1-i) A solution of hydrazine (0.59 mL, 18.94 mmol) dissolved in THF (5 mL) was added dropwise at 0 °C to a suspension of isobutoxycarbonyl 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxylate (B1-h, 3.0 g, 8.32 mmol) suspended in THF (30 mL). The mixture was stirred at room temperature for 0.5 h and then concentrated to obtain compound B1-i (1.6 g). LCMS (M+H) + : 275

[0110] Step 9: Preparation of 1-[(4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carbonyl)amino]-3-[(4-methoxyphenyl)methyl]thiourea (Compound B1-j) To a solution of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carbohydrazide (B1-i, 1.6 g, 5.83 mmol) dissolved in THF (20 mL) were added DIPEA (1.52 g, 11.67 mmol) and PMBNCS (1.57 g, 8.75 mmol), and the mixture was stirred at room temperature for 16 h. Then the mixture was diluted with EA (200 mL), filtered, the filtrate was washed with water, and the organic phase was dried over anhydrous Na 2 SO 4 and concentrated to obtain compound B1-j (3.0 g). LCMS (M+H) + : 454

[0111] Step 10: Preparation of 5-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole-3-thiol (Compound B1-k) To a solution of 1-[(4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carbonyl)amino]-3-[(4-methoxyphenyl)methyl]thiourea (B1-j, 3.0 g, 6.61 mmol) dissolved in water (12 mL) was added NaOH (6.0 mL, 18.0 mmol, 3N), and the mixture was stirred at 100 °C for 16 h. Then the mixture was poured into water (500 mL) and extracted with EA (200 mL × 3). The combined organic phases were washed with saturated NaHCO 3 solution and brine, and dried over anhydrous Na2 SO 4 It was dried with SO and concentrated to obtain Compound B1-k (3.0 g). LCMS (M+H) + : 436

[0112] Step 11: Preparation of 3-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole (Intermediate B1) To a solution of 5-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)-methyl]-1,2,4-triazole-3-thiol (B1-k, 1.5 g, 3.44 mmol) dissolved in AcOH (60 mL), H 2 O 2 (15.66 g, 138.12 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, the mixture was poured into ice water (600 mL) and extracted with EA (300 mL×3). The combined organic phases were washed with brine and dried with anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography to obtain Intermediate B1 (1.02 g). LCMS (M+H) + : 404

[0113] Intermediate B2 3-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-1-methyl-1,2,4-triazole

Chemical Structure

[0114] The title compound was prepared according to the following scheme.

Chemical Structure

[0115] Step 1: Preparation of 1-[(4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carbonyl)amino]-1-methyl-thiourea (Compound B2-a) A solution of isobutoxycarbonyl 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxylate (B1-h, 1.0 g, 2.77 mmol) in THF (100 mL) was added with 1-amino-1-methyl-thiourea (291.8 mg, 2.77 mmol), and the mixture was stirred at 50 °C for 12 h. Then, the mixture was poured into water (100 mL) and extracted with EA (100 mL × 3). The combined organic phases were washed with saturated NaHCO 3 solution and brine, dried over anhydrous Na 2 SO 4 and concentrated to obtain compound B2-a (0.85 g). LCMS (M+H) + : 348

[0116] Step 2: Preparation of 5-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-2-methyl-1,2,4-triazole-3-thiol (Compound B2-b) To a solution of 1-[(4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carbonyl)amino]-1-methyl-thiourea (B2-a, 0.8 g, 2.3 mmol) in water (12 mL) was added NaOH (2.09 mL, 6.27 mmol, 3N), and the mixture was stirred at 100 °C for 6 h. Then, the mixture was poured into water (200 mL) and extracted with EA (200 mL × 3). The combined organic phases were washed with saturated NaHCO 3 solution and brine, dried over anhydrous Na 2 SO 4 and concentrated to obtain compound B2-b (0.75 g). LCMS (M+H)+: 330

[0117] Step 3: Preparation of 3-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-1-methyl-1,2,4-triazole (Intermediate B2) To a solution of 5-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-2-methyl-1,2,4-triazole-3-thiol (B2-b, 0.7 g, 2.12 mmol) in AcOH (60 mL) was added H 2 O 2(9.64 g, 85.02 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, the mixture was poured into ice water (200 mL) and extracted with EA (300 mL × 3). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 , concentrated, and the residue was purified by column chromatography to obtain Intermediate B2 (300.0 mg). LCMS (M+H) + : 298

[0118] Example 1 1-[3-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

Chemical Structure

[0119] The title compound was prepared according to the following scheme. TIFF2025516688000052.tif34170

[0120] Step 1: Preparation of Ethyl 1-[5-(4-Benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-2-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxylate (Compound 1-a) To a solution of Ethyl 1-bromo-6-methyl-imidazo[1,5-a]pyrazine-3-carboxylate (A1-d, 338.0 mg, 1.19 mmol) dissolved in 1,4-dioxane (1 mL), 3-(4-Benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole (Intermediate B1, 400.0 mg, 0.99 mmol), Pd(OAc) 2 (66.8 mg, 0.3 mmol), CuI (566.4 mg, 2.97 mmol), PCy 3 HBF 4 (145.9 mg, 0.4 mmol) and Cs2 CO 3 (322.2 mg, 0.99 mmol) was added, and the mixture was stirred at 140 °C for 12 h. Then, the mixture was concentrated, and the residue was purified by prep-TLC to give compound 1-a (190.0 mg). LCMS (M+H) + : 607

[0121] Step 2: Preparation of 1-[5-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-2-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Compound 1-b) To a solution of ethyl 1-[5-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-2-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxylate (1-a, 150.0 mg, 0.25 mmol) dissolved in THF (10 mL), NaOH (49.5 mg, 1.24 mmol) and water (2 mL) were added, and the mixture was stirred at room temperature for 12 h. Then, the mixture was dissolved in EA (30 mL), washed with brine, and the organic layer was concentrated. The residue was dissolved in DMF (2 mL), and then DIEA (67.0 mg, 0.52 mmol), NH 4 Cl (27.7 mg, 0.52 mmol) and HATU (98.6 mg, 0.26 mmol) were added, and the mixture was stirred at 50 °C for 2 h. Then, the mixture was concentrated, and the residue was purified by reverse-phase column chromatography to give compound 1-b (50.0 mg). LCMS (M+H) + : 578

[0122] Step 3: Preparation of 1-[3-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Example 1) A solution of 1-[5-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-2-[(4-methoxyphenyl)-methyl]-1,2,4-triazol-3-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (1-b, 50.0 mg, 0.09 mmol) dissolved in TFA (1.97 g, 17.31 mmol) was stirred at 80 °C for 0.5 h. Subsequently, the mixture was purified by reverse-phase column chromatography to obtain Example 1 (8.2 mg). LCMS (M+H) + : 368 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.69 (s, 1H), 9.10 (s, 1H), 8.00 - 7.82 (m, 1H), 4.48 (q, J = 6.7 Hz, 2H), 2.58 - 2.55 (m, 3H), 2.15 (s, 3H), 1.34 (t, J = 7.0 Hz, 3H)

[0123] Example 2 1-[5-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-2-methyl-1,2,4-triazol-3-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

Chemical formula

[0124] The title compound was prepared according to the following scheme.

Chemical formula

[0125] Step 1: Preparation of 1-[5-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-2-methyl-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Compound 2-a) To a solution of 3-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-1-methyl-1,2,4-triazole (Intermediate B2, 200.0 mg, 0.67 mmol) and 1-bromo-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Intermediate A1, 272.6 mg, 0.67 mmol) in 1,4-dioxane (2 mL) was added Pd(OAc) 2 (45.3 mg, 0.2 mmol), CuI (256.2 mg, 1.35 mmol), PCy 3 HBF 4 (99.0 mg, 0.27 mmol) and Cs 2 CO 3 (218.6 mg, 0.67 mmol), and the mixture was stirred at 140 °C for 18 h. The mixture was then concentrated and the residue was purified by prep-TLC to give Compound 2-a (190.0 mg). LCMS (M+H) + : 622

[0126] Step 2: Preparation of 1-[5-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-2-methyl-1,2,4-triazol-3-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Example 2) A solution of 1-[5-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-2-methyl-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Compound 2-a, 0.1 g, 0.16 mmol) in TFA (5.0 mL) was stirred at 80 °C for 2 h. The mixture was then concentrated and the residue was dissolved in ACN (5 mL) and stirred at room temperature for 0.5 h. The mixture was filtered and the filter cake was dried to give Example 2 (34.7 mg). LCMS (M+H) + : 382. 1 H NMR (400 MHz, DMSO-d 6) δ = 9.73 (s, 1H), 9.15 (s, 1H), 8.38 (s, 1H), 7.97 (s, 1H), 7.93 (brs, 1H), 4.45 (s, 3H), 4.45 - 4.40 (m, 2H), 2.52 (brs, 3H), 2.12 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H)

[0127] Example 3 8 - [3 - (2 - ethyl - 4 - hydroxy - 5 - methyl - pyrazol - 3 - yl) - 1H - 1,2,4 - triazol - 5 - yl] - 3 - methyl - pyrrolo[1,2 - a]pyrazine - 6 - carboxamide

Chemical Structure

[0128] The title compound was prepared according to the following scheme.

Chemical Structure

[0129] Step 1: Preparation of methyl 1 - acetonyl - 5 - formyl - pyrrole - 2 - carboxylate (Compound 3 - b) To a solution of methyl 5 - formyl - 1H - pyrrole - 2 - carboxylate (3 - a, 2.0 g, 13.06 mmol) in ACN (30 mL), 1 - chloropropan - 2 - one (1.47 g, 15.93 mmol), Cs 2 CO 3 (5.19 g, 15.93 mmol) and KI (4.33 g, 26.12 mmol) were added, and the mixture was stirred at 60 °C for 3 h. Then, the mixture was quenched with saturated NaHCO 3 solution (50 mL), then diluted with water (200 mL), and extracted with EA (250 mL × 3). The combined organic phases were dried over anhydrous Na 2 SO 4 and filtered and concentrated. The residue was purified by column chromatography to give Compound 3 - b (1.5 g).

[0130] Step 2: Preparation of methyl 3-methylpyrrolo[1,2-a]pyrazine-6-carboxylate (Compound 3-c) To a solution of methyl 1-acetonyl-5-formyl-pyrrole-2-carboxylate (3-b, 2.07 g, 9.89 mmol) dissolved in EtOH (40 mL), NH 4 OAc (2.288 g, 29.68 mmol) was added and the mixture was stirred at 90 °C for 2 h. Then, the mixture was concentrated, diluted with water (150 mL), and extracted with EA (150 mL × 3). The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated to give Compound 3-c (2.1 g). LCMS (M+H) + : 191

[0131] Step 3: Preparation of methyl 8-bromo-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxylate (Compound 3-d) To a solution of methyl 3-methylpyrrolo[1,2-a]pyrazine-6-carboxylate (3-c, 2.1 g, 11.04 mmol) dissolved in DMF (20 mL), NBS (2.36 g, 13.25 mmol) was added and the mixture was stirred at room temperature for 3 h. Then, the mixture was diluted with water (100 mL) and extracted with EA (120 mL × 3). The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography to give Compound 3-d (2.02 g). LCMS (M+H) + : 269

[0132] Step 4: Preparation of 8-bromo-N-[(2,4-dimethoxyphenyl)methyl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (Compound 3-e) A solution of methyl 8-bromo-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxylate (3-d, 1.2 g, 4.46 mmol) in THF (10 mL) was added with a solution of NaOH (750.0 mg, 18.75 mmol) in water (3 mL), and the mixture was stirred at 40 °C for 12 h. Then, the mixture was diluted with water (30 mL), HCl (1 N) was added to adjust the pH to about 3, filtered, the filter cake was dissolved in DMF (4 mL), DIPEA (0.41 mL, 2.35 mmol), HATU (595.9 mg, 1.57 mmol) and 2,4-dimethoxybenzylamine (0.12 mL, 0.78 mmol) were added, and the mixture was stirred at room temperature for 2 h. Then, the mixture was poured into water (20 mL), then filtered, and the filter cake was recovered to obtain compound 3-e (252.0 mg). LCMS (M+H) + :404

[0133] Step 5: Preparation of 8-[5-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (Compound 3-f) To toluene (1 mL), K 2 CO 3 (51.2 mg, 0.37 mmol), Pd(OAc)2 (8.3 mg, 0.04 mmol), PivOH (7.6 mg, 0.07 mmol), cataCXium A (13.3 mg, 0.04 mmol), 8-bromo-N-[(2,4-dimethoxyphenyl)-methyl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (3-e, 50.0 mg, 0.12 mmol), 3-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole (Intermediate B1, 49.9 mg, 0.12 mmol) were dissolved in a solution and stirred at 120 °C for 12 h. Then, the mixture was purified by prep-TLC to obtain compound 3-f (32.0 mg). LCMS (M+H) + :727

[0134] Step 6: Preparation of 6:8-[3-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (Example 3) A solution of 8-[5-(4-Benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)-methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (3-f, 32.0 mg, 0.04 mmol) in TFA (2.0 mL) was stirred at 70 °C for 2 hours. Subsequently, the mixture was purified by reverse-phase column chromatography to obtain Example 3 (4.6 mg). LCMS (M+H) + : 367. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.64 (s, 1H), 9.36 (s, 1H), 8.17 (brs, 1H), 4.49 (brd, J = 6.8 Hz, 2H), 2.47 (s, 3H), 2.15 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H)

[0135] Example 4 8-[3-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide

Chemical Structure

[0136] The title compound was prepared according to the following scheme.

Chemical Structure

[0137] Step 1: Preparation of Ethyl 3-Fluoro-5-formyl-1H-pyrrole-2-carboxylate (Compound 4-b) POCl3 (3.57 mL, 38.18 mmol) was added to a solution of DMF (3.7 mL, 47.73 mmol) dissolved in DCM (10 mL) at 0 °C, and the mixture was stirred at 0 °C for 15 minutes. Then, a solution of ethyl 3-fluoro-1H-pyrrole-2-carboxylate (4-a, 3.0 g, 19.09 mmol) dissolved in DCM (5 mL) was added dropwise. The mixture was slowly poured into ice. Then, the pH of the mixture was adjusted to about 9 - 10 with 30% aqueous NaOH solution, and then extracted with EA (50 mL × 3). The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography to obtain compound 4-b (1.8 g). (M + H) + : 186

[0138] Steps 2 - 7: Preparation of 8-[5-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (Compound 4-h) Compound 4-h was prepared in the same manner as the preparation of compound 3-f, using compound 4-b instead of methyl 5-formyl-1H-pyrrole-2-carboxylate (3-a). LCMS (M + H) + : 745

[0139] Step 8: Preparation of 8-[3-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (Example 4) A solution of 8-[5-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)-methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-7-fluoro-3-methyl-pyrrolo[1,2-a]-pyrazine-6-carboxamide (4-h, 62.0 mg, 0.08 mmol) in HFIP (2.0 mL) was added with MsOH (79.91 mg, 0.83 mmol), and the mixture was stirred at room temperature for 1 hour. Then, it was purified by reverse-phase column chromatography to obtain Example 4 (22.0 mg). LCMS (M+H) + : 385. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.63 (s, 1H), 9.23 (s, 1H), 7.93 - 7.71 (m, 1H), 7.57 - 7.35 (m, 1H), 4.49 (q, J = 6.9 Hz, 2H), 2.49 (brs, 3H), 2.16 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H)

[0140] Example 5 4-Acetyl-6-[3-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]pyridine-2-carboxamide

Chemical formula

[0141] The title compound was prepared according to the following scheme.

Chemical formula

[0142] Step 1: Preparation of 4-bromo-2-methoxy-1-oxide-pyridin-1-ium (Compound 5-b) To a solution of 4-bromo-2-methoxypyridine (5-a, 25.0 g, 132.96 mmol) in DCM (400 mL) was added m-CPBA (32.39 g, 159.56 mmol) portionwise, and the mixture was stirred at room temperature for 12 hours. The mixture was then purified by column chromatography to give compound 5-b (16 g). LCMS (M+H) + : 204

[0143] Step 2: Preparation of 4-bromo-6-methoxypyridine-2-carbonitrile (Compound 5-c) To a solution of 4-bromo-2-methoxy-1-oxide-pyridin-1-ium (5-b, 16.0 g, 78.42 mmol) in ACN (150 mL) were added TEA (15.84 g, 156.85 mmol) and TMSCN (23.34 g, 235.27 mmol) portionwise, and the mixture was stirred at 80 °C for 12 hours under N 2 2. The mixture was then concentrated, and the residue was poured into saturated Na 2 CO 3 3 solution (200 mL) and extracted with EA (400 mL × 2). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 4, and concentrated. The residue was purified by column chromatography to give compound 5-c (12 g). LCMS (M+H) + : 213

[0144] Step 3: Preparation of 4-acetyl-6-methoxypyridine-2-carbonitrile (Compound 5-d) To a solution of 4-bromo-6-methoxypyridine-2-carbonitrile (5-c, 3 g, 14.08 mmol) in 1,4-dioxane (30 mL) were added tributyl(1-ethoxyvinyl)tin (5.23 g, 14.48 mmol) and Pd(PPh 3 ) 2 Cl 2 (988.5 mg, 1.41 mmol) under N 2It was added below. The mixture was stirred at 90 °C for 12 hours. Then, the mixture was quenched with a KF solution (45 mL, 1 N). Then, an HCl solution (60 mL, 1 N) was added to the mixture and stirred at 50 °C for 0.5 hour. The mixture was extracted with DCM (100 mL), and the organic phase was washed with brine and dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography to obtain compound 5-d (1.8 g). LCMS (M+H) + : 177

[0145] Step 4: Preparation of methyl 4-acetyl-6-hydroxy-pyridine-2-carboxylate (Compound 5-e) A solution of 4-acetyl-6-methoxy-pyridine-2-carbonitrile (5-d, 1 g, 5.68 mmol) dissolved in HCl / MeOH (30 mL, 4 N) was stirred at 80 °C for 12 hours and then concentrated to obtain compound 5-e (1.1 g). LCMS (M+H) + : 196

[0146] Step 5: Preparation of methyl 4-acetyl-6-bromo-pyridine-2-carboxylate (Compound 5-f) To a solution of methyl 4-acetyl-6-hydroxy-pyridine-2-carboxylate (5-e, 1.1 g, 5.64 mmol) dissolved in ACN (30 mL), POBr 3 (4.85 g, 16.91 mmol) was added, and the mixture was stirred at 80 °C for 2 hours. Then, the mixture was quenched with a saturated Na 2 CO 3 solution (50 mL) and extracted with EA (50 mL × 2). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 and concentrated to obtain compound 5-f (1.2 g). LCMS (M+H) + : 258

[0147] Step 6: Preparation of 4-acetyl-6-bromo-pyridine-2-carboxylic acid (Compound 5-g) A solution prepared by dissolving methyl 4-acetyl-6-bromo-pyridine-2-carboxylate (5-f, 1.2 g, 4.65 mmol) in THF (10 mL) and water (3 mL) was added with LiOH·H 2 O (780.5 mg, 18.6 mmol), and the mixture was stirred at room temperature for 2 hours. Then, the mixture was diluted with water (50 mL), HCl solution (1 N) was added to adjust the pH to about 5, and the mixture was extracted with EA (50 mL×2). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 , and concentrated to obtain compound 5-g (900 mg). LCMS (M+H) + : 244

[0148] Step 7: Preparation of 4-acetyl-6-bromo-N-[(2,4-dimethoxyphenyl)methyl]pyridine-2-carboxamide (Compound 5-h) To a solution prepared by dissolving 4-acetyl-6-bromo-pyridine-2-carboxylic acid (5g, 850.0 mg, 3.48 mmol) in DMF (10 mL) were added DMBNH 2 (0.58 mL, 3.83 mmol), DIEA (1.348 g, 10.45 mmol) and HATU (1.588 g, 4.18 mmol), and the mixture was stirred at room temperature for 2 hours. Then, the mixture was poured into water (50 mL) and extracted with EA (50 mL×2). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 , and concentrated. The residue was purified by column chromatography to obtain compound 5-h (670 mg). LCMS (M+H) + : 393

[0149] Step 8: Preparation of 4-acetyl-6-[5-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]pyridine-2-carboxamide (Compound 5-i) A solution of 4-acetyl-6-bromo-N-[(2,4-dimethoxyphenyl)methyl]pyridine-2-carboxamide (150.0 mg, 0.38 mmol) in 1,4-dioxane (3 mL) was added to 3-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole (Intermediate B1, 153.9 mg, 0.38 mmol), Pd(OAc) 2 (25.7 mg, 0.11 mmol), CuI (145.3 mg, 0.76 mmol), PCy 3 HBF 4 (56.2 mg, 0.15 mmol) and Cs 2 CO 3 (124.0 mg, 0.38 mmol) were added, and the mixture was stirred at 140 °C for 12 h. The mixture was then filtered and concentrated. The residue was purified by prep-TLC to give Compound 5-i (40 mg). LCMS (M+H) + : 716

[0150] Step 9: Preparation of 4-acetyl-6-[3-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]pyridine-2-carboxamide (Example 5) To a solution of 4-acetyl-6-[5-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]pyridine-2-carboxamide (5-i, 40 mg, 0.06 mmol) in HFIP (1.0 mL) was added MsOH (53.7 mg, 0.56 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was then purified by prep-HPLC to give Example 5 (11.8 mg). LCMS (M+H) + : 356. 1 H NMR (400 MHz, DMSO-d 6)δ = 15.4 - 15.0 (m, 1H), 8.8 - 8.7 (m, 1H), 8.65 (d, J = 1.2 Hz, 1H), 8.46 (d, J = 1.6 Hz, 1H), 8.01 (brs, 1H), 4.41 (q, J = 6.8 Hz, 2H), 2.77 (s, 3H), 2.13 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H)

[0151] Example 6 6-[3-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-4-imidazol-1-yl-pyridine-2-carboxamide

Chemical formula

[0152] The title compound was prepared according to the following scheme.

Chemical formula

[0153] Step 1: Preparation of 4-imidazol-1-yl-6-methoxy-pyridine-2-carbonitrile (Compound 6-a) To a solution of 4-bromo-6-methoxy-pyridine-2-carbonitrile (5-c, 5.0 g, 23.47 mmol) dissolved in DMSO (100 mL), imidazole (2.4 g, 35.21 mmol) and K 2 CO 3 (4.87 g, 35.21 mmol) were added, and the mixture was stirred at 100 °C for 16 hours. Then, the mixture was poured into H 2 O (100 mL), filtered, and the filter cake was dried to obtain Compound 6-a (3.0 g, 14.99 mmol). LCMS (M + H) + : 201

[0154] Steps 2 - 7: Preparation of 6-[3-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-4-imidazol-1-yl-pyridine-2-carboxamide (Example 6) Example 6 was prepared in the same manner as in the preparation of Example 5, using Compound 6-a instead of 4-acetyl-6-methoxy-pyridine-2-carbonitrile (Compound 5-d). Example 6 (10.7 mg) was obtained. LCMS (M+H) + : 380. 1 H NMR (400 MHz, DMSO-d 6 +D 2 O) δ=9.70 (brs, 1H), 8.77 (s, 1H), 8.52 (brs, 2H), 7.75 (brs, 1H), 4.43 (q, J=7.1 Hz, 2H), 2.14 (s, 3H), 1.30 (t, J=7.1 Hz, 3H)

[0155] Example 7 4-[2-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)pyrimidin-4-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide

Chemical Structure

[0156] The title compound was prepared according to the following scheme.

Chemical Structure

[0157] Step 1: Preparation of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxamide (Compound 7-a) To a solution of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxylic acid (B1-g, 5 g, 19.21 mmol) in DMF (50 mL), DIEA (7.448 g, 57.63 mmol), NH 4 Cl (3.08 g, 57.63 mmol) and HATU (10.96 g, 28.81 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Then, the mixture was concentrated. The residue was purified by column chromatography to obtain Compound 7-a (2.5 g). LCMS (M+H) + : 260

[0158] Step 2: Preparation of 4 - Benzyloxy - 2 - ethyl - 5 - methyl - pyrazole - 3 - carbonitrile (Compound 7 - b) To a solution of 4 - Benzyloxy - 2 - ethyl - 5 - methyl - pyrazole - 3 - carboxamide (7 - a, 2.5 g, 9.64 mmol) dissolved in DCM (50 mL), TEA (2.95 g, 28.92 mmol) was added and the mixture was cooled to - 5 °C. Then, a solution of TFAA (2.72 mL, 19.28 mmol) dissolved in DCM (10 mL) was added dropwise. Then, the mixture was stirred at room temperature for 1 hour and then quenched with saturated NaHCO 3 solution (800 mL). The mixture was extracted with EA (450 mL × 2). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography to obtain Compound 7 - b (1.5 g). LCMS (M + H) + : 242

[0159] Step 3: Preparation of 4 - Benzyloxy - 2 - ethyl - 5 - methyl - pyrazole - 3 - carboxamidine (Compound 7 - c) To a suspension of 4 - Benzyloxy - 2 - ethyl - 5 - methyl - pyrazole - 3 - carbonitrile (Compound 7 - b, 1.0 g, 4.14 mmol) suspended in THF (10 mL), LiHMDS (1 M in THF solution, 12.43 mL, 12.43 mmol) was added and the mixture was stirred at 30 °C for 48 hours. Then, HCl solution (3 N) was added to adjust the pH to about 3 and the mixture was stirred at 0 °C for 1 hour. Then, the mixture was washed with EA. The aqueous phase was adjusted to a pH of about 14 with NaOH solution (3 N) and extracted with EA (900 mL × 3). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 and concentrated to obtain Compound 7 - c (1.2 g). LCMS (M + H) + : 259

[0160] Step 4: Preparation of 4-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 7-d) To a solution of 4-bromo-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]-pyridine-6-carboxamide (Intermediate A2, 200 mg, 0.49 mmol) dissolved in DMF (5 mL), TEA (149.8 mg, 1.48 mmol), Pd(PPh 3 ) 4 (57.0 mg, 0.05 mmol), tert-butyldimethyl(2-propynyloxy)silane (252.2 mg, 1.48 mmol) and CuI (18.8 mg, 0.1 mmol) were added, and the mixture was stirred at 80 °C for 16 h under N 2 . Then the mixture was poured into water (300 mL) and extracted with EA (100 mL × 3). The combined organic phases were washed with saturated NaHCO 3 solution and brine, then dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography to give Compound 7-d (200 mg). LCMS (M+H) + : 495

[0161] Step 5: Preparation of N-[(2,4-dimethoxyphenyl)methyl]-4-(3-hydroxyprop-1-ynyl)-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 7-e) To a solution of 4-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (7-d, 50.0 mg, 0.1 mmol) dissolved in MeOH (5 mL), NH 4 F (0.6 g, 16.17 mmol) was added, and the mixture was stirred at 60 °C for 0.5 h under N 2 . Then the mixture was filtered and concentrated to give Compound 7-e (50 mg). LCMS (M+H) + : 381

[0162] Preparation of N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-4-(3-oxoprop-1-ynyl)pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 7-f) in Step 6 To a solution of N-[(2,4-dimethoxyphenyl)methyl]-4-(3-hydroxyprop-1-ynyl)-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (7-e, 30 mg, 0.08 mmol) dissolved in DCM (2 mL), DMP (50.2 mg, 0.12 mmol) was added, and the mixture was stirred at N 2 under room temperature for 0.5 h. Then the mixture was concentrated. The residue was purified by prep-TLC to obtain Compound 7-f (28 mg).

[0163] Preparation of 4-[2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)pyrimidin-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 7-g) in Step 7 To a solution of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxamidine (7-c, 23.8 mg, 0.09 mmol) dissolved in DCM (20 mL), N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-4-(3-oxoprop-1-ynyl)pyrazolo[4,3-c]pyridine-6-carboxamide (7-f, 28 mg, 0.08 mmol), PPh 3 AuCl 3 (39 mg, 0.1 mmol) and K 2 CO 3 (21.2 mg, 0.15 mmol) were added, and the mixture was stirred at room temperature for 1 h. Then the mixture was concentrated. The residue was purified by prep-TLC to obtain Compound 7-g (45 mg). LCMS (M+H) + : 619

[0164] Step 8: Preparation of 8:4-[2-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)pyrimidin-4-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Example 7) To a solution of 4-[2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)pyrimidin-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (7 g, 40 mg, 0.06 mmol) dissolved in HFIP (2.0 mL) was added MsOH (62.1 mg, 0.65 mmol), and the mixture was stirred at room temperature for 1 hour. Then, the mixture was diluted with DMF (1 mL) and purified by reverse-phase column chromatography to obtain Example 7 (11.2 mg). LCMS (M+H) + : 379. 1 H NMR (400 MHz, DMSO-d 6 ) δ=9.34 (brs, 1H), 9.17 - 9.08 (m, 2H), 8.79 (d, J=5.4 Hz, 1H), 8.59 (brs, 1H), 8.54 (s, 1H), 7.87 (brs, 1H), 4.65 (q, J=7.2 Hz, 2H), 4.23 (s, 3H), 2.19 (s, 3H), 1.31 (t, J=7.2 Hz, 3H)

[0165] Example 8 1-[2-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)pyrimidin-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

Chemical Structure

[0166] The title compound was prepared according to the following scheme.

Chemical Structure

[0167] Example 8 was prepared in the same manner as the preparation of Example 7, using Intermediate A1 instead of 4-bromo-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Intermediate A2). 13.5 mg of Example 8 was obtained. LCMS (M+H + ): 379. 1 H NMR (400 MHz, DMSO-d 6 +D 2 O) δ=9.85 (d, J=1.6 Hz, 1H), 9.10 (s, 1H), 8.89 (d, J=5.4 Hz, 1H), 8.03 (d, J=5.4 Hz, 1H), 4.64 (q, J=7.2 Hz, 2H), 2.48 (brs, 3H), 2.15 (s, 3H), 1.34 (t, J=7.2 Hz, 3H)

[0168] Example 9 1-[2-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

Chemical formula

[0169] The title compound was prepared according to the following scheme.

Chemical formula

[0170] Step 1: Preparation of ethyl 1-(1-ethoxyvinyl)-6-methyl-imidazo[1,5-a]pyrazine-3-carboxylate (Compound 9-a) To a solution of ethyl 1-bromo-6-methyl-imidazo[1,5-a]pyrazine-3-carboxylate (A1-d, 600 mg, 2.11 mmol) and tributyl(1-ethoxyvinyl)tin (762.7 mg, 2.11 mmol) dissolved in DMF (8 mL), Pd(PPh 3 ) 2 Cl 2 .CH 2 Cl 2An adduct (148.2 mg, 0.21 mmol) was added and the mixture was stirred at 90 °C for 12 h under N 2 Then the mixture was quenched with a KF solution (15 mL, 1 N) and filtered. The filtrate was extracted with DCM (100 mL), the organic phase was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to afford Compound 9a (400 mg). LCMS (M+H) + : 276

[0171] Step 2: Preparation of Ethyl 1-(2-bromoacetyl)-6-methylimidazo[1,5-a]pyrazine-3-carboxylate (Compound 9-b) To a solution of ethyl 1-(1-ethoxyvinyl)-6-methylimidazo[1,5-a]pyrazine-3-carboxylate (9-a, 400 mg, 1.45 mmol) in THF (8 mL) and water (3 mL) was added NBS (258.6 mg, 1.45 mmol) at 0 °C and the mixture was stirred at room temperature for 1 h. Then the mixture was diluted with DCM (50 mL), poured into water (30 mL) and extracted with DCM (30 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography to afford Compound 9-b (250 mg). LCMS (M+H) + : 326

[0172] Step 3: Preparation of 1-(2-bromoacetyl)-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Compound 9-c) To a solution of ethyl 1-(2-bromoacetyl)-6-methylimidazo[1,5-a]pyrazine-3-carboxylate (9-b, 580 mg, 1.78 mmol) in THF (10 mL) and water (3 mL) was added NaOH (355.7 mg, 8.89 mmol) and the mixture was stirred at room temperature for 4 h. Then the mixture was concentrated, the residue was dissolved in DMF (5 mL), and then DMBNH 2(0.28 mL, 1.87 mmol), DIEA (689.5 mg, 5.33 mmol) and HATU (627.6 mg, 2.67 mmol) were added. The mixture was stirred at room temperature for 12 hours. Then, the mixture was diluted with DCM (100 mL), poured into water (60 mL), and extracted with DCM (100 mL × 2). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 , concentrated, and the residue was purified by column chromatography to obtain compound 9-c (350 mg). LCMS (M+H) + : 447

[0173] Step 4: Preparation of 1-[2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Compound 9-d) To a solution of 1-(2-bromoacetyl)-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (9-c, 300 mg, 0.67 mmol) dissolved in EA (15 mL), silver trifluoromethanesulfonate (258.5 mg, 1.01 mmol) and 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxamide (7-a, 260.9 mg, 1.01 mmol) were added, and the mixture was stirred at 70 °C for 12 hours under N 2 in the dark. Then, the mixture was concentrated, and the residue was purified by reverse-phase column chromatography to obtain compound 9-d (100 mg). LCMS (M+H) + : 608

[0174] Step 5: Preparation of 1-[2-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Example 9) A solution of 1-[2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (9-d, 98 mg, 0.16 mmol) in TFA (2 mL) was stirred at 80 °C for 4 hours. The mixture was purified by reverse-phase column chromatography and prep-TLC to give Example 9 (3.6 mg). LCMS (M+H) + : 368. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.64 (s, 1H), 9.05 (s, 1H), 8.79 (s, 1H), 8.63 (s, 1H), 8.05 (brd, J = 1.5 Hz, 1H), 7.86 (s, 1H), 4.55 - 4.49 (m, 2H), 2.46 (brs, 3H), 2.15 (s, 3H), 1.39 (t, J = 7.0 Hz, 3H)

[0175] Example 10 4-[5-(Difluoromethyl)-2-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide

Chemical formula

[0176] The title compound was prepared according to the following scheme.

Chemical formula

[0177] Step 1: Preparation of 1-ethyl-4-[(4-methoxyphenyl)methoxy]-3-methyl-pyrazole (Compound 10-a) To a solution of 1-ethyl-3-methyl-pyrazol-4-ol (B1-e, 25.0 g, 198.16 mmol) in DMF (300 mL) was added K 2 CO 3(54.7 g, 396.32 mmol) and PMBBr (59.76 g, 297.24 mmol) were added, and the mixture was stirred at room temperature for 16 h. Then, the mixture was poured into water (300 mL) and extracted with EA (300 mL × 3). The combined organic phases were washed with saturated NaHCO 3 solution and brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by flash chromatography to obtain compound 10-a (10 g). LCMS (M+H) + : 247

[0178] Step 2: Preparation of 5-bromo-1-ethyl-4-[(4-methoxyphenyl)methoxy]-3-methyl-pyrazole (Compound 10-b) To a solution of 1-ethyl-4-[(4-methoxyphenyl)methoxy]-3-methyl-pyrazole (10-a, 1.0 g, 4.06 mmol) dissolved in THF (10 mL), NBS (794.9 mg, 4.47 mmol) was added, and the mixture was stirred at room temperature for 3 h. Then, the mixture was concentrated, and the residue was purified by flash column chromatography to obtain compound 10-b (1.11 g). LCMS (M+H) + : 325

[0179] Step 3: Preparation of ethyl 4-bromooxazole-5-carboxylate (Compound 10-d) To a solution of ethyl oxazole-5-carboxylate (10-c, 20 g, 141.72 mmol) dissolved in THF (200 mL) and DMF (200 mL), LiHMDS (184.24 mL, 184.24 mmol) was added at -70 °C. After stirring for 2 h, Br 2 (29.44 g, 184.24 mmol) was added dropwise. The mixture was stirred at -70 °C for 2 h. Then, the mixture was poured into saturated NH 4 Cl solution (600 mL) and extracted with EA (500 mL × 2). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4It was dried and concentrated. The residue was purified by flash chromatography to obtain Compound 10-d (10 g). LCMS (M+H) + : 220

[0180] Step 4: Preparation of Ethyl 4-[6-[(2,4-Dimethoxyphenyl)methylcarbamoyl]-1-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxazole-5-carboxylate (Compound 10-e) To a solution of Ethyl 4-bromooxazole-5-carboxylate (10-d, 2.99 g, 13.57 mmol) and 4-Bromo-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Intermediate A2, 5.0 g, 12.34 mmol) dissolved in Toluene (100 mL) and Water (25 mL), K 3 PO 4 (7.86 g, 37.01 mmol), B 2 Pin 2 (6.27 g, 24.68 mmol) and Pd(dppf)Cl 2 (1.81 g, 2.47 mmol) were added, and the mixture was stirred at 80 °C for 5 hours under N 2 . Then, the mixture was concentrated, and the residue was purified by flash chromatography to obtain Compound 10-e (860 mg). LCMS (M+H) + : 466

[0181] Step 5: Preparation of Ethyl 4-[6-[(2,4-Dimethoxyphenyl)methylcarbamoyl]-1-methyl-pyrazolo[4,3-c]pyridin-4-yl]-2-[2-ethyl-4-[(4-methoxyphenyl)methoxy]-5-methyl-pyrazol-3-yl]oxazole-5-carboxylate (Compound 10-f) To a solution of ethyl 4-[6-[(2,4-dimethoxyphenyl)methylcarbamoyl]-1-methyl-pyrazolo-[4,3-c]pyridin-4-yl]oxazole-5-carboxylate (10-e, 850 mg, 1.83 mmol) and 5-bromo-1-ethyl-4-[(4-methoxyphenyl)methoxy]-3-methyl-pyrazole (10-b, 593.9 mg, 1.83 mmol) in toluene (20 mL), K 2 CO 3 (756.0 mg, 5.48 mmol), cataCXium A (327.3 mg, 0.91 mmol), PivOH (93.1 mg, 0.91 mmol) and Pd(OAc) 2 (123.0 mg, 0.55 mmol) were added, and the mixture was stirred at 120 °C for 18 h under N 2 . The mixture was then filtered, and the filter cake was washed with DCM / MeOH (V / V = 20 / 1). The residue was purified by column chromatography to give compound 10-f (800 mg). LCMS (M+H) + : 710

[0182] Step 6: Preparation of N-[(2,4-dimethoxyphenyl)methyl]-4-[2-[2-ethyl-4-[(4-methoxyphenyl)methoxy]-5-methyl-pyrazol-3-yl]-5-(hydroxymethyl)oxazol-4-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 10-g) To a solution of ethyl 4-[6-[(2,4-dimethoxyphenyl)methylcarbamoyl]-1-methyl-pyrazolo[4,3-c]pyridin-4-yl]-2-[2-ethyl-4-[(4-methoxyphenyl)methoxy]-5-methyl-pyrazol-3-yl]-oxazole-5-carboxylate (10-f, 800 mg, 1.13 mmol) in THF (20 mL) and TFE (2.0 mL), LiBH 4 (2.82 mL, 11.27 mmol) was added at 0 °C, and the mixture was stirred at 15 °C for 4 h under N 2 . The mixture was then saturated with NH 4It was poured into a Cl solution (20 mL) and extracted with DCM (50 mL × 2). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by flash chromatography to obtain compound 10-g (550 mg). LCMS (M+H) + : 668

[0183] Step 7: Preparation of N-[(2,4-dimethoxyphenyl)methyl]-4-[2-[2-ethyl-4-[(4-methoxyphenyl)methoxy]-5-methyl-pyrazol-3-yl]-5-formyloxyoxazol-4-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 10-h) To a solution of N-[(2,4-dimethoxyphenyl)methyl]-4-[2-[2-ethyl-4-[(4-methoxyphenyl)methoxy]-5-methyl-pyrazol-3-yl]-5-(hydroxymethyl)oxazol-4-yl]-1-methyl-pyrazolo[4,3-c]-pyridine-6-carboxamide (10-g, 500 mg, 0.75 mmol) dissolved in DCM (10 mL), DMP (635.2 mg, 1.5 mmol) was added and the mixture was stirred at room temperature under N 2 for 1 hour. Then, the mixture was filtered, the filter cake was washed with DCM / MeOH (V / V = 20 / 1), and the filtrate was concentrated. The residue was purified by column chromatography to obtain compound 10-h (250 mg). LCMS (M+H) + : 666

[0184] Step 8: Preparation of 4-[5-(difluoromethyl)-2-[2-ethyl-4-[(4-methoxyphenyl)methoxy]-5-methyl-pyrazol-3-yl]oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 10-i) To a solution of DAST (3.0 mL, 29.42 mmol) dissolved in DCM (3 mL), a suspension of N-[(2,4-dimethoxyphenyl)methyl]-4-[2-[2-ethyl-4-[(4-methoxyphenyl)methoxy]-5-methyl-pyrazol-3-yl]-5-formyl-oxazol-4-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (10-h, 70 mg, 0.11 mmol) suspended in DCM (6 mL) was added dropwise at 0 °C, and the mixture was stirred at 0 °C for 8 hours. Then, the mixture was poured into saturated NaHCO 3 solution (20 mL) and extracted with DCM (20 mL × 2). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by prep-TLC to obtain compound 10-i (20 mg). LCMS (M+H) + : 688

[0185] Step 9: Preparation of 4-[5-(difluoromethyl)-2-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Example 10) To a solution of 4-[5-(difluoromethyl)-2-[2-ethyl-4-[(4-methoxyphenyl)methoxy]-5-methyl-pyrazol-3-yl]oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (10-i, 20.0 mg, 0.03 mmol) dissolved in HFIP (0.5 mL), MsOH (27.9 mg, 0.29 mmol) was added, and the mixture was stirred at room temperature for 0.5 hour. Then, the mixture was diluted with MeOH (1 mL) and purified by reverse-phase column chromatography to obtain Example 10 (6.5 mg). LCMS (M+H) + : 418. 1 H NMR (400 MHz, DMSO-d 6)δ = 9.07 (s, 1H), 8.79 (s, 1H), 8.43 (s, 1H), 7.87 - 8.26 (m, 2H), 4.56 (q, J = 7.05 Hz, 2H), 4.21 (s, 3H), 2.18 (s, 3H), 1.42 (t, J = 7.09 Hz, 3H)

[0186] Example 11 1 - [5 - (aminomethyl) - 2 - (2 - ethyl - 4 - hydroxy - 5 - methyl - pyrazol - 3 - yl)oxazol - 4 - yl] - 6 - methyl - imidazo[1,5 - a]pyrazine - 3 - carboxamide

Chemical Structure

[0187] The title compound was prepared according to the following scheme.

Chemical Structure

[0188] Step 1: Preparation of 4 - benzyloxy - 2 - ethyl - 5 - methyl - N - prop - 2 - yn - 1 - yl - pyrazole - 3 - carboxamide (Compound 11 - a) To a solution of isobutoxycarbonyl 4 - benzyloxy - 2 - ethyl - 5 - methyl - pyrazole - 3 - carboxylate (B1 - h, 7.0 g, 19.42 mmol) in THF (70 mL), propargylamine (1.65 g, 29.92 mmol) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 12 hours. Then, the mixture was concentrated, and the residue was purified by column chromatography to obtain Compound 11 - a (2.4 g). LCMS (M + H) + : 298

[0189] Step 2: Preparation of (5E) - 2 - (4 - benzyloxy - 2 - ethyl - 5 - methyl - pyrazol - 3 - yl) - 5 - (iodomethylene) - 4H - oxazole (Compound 11 - b) A solution of 4-benzyloxy-2-ethyl-5-methyl-N-propan-2-yl-pyrazole-3-carboxamide (11-a, 2.4 g, 8.07 mmol) in DCM (35 mL) was added with NIS (2.72 g, 12.11 mmol), and the mixture was stirred at room temperature for 4 hours. Then, the mixture was concentrated to obtain compound 11-b (3.0 g). LCMS (M+H) + :424

[0190] Step 3: Preparation of 2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazole-5-carbaldehyde (Compound 11-c) A solution of (5E)-2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-5-(iodomethylene)-4H-oxazole (11-b, 2.8 g, 6.62 mmol) in DCE (15 mL) was stirred at 80 °C for 12 hours under O 2 Then, EA (100 mL) was added, and the mixture was washed with saturated Na 2 SO 3 solution and brine. The organic phase was dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography to obtain compound 11-c (1.0 g). LCMS (M+H) + :312

[0191] Step 4: Preparation of (5E)-2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazole-5-carbaldehyde oxime (Compound 11-d) A solution of 2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazole-5-carbaldehyde (11-c, 900 mg, 2.89 mmol) in EtOH (2 mL) was added with NH 2OH.HCl (301.3 mg, 4.34 mmol) and KOAc (474.1 mg, 5.78 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated (below 30 °C), the residue was dissolved in water (30 mL), and then extracted with DCM (60 mL × 2). The combined organic phases were concentrated to obtain compound 11-d (800 mg). LCMS (M+H) + : 327

[0192] Step 5: Preparation of [2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazol-5-yl]methanamine (Compound 11-e) To a solution of (5E)-2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazole-5-carbaldehyde oxime (11-d, 800 mg, 2.45 mmol) dissolved in AcOH (20 mL), Zn (2.745 g, 49.03 mmol) was added portionwise. The mixture was stirred at room temperature under N 2 2 for 16 hours. EA (400 mL) was added to the mixture, and then saturated Na 2 CO 3 3 solution was added to adjust the pH above 7. The mixture was extracted with EA (300 mL × 2). The combined organic phases were concentrated to obtain compound 11-e (600 mg). LCMS (M+H) + : 313

[0193] Step 6: Preparation of tert-butyl N-[[2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazol-5-yl]methyl]carbamate (Compound 11-f) To a solution of [2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazol-5-yl]methanamine (11-e, 600 mg, 1.92 mmol) dissolved in THF (15 mL), Boc 2 2O (628 mg, 2.88 mmol) and TEA (582 mg, 5.76 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Then, the mixture was poured into water (50 mL) and extracted with EA (80 mL × 3). The combined organic phases were saturated with NaHCO 3Washed with solution and brine, dried over anhydrous Na 2 SO 4 and concentrated, and the residue was purified by column chromatography to obtain Compound 11-f (660 mg). LCMS (M+H) + : 413

[0194] Step 7: Preparation of tert-butyl N-[[2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[3-[(2,4-dimethoxyphenyl)methylcarbamoyl]-6-methyl-imidazo[1,5-a]pyrazin-1-yl]oxazol-5-yl]methyl]carbamate (Compound 11-g) To toluene (25 mL), tert-butyl N-[[2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazol-5-yl]methyl]carbamate (11-f, 560 mg, 1.36 mmol), K 2 CO 3 (562.1 mg, 4.07 mmol), Pd(OAc) 2 (91.4 mg, 0.41 mmol), PivOH (83.1 mg, 0.81 mmol), cataCXium A (146.0 mg, 0.41 mmol), and a solution of 1-bromo-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Intermediate A1, 550.2 mg, 1.36 mmol) were dissolved and stirred at 115 °C for 12 hours. DCM (100 mL) was added, then the mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography and then by prep-TLC to obtain Compound 11-g (27 mg). LCMS (M+H) + : 737

[0195] Step 8: Preparation of 1-[5-(aminomethyl)-2-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Example 11) A solution of tert-butyl N-[[2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[3-[(2,4-dimethoxyphenyl)methylcarbamoyl]-6-methyl-imidazo[1,5-a]pyrazin-1-yl]oxazol-5-yl]methyl]-carbamate (Compound 11 g, 27 mg, 0.04 mmol) dissolved in TFA (2.09 g, 18.32 mmol) was stirred at 70 °C for 2 hours. The mixture was purified by prep-HPLC to obtain Example 11 (4.7 mg). LCMS (M+H) + : 397. 1 H NMR (400 MHz, DMSO-d 6 +D 2 O) δ = 9.59 (d, J = 1.1 Hz, 1H), 8.99 (s, 1H), 4.72 (s, 2H), 4.48 (q, J = 6.8 Hz, 2H), 2.43 (s, 3H), 2.13 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H)

[0196] Example 12 4-(6-Carbamoyl-1-methyl-pyrazolo[4,3-c]pyridin-4-yl)-2-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazole-5-carboxamide

Chemical formula

[0197] The title compound was prepared according to the following scheme.

Chemical formula

[0198] Step 1: Preparation of 2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazole-5-carbonitrile (Compound 12-a) A solution of 2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazole-5-carbaldehyde (11-c, 3.5 g, 11.24 mmol) in toluene (150 mL) was added with O-diphenylphosphorylhydroxylamine (3.93 g, 16.86 mmol), and the mixture was stirred at 100 °C for 2 hours. Then, the mixture was concentrated. The residue was purified by prep-HPLC to obtain compound 12-a (1.2 g). LCMS (M+H) + : 309

[0199] Step 2: Preparation of 4-[2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-5-cyano-oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 12-b) To 1,4-dioxane (4 mL), 4-bromo-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Intermediate A2, 262.9 mg, 0.65 mmol), 2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazole-5-carbonitrile (12-a, 200 mg, 0.65 mmol), Pd(OAc) 2 (43.7 mg, 0.19 mmol), CuI (247.1 mg, 1.3 mmol), PCy 3 .HBF 4 (95.5 mg, 0.26 mmol), Cs 2 CO 3 (2.108 g, 0.65 mmol) were dissolved, and the solution was stirred at 140 °C for 18 hours. Then, the mixture was concentrated. The residue was purified by prep-HPLC to obtain compound 12-b (70 mg). LCMS (M+H) + : 633

[0200] Step 3: Preparation of 4-(6-carbamoyl-1-methyl-pyrazolo[4,3-c]pyridin-4-yl)-2-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazole-5-carboxamide (Example 12) A solution prepared by dissolving 4-[2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-5-cyanooxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (12-b, 10 mg, 0.02 mmol) in TFA (2.0 mL) was stirred at 80 °C for 0.5 h. Subsequently, the mixture was concentrated and the residue was purified by prep-HPLC to obtain Example 12 (1.6 mg). LCMS (M+H) + : 411. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 10.12 (brs, 1H), 8.78 (s, 1H), 8.40 (s, 1H), 8.39 - 8.38 (m, 1H), 8.37 (brs, 1H), 8.14 (brs, 1H), 7.83 (brs, 1H), 4.55 (brd, J = 6.8 Hz, 2H), 4.20 (s, 3H), 2.11 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H)

[0201] Example 13 4-[3-(2-Ethyl-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide

Chemical formula

[0202] The title compound was prepared according to the following scheme.

Chemical formula

[0203] Step 1: Preparation of ethyl 2-(2-hydroxycyclopenten-1-yl)-2-oxo-acetate (Compound 13-b) A solution of cyclopentanone (13-a, 10.52 mL, 118.88 mmol) dissolved in EtOH (60 mL) was added dropwise with EtONa (42.37 g, 130.77 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then diethyl oxalate (16.15 mL, 118.88 mmol) was added dropwise, and then the mixture was stirred at room temperature for 12 h. The mixture was concentrated (below 40 °C), the residue was poured into water (200 mL), then HCl (30 mL, 1 N) was added to adjust the pH to about 7, and the mixture was extracted with EA (500 mL × 2). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 , and concentrated to obtain compound 13-b (20 g). LCMS (M+H) + : 185

[0204] Step 2: Preparation of ethyl 2-ethyl-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-carboxylate (Compound 13-c) To a solution of ethyl 2-(2-hydroxycyclopenten-1-yl)-2-oxo-acetate (13-b, 15.0 g, 81.44 mmol) dissolved in EtOH (150 mL) were added ethylhydrazine dihydrochloride (10.83 g, 81.44 mmol) and KOAc (15.98 g, 162.88 mmol), and the mixture was stirred at 80 °C for 12 h. Then the mixture was concentrated, and the residue was extracted with EA (200 mL × 2). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 , and concentrated to obtain compound 13-c (8 g). LCMS (M+H) + : 181

[0205] Step 3: Preparation of ethyl 2-ethyl-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-carboxylate (Compound 13-d) To a solution of 2-ethyl-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-carboxylic acid (13-c, 8.0 g, 44.4 mmol) dissolved in THF (80 mL) were added iodoethane (7.1 mL, 88.79 mmol) and K 2 CO 3(18.38 g, 133.19 mmol) was added, and the mixture was stirred at 60 °C for 2 h. Water (200 mL) was added, and then the mixture was extracted with EA (300 mL × 2). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 , concentrated, and the residue was purified by column chromatography to obtain Compound 13-d (5.2 g). LCMS (M+H) + : 209

[0206] Steps 4 - 7: Preparation of 2-ethyl-3-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]pyrazole (Compound 13-h) Compound 13-h was prepared in the same manner as the preparation of Intermediate B1, using Compound 13-d instead of isobutoxycarbonyl 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxylate (B1-h). Compound 13-h (400 mg) was obtained. LCMS (M+H) + : 324

[0207] Step 8: Preparation of N-[(2,4-dimethoxyphenyl)methyl]-4-[5-(2-ethyl-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 13-i) To a solution of 2-ethyl-3-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]pyrazole (13-h, 50.0 mg, 0.15 mmol) and 4-bromo-N-[(2,4-dimethoxyphenyl)-methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Intermediate A2, 62.7 mg, 0.15 mmol) dissolved in toluene (5 mL), K 2 CO 3 (64.0 mg, 0.46 mmol), cataCXium A (27.7 mg, 0.08 mmol), PivOH (7.9 mg, 0.08 mmol) and Pd(OAc)2 (10.4 mg, 0.05 mmol) was added. The mixture was stirred at 120 °C for 18 h under N 2 atmosphere. Then, the mixture was filtered, the filter cake was washed with DCM / MeOH (V / V = 20 / 1), the filtrates were combined and concentrated. The residue was purified by prep-TLC to afford Compound 13-i (60 mg). LCMS (M+H) + : 648

[0208] Step 9: Preparation of 4-[3-(2-Ethyl-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Example 13) To a solution of N-[(2,4-dimethoxyphenyl)methyl]-4-[5-(2-ethyl-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 13-i, 45 mg, 0.07 mmol) dissolved in HFIP (0.5 mL) was added MsOH (66.7 mg, 0.69 mmol), and the mixture was stirred at room temperature for 0.5 h. Then, the mixture was diluted with ACN (1 mL) and then purified by prep-HPLC to afford Example 13 (13.7 mg). LCMS (M+H) + : 378 1 H NMR (400 MHz, DMSO-d 6 ) δ = 15.34 (brs, 1H), 8.81 (brs, 1H), 8.75 (d, J = 0.8 Hz, 1H), 8.46 (d, J = 0.6 Hz, 1H), 7.89 (brs, 1H), 4.66 (q, J = 7.1 Hz, 2H), 4.22 (s, 3H), 2.90 (t, J = 7.1 Hz, 2H), 2.71 - 2.63 (m, 2H), 2.47 - 2.40 (m, 2H), 1.42 (t, J = 7.1 Hz, 3H)

[0209] Example 14 1-[3-[2-(3-Hydroxypropyl)-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

Chem.

[0210] The title compound was prepared according to the following scheme.

Chem.

[0211] Step 1: Preparation of ethyl 3-methyl-1H-pyrazole-5-carboxylate (Compound 14-b) Hydrazine hydrate (3.48 g, 69.55 mmol) was added to a solution of ethyl 2,4-dioxopentanoate (14-a, 10 g, 63.23 mmol) dissolved in EtOH (40 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 hour and then concentrated at room temperature to obtain Compound 14-b (9.6 g). LCMS (M+H) + : 155

[0212] Step 2: Preparation of ethyl 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-1H-pyrazole-5-carboxylate (Compound 14-c) (3-Bromopropoxy)-tert-butyldimethylsilane (31.54 g, 124.54 mmol), NaI (18.67 g, 124.54 mmol) and K 2 CO 3 (17.21 g, 124.54 mmol) were added to a solution of ethyl 3-methyl-1H-pyrazole-5-carboxylate (14-b, 9.6 g, 62.27 mmol) dissolved in DMF (50 mL), and the mixture was stirred at 80 °C for 36 hours. Then, the mixture was diluted with water (800 mL) and extracted with EA (200 mL × 3). The combined organic phases were washed with brine and anhydrous Na 2 SO 4It was dried, concentrated, and the residue was purified by flash column chromatography to obtain Compound 14-c (8.0 g). LCMS (M+H) + : 327

[0213] Steps 3 - 6: Preparation of 3-[5-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-3-methyl-pyrazol-1-yl]propan-1-ol (Compound 14-g) Compound 14-g was prepared in the same manner as the preparation of Intermediate B1, using Compound 14-c instead of isobutoxycarbonyl 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxylate (B1-h). Compound 14-g (1.6 g) was obtained. LCMS (M+H) + : 328

[0214] Step 7: Preparation of tert-butyl-[3-[5-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-3-methyl-pyrazol-1-yl]propoxy]-dimethyl-silane (Compound 14-h) To a solution of 3-[5-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-3-methyl-pyrazol-1-yl]propan-1-ol (14 g, 800 mg, 2.44 mmol) dissolved in DMF (3 mL), imidazole (998.2 mg, 14.66 mmol) and TBSCl (1.105 g, 7.33 mmol) were added, and the mixture was stirred at 60 °C for 1 hour. Then, the mixture was concentrated, and the residue was purified by flash column chromatography to obtain Compound 14-h (600 mg). LCMS (M+H) + : 442

[0215] Step 8: Preparation of 1-[5-[2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-5-methyl-pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)-methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Compound 14-i) To a solution of tert-butyl-[3-[5-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-3-methyl-pyrazol-1-yl]propoxy]-dimethyl-silane (14-h 183.5 mg, 0.45 mmol) dissolved in 1,4-dioxane (5 mL), 1-bromo-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Intermediate A1, 200 mg, 0.45 mmol), Pd(OAc) 2 (30.5 mg, 0.14 mmol), CuI (172.5 mg, 0.91 mmol), PCy 3 .HBF 4 (66.7 mg, 0.18 mmol) and Cs 2 CO 3 (147.2 mg, 0.45 mmol) were added, and the mixture was stirred at 140 °C for 16 h. The mixture was then dissolved in DCM / MeOH (30 mL / 5 mL), filtered, and then the filtrate was concentrated. The residue was purified by prep-TLC to give Compound 14-i (42.0 mg). LCMS (M+H) + : 766

[0216] Step 9: Preparation of 1-[3-[2-(3-hydroxypropyl)-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Example 14) A mixture of 1-[5-[2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-5-methyl-pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)-methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (14-i, 40 mg, 0.05 mmol) mixed in TFA (2.5 mL) was stirred at 70 °C for 1.5 h. The mixture was then concentrated, and the residue was dissolved in MeOH (1 mL) and NH 3 ·H 2Added to O(0.5 mL), and then the suspension was stirred at room temperature for 15 minutes. The mixture was concentrated, and the residue was purified by prep-HPLC to obtain Example 14 (9.2 mg). LCMS (M+H) + : 382 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.72 (d, J = 1.34 Hz, 1H), 9.08 (s, 1H), 8.01 - 7.82 (m, 2H), 6.62 (s, 1H), 4.67 (t, J = 7.03 Hz, 2H), 3.45 (t, J = 6.11 Hz, 2H), 2.52 (brs, 3H), 2.22 (s, 3H), 1.98 (brt, J = 6.72 Hz, 2H)

[0217] Example 15 1-[3-(2-Ethyl-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

Chemical Structure

[0218] The title compound was prepared according to the following scheme.

Chemical Structure

[0219] Step 1: Preparation of ethyl 2-ethyl-5-methyl-pyrazole-3-carboxylate (Compound 15-a) To a solution of ethylhydrazine dihydrochloride (1.0 g, 7.52 mmol) dissolved in EtOH (12 mL), K 2 CO 3 (2.28 g, 16.54 mmol) and ethyl 2,4-dioxopentanoate (14-a, 1.31 g, 8.27 mmol) were added dropwise at 0 °C, and the mixture was stirred at room temperature for 12 hours. Then, the mixture was concentrated, and the residue was extracted with EA (80 mL). The organic layer was washed with water and dried over anhydrous Na 2 SO 4It was dried, filtered, and concentrated to obtain Compound 15-a (400 mg). LCMS (M+H) + : 183

[0220] Step 2: Preparation of 2-Ethyl-5-methyl-pyrazole-3-carbohydrazide (Compound 15-b) Hydrazine hydrate (4.76 g, 80.87 mmol) was added to a solution of ethyl 2-ethyl-5-methyl-pyrazole-3-carboxylate (15-a, 2.4 g, 13.17 mmol) dissolved in EtOH (30 mL), and the mixture was stirred at 80 °C for 16 hours, then concentrated to obtain Compound 15-b (2 g). LCMS (M+H) + : 169

[0221] Step 3: Preparation of 3-(2-Ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)-methyl]-1,2,4-triazole (Compound 15-c) A suspension of 2-ethyl-5-methyl-pyrazole-3-carbohydrazide (15-b, 2.0 g, 11.89 mmol) in DMF-DMA (20 mL) was stirred at 100 °C for 1 hour. Then the mixture was concentrated. The residue was dissolved in toluene (60 mL), then 4-methoxybenzylamine (2.456 g, 17.92 mmol) and AcOH (10 mL) were added, and the mixture was stirred at 100 °C for 16 hours. Then the mixture was concentrated, and the residue was purified by column chromatography to obtain Compound 15-c (2.1 g). LCMS (M+H) + : 298

[0222] Step 4: Preparation of N-[(2,4-Dimethoxyphenyl)methyl]-1-[5-(2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Compound 15-d) A solution of 3-(2-ethyl-5-methyl-pyrazol-3-yl)-4-[(2,4-dimethoxyphenyl)methyl]-1,2,4-triazole (15-c, 200 mg, 0.67 mmol) dissolved in 1,4-dioxane (2 mL) was added to 1-bromo-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Intermediate A1, 272.6 mg, 0.67 mmol), Pd(OAc) 2 (45.3 mg, 0.2 mmol), CuI (256.2 mg, 1.35 mmol), PCy 3 .HBF4 (99.0 mg, 0.27 mmol) and Cs 2 CO 3 (218.6 mg, 0.67 mmol). The mixture was stirred at 140 °C for 18 h. The mixture was then filtered, concentrated, and the residue was purified by prep-TLC to afford Compound 15-d (40 mg). LCMS (M+H) + : 622

[0223] Step 5: Preparation of 1-[3-(2-ethyl-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Example 15) A solution of N-[(2,4-dimethoxyphenyl)methyl]-1-[5-(2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (15-d, 30 mg, 0.05 mmol) dissolved in TFA (1.5 mL) was stirred at 80 °C for 1 h. The mixture was purified by prep-HPLC to afford Example 15 (2.6 mg). LCMS (M+H) + : 352. 1 H NMR (400 MHz, DMSO-d 6)δ = 15.2 - 14.4 (m, 1H), 9.68 (s, 1H), 9.10 (s, 1H), 8.2 - 7.7 (m, 2H), 6.8 - 6.6 (m, 1H), 4.64 (brd, J = 6.4 Hz, 2H), 2.5 (s, 3H), 2.23 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H)

[0224] Example 16 1-[3-(2-Ethyl-4-fluoro-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide [Chemical Structure Diagram]

[0225] The title compound was prepared according to the following scheme. [Chemical Structure Diagram]

[0226] Step 1: Preparation of 3-(2-Ethyl-4-fluoro-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole (Compound 16-a) To a solution of 3-(2-Ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole (15-c, 1.6 g, 5.38 mmol) in ACN (50 mL) was added Selectfluor (3.8 g, 10.76 mmol), and the mixture was stirred at 50 °C for 16 h. The mixture was then concentrated, and the residue was purified by column chromatography to give Compound 16-a (400 mg). LCMS (M+H) + : 316

[0227] Steps 2 - 3: Preparation of 1-[3-(2-Ethyl-4-fluoro-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Example 16) Example 16 was prepared in the same manner as the preparation of Example 15, using compound 16-a instead of 3-(2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole (15-c). 13.2 mg of Example 16 was obtained. LCMS (M+H) + : 370. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.65 (s, 1H), 9.11 (s, 1H), 7.6 - 8.2 (m, 2H), 4.53 (q, J = 7.2 Hz, 2H), 3.31 (brs, 3H), 2.23 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H)

[0228] Example 17 1-[3-(4-amino-2-ethyl-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

Chemical formula

[0229] The title compound was prepared according to the following scheme.

Chemical formula

[0230] Step 1: Preparation of methyl 2-ethyl-5-methyl-pyrazole-3-carboxylate (Compound 17-b) To a solution of methyl 3-methyl-1H-pyrazole-5-carboxylate (17-a, 10.0 g, 71.36 mmol) and Cs 2 CO 3 (46.38 g, 142.71 mmol) dissolved in ACN (100 mL), iodoethane (8.56 mL, 107.04 mmol) was added. The mixture was stirred at 80 °C for 2 hours. Then, the mixture was poured into water (100 ml) and extracted with EA (100 mL × 2). The combined organic phases were washed with water and brine, and dried over anhydrous Na 2 SO 4It was dried and concentrated. The residue was purified by flash chromatography to obtain Compound 17-b (5 g). 1 H NMR (400 MHz, DMSO-d6) δ = 6.64 (s, 1H), 4.42 (q, J = 7.21 Hz, 2H), 3.81 (s, 3H), 2.18 (s, 3H), 1.30 (t, J = 7.19 Hz, 3H)

[0231] Step 2: Preparation of Methyl 2-Ethyl-5-Methyl-4-Nitro-Pyrazole-3-Carboxylate (Compound 17-c) H 2 SO 4 (23.75 mL, 445.92 mmol) was added dropwise to a solution of methyl 2-ethyl-5-methyl-pyrazole-3-carboxylate (17-b, 5 g, 29.73 mmol) in HNO 3 (15.45 mL, 311.14 mmol) at 0 °C. The mixture was stirred at 60 °C for 18 hours. Then, the mixture was poured into ice water (500 mL) and extracted with EA (300 mL × 2). The combined organic phases were washed with saturated NaHCO 3 solution and brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography to obtain Compound 17-c (3.5 g). LCMS (M + H) + : 214

[0232] Step 3: Preparation of Methyl 4-Amino-2-Ethyl-5-Methyl-Pyrazole-3-Carboxylate (Compound 17-d) To a solution of methyl 2-ethyl-5-methyl-4-nitro-pyrazole-3-carboxylate (17-c, 2.0 g, 9.38 mmol) in MeOH (40 mL), Pd / C (1.0 g, 9.38 mmol) was added, and the mixture was stirred at room temperature under a H2 balloon for 16 hours. Then, the mixture was filtered, the filter cake was washed with MeOH, and the combined filtrates were concentrated to obtain Compound 17-d (1.7 g). LCMS (M + H) + : 184.

[0233] Step 4: Preparation of Methyl 4-Benzamido-2-Ethyl-5-Methyl-Pyrazole-3-Carboxylate (Compound 17-e) To a solution of methyl 4-amino-2-ethyl-5-methyl-pyrazole-3-carboxylate (17-d, 1.4 g, 7.64 mmol) and Et 3 N (1.98 mL, 15.28 mmol) dissolved in DCM (30 mL), BzCl (0.98 mL, 8.41 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 2 h. The mixture was then concentrated. The residue was purified by flash column chromatography to obtain compound 17-d (2 g). LCMS (M+H) + : 288

[0234] Steps 5 - 8: Preparation of N-[1-Ethyl-5-[4-[(4-Methoxyphenyl)Methyl]-1,2,4-Triazol-3-Yl]-3-Methyl-Pyrazol-4-Yl]Benzamide (Compound 17-i) Compound 17-i was prepared in the same manner as the preparation of intermediate B1, using compound 17-e instead of isobutoxycarbonyl 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxylate (B1-h). Compound 17-i (2 g) was obtained. LCMS (M+H) + : 417

[0235] Step 9: Preparation of 1-Ethyl-5-[4-[(4-Methoxyphenyl)Methyl]-1,2,4-Triazol-3-Yl]-3-Methyl-Pyrazol-4-Amine (Compound 17-j) To a solution of N-[1-ethyl-5-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-3-methyl-pyrazol-4-yl]benzamide (17-i, 1.0 g, 2.4 mmol) dissolved in n-butanol (20 mL), KOH (4.29 g, 76.53 mmol) was added, and the mixture was stirred at 130 °C for 16 h. The mixture was then diluted with water (200 mL) and extracted with EA (200 mL × 2). The combined organic phases were washed with brine and anhydrous Na 2 SO 4It was dried and concentrated to obtain Compound 17-j (400 mg). LCMS (M+H) + : 313

[0236] Step 10: Preparation of tert-butyl N-tert-butoxycarbonyl-N-[1-ethyl-5-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-3-methyl-pyrazol-4-yl]carbamate (Compound 17-k) To a solution of 1-ethyl-5-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-3-methyl-pyrazol-4-amine (17-j, 400 mg, 1.28 mmol), Et 3 N (388.0 mg, 3.84 mmol) and DMAP (15.9 mg, 0.13 mmol) dissolved in THF (0.3 mL), Boc 2 O (837.5 mg, 3.84 mmol) was added, and the mixture was stirred at room temperature for 16 h. Then the mixture was concentrated, and the residue was purified by flash column chromatography to obtain Compound 17-k (250 mg). LCMS (M+H) + : 513

[0237] Steps 11-12: Preparation of 1-[3-(4-amino-2-ethyl-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Example 17) Example 17 was prepared in the same manner as the preparation of Example 14, using Compound 17-k instead of tert-butyl-[3-[5-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-3-methyl-pyrazol-1-yl]propoxy]-dimethyl-silane (14-h). Example 17 (3.7 mg) was obtained. LCMS (M+H) + : 367. 1 H NMR (400 MHz, DMSO-d 6 +D 2O) δ = 9.63 (brs, 1H), 9.07 (brd, J = 3.4 Hz, 1H), 4.51 (brd, J = 5.1 Hz, 2H), 2.52 (d, J = 1.9 Hz, 3H), 2.15 - 2.03 (m, 3H), 1.31 (brt, J = 6.8 Hz, 3H)

[0238] Example 18 6-Chloro-1-[3-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]imidazo[1,5-a]pyrazine-3-carboxamide

Chemical Structure

[0239] The title compound was prepared according to the following scheme.

Chemical Structure

[0240] Step 1: Preparation of ethyl 2-(benzhydrylideneamino)-2-(5-chloropyrazin-2-yl)acetate (Compound 18-b) To a solution of 2,5-dichloropyrazine (5.0 g, 33.56 mmol) dissolved in DMF (100 mL), Cs 2 CO 3 (10.94 g, 33.56 mmol) and ethyl 2-(benzhydrylideneamino)acetate (18-a, 9.87 g, 36.92 mmol) were added, and the mixture was stirred at room temperature for 12 hours. Then, the mixture was diluted with EA (900 mL) and water (1 L), the organic layer was washed with water, and then dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography to obtain Compound 18-b (8.0 g). LCMS (M + H) + : 380.

[0241] Step 2: Preparation of (5-chloropyrazin-2-yl)methanamine (Compound 18-c) A solution of ethyl 2-(benzhydrylideneamino)-2-(5-chloropyrazin-2-yl)acetate (18-b, 8.0 g, 19.52 mmol) in toluene (36 mL) was added with water (12 mL) and HCl (2.0 mL, 24.0 mmol, 12 N), and the mixture was stirred at room temperature for 12 hours. Then, the mixture was extracted with toluene (100 mL × 3). The aqueous layer was added to water (12 mL) and HCl (1.78 mL, 21.31 mmol, 12 N), and the mixture was stirred at 60 °C for 12 hours and then concentrated to obtain Compound 18-c (4.0 g). LCMS (M+H) + :144

[0242] Steps 3-7: Preparation of 1-bromo-6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-imidazo[1,5-a]pyrazine-3-carboxamide (Compound 18-h) Compound 18-h was prepared in the same manner as the preparation of Intermediate A1, using Compound 18-c instead of 2-(aminomethyl)-5-methylpyrazine (A1-a). 18 hours of the compound (360 mg) was obtained. LCMS (M+H) + :425

[0243] Step 8: Preparation of 1-[5-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-imidazo[1,5-a]pyrazine-3-carboxamide (Compound 18-i) Compound 18-i was prepared in the same manner as the preparation of Compound 3-f, using Compound 18-h instead of 8-bromo-N-[(2,4-dimethoxyphenyl)methyl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (3-e). Compound 18-i (60 mg) was obtained. LCMS (M+H) + :748

[0244] Step 9: Preparation of 9:6-chloro-1-[3-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]imidazo[1,5-a]pyrazine-3-carboxamide (Example 18) Example 18 was prepared in the same manner as the preparation of Example 4, using Compound 18-i instead of 8-[5-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (4-h). 2.2 mg of Example 18 was obtained. LCMS (M+H) + : 388. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.60 (s, 1H), 9.31 (s, 1H), 4.49 (brd, J = 7.4 Hz, 2H), 2.15 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H)

[0245] Example 19 1-[3-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyridine-3-carboxamide

Chemical Structure

[0246] The title compound was prepared according to the following scheme.

Chemical Structure

[0247] Steps 1 - 6: Preparation of 1-[5-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyridine-3-carboxamide (Compound 19-g) Compound 19-g was prepared in the same manner as the preparation of Compound 2-a, using (5-methyl-2-pyridyl)methanamine (19-a) and 3-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole (Intermediate B1) instead of 2-(aminomethyl)-5-methyl-pyrazine (A1-a) and 3-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-1-methyl-1,2,4-triazole (Intermediate B2). 120 mg of Compound 19-g was obtained. LCMS (M+H) + : 727

[0248] Step 7: Preparation of 1-[3-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyridine-3-carboxamide (Example 19) To a solution of 1-[5-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)-methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyridine-3-carboxamide (19-g, 120 mg, 0.17 mmol) dissolved in HFIP (2.0 mL), MsOH (158.5 mg, 1.65 mmol) was added. The mixture was stirred at room temperature and then concentrated for 12 hours and purified by prep-HPLC to obtain Example 19 (12.7 mg). LCMS (M+H) + : 367. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.31 (s, 1H), 8.28 (d, J = 9.3 Hz, 1H), 7.88 - 7.45 (m, 2H), 7.25 (brd, J = 8.6 Hz, 1H), 4.46 (q, J = 6.8 Hz, 2H), 2.36 (s, 3H), 2.14 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H)

[0249] Example 20 7-[3-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxamide

Chem.

[0250] The title compound was prepared according to the following scheme.

Chem.

[0251] Step 1: Preparation of ethyl 2-(6-methylpyrimidin-4-yl)acetate (Compound 20-b) To a solution of ethyl 2-(6-chloropyrimidin-4-yl)acetate (20-a, 4.0 g, 19.94 mmol) in 1,4-dioxane (100 mL) was added Pd(PPh 3 ) 4 (2.304 g, 1.99 mmol), and then trimethylaluminum (29.91 mL, 59.81 mmol) was added slowly. The mixture was stirred at 15 °C for 2 h. Then the mixture was poured into HCl (100 mL, 1 N) and extracted with EA (50 mL). The aqueous phase was adjusted to pH about 9 with saturated K 2 CO 3 solution and extracted with EA (100 mL × 3). The combined organic phases were dried over anhydrous Na 2 SO 4 and filtered, and concentrated to give Compound 20-b (3.0 g). LCMS (M+H) + : 181

[0252] Step 2: Preparation of ethyl 3-methylpyrrolo[1,2-c]pyrimidine-5-carboxylate (Compound 20-c) To a solution of ethyl 2-(6-methylpyrimidin-4-yl)acetate (20-b, 3.0 g, 16.65 mmol) in acetone (100 mL) were added chloroacetaldehyde (1.634 g, 83.24 mmol) and NaHCO 3(5.594 g, 66.59 mmol) was added and the mixture was stirred at 65 °C for 12 h under N 2 atmosphere. The mixture was then concentrated. The residue was purified by column chromatography to afford compound 20-c (2.7 g). LCMS (M+H) + : 205

[0253] Step 3: Preparation of ethyl 7-bromo-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxylate (Compound 20-d) To a solution of ethyl 3-methylpyrrolo[1,2-c]pyrimidine-5-carboxylate (20-c, 2.7 g, 13.22 mmol) in DCM (50 mL) was added NBS (2.353 g, 13.22 mmol) at 0 °C, and the mixture was stirred at 15 °C for 1 h. The mixture was then quenched with saturated NaHCO 3 solution (500 mL) and extracted with DCM (500 mL×2). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography to afford compound 20-d (1.4 g). LCMS (M+H) + : 283

[0254] Step 4: Preparation of 7-bromo-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxylic acid (Compound 20-e) To a solution of ethyl 7-bromo-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxylate (20-d, 400 mg, 1.41 mmol) in EtOH (6 mL) and water (1 mL) was added NaOH (282.6 mg, 7.06 mmol), and the mixture was stirred at 30 °C for 12 h. Then, water (150 mL) was added and the mixture was washed with EA. The aqueous phase was adjusted to pH ~5 with HCl (1 N) and extracted with EA (100 mL×3). The combined organic phases were dried over anhydrous Na 2 SO 4 and filtered and concentrated to afford compound 20-e (150 mg). LCMS (M+H) + : 255

[0255] Step 5: Preparation of 7-Bromo-N-[(2,4-dimethoxyphenyl)methyl]-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxamide (Compound 20-f) To a suspension of 7-bromo-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxylic acid (20-e, 135 mg, 0.53 mmol) in DMF (1 mL) was added DIEA (0.24 mL, 1.59 mmol), DMBNH 2 (0.1 mL, 0.64 mmol) and HATU (301.9 mg, 0.79 mmol), and the mixture was stirred at room temperature for 1 hour. Then the mixture was poured into H 2 O (100 mL) and extracted with EA (150 mL×3). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 4, filtered, and concentrated. The residue was purified by column chromatography to obtain Compound 20-f (80 mg). LCMS (M+H) + : 404

[0256] Step 6: Preparation of 7-[5-(4-Benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxamide (Compound 20-g) To a solution of 7-bromo-N-[(2,4-dimethoxyphenyl)methyl]-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxamide (Compound 20-f, 150.3 mg, 0.37 mmol) in DMF (10 mL) were added 3-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole (Intermediate B1, 100.0 mg, 0.25 mmol), Li 2 CO 3 (55.0 mg, 0.74 mmol) and CuI (4.7 mg, 0.02 mmol), and the mixture was placed under N 2Below, it was stirred at 140 °C for 12 hours. Subsequently, the mixture was concentrated. The residue was purified by prep-TLC to obtain compound 20-g (15.0 mg). LCMS (M+H) + : 727

[0257] Step 7: Preparation of 7-[3-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxamide (Example 20) To a solution of 7-[5-(4-Benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)-methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-3-methyl-pyrrolo[1,2-c]-pyrimidine-5-carboxamide (Compound 20-g, 10.0 mg, 0.01 mmol) dissolved in HFIP (0.5 mL), MsOH (105.7 mg, 1.1 mmol) was added and the mixture was stirred at room temperature for 3 hours. Then, it was purified by reverse-phase column chromatography to obtain Example 20 (2.5 mg). LCMS (M+H) + : 367. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 14.32 - 13.83 (m, 1H), 10.16 (s, 1H), 9.24 - 8.88 (m, 1H), 8.05 (brd, J = 3.8 Hz, 2H), 7.86 - 7.67 (m, 1H), 7.18 - 6.98 (m, 1H), 4.48 (q, J = 6.8 Hz, 2H), 2.46 (brs, 3H), 2.15 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H)

[0258] Example 21 1-[2-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical Structure

[0259] The title compound was prepared according to the following scheme. [Chemical formula]

[0260] Step 1: Preparation of 4-benzyloxy-5-bromo-1-ethyl-3-methyl-pyrazole (Compound 21-a) To a solution of 4-benzyloxy-1-ethyl-3-methyl-pyrazole (B1-f, 1.0 g, 4.62 mmol) dissolved in THF (10 mL) was added NBS (0.91 g, 5.09 mmol), and the mixture was stirred at room temperature for 2 hours. Then, the mixture was concentrated, and the residue was purified by column chromatography to obtain Compound 21-a (1.3 g). LCMS (M+H) + : 295

[0261] Step 2: Preparation of 5-methyl-1H-pyrazolo[3,4-c]pyridine (Compound 21-c) To a solution of 4,6-dimethylpyridin-3-amine (21-b, 10.0 g, 81.85 mmol) dissolved in AcOH (200 mL) was added a solution of NaNO 2 (6.21 g, 90.04 mmol) dissolved in water (20 mL), and the mixture was stirred at 15 °C for 12 hours. Then, the mixture was concentrated, diluted with water (200 mL), and then extracted with EA (200 mL × 3). The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography to obtain Compound 21-c (10.0 g). LCMS (M+H) + : 134

[0262] Step 3: Preparation of 3-bromo-5-methyl-1H-pyrazolo[3,4-c]pyridine (Compound 21-d) To a solution of 5-methyl-1H-pyrazolo[3,4-c]pyridine (21-c, 10.0 g, 75.1 mmol) in DMF (200 mL) was added NBS (14.70 g, 82.61 mmol), and the mixture was stirred at 30 °C for 1 h. Then, the mixture was concentrated, diluted with water (200 mL), and then extracted with EA (200 mL × 3). The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated to give compound 21-d (15.9 g). LCMS (M+H) + : 212

[0263] Step 4: Preparation of 2-[(3-bromo-5-methyl-pyrazolo[3,4-c]pyridin-1-yl)methoxy]-ethyl-trimethyl-silane (Compound 21-e) To a solution of 3-bromo-5-methyl-1H-pyrazolo[3,4-c]pyridine (21-d, 10.0 g, 47.16 mmol) in DMF (20 mL) were added Cs 2 CO 3 (30.73 g, 94.32 mmol) and SEMCl (11.79 g, 70.74 mmol), and the mixture was stirred at 60 °C for 2 h. Then, the mixture was poured into H 2 O (100 mL) and extracted with EA (200 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 and filtered and concentrated. The residue was purified by column chromatography to give compound 21-e (4.0 g). LCMS (M+H) + : 342

[0264] Step 5: Preparation of methyl 5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-c]pyridine-3-carboxylate (Compound 21-f) To a solution of 2-[(3-bromo-5-methyl-pyrazolo[3,4-c]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (21-e, 4.0 g, 11.69 mmol) in DMF (30 mL) and MeOH (30 mL) were added DPPF (1.29 g, 2.34 mmol), Pd(OAc) 2(262.3 mg, 1.17 mmol) and TEA (2.95 g, 29.21 mmol) were added, and the mixture was stirred at 60 °C for 16 h under CO (45 psi). The mixture was then filtered and washed with MeOH. The filtrate was concentrated, and the residue was purified by column chromatography to give compound 21-f (3.7 g). LCMS (M+H) + : 322

[0265] Step 6: Preparation of 5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-c]pyridine-3-carboxylic acid (Compound 21-g) To a solution of methyl 5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-c]pyridine-3-carboxylate (21-f, 3.4 g, 10.58 mmol) dissolved in THF (20 mL) was added a solution of LiOH·H 2 2O (887.7 mg, 21.15 mmol) dissolved in water (20 mL), and the mixture was stirred at room temperature for 1 h. The mixture was then cooled to 0 °C, and HCl solution (0.5 N) was added dropwise to adjust the pH to about 4. The suspension was filtered, and the filter cake was washed with water and dried to give compound 21g (3.2 g). LCMS (M+H) + : 308

[0266] Step 7: Preparation of N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 21-h) To a solution of 5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-c]pyridine-3-carboxylic acid (21-g, 3.2 g, 10.41 mmol) dissolved in DMF (60 mL) were added DIPEA (6.72 g, 52.05 mmol), HATU (5.93 g, 15.61 mmol), and 2,4-dimethoxybenzylamine (2.61 g, 15.61 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was then poured into H 2 2O (30 mL) and extracted with EA (30 mL×3). The combined organic phases were washed with brine and anhydrous Na 2 2SO 4It was dried, filtered, and concentrated. The residue was purified by column chromatography to obtain Compound 21-h (4.0 g). LCMS (M+H) + : 457

[0267] Step 8: Preparation of N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 21-i) To a solution of N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-c]pyridine-3-carboxamide (21-h, 4.0 g, 8.76 mmol) dissolved in THF (50 mL) was added TBAF (25.0 mL, 25.0 mmol, 1 N in THF), and the mixture was stirred at 60 °C for 16 hours. Then, the mixture was concentrated, and the residue was dissolved in DCM (100 mL). Then, saturated NaHCO 3 solution (100 mL) was added, and the mixture was extracted with DCM (100 mL × 3). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 and filtered and concentrated. The residue was purified by column chromatography to obtain Compound 21-i (2.5 g). LCMS (M+H) + : 327

[0268] Step 9: Preparation of ethyl 4-[3-[(2,4-dimethoxyphenyl)methylcarbamoyl]-5-methyl-pyrazolo[3,4-c]pyridin-1-yl]oxazole-5-carboxylate (Compound 21-j) To a solution of N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (21-i, 500.0 mg, 1.53 mmol) and ethyl 4-bromooxazole-5-carboxylate (10-d, 674.2 mg, 3.06 mmol) dissolved in DMF (6 mL) were added CuI (58.4 mg, 0.31 mmol), (1R,2R)-1,2-diaminocyclohexane (35.0 mg, 0.31 mmol), and K 3 PO 4(650.4 mg, 3.06 mmol) was added, and the mixture was stirred at 120 °C for 12 hours. Then, the mixture was filtered, concentrated, and the residue was purified by column chromatography to obtain Compound 21-j (200.0 mg). LCMS (M+H) + : 466

[0269] Step 10: Preparation of Ethyl 2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[3-[(2,4-dimethoxyphenyl)methylcarbamoyl]-5-methyl-pyrazolo[3,4-c]pyridin-1-yl]oxazole-5-carboxylate (Compound 21-k) To a solution of Ethyl 4-[3-[(2,4-dimethoxyphenyl)methylcarbamoyl]-5-methyl-pyrazolo[3,4-c]pyridin-1-yl]oxazole-5-carboxylate (21-j, 200.0 mg, 0.43 mmol) and 4-benzyloxy-5-bromo-1-ethyl-3-methyl-pyrazole (21-a, 200.0 mg, 0.68 mmol) dissolved in 1,4-dioxane (1 mL), Pd(OAc) 2 (45.6 mg, 0.2 mmol), PCy 3 HBF 4 (99.7 mg, 0.27 mmol), CuI (258.1 mg, 1.36 mmol) and Cs 2 CO 3 (220.2 mg, 0.68 mmol) were added, and the mixture was stirred at 140 °C for 18 hours under N 2 . Then, the mixture was filtered, the filter cake was washed with DCM / MeOH (V / V = 20 / 1), the filtrate was concentrated, and the residue was purified by prep-TLC to obtain Compound 21-k (30.0 mg). LCMS (M+H) + : 680

[0270] Step 11: Preparation of 2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[3-[(2,4-dimethoxyphenyl)methylcarbamoyl]-5-methyl-pyrazolo[3,4-c]pyridin-1-yl]oxazole-5-carboxylic acid (Compound 21-l) THF / H 2To a solution of ethyl 2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[3-[(2,4-dimethoxyphenyl)methylcarbamoyl]-5-methyl-pyrazolo[3,4-c]pyridin-1-yl]oxazole-5-carboxylate (21-k, 30.0 mg, 0.04 mmol) in O / MeOH (V / V / V = 1 / 1 / 1, 1 mL), NaOH (17.6 mg, 0.44 mmol) was added and the mixture was stirred at 30 °C for 2 hours. Then, HCl solution (1 N) was added to adjust the pH to about 4, and the mixture was extracted with EA (30 mL × 3). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain compound 21-l (28.0 mg). LCMS (M+H) + : 652

[0271] Step 12: Preparation of 1-[2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 21-m) To a solution of 2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[3-[(2,4-dimethoxyphenyl)methylcarbamoyl]-5-methyl-pyrazolo[3,4-c]pyridin-1-yl]oxazole-5-carboxylic acid (21-l, 28.0 mg, 0.04 mmol) in DMSO (1 mL), AcOH (0.5 mg, 0.01 mmol) and Ag 2 CO 3 (2.4 mg, 0.01 mmol) were added and the mixture was stirred at 80 °C for 12 hours. Then, the mixture was filtered, the filtrate was poured into water (10 mL), and extracted with EA (10 mL × 2). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain compound 21-m (20.0 mg). LCMS (M+H) + : 608

[0272] Preparation of 13:1-[2-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Example 21) To a solution of 1-[2-(4-Benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (21-m, 20.0 mg, 0.03 mmol) dissolved in HFIP (2.0 mL) was added MsOH (31.6 mg, 0.33 mmol), and the mixture was stirred at 50 °C for 12 hours. Then, it was purified by reverse-phase column chromatography to obtain Example 21 (3.5 mg). LCMS (M+H) + : 368. 1 H NMR (400 MHz, DMSO-d 6 +D 2 O) δ = 9.57 (s, 1H), 8.69 (s, 1H), 8.06 (s, 1H), 4.49 (q, J = 7.2 Hz, 2H), 2.66 (s, 3H), 2.15 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H)

[0273] Example 22 1-[3-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical Structure

[0274] The title compound was prepared according to the following scheme.

Chemical Structure

[0275] Step 1: Preparation of 3-Bromo-1-[(4-methoxyphenyl)methyl]-1,2,4-triazole (Compound 22-b) To a solution of 4-methoxybenzyl chloride (6.35 g, 40.55 mmol), DIEA (8.73 g, 67.59 mmol) and KI (2.8 g, 16.9 mmol) in MeCN (50 mL), 3-bromo-1H-1,2,4-triazole (22-a, 5.0 g, 33.79 mmol) was added and the mixture was stirred at 80 °C for 16 h. Then the mixture was concentrated and the residue was purified by column chromatography to give compound 22-b (5.0 g). LCMS (M+H) + : 268

[0276] Steps 2-3: Preparation of 1-[5-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-1-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 22-d) Compound 22-d was prepared in the same manner as the preparation of compound 21-k, using compound 22-b instead of ethyl 4-bromooxazole-5-carboxylate (10-d). Compound 22-d (10 mg) was obtained. LCMS (M+H) + : 728

[0277] Step 4: Preparation of 1-[3-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Example 22) Example 22 was prepared in the same manner as the preparation of Example 21, using compound 22-d instead of 1-[2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (21-m). Example 22 (2.1 mg) was obtained. LCMS (M+H) + : 368. 1 H NMR (400 MHz, DMSO-d 6 +D 2O) δ = 9.64 (s, 1H), 8.12 (s, 1H), 4.48 (q, J = 7.2 Hz, 2H), 2.69 (s, 3H), 2.17 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H)

[0278] Example 23 4-[3-[4-Hydroxy-2-(2-imidazol-1-ylethyl)-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide

Chemical Structure

[0279] The title compound was prepared according to the following scheme.

Chemical Structure

[0280] Step 1: Preparation of Methyl (2E)-2-[(2-ethoxy-2-oxo-ethyl)hydrazono]propanoate (Compound 23-b) To a solution of methyl 2-oxopropanoate (16.51 g, 161.71 mmol) in MeOH (250 mL) were added AcONa (13.27 g, 161.71 mmol) and ethyl 2-hydrazinoacetate hydrochloride (23-a, 25.0 g, 161.71 mmol), and the mixture was stirred at room temperature for 18 h. Then, H 2 O (80 mL) was added to the mixture. The mixture was then concentrated to remove MeOH. The aqueous phase was extracted with EA (400 mL × 3). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 4, filtered, and concentrated to give Compound 23-b (28.5 g). LCMS (M + H) + : 203

[0281] Step 2: Preparation of Methyl 4-hydroxy-3-methyl-1H-pyrazole-5-carboxylate (Compound 23-c) A solution of methyl (2E)-2-[(2-ethoxy-2-oxo-ethyl)hydrazono]propanoate (23-b, 47.0 g, 232.43 mmol) in MeOH (470 mL) was added with MeONa (139.46 mL, 697.29 mmol, 5N in MeOH), and the mixture was stirred at 70 °C for 16 h. Then, HCl (2N) was added to adjust the pH to about 7 at 0 °C, and then the mixture was extracted with EA (500 mL × 3). The combined organic phases were dried over anhydrous Na 2 SO 4 and filtered and concentrated to give Compound 23-c (17.0 g). LCMS (M+H) + : 157

[0282] Step 3: Preparation of methyl 4-benzyloxy-3-methyl-1H-pyrazole-5-carboxylate (Compound 23-d) Compound 23-d was prepared in the same manner as the preparation of Compound B1-f, using 1-ethyl-3-methyl-pyrazol-4-ol (B1-e) and Cs 2 CO 3 instead of Compound 23-c and Na 2 CO 3 . Compound 23-d (16.6 g) was obtained. LCMS (M+H) + : 247

[0283] Step 4: Preparation of methyl 4-benzyloxy-2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-methyl-pyrazole-3-carboxylate (Compound 23-e) To a solution of methyl 4-benzyloxy-3-methyl-1H-pyrazole-5-carboxylate (23-d, 20.0 g, 81.21 mmol) in DMF (200 mL) were added K 2 CO 3 (22.45 g, 162.43 mmol), 2-bromoethoxy-tert-butyl-dimethyl-silane (23.31 g, 97.46 mmol) and NaI (10.64 g, 71 mmol), and the mixture was stirred at 40 °C for 28 h. Then, an additional 2-bromoethoxy-tert-butyl-dimethyl-silane (9.71 g, 40.61 mmol) and K 2CO 3 (11.22 g, 81.21 mmol) was added, and the mixture was further stirred at 40 °C for 16 h. Then, the mixture was poured into water (600 mL) and extracted with EA (300 mL × 3). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 and filtered, concentrated, and the residue was purified by column chromatography to give compound 23-e (9.0 g). LCMS (M+H) + : 405

[0284] Steps 5-8: Preparation of 2-[4-benzyloxy-5-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-3-methyl-pyrazol-1-yl]ethanol (Compound 23-i) Compound 23-i was prepared in the same manner as the preparation of Intermediate B1, using compound 23-e instead of isobutoxycarbonyl 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxylate (B1-h). Compound 23-i (3.6 g) was obtained. LCMS (M+H) + : 420

[0285] Step 9: Preparation of 2-[4-benzyloxy-5-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-3-methyl-pyrazol-1-yl]ethoxy-tert-butyl-dimethyl-silane (Compound 23-j) To a solution of 2-[4-benzyloxy-5-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-3-methyl-pyrazol-1-yl]ethanol (23-i, 4.0 g, 9.54 mmol) dissolved in DCM (100 mL), imidazole (3.9 g, 57.21 mmol) and TBSCl (4.31 g, 28.61 mmol) were added, and the mixture was stirred at 60 °C for 1 h. Then, the mixture was concentrated, and the residue was purified by column chromatography to give compound 23-j (2.0 g). LCMS (M+H) + : 534

[0286] Preparation of 10:4-[5-[4-benzyloxy-2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-methyl-pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 23-k) Compound 23-k was prepared in the same manner as the preparation of Compound 1-a, using Compound 23-j and Intermediate A2 instead of Ethyl 1-bromo-6-methyl-imidazo[1,5-a]pyrazine-3-carboxylate (A1-d) and 3-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)-methyl]-1,2,4-triazole (Intermediate B1). 150 mg of Compound 23-k was obtained. LCMS(M+H) + :858

[0287] Preparation of 11:4-[5-[4-benzyloxy-2-(2-hydroxyethyl)-5-methyl-pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 23-l) To a solution of 4-[5-[4-benzyloxy-2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-methyl-pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)-methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (23-k, 150 mg, 0.17 mmol) dissolved in MeOH (4 mL), NH 4 F (232.5 mg, 6.12 mmol) was added and the mixture was stirred at 60 °C for 12 h. Then the mixture was concentrated and the residue was purified by column chromatography to obtain 120 mg of Compound 23-l. LCMS(M+H) + :744

[0288] Project 12: 4-[5-[4-Benzyloxy-2-(2-imidazol-1-ylethyl)-5-methyl-pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 23-m) To a solution of 4-[5-[4-benzyloxy-2-(2-hydroxyethyl)-5-methyl-pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (23-l, 33 mg, 0.04 mmol) and CMBP (0.07 mL, 0.22 mmol) dissolved in anhydrous toluene (1.5 mL), imidazole (15.1 mg, 0.22 mmol) was added, and the mixture was stirred at 60 °C for 12 hours. Then, the mixture was concentrated, and the residue was purified by column chromatography to obtain Compound 23-m (10 mg). LCMS (M+H) + : 794

[0289] Project 13: Preparation of 4-[3-[4-Hydroxy-2-(2-imidazol-1-ylethyl)-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Example 23) Example 23 was prepared in the same manner as the preparation of Example 21, using Compound 23-m instead of 1-[2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (21-m). 2.5 mg of Example 23 was obtained. LCMS (M+H) + : 434. 1 H NMR (400 MHz, DMSO-d 6)δ = 15.36 (s, 1H), 8.91 - 8.81 (m, 2H), 8.68 (s, 1H), 8.49 (s, 1H), 8.15 (s, 1H), 7.90 (s, 1H), 7.46 (s, 2H), 4.95 (d, J = 4.4 Hz, 2H), 4.69 (d, J = 4.4 Hz, 2H), 4.24 (s, 3H), 2.11 (s, 3H)

[0290] Example 24 4-[3-[2-(3-Cyanopropyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide

Chemical Structure

[0291] The title compound was prepared according to the following scheme.

Chemical Structure

[0292] Step 1: Preparation of 4-[5-[4-Benzyloxy-5-methyl-2-(2-oxoethyl)pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 24-a) To a solution of 4-[5-[4-Benzyloxy-2-(2-hydroxyethyl)-5-methyl-pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (23-l, 200 mg, 0.27 mmol) in DCM (5 mL), DMP (228.1 mg, 0.54 mmol) was added at 0 °C, and the mixture was stirred at 30 °C for 1 hour. Then, saturated Na 2 SO 3 solution (50 mL) and saturated NaHCO 3The solution (100 mL) was added to the mixture at 0 °C. The mixture was extracted with DCM (100 mL × 3). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 , filtered, concentrated, and the residue was purified by prep-TLC to give compound 24-a (100 mg). LCMS (M+H) + : 742

[0293] Step 2: Preparation of 4-[5-[4-benzyloxy-2-[(E)-3-cyanoallyl]-5-methyl-pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 24-b) To a solution of 4-[5-[4-benzyloxy-5-methyl-2-(2-oxoethyl)pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (24-a, 100 mg, 0.13 mmol) dissolved in EtOH (3 mL) was added (cyanomethyl)triphenylphosphonium chloride (91.13 mg, 0.27 mmol), and then TEA (0.06 mL, 0.4 mmol) in EtOH (3 mL) was added dropwise to the mixture at 0 °C. The mixture was stirred at 30 °C for 3 h. The mixture was then purified by prep-TLC to give compound 24-b (80 mg). LCMS (M+H) + : 765

[0294] Step 3: Preparation of 4-[5-[2-(3-cyanopropyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 24-c) A solution of 4-[5-[4-benzyloxy-2-[(E)-3-cyanoallyl]-5-methyl-pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (24-b, 80 mg, 0.1 mmol) in MeOH (5 mL) was added with N 2 under which Pd / C (300 mg) was added, and the mixture was stirred at room temperature for 2 hours under H 2 (15 psi). Then the mixture was purified by prep-TLC to obtain compound 24-c (50 mg). LCMS (M+H) + : 677

[0295] Step 4: Preparation of 4-[3-[2-(3-cyanopropyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Example 24) A solution of 4-[5-[2-(3-cyanopropyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (24-c, 12 mg, 0.02 mmol) and TFA (8.1 mg, 0.07 mmol) in DCM (1.5 mL) was stirred at 30 °C for 3 hours. Then it was purified by reverse-phase column chromatography to obtain Example 24 (2.2 mg). LCMS (M+H) + : 407. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 15.38 (s, 1H), 8.88 (s, 1H), 8.84 (s, 1H), 8.48 (s, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 4.53 - 4.50 (m, 2H), 4.22 (s, 3H), 3.31 (s, 2H), 2.15 (s, 3H), 2.15 - 2.07 (m, 2H)

[0296] Example 25 4-[3-[2-(2-Cyanoethyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide

Chem.

[0297] The title compound was prepared according to the following scheme.

Chem.

[0298] Step 1: Preparation of 2-[4-benzyloxy-5-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-3-methyl-pyrazol-1-yl]ethyl methanesulfonate (Compound 25-a) To a solution of 2-[4-benzyloxy-5-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-3-methyl-pyrazol-1-yl]ethanol (23-i, 1.0 g, 2.38 mmol) in THF (10 mL), Py (565 mg, 7.15 mmol) and Ms 2 O (830.5 mg, 4.77 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 1 h. Then, H 2 O (20 mL) was added to the mixture, and the mixture was extracted with DCM (100 mL × 2). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain Compound 25-a (1.0 g). LCMS (M+H) + : 498

[0299] Step 2: Preparation of 3-[4-benzyloxy-5-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-3-methyl-pyrazol-1-yl]propanenitrile (Compound 25-b) A solution of 2-[4-benzyloxy-5-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-3-methyl-pyrazol-1-yl]ethyl methanesulfonate (25-a, 800 mg, 1.61 mmol) in DMF (8 mL) was added with NaCN (760 mg, 15.51 mmol), and the mixture was stirred at 60 °C for 18 h. Then, saturated NaHCO 3 solution (50 mL) was added to the mixture, and the mixture was extracted with DCM (50 mL × 2). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 , filtered, concentrated, and the residue was purified by column chromatography to obtain compound 25-b (330.0 mg). LCMS (M+H) + : 429

[0300] Step 3: Preparation of 4-[5-[4-benzyloxy-2-(2-cyanoethyl)-5-methyl-pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 25-c) Compound 25-c was prepared in the same manner as the preparation of compound 3-f, using compound 25-b and intermediate A2 instead of 8-bromo-N-[(2,4-dimethoxyphenyl)-methyl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (3-e) and 3-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole (Intermediate B1). Compound 25-c (120 mg) was obtained. LCMS (M+H) + : 753

[0301] Steps 4 - 5: Preparation of 4-[3-[2-(2-cyanoethyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Example 25) Example 25 was prepared in the same manner as in Example 24, using Compound 25-c instead of 4-[5-[4-benzyloxy-2-[(E)-3-cyanoallyl]-5-methyl-pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (24-b). Example 25 (12.4 mg) was obtained. LCMS (M+H) + : 393. 1 H NMR (400 MHz, DMSO-d6) δ = 15.39 (s, 1H), 8.87 (s, 2H), 8.47 (s, 1H), 8.15 (s, 1H), 7.88 (brd, J = 1.2 Hz, 1H), 4.75 (brt, J = 6.6 Hz, 2H), 4.23 (s, 3H), 3.09 (t, J = 6.6 Hz, 2H), 2.16 (s, 3H)

[0302] Example 26 6-(Difluoromethyl)-1-[3-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]imidazo[1,5-a]pyrazine-3-carboxamide

Chemical formula

[0303] The title compound was prepared according to the following scheme.

Chemical formula

[0304] Step 1: Preparation of ethyl 1-bromo-6-(bromomethyl)imidazo[1,5-a]pyrazine-3-carboxylate (Compound 26-a) CCl 4A solution of ethyl 1-bromo-6-methyl-imidazo[1,5-a]pyrazine-3-carboxylate (A1-d, 1.9 g, 6.69 mmol) in (40 mL) was added with NBS (1.31 g, 7.36 mmol) and AIBN (109.8 mg, 0.67 mmol), and the mixture was stirred at 90 °C for 16 h. Then, the mixture was concentrated, and the residue was purified by column chromatography to obtain compound 26-a (2.1 g). LCMS (M+H) + : 362

[0305] Step 2: Preparation of ethyl 1-bromo-6-(hydroxymethyl)imidazo[1,5-a]pyrazine-3-carboxylate (Compound 26-b) To a solution of ethyl 1-bromo-6-(bromomethyl)imidazo[1,5-a]pyrazine-3-carboxylate (26-a, 2.1 g, 5.78 mmol) in 1,4-dioxane (20 mL) was added CaCO 3 (2.89 g, 28.92 mmol) and water (20 mL), and the mixture was stirred at 90 °C for 16 h. Water (100 mL) was added to the mixture, and the mixture was extracted with EA (50 mL × 3). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain compound 26-b (1.6 g). LCMS (M+H) + : 300

[0306] Step 3: Preparation of ethyl 1-bromo-6-formyl-imidazo[1,5-a]pyrazine-3-carboxylate (Compound 26-c) To a solution of ethyl 1-bromo-6-(hydroxymethyl)imidazo[1,5-a]pyrazine-3-carboxylate (26-b, 1.6 g, 5.33 mmol) in DCM (40 mL) was added DMP (3.61 g, 8.53 mmol), and the mixture was stirred at room temperature for 1 h. Then, the mixture was filtered, the filter cake was washed with DCM, the filtrate was concentrated, and the residue was purified by column chromatography to obtain compound 26-c (1.0 g). LCMS (M+H) + : 298

[0307] Step 4: Preparation of Ethyl 1-Bromo-6-(difluoromethyl)imidazo[1,5-a]pyrazine-3-carboxylate (Compound 26-d) To a solution of ethyl 1-bromo-6-formyl-imidazo[1,5-a]pyrazine-3-carboxylate (26-c, 1.0 g, 3.35 mmol) dissolved in DCM (20 mL), DAST (1.62 g, 10.06 mmol) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, saturated NaHCO 3 solution (100 mL) was added to the mixture, and the mixture was extracted with DCM (100 mL × 3). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 , filtered, concentrated, and the residue was purified by column chromatography to obtain Compound 26-d (650 mg). LCMS (M+H) + : 320

[0308] Steps 5 - 8: Preparation of 6-(Difluoromethyl)-1-[3-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]imidazo[1,5-a]pyrazine-3-carboxamide (Example 26) Example 26 was prepared in the same manner as the preparation of Example 5, using Compound 26-d instead of methyl 4-acetyl-6-bromo-pyridine-2-carboxylate (5-f). 17.1 mg of Example 26 was obtained. LCMS (M+H) + : 404. 1 H NMR (400 MHz, DMSO-d 6 +D 2 O) δ = 9.78 (s, 1H), 9.53 (s, 1H), 7.15 (t, J = 54.4 Hz, 1H), 4.56 - 4.39 (m, 2H), 2.15 (s, 3H), 1.34 (t, J = 7.0 Hz, 3H)

[0309] Example 27 7-[3-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1,2,4-oxadiazol-5-yl]-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxamide

Chem.

[0310] The title compound was prepared according to the following scheme.

Chem.

[0311] Step 1: Preparation of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxamide (Compound 27-a) To a solution of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxylic acid (B1-g, 1.0 g, 3.84 mmol) in DMF (10 mL) were added DIEA (1.48 g, 11.53 mmol), NH 4 Cl (616.5 mg, 11.53 mmol) and HATU (2.19 g, 5.76 mmol), and the mixture was stirred at 50 °C for 2 h. Then the mixture was concentrated, and the residue was purified by reverse-phase column chromatography to obtain Compound 27-a (850 mg). LCMS (M+H) + : 260

[0312] Step 2: Preparation of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carbonitrile (Compound 27-b) To a solution of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxamide (27-a, 0.6 g, 2.31 mmol) in DCM (5 mL) was added TEA (708.1 mg, 6.94 mmol), and then TFAA (972 mg, 4.63 mmol) in DCM (2 mL) was added dropwise at -5 °C, and the mixture was stirred at 0 °C for 1 h. Then a NaHCO 3 solution (5%, 100 mL) was added to the mixture, and the mixture was extracted with EA (250 mL × 2). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 and filtered, concentrated, and the residue was purified by column chromatography to obtain Compound 27-b (0.5 g). LCMS (M+H)+ : 242

[0313] Step 3: Preparation of 3:4 - Benzyloxy - 2 - ethyl - N - hydroxy - 5 - methyl - pyrazole - 3 - carboxamidine (Compound 27 - c) To a mixture of 4 - benzyloxy - 2 - ethyl - 5 - methyl - pyrazole - 3 - carbonitrile (27 - b, 0.4 g, 1.66 mmol), hydroxylamine hydrochloride (0.34 g, 4.97 mmol) and TEA (2.29 mL, 16.58 mmol) in EtOH (10 mL) was stirred at 80 °C for 1 h. Then the mixture was extracted with EA (150 mL×2). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 and filtered, concentrated, and the residue was purified by column chromatography to obtain Compound 27 - c (450 mg). LCMS (M + H) + : 275

[0314] Step 4: Preparation of 3 - (4 - benzyloxy - 2 - ethyl - 5 - methyl - pyrazol - 3 - yl) - 1,2,4 - oxadiazole (Compound 27 - d) To a solution of 4 - benzyloxy - 2 - ethyl - N - hydroxy - 5 - methyl - pyrazole - 3 - carboxamidine (27 - c, 0.4 g, 1.46 mmol) dissolved in trimethyl orthoformate (154.7 mg, 1.46 mmol) was added p - toluenesulfonic acid monohydrate (0.04 g, 0.21 mmol), and the mixture was stirred at 110 °C for 1 h. Then NaHCO 3 solution (5%, 100 mL) was added to the mixture, and the mixture was extracted with EA (150 mL×2). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 and filtered, concentrated, and the residue was purified by column chromatography to obtain Compound 27 - d (350 mg). LCMS (M + H) + : 285

[0315] Step 5: Preparation of 7-[3-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-1,2,4-oxadiazol-5-yl]-N-[(2,4-dimethoxyphenyl)methyl]-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxamide (Compound 27-e) To a solution of 3-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-1,2,4-oxadiazole (27-d, 200 mg, 0.7 mmol) dissolved in toluene (5 mL), 7-bromo-N-[(2,4-dimethoxyphenyl)methyl]-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxamide (20-f, 200 mg, 0.49 mmol), Pd(OAc) 2 (15.8 mg, 0.07 mmol), PPh 3 (36.9 mg, 0.14 mmol) and AgOAc (350.3 mg, 2.11 mmol) were added, and the mixture was stirred at 120 °C for 12 h. Then, the mixture was concentrated, and the residue was purified by prep-TLC to obtain Compound 27-e (18 mg). LCMS (M+H) + : 608

[0316] Step 6: Preparation of 7-[3-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1,2,4-oxadiazol-5-yl]-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxamide (Example 27) Example 27 was prepared in the same manner as the preparation of Example 21, using Compound 27-e instead of 1-[2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (21-m). Example 27 (2.1 mg) was obtained. LCMS (M+H) + : 368. 1 H NMR (400 MHz, DMSO-d 6 +D 2O) δ = 10.11 (s, 1H), 8.43 (s, 1H), 8.17 (s, 1H), 4.39 (d, J = 6.8 Hz, 2H), 2.54 (s, 3H), 2.15 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H)

[0317] Example 28 8-[2-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide

Chemical formula

[0318] The title compound was prepared according to the following scheme.

Chemical formula

[0319] Step 1: Preparation of tributyl-[2-ethyl-4-[(4-methoxyphenyl)methoxy]-5-methyl-pyrazol-3-yl]stannane (Compound 28-a) To a solution of 1-ethyl-4-[(4-methoxyphenyl)methoxy]-3-methyl-pyrazole (10-a, 2.0 g, 8.12 mmol) in THF (20 mL), n-BuLi (6.5 mL, 16.24 mmol, 2.5 N in hexane) was added dropwise at -78 °C, and the mixture was stirred at -78 °C for 1 hour. Then, tributyltin chloride (5.7 g, 17.51 mmol) was added to the mixture at -78 °C, and the mixture was stirred at room temperature for 3 hours. Then, the mixture was poured into water (100 mL), and HCl (1 N) was added to adjust the pH to about 5. The mixture was extracted with DCM (50 mL × 3). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 4, filtered, concentrated, and the residue was purified by column chromatography to obtain Compound 28-a (3.7 g). LCMS (M+H) + : 537

[0320] Step 2: Preparation of Ethyl 2-(1-Ethyl-4-((4-Methoxybenzyl)oxy)-3-Methyl-1H-Pyrazol-5-yl)Oxazole-5-Carboxylate (Compound 28-b) To a solution of ethyl 2-bromooxazole-5-carboxylate (1.0 g, 4.55 mmol) in 1,4-dioxane (40 mL) was added tributyl-[2-ethyl-4-[(4-methoxyphenyl)methoxy]-5-methyl-pyrazol-3-yl]stannane (28-a, 3.65 g, 6.82 mmol) and Pd(PPh 3 ) 2 Cl 2 (0.32 g, 0.45 mmol), and the mixture was stirred at 110 °C for 18 h. The mixture was then filtered and washed with EA. The filtrate was concentrated, and the residue was purified by column chromatography to afford compound 28-b (720 mg). LCMS (M+H) + : 386

[0321] Step 3: Preparation of Ethyl 4-[6-[(2,4-Dimethoxyphenyl)Methylcarbamoyl]-7-Fluoro-3-Methyl-Pyrrolo[1,2-a]Pyrazin-8-yl]-2-[2-Ethyl-4-[(4-Methoxyphenyl)Methoxy]-5-Methyl-Pyrazol-3-yl]Oxazole-5-Carboxylate (Compound 28-c) To a solution of 8-bromo-N-[(2,4-dimethoxyphenyl)methyl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (4-g, 322 mg, 0.76 mmol) and ethyl 2-(1-ethyl-4-((4-methoxybenzyl)oxy)-3-methyl-1H-pyrazol-5-yl)oxazole-5-carboxylate (28-b, 294.8 mg, 0.76 mmol) in toluene (1 mL), KOPiv (321.8 mg, 2.29 mmol), CataCXium A Pd G3 (167.1 mg, 0.23 mmol) and PivOH (46.8 mg, 0.46 mmol) were added, and the mixture was stirred at 120 °C for 12 h. Then, the mixture was diluted with DCM / MeOH (V / V = 10 / 1, 20 mL), filtered, concentrated, and the residue was purified by prep-TLC to give compound 28-c (30 mg). LCMS (M+H) + : 727

[0322] Steps 4 - 6: Preparation of 8-[2-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (Example 28) Example 28 was prepared in the same manner as the preparation of Example 21, using compound 28-c instead of ethyl 2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[3-[(2,4-dimethoxyphenyl)methylcarbamoyl]-5-methyl-pyrazolo[3,4-c]pyridin-1-yl]oxazole-5-carboxylate (21-k). 3.7 mg of Example 28 was obtained. LCMS (M+H) + : 385. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.55 (s, 1H), 9.15 (s, 1H), 8.77 (brs, 1H), 8.58 (s, 1H), 7.79 (s, 1H), 7.41 (s, 1H), 4.50 (q, J = 6.8 Hz, 2H), 2.45 (s, 3H), 2.15 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H)

[0323] Example 29 1-[2-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-5-methyl-pyrrolo[2,3-c]pyridine-3-carboxamide

Chemical formula

[0324] The title compound was prepared according to the following scheme.

Chemical formula

[0325] Step 1: Preparation of (E)-N,N-dimethyl-2-(2-methyl-5-nitro-4-pyridyl)ethenamine (Compound 29-b) To a solution of 2,4-dimethyl-5-nitro-pyridine (29-a, 20.0 g, 131.45 mmol) dissolved in DMF (400 mL), DMF-DMA (32.29 g, 271.0 mmol) was added, and the mixture was stirred at 100 °C for 2 hours. Subsequently, the mixture was purified by column chromatography to obtain Compound 29-b (24.0 g). LCMS (M+H) + : 208

[0326] Step 2: Preparation of 1-hydroxy-5-methyl-pyrrolo[2,3-c]pyridine (Compound 29-c) A mixture of (E)-N,N-dimethyl-2-(2-methyl-5-nitro-4-pyridyl)ethenamine (29-b, 24.0 g, 115.81 mmol) and Pd / C (10.0 g) in EtOH (300 mL) was stirred at room temperature for 12 hours under H 2 (15 psi). Subsequently, the mixture was filtered through diatomite and concentrated to obtain Compound 29-c (20.0 g). LCMS (M+H) + : 149

[0327] Step 3: Preparation of 5-methyl-1H-pyrrolo[2,3-c]pyridine (Compound 29-d) A mixture of 1-hydroxy-5-methyl-pyrrolo[2,3-c]pyridine (29-c, 20.0 g, 134.99 mmol) and Pd / C (10.0 g) in EtOH (300 mL) was stirred at room temperature for 12 h under H 2 (15 psi). The mixture was then filtered through Celite, concentrated, and the residue was purified by reverse-phase column chromatography to give compound 29-d (10.0 g). LCMS (M+H) + : 133

[0328] Step 4: Preparation of 3-bromo-5-methyl-1H-pyrrolo[2,3-c]pyridine (Compound 29-e) To a solution of NBS (4.04 g, 22.7 mmol) in ACN (50 mL) was added 5-methyl-1H-pyrrolo[2,3-c]pyridine (29-d, 3.0 g, 22.7 mmol), and the mixture was stirred at room temperature for 12 h. The mixture was then filtered and concentrated to give compound 29-e (3.0 g). LCMS (M+H) + : 211

[0329] Step 5: Preparation of methyl 5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (Compound 29-f) To a solution of 3-bromo-5-methyl-1H-pyrrolo[2,3-c]pyridine (29-e, 3.0 g, 14.21 mmol) in MeOH (60 mL) were added Pd(OAc) 2 (1.27 g, 5.69 mmol), dicyclohexyl(3-dicyclohexylphosphaniumpropyl)phosphanium, ditetrafluoroborate (DCPP, 3.48 g, 5.69 mmol) and K 2 CO 3 (5.88 g, 42.64 mmol), and the mixture was stirred at 80 °C for 12 h under CO (50 Psi). The mixture was then filtered and concentrated, and the residue was purified by reverse-phase column chromatography to give compound 29-f (2.0 g). LCMS (M+H) + : 191

[0330] Step 6: Preparation of 5-Methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (Compound 29-g) THF / H 2 To a solution of methyl 5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (29-f, 2.0 g, 10.52 mmol) in THF / H 2 O / MeOH (V / V / V = 1 / 1 / 1, 30 mL), NaOH (4.21 g, 105.15 mmol) was added, and the mixture was stirred at 60 °C for 12 hours. Then, the mixture was purified by reverse-phase column chromatography to obtain Compound 29g (1.7 g). LCMS (M-H) - : 175

[0331] Step 7: Preparation of N-[(2,4-Dimethoxyphenyl)methyl]-5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (Compound 29-h) Compound 29-h was prepared in the same manner as the preparation of Compound 21-h, using Compound 29-g instead of 5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-c]pyridine-3-carboxylic acid (21-g). Compound 29-h (1.1 g) was obtained. LCMS (M-H) - : 324

[0332] Steps 8 - 12: Preparation of 1-[2-(2-Ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-5-methyl-pyrrolo[2,3-c]pyridine-3-carboxamide (Example 29) Example 29 was prepared in the same manner as the preparation of Example 21, using Compound 29-h instead of N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (21-i). Example 29 (2.9 mg) was obtained. LCMS (M + H) + : 367. 1 H NMR (400 MHz, DMSO-d 6 +D 2O) δ 9.29 (s, 1H), 9.03 (s, 1H), 8.79 (s, 1H), 8.39 (s, 1H), 4.44 (q, J = 7.0 Hz, 2H), 2.73 (s, 3H), 2.13 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H)

[0333] Example 30 8-[3-[2-(2-Cyanoethyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide

Chemical Structure

[0334] The title compound was prepared according to the following scheme.

Chemical Structure

[0335] Steps 1 - 2: Preparation of 8-[5-[2-(2-Cyanoethyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (Compound 30-b) Compound 30-b was prepared in the same manner as the preparation of Compound 25-d, using Compound 4-g instead of 4-bromo-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Intermediate A2). 16 mg of Compound 30-b was obtained. LCMS (M + H) + : 680

[0336] Step 3: Preparation of 8-[3-[2-(2-Cyanoethyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (Example 30) Example 30 was prepared in the same manner as in Example 21, using Compound 30-b instead of 1-[2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (21-m). Example 30 (1.5 mg) was obtained. LCMS (M+H) + : 410. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 14.20 - 13.95 (m, 1H), 9.61 (s, 1H), 9.38 - 9.26 (m, 1H), 9.22 (s, 1H), 7.89 - 7.77 (m, 1H), 7.57 - 7.39 (m, 1H), 4.77 (brt, J = 6.6 Hz, 2H), 3.11 (t, J = 6.6 Hz, 2H), 2.48 (s, 3H), 2.18 (s, 3H)

[0337] Example 31 1-[3-(4-Hydroxy-5-methyl-2-propyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical formula

[0338] The title compound was prepared according to the following scheme.

Chemical formula

[0339] Step 1: Preparation of 3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carbaldehyde (Compound 31-b) To a mixture of NaH (871.9 mg, 21.8 mmol) in THF (15 mL), a solution of 3-methyl-1H-pyrazole-4-carbaldehyde (32-a, 2.0 g, 18.16 mmol) in THF (15 mL) was added dropwise at 0 °C, and the mixture was stirred at 0 °C for 30 minutes. Then, SEMCl (4.54 g, 27.25 mmol) was added dropwise to the mixture. The mixture was stirred at room temperature for 16 hours. Then, the mixture was poured into water (50 mL) and extracted with EA (50 mL × 3). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 and filtered, and concentrated. The residue was purified by column chromatography to obtain compound 32-b (3.8 g). LCMS (M+H) + : 241

[0340] Steps 2 - 4: Preparation of 2-[(4-benzyloxy-3-methyl-pyrazol-1-yl)methoxy]ethyl-trimethyl-silane (Compound 31-e) Compound 31-e was prepared in the same manner as the preparation of Compound B1-f, using Compound 31-b instead of 1-ethyl-3-methyl-pyrazole-4-carbaldehyde (B1-c). 3.13 g of Compound 31-e was obtained. LCMS (M+H) + : 319

[0341] Step 5: Preparation of 4-benzyloxy-3-methyl-1H-pyrazole (Compound 31-f) To a solution of 2-[(4-benzyloxy-3-methyl-pyrazol-1-yl)methoxy]ethyl-trimethyl-silane (31-e, 2.0 g, 6.28 mmol) in DCM (30 mL), TFA (14.8 g, 129.8 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Then, the mixture was concentrated, and the residue was dissolved in DCM (10 mL). Then, saturated NaHCO 3 solution was added to adjust the pH to about 8. Then, the mixture was extracted with DCM (50 mL × 3), the combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4It was dried, filtered, and concentrated. The residue was purified by column chromatography to obtain Compound 31-f (1.2 g). LCMS (M+H) + : 189

[0342] Step 6: Preparation of 4-benzyloxy-3-methyl-1-propyl-pyrazole (Compound 31-g) To a solution of 4-benzyloxy-3-methyl-1H-pyrazole (31-f, 500 mg, 2.66 mmol) dissolved in DMF (10 mL), 1-iodopropane (903.1 mg, 5.31 mmol) and Cs 2 CO 3 (2.59 g, 7.97 mmol) were added, and the mixture was stirred at 80 °C for 16 h. Then, the mixture was diluted with water (10 mL) and extracted with EA (30 mL×3). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 and filtered and concentrated. The residue was purified by prep-TLC to obtain Compound 31-g (450 mg). LCMS (M+H) + : 231

[0343] Step 7: Preparation of 4-benzyloxy-5-bromo-3-methyl-1-propyl-pyrazole (Compound 31-h) Compound 31-h was prepared in the same manner as the preparation of Compound 21-a, using Compound 31-g instead of 4-benzyloxy-1-ethyl-3-methyl-pyrazole (B1-f). Compound 31-h (200 mg) was obtained. LCMS (M+H) + : 309

[0344] Step 8: Preparation of 1-[5-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-1-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 31-i) In toluene (3 mL), N-[(2,4-dimethoxyphenyl)methyl]-1-[1-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (22-c, 120 mg, 0.23 mmol), 4-benzyloxy-5-bromo-3-methyl-1-propyl-pyrazole (31-h72.2 mg, 0.23 mmol), Pd(OAc) 2 (10.5 mg, 0.05 mmol), CuI (14.3 mg, 0.14 mmol), PPh 3 (33.5 mg, 0.09 mmol) and K 2 CO 3 (96.7 mg, 0.7 mmol) were dissolved in a solution, and the mixture was stirred at 120 °C for 12 hours under N 2 . Then, the mixture was diluted with DCM (10 mL) and filtered. The filtrate was concentrated, and the residue was purified by prep-TLC to obtain compound 31-i (10 mg). LCMS (M+H) + : 742

[0345] Step 9: Preparation of 1-[3-(4-hydroxy-5-methyl-2-propyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Example 31) Example 31 was prepared in the same manner as the preparation of Example 21, using compound 31-i instead of 1-[2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (21-m). 1.7 mg of Example 31 was obtained. LCMS (M+H) + : 382. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 14.20 (brs, 1H), 9.64 (s, 1H), 9.20 (s, 1H), 8.06 (s, 2H), 7.78 (brs, 1H), 4.43 (t, J = 6.8 Hz, 2H), 2.67 (s, 3H), 2.18 (s, 3H), 1.86 - 1.75 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H)

[0346] Example 32 1-[3-[2-(Cyclopropylmethyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide [Chemical formula] Example 32 was prepared in the same manner as the preparation of Example 31, using bromomethylcyclopropane instead of 1-iodopropane. 3.4 mg of Example 32 was obtained. LCMS (M+H) + : 394. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.61 (s, 1H), 8.04 - 7.95 (m, 2H), 7.70 (brs, 1H), 4.37 (d, J = 6.8 Hz, 2H), 2.65 (s, 3H), 2.15 (s, 3H), 1.37 - 1.28 (m, 1H), 0.47 - 0.41 (m, 2H), 0.40 - 0.35 (m, 2H)

[0347] Example 33 1-[3-(2-Cyclopropyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide [Chemical formula]

[0348] The title compound was prepared according to the following scheme. [Chemical formula]

[0349] Step 1: Preparation of 4-benzyloxy-1-cyclopropyl-3-methyl-pyrazole (Compound 33-a) A solution of 4-benzyloxy-3-methyl-1H-pyrazole (31-f, 500 mg, 2.66 mmol) in 1,4-dioxane (20 mL) was added with cyclopropylboronic acid (456.4 mg, 5.31 mmol), Cu(OAc) 2 (482.5 mg, 2.66 mmol), DMAP (1.29 g, 10.63 mmol) and Py (524.6 mg, 6.64 mmol), and the mixture was stirred at 100 °C for 16 h under O 2 . Then the mixture was diluted with water (50 mL) and extracted with EA (30 mL × 2). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography to give compound 33-a (540 mg). LCMS (M+H) + : 229

[0350] Steps 2-4: Preparation of 1-[3-(2-cyclopropyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Example 33) Example 33 was prepared in the same manner as the preparation of Example 31, using compound 33-a instead of 4-benzyloxy-3-methyl-1-propyl-pyrazole (31-g). 1.5 mg of Example 33 was obtained. LCMS (M+H) + : 380. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 14.31 (brs, 1H), 9.67 (d, J = 1.2 Hz, 1H), 9.15 (brs, 1H), 8.10 - 8.00 (m, 2H), 7.77 (brs, 1H), 4.20 - 4.16 (m, 1H), 2.67 (s, 3H), 2.15 (s, 3H), 1.07 - 1.05 (m, 2H), 0.99 - 0.96 (m, 2H)

[0351] Example 34 4-[3-[2-(3,3-Difluoroallyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide

Chem.

[0352] The title compound was prepared according to the following scheme. TIFF2025516688000117.tif53170

[0353] Step 1: Preparation of 4-[5-[4-benzyloxy-2-(3,3-difluoroallyl)-5-methyl-pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 34-a) To a solution of 4-[5-[4-benzyloxy-5-methyl-2-(2-oxoethyl)pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (24-a, 50 mg, 0.07 mmol) and PPh 3 (22.1 mg, 0.08 mmol) in DMF (1 mL) was added sodium 2-chloro-2,2-difluoro-acetate (16.1 mg, 0.11 mmol), and the mixture was stirred at 100 °C for 12 h. Then water (50 mL) was added to the mixture, and the mixture was extracted with EA (50 mL × 3). The combined organic phases were washed with water and dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The residue was purified by prep-TLC to give Compound 34-a (12 mg). LCMS (M+H) + : 776

[0354] Procedure 2: Preparation of 4-[3-[2-(3,3-difluoroallyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Example 34) Example 34 was prepared in the same manner as the preparation of Example 21, using Compound 34-a instead of 1-[2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (21-m). 1.3 mg of Example 34 was obtained. LCMS (M+H) + : 416. 1 H NMR (400 MHz, METHANOL-d 4 ) δ = 8.86 (s, 1H), 8.43 (s, 1H), 5.26 (brd, J = 7.6 Hz, 2H), 4.90 (s, 1H), 4.23 (s, 3H), 2.25 (s, 3H)

[0355] Example 35 4-[3-[4-hydroxy-5-methyl-2-[2-(1,2,3-triazol-2-yl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide

Chemical Structure

[0356] Example 36 4-[3-[4-Hydroxy-5-methyl-2-[2-(1H-1,2,4-triazol-1-yl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide

Chemical formula

[0357] Example 37 4-[3-[2-(3,3-Difluoropropyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide

Chemical formula

[0358] The title compound was prepared according to the following scheme.

Chemical formula

[0359] Step 1: Preparation of 4-[3-[2-(3,3-difluoropropyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Example 37) To a solution of 4-[3-[2-(3,3-difluoroallyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Example 34, 10 mg, 0.02 mmol) in THF (3 mL), Pd / C (10 mg) was added, and the mixture was stirred at 30 °C for 12 h under an H 2 balloon. Then the mixture was purified by reverse-phase column chromatography to give Example 37 (2.9 mg). LCMS (M+H) + : 418. 1 H NMR (400 MHz, DMSO-d 6 ) δ=15.39 (s, 1H), 8.86 (d, J = 1.6 Hz, 1H), 8.83 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.87 (d, J = 2.6 Hz, 1H), 6.34 - 6.00 (m, 1H), 4.64 (t, J = 7.4 Hz, 2H), 4.22 (s, 3H), 2.53 - 2.52 (m, 1H), 2.46 - 2.45 (m, 1H), 2.15 (s, 3H)

[0360] Example 38 4-[3-[4-Hydroxy-5-methyl-2-[2-(1,2,4-triazol-4-yl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide

Chemical formula

[0361] The title compound was prepared according to the following scheme.

Chemical formula

[0362] Step 1: Preparation of 4-[5-[4-benzyloxy-5-methyl-2-[2-(1,2,4-triazol-4-yl)ethyl]pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 38-a) Compound 38-a was prepared in the same manner as the preparation of Compound 23-m, using 1,2,4-triazole instead of imidazole. The residue was purified by prep-TLC (DCM / MeOH = 30 / 1), and the minor spot (Rf = 0.25) was defined as Compound 38-a (10 mg), and no further structure confirmation was performed. LCMS (M+H) + : 795

[0363] Step 2: Preparation of 4-[3-[4-hydroxy-5-methyl-2-[2-(1,2,4-triazol-4-yl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Example 38) Example 38 was prepared in the same manner as the preparation of Example 21, using Compound 38-a instead of 1-[2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (21-m). 2.0 mg of Example 38 was obtained. LCMS (M+H) + : 435. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 15.21 (s, 1H), 8.72 (s, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.86 (s, 1H), 7.61 (s, 1H), 7.34 (s, 1H), 4.87 (t, J = 5.8 Hz, 2H), 4.63 (t, J = 5.8 Hz, 2H), 2.97 (d, J = 4.4 Hz, 3H), 2.09 (s, 3H)

[0364] Example 39 4-[3-[4-Hydroxy-5-methyl-2-[2-(1,2,4-triazol-1-yl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide

Chem.

[0365] The title compound was prepared according to the following scheme.

Chem.

[0366] Step 1: Preparation of 4-[5-[4-benzyloxy-5-methyl-2-[2-(1,2,4-triazol-1-yl)ethyl]pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 39-a) Compound 39-a was prepared using 1,2,4-triazole instead of imidazole in the same manner as the preparation of Compound 23-m. The residue was purified by prep-TLC (DCM / MeOH = 30 / 1), and the major spot (Rf = 0.3) was defined as Compound 39-a (20 mg), and no further structure confirmation was performed. LCMS (M+H) + : 795

[0367] Step 2: Preparation of 4-[3-[4-Hydroxy-5-methyl-2-[2-(1,2,4-triazol-1-yl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Example 39) Example 39 was prepared in the same manner as in Example 21, using Compound 39-a instead of 1-[2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (21-m). Example 39 (6.7 mg) was obtained. LCMS (M+H) + : 435. 1 H NMR (400 MHz, DMSO-d 6 ) δ=15.33 (s, 1H), 8.90 - 8.82 (m, 2H), 8.47 (s, 1H), 8.24 (s, 1H), 8.05 (brs, 1H), 7.89 - 7.85 (m, 1H), 7.83 (s, 1H), 4.91 (t, J=6.2 Hz, 2H), 4.66 (t, J=6.2 Hz, 2H), 4.23 (s, 3H), 2.13 (s, 3H)

[0368] Example 40 1-[3-[4-Hydroxy-5-methyl-2-(2-phenylethyl)pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical formula

[0369] The title compound was prepared according to the following scheme.

Chemical formula

[0370] Step 1: Preparation of 4-benzyloxy-3-methyl-1-(2-phenylethyl)pyrazole (Compound 40-a) To a solution of 4-benzyloxy-3-methyl-1H-pyrazole (31-f, 500 mg, 2.66 mmol) dissolved in DMF (4 mL), Cs 2 CO 3(2596 mg, 7.97 mmol) and 1-bromo-2-phenylethane (1.09 mL, 7.97 mmol) were added. The mixture was stirred at 100 °C for 12 h. The reaction mixture was cooled and diluted with EtOAc (20 mL) and water (20 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (20 mL × 2). The combined organic layers were dried over Na 2 SO 4 and concentrated to give a residue, which was purified by prep-TLC to give compound 40-a (500 mg). LCMS (M+H) + : 293. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.40 - 7.35 (m, 4H), 7.29 - 7.22 (m, 4H), 7.13 - 7.07 (m, 2H), 6.75 (s, 1H), 4.82 (s, 2H), 4.20 - 4.11 (m, 2H), 3.08 (t, J = 7.4 Hz, 2H), 2.22 (s, 3H)

[0371] Step 2: Preparation of 4-benzyloxy-5-bromo-3-methyl-1-(2-phenylethyl)pyrazole (Compound 40-b) To a solution of compound 40-a (500.0 mg, 1.71 mmol) dissolved in THF (5 mL), NBS (365 mg, 2.05 mmol) was added. The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated and purified by prep-TLC to give compound 40-b (450.0 mg). LCMS (M+H) + : 371. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.36 (s, 4H), 7.33 - 7.22 (m, 4H), 7.19 - 6.99 (m, 2H), 4.90 (s, 2H), 4.24 (dd, J = 7.2, 8.4 Hz, 2H), 3.14 - 3.01 (m, 2H), 2.10 (s, 3H)

[0372] Step 3: Preparation of 3:1-[5-[4-benzyloxy-5-methyl-2-(2-phenylethyl)pyrazol-3-yl]-1-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 40-c) To toluene (10 mL), compound 40-b (200.0 mg, 0.54 mmol), N-[(2,4-dimethoxyphenyl)methyl]-1-[1-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (22-c, 276 mg, 0.54 mmol), Pd(OAc) 2 (24 mg, 0.11 mmol), CuI (61 mg, 0.32 mmol), PPh 3 (56 mg, 0.22 mmol), K 2 CO 3 (223 mg, 1.62 mmol) were mixed and the mixture was stirred at 120 °C for 12 h under N 2 atmosphere. The reaction mixture was diluted with DCM (10 mL) and filtered. The filtrate was concentrated and purified by prep-TLC to obtain compound 40-c (10 mg). LCMS (M+H) + : 804

[0373] Step 4: Preparation of 1-[3-[4-hydroxy-5-methyl-2-(2-phenylethyl)pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Example 40) A solution of compound 40-c (10 mg, 0.01 mmol) and MsOH (12 mg, 0.12 mmol) dissolved in HFIP (0.3 mL) was stirred at 30 °C for 3 h. The reaction mixture was purified by HPLC to obtain Example 40 (1.8 mg). LCMS (M+H) + : 444, 11H NMR (400 MHz, DMSO-d6) δ = 14.14 (s, 1H), 9.62 (s, 1H), 9.23 (s, 1H), 8.05 (s, 1H), 8.00 - 7.92 (m, 1H), 7.88 - 7.79 (m, 1H), 7.28 - 7.21 (m, 2H), 7.21 - 7.10 (m, 3H), 4.67 (t, J = 7.4 Hz, 2H), 3.09 - 3.05 (m, 2H), 2.67 (s, 3H), 2.18 (s, 3H)

[0374] Example 41 1-[3-[2-(3-Fluoropropyl)-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical Structure

Chemical Structure

[0375] Step 1: Preparation of 4-benzyloxy-1-(3-fluoropropyl)-3-methyl-pyrazole (Compound 41-a) and 4-benzyloxy-1-(3-fluoropropyl)-5-methyl-pyrazole (Compound 41-b) To a solution of 4-benzyloxy-3-methyl-1H-pyrazole (31-f, 500 mg, 2.66 mmol) in acetonitrile (5 mL) was added Cs 2 CO 3 (2.6 g, 7.97 mmol, 3.0 equivalents) and 1-bromo-3-fluoropropane (1.12 g, 7.97 mmol). The mixture was stirred at 80 °C for 12 hours. Then, the mixture was filtered and concentrated. The residue was purified by prep-TLC to obtain Compound 41-a (250 mg) and Compound 41-b (150 mg). Compound 41-a, LCMS (M+H)+ : 249. 1 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.45 - 7.31 (m, 5H), 6.97 (s, 1H), 4.89 (s, 2H), 4.44 (t, J = 5.6 Hz, 1H), 4.32 (t, J = 5.6 Hz, 1H), 4.08 (t, J = 6.7 Hz, 2H), 2.25 - 2.09 (m, 5H) Compound 41-b, LCMS (M+H) + : 249. 1 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.43 - 7.29 (m, 5H), 7.24 (s, 1H), 4.94 (s, 2H), 4.44 (t, J = 5.6 Hz, 1H), 4.32 (t, J = 5.6 Hz, 1H), 4.11 (t, J = 6.8 Hz, 2H), 2.29 - 2.06 (m, 5H)

[0376] Step 2: Preparation of 4-benzyloxy-5-bromo-1-(3-fluoropropyl)-3-methyl-pyrazole (Compound 41-c) To a solution of 4-benzyloxy-1-(3-fluoropropyl)-3-methyl-pyrazole (41-a, 220 mg, 0.89 mmol) in THF (2 mL) was added NBS (205 mg, 1.15 mmol). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated and the residue was purified by flash chromatography on silica gel to give Compound 41-c (220 mg). LCMS (M+H) + : 327 Example 41 (2.4 mg), LCMS (M+H) + : 400, 1 1H NMR (400 MHz, DMSO-d6) δ = 14.37 - 14.11 (m, 1H), 9.64 (d, J = 1.0 Hz, 1H), 9.44 - 9.15 (m, 1H), 8.08 (s, 2H), 7.80 (brs, 1H), 4.60 (t, J = 7.0 Hz, 2H), 4.54 (t, J = 5.8 Hz, 1H), 4.42 (t, J = 5.8 Hz, 1H), 2.68 (s, 3H), 2.23 - 2.13 (m, 5H)

[0377] Example 42 1-[3-[4-Hydroxy-2-(2-methoxyethyl)-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chem.

[0378] Example 43 1-[3-(2-Butyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chem.

[0379] Example 44 1-[3-[4-Hydroxy-2-(3-methoxypropyl)-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical formula

[0380] Example 45 4-[3-(4-Hydroxy-5-methyl-2-pent-3-ynyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide

Chemical formula

[0381] The title compound was prepared according to the following scheme.

Chemical formula

[0382] Step 1: Preparation of methyl 4-benzyloxy-5-methyl-2-pent-3-ynyl-pyrazole-3-carboxylate (Compound 45-a) A solution of methyl 4-benzyloxy-3-methyl-1H-pyrazole-5-carboxylate (1.5 g, 6.09 mmol) in toluene (15 mL) was added with CMBP (7.36 g, 30.46 mmol) and 3-pentyn-1-ol (2.81 mL, 30.46 mmol), and then the mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated to obtain a residue. The residue was purified by column chromatography to obtain compound 45-a (1.8 g). LCMS (M+H) + : 313

[0383] Step 2: Preparation of 4-benzyloxy-5-methyl-2-pent-3-ynyl-pyrazole-3-carbohydrazide (Compound 45-b) Hydrazine hydrate (2.94 g, 57.63 mmol) was added to a solution of compound 45-a (1.8 g, 5.76 mmol) in methanol (20 mL) at room temperature. Then the mixture was stirred at 80 °C for 4 h. The mixture was concentrated to obtain compound 45-b (1.8 g). LCMS (M+H) + : 313

[0384] Step 3: Preparation of 1-[(4-benzyloxy-5-methyl-2-pent-3-ynyl-pyrazole-3-carbonyl)amino]-3-[(4-methoxyphenyl)methyl]thiourea (Compound 45-c) 4-Methoxybenzyl isothiocyanate (1.95 g, 10.88 mmol) was added to a yellow solution of compound 45-b (1.7 g, 5.44 mmol) and DIPEA (2.69 mL, 16.33 mmol) in THF (80 mL) at room temperature. The mixture was stirred for 12 h and concentrated to obtain compound 45-c (2.3 g). LCMS (M+H) + : 492

[0385] Step 4: Preparation of 5-(4-benzyloxy-5-methyl-2-pent-3-ynyl-pyrazole-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole-3-thiol (Compound 45-d) A yellow solution obtained by dissolving compound 45-c (2.3 g, 4.68 mmol) in 3N NaOH (25 mL) was stirred at 100 °C for 3 hours. The mixture was washed with EA (3 × 900 mL). The combined organic layers were washed with water (3 × 800 mL) and brine (1050 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to obtain compound 45-d (2.0 g). LCMS (M+H) + : 474

[0386] Step 5: Preparation of 3-(4-benzyloxy-5-methyl-2-pent-3-ynyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole (compound 45-e) To a solution of compound 45-d (2.5 g, 5.28 mmol) dissolved in acetic acid (8 mL), H 2 O 2 (11.27 g, 99.44 mmol) was added slowly, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous solution of Na 2 SO 3 (200 mL) and extracted with ethyl acetate (3 × 250 mL). The combined organic layers were washed with brine (200 mL), dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by column chromatography to obtain compound 45-e (1.2 g). LCMS (M+H) + : 442

[0387] Step 6: Preparation of 4-[5-(4-benzyloxy-5-methyl-2-pent-3-ynyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (compound 45-f) A solution of compound 45-e (100 mg, 0.23 mmol) in 1,4-dioxane (2 mL) was added with 4-bromo-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Intermediate A2, 92 mg, 0.23 mmol), Pd(OAc) 2 (15 mg, 0.07 mmol), CuI (86 mg, 0.45 mmol), PCy 3 HBF 4 (33 mg, 0.09 mmol) and Cs 2 CO 3 (73 mg, 0.23 mmol) under N 2 atmosphere, and the mixture was stirred at 140 °C for 12 h. The mixture was added to DCM / MeOH (30 mL / 6 mL), and then filtered. The filtrate was evaporated and purified by prep-TLC to obtain compound 45-f (20 mg). LCMS (M+H) + : 766

[0388] Step 7: Preparation of 4-[3-(4-hydroxy-5-methyl-2-pent-3-ynyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Example 45) A solution of compound 45-f (15.0 mg, 0.02 mmol) and MsOH (19 mg, 0.2 mmol) in HFIP (0.5 mL) was stirred at 30 °C for 3 h under N 2 atmosphere. The reaction mixture was purified by reverse-phase HPLC to obtain Example 45 (5.5 mg). LCMS (M+H) + : 406, 1 H NMR (400 MHz, DMSO-d6) δ = 15.37 (s, 1H), 8.93 (s, 1H), 8.89 - 8.84 (m, 1H), 8.47 (s, 1H), 8.02 (s, 1H), 7.88 (s, 1H), 4.57 (t, J = 7.4 Hz, 2H), 4.23 (s, 3H), 2.63 (d, J = 5.6 Hz, 2H), 2.14 (s, 3H), 1.73 (s, 3H)

[0389] Example 46 1-[3-[4-Hydroxy-5-methyl-2-[2-(4-pyridyl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chem.

[0390] The title compound was prepared according to the following scheme.

Chem.

[0391] Step 1: Preparation of 4-(benzyloxy)-5-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Compound 46-a) To a stirred mixture of 4-(benzyloxy)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (31-e, 15.0 g, 47.1 mmol) in ACN (150 mL) was added NBS (16.8 g, 94.2 mmol) portionwise. The resulting mixture was stirred at 60 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to 25 °C. The resulting mixture was concentrated and the residue was purified by silica gel column chromatography to give Compound 46-a (11.0 g). LCMS (M+H) + : 397

[0392] Step 2: Preparation of 4-(benzyloxy)-5-bromo-3-methyl-1H-pyrazole (Compound 46-b) To a stirred mixture of Compound 46-a (11.0 g, 28 mmol) in THF (30 mL) was added tetrabutylammonium fluoride (150 mL, 150 mmol) (1 M in THF) dropwise. The resulting mixture was stirred at 80 °C for 15 h under a nitrogen atmosphere. The mixture was cooled to 25 °C. The resulting mixture was concentrated and purified by silica gel column chromatography to give Compound 46-b (4.20 g). LCMS (M+H) + : 267

[0393] Step 3: Preparation of 3:4-[2-(4-benzyloxy-5-bromo-3-methyl-pyrazol-1-yl)ethyl]pyridine (Compound 46-c) and 4-[2-(4-benzyloxy-3-bromo-5-methyl-pyrazol-1-yl)ethyl]pyridine (Compound 46-d) To a solution of Compound 46-b (500 mg, 1.87 mmol) dissolved in toluene (5 mL), CMBP (1353 mg, 5.62 mmol) and 4-pyridineethanol (691 mg, 5.62 mmol) were added. The mixture was stirred at 80 °C for 12 hours. The mixture was concentrated and purified by preparative NPLC (Welch Ultimate XB-SiOH 250*70*10um, hexane-EtOH (0.1% FA, 10% - 50%)) to obtain Compound 46-c (250 mg) and Compound 46-d (300 mg). Compound 46-c, LCMS (M+H) + : 372, 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.61 - 8.46 (m, 2H), 7.43 - 7.33 (m, 5H), 7.09 - 7.00 (m, 2H), 4.91 (s, 2H), 4.28 (t, J = 7.4 Hz, 2H), 3.12 (t, J = 7.4 Hz, 2H), 2.10 (s, 3H) Compound 46-d, LCMS (M+H) + : 372, 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.53 (brd, J = 5.3 Hz, 2H), 7.37 (s, 5H), 7.08 (d, J = 5.9 Hz, 2H), 4.93 (s, 2H), 4.15 (t, J = 7.0 Hz, 2H), 3.17 (t, J = 6.8 Hz, 2H), 1.68 (s, 3H)

[0394] Step 4: Preparation of 1-[5-[4-benzyloxy-5-methyl-2-[2-(4-pyridyl)ethyl]pyrazol-3-yl]-1-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 46-e) To toluene (3 mL), a mixture of compound 46-c (119 mg, 0.32 mmol), N-[(2,4-dimethoxyphenyl)methyl]-1-[1-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (22-c, 150 mg, 0.29 mmol), Pd(OAc) 2 (19 mg, 0.09 mmol), CuI (33 mg, 0.18 mmol), PPh 3 (38 mg, 0.15 mmol), K 2 CO 3 (121 mg, 0.88 mmol) was stirred at 120 °C for 12 h under a N 2 atmosphere. The reaction mixture was diluted with DCM (10 mL) and filtered. The filtrate was concentrated and purified by prep-TLC to give compound 46-e (35 mg). LCMS (M+H) + : 805

[0395] Step 5: Preparation of 1-[3-[4-hydroxy-5-methyl-2-[2-(4-pyridyl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Example 46) To a solution of 1-[5-[4-benzyloxy-5-methyl-2-[2-(4-pyridyl)ethyl]pyrazol-3-yl]-1-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (46-e, 30 mg, 0.04 mmol) dissolved in HFIP (1.0 mL), MsOH (120 mg, 0.88 mmol) was added. The mixture was stirred at 60 °C for 2 h and purified by reverse-phase HPLC to give Example 46 (11.2 mg). LCMS (M+H) + : 445, 11H NMR (400 MHz, DMSO-d6) δ = 14.30 - 14.11 (m, 1H), 9.57 (d, J = 1.0 Hz, 1H), 9.45 - 9.23 (m, 1H), 8.65 (d, J = 6.4 Hz, 2H), 8.07 (s, 2H), 7.85 (brs, 1H), 7.79 (brd, J = 5.8 Hz, 2H), 4.84 (brt, J = 7.2 Hz, 2H), 3.38 (brt, J = 7.0 Hz, 2H), 2.68 (s, 3H), 2.16 (s, 3H)

[0396] Example 47 1-[3-[4-Hydroxy-5-methyl-2-[2-(3-pyridyl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical Structure

[0397] Example 48 1-[5-[4-Hydroxy-5-methyl-2-(2-phenylethyl)pyrazol-3-yl]-2-methyl-1,2,4-triazol-3-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical Structure

[0398] The title compound was prepared according to the following scheme. [Chemical formula]

[0399] Step 1: Preparation of [4-benzyloxy-5-methyl-2-(2-phenylethyl)pyrazol-3-yl]boronic acid (Compound 48-a) To a solution of 4-benzyloxy-5-bromo-3-methyl-1-(2-phenylethyl)pyrazole (40-b, 90 mg, 0.24 mmol) in THF (2 mL), N 2 Under an N atmosphere, n-BuLi (2.5 M, 0.15 mL, 0.36 mmol) was added dropwise at -78 °C. The mixture was stirred at -78 °C for 1 hour, then triisopropyl borate (273 mg, 0.34 mL, 1.45 mmol) was added. The mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into an aqueous NH 4 Cl solution (50 ml) and extracted with EA (3 × 60 mL). The combined organic layers were washed with brine and dried over Na 2 SO 4 and concentrated to obtain Compound 48-a (80.0 mg). LCMS (M+H) + : 337

[0400] Step 2: Preparation of 1-(5-bromo-2-methyl-1,2,4-triazol-3-yl)-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 48-b) To a stirred mixture of DMF (15.0 mL) containing N-(2,4-dimethoxybenzyl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (21-i, 800 mg, 2.45 mmol) and 3,5-dibromo-1-methyl-1,2,4-triazole (1.76 g, 7.35 mmol), copper(I) iodide (233 mg, 1.23 mmol), 1,10-phenanthroline (441 mg, 2.45 mmol) and potassium carbonate (846 mg, 6.13 mmol) were added portionwise. The resulting mixture was stirred at 100 °C for 16 h. The mixture was cooled, diluted with ice-water (60 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to afford compound 48-b (415 mg). LCMS (M+H) + : 485

[0401] Step 3: Preparation of 1-[5-[4-benzyloxy-5-methyl-2-(2-phenylethyl)pyrazol-3-yl]-2-methyl-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 48-c) To a solution of 1-(5-bromo-2-methyl-1,2,4-triazol-3-yl)-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (48-b, 55 mg, 0.11 mmol) and compound 48-a (76 mg, 0.23 mmol) dissolved in 1,4-dioxane (3 mL) and water (0.3 mL), K 2 CO 3 (280 mg, 2.04 mmol) and Pd(dppf)Cl 2 (56 mg, 0.07 mmol) were added. The mixture was stirred at 100 °C for 12 h under N 2 atmosphere. The mixture was concentrated and purified by prep-TLC to afford compound 48-c (30 mg). LCMS (M+H) + : 698

[0402] Step 4: Preparation of 1-[5-[4-Hydroxy-5-methyl-2-(2-phenylethyl)pyrazol-3-yl]-2-methyl-1,2,4-triazol-3-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Example 48) A solution of compound 48-c (20 mg, 0.03 mmol) and MsOH (1.0 mL, 0.29 mmol) dissolved in HFIP (2.0 mL) was stirred at 30 °C for 3 hours. The reaction mixture was purified by reverse-phase HPLC to obtain Example 48 (10 mg). LCMS (M+H) + : 458, 1 H NMR (400 MHz, DMSO-d6) δ = 9.58 (s, 1H), 8.29 (brs, 1H), 8.07 (s, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 7.25 - 7.11 (m, 5H), 4.58 (t, J = 7.6 Hz, 2H), 4.29 (s, 3H), 3.04 (t, J = 7.8 Hz, 2H), 2.68 (s, 3H), 2.14 (s, 3H)

[0403] Example 49 1-[5-(2-Butyl-4-hydroxy-5-methyl-pyrazol-3-yl)-2-methyl-1,2,4-triazol-3-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical Structure

Chemical Structure

[0404] Step 1: Preparation of 4-Benzyloxy-1-butyl-3-methyl-pyrazole (Compound 49-a) To a solution of 4-benzyloxy-3-methyl-1H-pyrazole (31-f, 0.5 g, 2.66 mmol) dissolved in DMF (5 mL), Cs 2 CO3 (2.6 g, 7.97 mmol) and 1-bromobutane (1.09 g, 7.97 mmol) were added. The mixture was stirred at 100 °C for 12 h. The reaction mixture was cooled and diluted with EtOAc (20 mL) and water (20 mL). The two-phase layer was separated, and the aqueous phase was extracted with EtOAc (300 mL × 2). All the organic layers were combined and dried over Na 2S O 4 and concentrated to obtain compound 49-a (400 mg). LCMS (M+H) + : 245

[0405] Step 2: Preparation of 4-benzyloxy-5-bromo-1-butyl-3-methyl-pyrazole (Compound 49-b) To a solution of compound 49-a (900 mg, 3.68 mmol) dissolved in THF (10 mL), NBS (786 mg, 4.42 mmol) was added. The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated and purified by prep-TLC to obtain compound 49-b (200 mg). LCMS (M+H) + : 323, 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.46 - 7.30 (m, 5H), 4.93 (s, 2H), 4.03 (t, J = 7.2 Hz, 2H), 2.10 (s, 3H), 1.83 - 1.72 (m, 2H), 1.37 - 1.26 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H)

[0406] Step 3: Preparation of (4-benzyloxy-2-butyl-5-methyl-pyrazol-3-yl)boronic acid (Compound 49-c) To a solution of compound 49-b (46 mg, 0.14 mmol) dissolved in THF (2 mL), n-BuLi (2.5 M, 0.09 mL, 0.21 mmol) was added dropwise under N 2 atmosphere at -78 °C. The mixture was stirred at -78 °C for 0.5 h. Then, triisopropyl borate (160 mg, 0.2 mL, 0.85 mmol) was added. The mixture was warmed to 25 °C, stirred for 0.5 h, and then poured into an aqueous solution of NH 4 Cl (50 ml) and extracted with EA (3 × 50 mL). The combined organic layers were dried over Na2 SO 4 It was dried with SO and concentrated to obtain Compound 49-c (50.0 mg). LCMS (M+H) + : 289 Example 49, LCMS (M+H) + : 410, 1 H NMR (400 MHz, DMSO-d6) δ = 9.59 (d, J = 0.8 Hz, 1H), 8.31 (s, 1H), 8.10 (s, 2H), 7.92 (s, 1H), 4.37 (t, J = 7.2 Hz, 2H), 4.28 (s, 3H), 2.68 (s, 3H), 2.12 (s, 3H), 1.80 - 1.67 (m, 2H), 1.32 - 1.20 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H)

[0407] Example 50 1-[3-[4-Hydroxy-2-[2-(4-methoxyphenyl)ethyl]-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical formula

[0408] Example 51 1-[3-(4-Hydroxy-5-methyl-2-pent-3-ynyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chem.

[0409] The title compound was prepared according to the following scheme.

Chem.

[0410] Step 1: Preparation of 4-benzyloxy-5-bromo-3-methyl-1-pent-3-ynyl-pyrazole (Compound 51-a) To a solution of 4-benzyloxy-5-bromo-3-methyl-1H-pyrazole (46-b, 300 mg, 1.12 mmol) and 3-pentyn-1-ol (113 mg, 0.12 mL, 1.35 mmol) in toluene (5 mL) was added CMBP (541 mg, 2.25 mmol). The mixture was stirred 2 under a N balloon at 80 °C for 16 h. The mixture was concentrated and purified by prep-TLC to give Compound 51-a (140 mg). LCMS (M+H) + : 332

[0411] Step 2: Preparation of (4-benzyloxy-5-methyl-2-pent-3-ynyl-pyrazol-3-yl)boronic acid (Compound 51-b) To a solution of 4-benzyloxy-5-bromo-3-methyl-1-pent-3-ynyl-pyrazole (51-a, 80 mg, 0.24 mmol) in THF (2 mL) was added 2 n-BuLi (2.5 M, 0.14 mL, 0.36 mmol) dropwise at -70 °C under N atmosphere. The mixture was stirred at -70 °C for 1 h, then triisopropyl borate (270 mg, 0.33 mL, 1.44 mmol) was added. The mixture was slowly warmed to 20 °C and stirred for 2 h. The reaction mixture was quenched with NH 4Poured into a saturated aqueous solution of Cl (10 ml) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 and filtered, concentrated to give the crude compound 51-b (60.0 mg). LCMS (M + H) + : 299

[0412] Step 3: Preparation of 3,5-dibromo-1-[(4-methoxyphenyl)methyl]-1,2,4-triazole (Compound 51-c) To MeCN (200 mL), a mixture of 3,5-dibromo-1H-1,2,4-triazole (30 g, 132 mmol), 4-methoxybenzyl chloride (21.5 mL, 158.69 mmol), KI (10.98 g, 66 mmol), and DIEA (43.7 mL, 264 mmol) was added, and the mixture was stirred at 80 °C for 16 h under a N 2 balloon. The mixture was concentrated and purified by column chromatography to give Compound 51-c (30 g). LCMS (M + H) + : 346, 1 1H NMR (400 MHz, DMSO-d6) δ = 7.24 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 5.32 (s, 2H), 3.74 (s, 3H)

[0413] Step 4: Preparation of 1-[5-bromo-2-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethylphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 51-d) To DMF (30 mL), a solution of N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (21-i, 5.0 g, 15.32 mmol) and Compound 51-c (7.97 g, 22.98 mmol) was added, and CuI (0.59 g, 3.06 mmol), 1-N,2-N-dimethylcyclohexane-1,2-diamine (435 mg, 3.06 mmol), and K 3 PO 4 (6.5 g, 30.64 mmol) were added. The mixture was heated at 120 °C under N2 Below, it was stirred for 12 hours. The reaction mixture was poured into ice water (1000 mL) and extracted with ethyl acetate (3 × 500 mL). The organic layer was washed with water (2 × 500 mL) and brine (2 × 500 mL). The combined organic layers were dried over Na 2 SO 4 and filtered, and concentrated. The residue was triturated with ethyl acetate (30 mL) and filtered to obtain Compound 51-d (4.8 g). LCMS (M+H) + : 592, 1 H NMR (400 MHz, DMSO-d6) δ = 9.45 (s, 1H), 9.06 (t, J = 5.6 Hz, 1H), 8.01 (s, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 2H), 6.58 (s, 1H), 6.47 (d, J = 8.2 Hz, 1H), 5.89 (s, 2H), 4.49 (d, J = 5.6 Hz, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 3.68 (s, 3H), 2.64 (s, 3H)

[0414] Step 5: Preparation of 1-[5-(4-benzyloxy-5-methyl-2-pent-3-ynyl-pyrazol-3-yl)-2-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(3,4-dimethylphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 51-e) To a solution of Compound 51-d (80 mg, 0.14 mmol) dissolved in 1,4-dioxane (5 mL) and water (0.500 mL), Compound 51-b (60 mg, 0.2 mmol), K 2 CO 3 (93 mg, 0.68 mmol) and Pd(dppf)Cl 2 .DCM (33 mg, 0.04 mmol) were added. The mixture was stirred at 100 °C for 12 hours under a N 2 atmosphere. The reaction mixture was concentrated, and the residue was purified by flash silica gel chromatography to obtain Compound 51-e (50 mg). LCMS (M+H) + : 766

[0415] Step 6: Preparation of 1-[3-(4-hydroxy-5-methyl-2-pent-3-ynyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Example 51) To a solution of compound 51-e (90 mg, 0.12 mmol) dissolved in HFIP (2 mL), MsOH (112 mg, 1.18 mmol) was added at 25 °C. The mixture was stirred at 25 °C for 1 hour to obtain a red solution. The mixture was purified by a reverse-phase column to obtain Example 51 (8 mg). LCMS (M+H) + : 406.1, 1 H NMR (400 MHz, DMSO-d6) δ = 14.25 (s, 1H), 9.71 (s, 1H), 9.35 - 9.09 (m, 1H), 8.06 (s, 2H), 7.78 (s, 1H), 4.59 (brt, J = 6.8 Hz, 2H), 2.67 (s, 3H), 2.64 - 2.58 (m, 2H), 2.18 (s, 3H), 1.61 (s, 3H)

[0416] Example 52 1-[3-[2-[2-(4-fluorophenyl)ethyl]-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical formula

[0417] Example 53 1 - [3 - [4 - Hydroxy - 5 - methyl - 2 - (2 - phenylethyl)pyrazol - 3 - yl] - 1H - 1,2,4 - triazol - 5 - yl] - 6 - methyl - imidazo[1,5 - a]pyrazine - 3 - carboxamide [Chemical formula]

[0418] The title compound was prepared according to the following scheme. [Chemical formula]

[0419] Step 1: Preparation of methyl 4 - benzyloxy - 5 - methyl - 2 - (2 - phenylethyl)pyrazole - 3 - carboxylate (Compound 53 - a) To a solution of methyl 4 - benzyloxy - 3 - methyl - 1H - pyrazole - 5 - carboxylate (23 - d, 2.0 g, 8.12 mmol) dissolved in DMF (20 mL), 1 - bromo - 2 - phenylethane (2.25 g, 1.66 mL, 12.18 mmol) and K 2 CO 3 (3.37 g, 24.36 mmol) were added. The mixture was stirred at 80 °C for 12 h and then concentrated. The residue was purified by column chromatography to give Compound 53 - a (1.7 g). LCMS (M + H) + : 351, 11H NMR (400 MHz, CHLOROFORM-d) δ = 7.49 - 7.41 (m, 5H), 7.35 (d, J = 7.4 Hz, 2H), 7.32 - 7.24 (m, 3H), 4.99 (s, 2H), 4.76 - 4.64 (m, 2H), 3.91 (s, 3H), 3.20 - 3.08 (m, 2H), 2.17 (s, 3H)

[0420] Step 2: Preparation of 4 - Benzyloxy - 5 - methyl - 2 - (2 - phenylethyl)pyrazole - 3 - carbohydrazide (Compound 53 - b) To a solution of Compound 53 - a (1.5 g, 4.28 mmol) dissolved in methanol (15 mL), hydrazine hydrate (2.19 g, 42.81 mmol) was added at 25 °C. Then, it was stirred at 80 °C for 4 hours. The mixture was concentrated to obtain Compound 53 - b (1.4 g). LCMS (M + H) + : 351

[0421] Step 3: Preparation of 1 - [[4 - Benzyloxy - 5 - methyl - 2 - (2 - phenylethyl)pyrazole - 3 - carbonyl]amino] - 3 - [(4 - methoxyphenyl)methyl]thiourea (Compound 53 - c) To a yellow solution of Compound 53 - b (1.5 g, 4.28 mmol) and DIPEA (2.12 mL, 12.84 mmol) dissolved in THF (20 mL), 4 - methoxybenzyl isothiocyanate (1.53 g, 8.56 mmol) was added at 25 °C. Then, it was stirred at 30 °C for 3 hours. The mixture was concentrated to obtain Compound 53 - c (2.2 g). LCMS (M + H) + : 530

[0422] Step 4: Preparation of 5 - [4 - Benzyloxy - 5 - methyl - 2 - (2 - phenylethyl)pyrazol - 3 - yl] - 4 - [(4 - methoxyphenyl)methyl] - 1,2,4 - triazole - 3 - thiol (Compound 53 - d) A yellow solution prepared by dissolving compound 53-c (2.0 g, 3.78 mmol) in 3N NaOH (20 mL) was stirred at 100 °C for 12 hours. The mixture was extracted with EA (3 × 100 mL). The organic layer was washed with water (3 × 200 mL) and brine (450 mL), dried over sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain compound 53-d (1.3 g) as a yellow oil. LCMS (M+H) + : 512

[0423] Step 5: Preparation of 3-[4-benzyloxy-5-methyl-2-(2-phenylethyl)pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole (Compound 53-e) To a solution of compound 53-d (1.3 g, 2.54 mmol) dissolved in acetic acid (4 mL), H 2 O 2 (2.91 g, 25.68 mmol) was slowly added, and then this was stirred at 25 °C for 1 hour. The reaction mixture was poured into a saturated solution of Na 2 SO 3 (300 mL) and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine (300 mL), dried over Na 2 SO 4 , and concentrated. The residue was purified by column chromatography to obtain compound 53-e (1.0 g). LCMS (M+H) + : 480

[0424] Step 6: Preparation of 1-[5-[4-benzyloxy-5-methyl-2-(2-phenylethyl)pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Compound 53-f) To a solution of 1-bromo-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Intermediate A1, 84 mg, 0.21 mmol) dissolved in 1,4-dioxane (2 mL), Pd(OAc) 2(14 mg, 0.06 mmol), Cs 2 CO 3 (67 mg, 0.21 mmol), PCy 3 HBF 4 (30 mg, 0.08 mmol), CuI (79 mg, 0.42 mmol) and compound 53-e (0.1 g, 0.21 mmol) were added all at once. The mixture was stirred at 140 °C for 12 h in a sealed tube. (The reactants were placed in a glove box). The mixture was concentrated and purified by Prep-TLC to afford compound 53-f (60 mg). LCMS (M+H) + : 804

[0425] Step 7: 1-[3-[4-Hydroxy-5-methyl-2-(2-phenylethyl)pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Example 53) A solution of compound 53-f (40 mg, 0.05 mmol) and MsOH (49 mg, 0.5 mmol) in HFIP (2 mL) was stirred at 30 °C for 3 h. The reaction mixture was purified by reverse-phase HPLC to afford Example 53 (18.0 mg). LCMS (M+H) + : 444, 1 H NMR (400 MHz, DMSO-d6) δ = 14.17 - 13.83 (m, 1H), 9.68 (d, J = 1.4 Hz, 1H), 9.32 - 8.79 (m, 2H), 8.21 - 7.80 (m, 2H), 7.29 - 7.11 (m, 5H), 4.69 (d, J = 1.8 Hz, 2H), 3.13 - 2.99 (m, 2H), 2.50 (s, 3H), 2.16 (s, 3H)

[0426] Example 54 1-[3-[4-Hydroxy-2-[2-(3-methoxyphenyl)ethyl]-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical Structure

[0427] Example 55 1-(3-(1-(3-Fluorophenethyl)-4-hydroxy-3-methyl-1H-pyrazol-5-yl)-1H-1,2,4-triazol-5-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical formula

Chemical formula

[0428] Step 1: Preparation of 4-(benzyloxy)-5-bromo-1-(3-fluorophenethyl)-3-methyl-1H-pyrazole (Compound 55-a) To a solution of 4-benzyloxy-5-bromo-3-methyl-1H-pyrazole (46-b, 400.0 mg, 1.5 mmol) dissolved in DMF (1 mL), Cs 2 CO 3(1463.7 mg, 4.49 mmol) and 1-(2-bromoethyl)-3-fluoro-benzene (912 mg, 4.49 mmol) were added. The mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography and prep-HPLC to give compound 55-a (130 mg). LCMS (M+H) + : 389, 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.43 - 7.33 (m, 5H), 7.26 - 7.21 (m, 1H), 6.98 - 6.87 (m, 2H), 6.82 (brd, J = 10.0 Hz, 1H), 4.90 (s, 2H), 4.33 - 4.16 (m, 2H), 3.08 (t, J = 7.6 Hz, 2H), 2.09 (s, 3H)

[0429] Step 2: Preparation of 4-(benzyloxy)-1-(3-fluorophenethyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Compound 55-b) To a solution of 4-(benzyloxy)-5-bromo-1-(3-fluorophenethyl)-3-methyl-1H-pyrazole (55-a, 100 mg, 0.26 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (72 mg, 0.39 mmol) in THF (0.5 mL) and toluene (2.5 mL), under N 2 atmosphere, n-BuLi (2.5 M, 0.12 mL, 0.31 mmol) was added dropwise at -78 °C. The mixture was stirred at -78 °C for 1 h, then slowly warmed to 20 °C and stirred for 1 h. The mixture was poured into a saturated aqueous solution of NH 4 Cl (10 ml) at 0 °C and extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine, dried over anhydrous Na 2 SO 4It was dried and concentrated to obtain crude compound 55-b (100 mg). The crude product was used in the next step without purification. LCMS (M+H) + : 437 Example 55 (18 mg), LCMS (M+H) + : 462, 1 H NMR (400 MHz, DMSO-d 6 ) δ = 14.16 (brs, 1H), 9.61 (s, 1H), 9.24 (brs, 1H), 8.08 (s, 1H), 7.99 (brs, 1H), 7.83 (brs, 1H), 7.25 - 7.14 (m, 1H), 7.07 - 6.92 (m, 3H), 4.70 (brt, J = 7.6 Hz, 2H), 3.10 (brt, J = 7.6 Hz, 2H), 2.68 (s, 3H), 2.17 (s, 3H)

[0430] Example 56 1-[3-[2-[2-(2-Fluorophenyl)ethyl]-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical formula

[0431] Example 57 7-Fluoro-8-[3-[4-hydroxy-5-methyl-2-(2-phenylethyl)pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide

Chemical Structure

[0432] Example 58 1-(2-(4-Hydroxy-3-methyl-1-propyl-1H-pyrazol-5-yl)oxazol-4-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical Structure

[0433] The title compound was prepared according to the following scheme.

Chemical Structure

[0434] Step 1: Preparation of Ethyl 2-(4-(Benzyloxy)-3-methyl-1-propyl-1H-pyrazol-5-yl)-4-(3-(2,4-dimethoxybenzylcarbamoyl)-5-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)oxazole-5-carboxylate (Compound 58-a) To a stirred mixture of 1,4-dioxane (8 mL), ethyl 4-(3-(2,4-dimethoxybenzylcarbamoyl)-5-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)oxazole-5-carboxylate (21-j, 80 mg, 0.17 mmol), and 4-(benzyloxy)-5-bromo-3-methyl-1-propyl-1H-pyrazole (31-h, 106 mg, 0.34 mmol), copper(I) iodide (98 mg, 0.52 mmol), palladium(II) acetate (38 mg, 0.17 mmol), cesium carbonate (111 mg, 0.34 mmol), and tricyclohexylphosphonium tetrafluoroborate (44 mg, 0.12 mmol) were added. The resulting mixture was stirred at 140 °C for 16 h under a nitrogen atmosphere. The mixture was cooled and concentrated. The residue was purified by silica gel column chromatography to give Compound 58-a (40 mg). LCMS (M+H) + : 694

[0435] Step 2: Preparation of 2-(4-(Benzyloxy)-3-methyl-1-propyl-1H-pyrazol-5-yl)-4-(3-(2,4-dimethoxybenzylcarbamoyl)-5-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)oxazole-5-carboxylic Acid (Compound 58-b) To a stirred mixture of ethyl Compound 58-a (35 mg, 0.05 mmol) in THF (1 mL) and methanol (1 mL), a solution of sodium hydroxide (22 mg, 0.55 mmol) dissolved in water (1 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 16 h and then acidified to pH = 5 at 0 °C using HCl (1.0 M aqueous solution). The suspension was filtered and the wet cake was dried to give Compound 58-b (25 mg). LCMS (M+H) + : 666

[0436] Step 3: Preparation of 1-(2-(4-(Benzyloxy)-3-methyl-1-propyl-1H-pyrazol-5-yl)oxazol-4-yl)-N-(2,4-dimethoxybenzyl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 58-c) To a stirred mixture of Compound 58-b (20 mg, 0.03 mmol) in DMSO (4 mL) were added acetic acid (0.5 mg, 0.01 mmol) and silver carbonate (2.1 mg, 0.01 mmol). The resulting mixture was stirred at 85 °C for 3 hours under a nitrogen atmosphere. The mixture was poured into ice / water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give Compound 58-c (18 mg). LCMS (M+H) + : 622

[0437] Step 4: Preparation of 1-(2-(4-Hydroxy-3-methyl-1-propyl-1H-pyrazol-5-yl)oxazol-4-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Example 58) To a stirred mixture of Compound 58-c (18 mg, 0.03 mmol) in 1,1,1,3,3,3-hexafluoro-2-propanol (0.5 mL) was added methanesulfonic acid (31 mg, 0.32 mmol). The resulting mixture was stirred at 50 °C for 5 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography to give Example 58 (5.7 mg) as a white solid. LCMS (M+H) + : 382. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.57 (s, 1H), 8.99 (s, 1H), 8.66 (s, 1H), 8.00 (s, 2H), 7.78 (s, 1H), 4.46 - 4.42 (m, 2H), 2.65 (s, 3H), 2.16 (s, 3H), 1.84 - 1.82 (m, 2H), 0.92 - 0.89 (m, 3H)

[0438] Example 59 1-(2-(1-Butyl-4-hydroxy-3-methyl-1H-pyrazol-5-yl)oxazol-4-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical Structure

[0439] Example 60 1-[3-[2-[2-(3-Cyanophenyl)ethyl]-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical Structure

[0440] Example 61 1-[3-[2-[2-(4-Cyanophenyl)ethyl]-4-hydroxy-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical Structure

[0441] Example 62 Methyl 4-[2-[5-[5-(3-carbamoyl-5-methyl-pyrazolo[3,4-c]pyridin-1-yl)-1H-1,2,4-triazol-3-yl]-4-hydroxy-3-methyl-pyrazol-1-yl]ethyl]benzoate [Chemical formula] Example 62 was prepared in the same manner as the preparation of Example 51, using methyl 4-(2-hydroxyethyl)benzoate instead of 3-pentyn-1-ol in Step 1 and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of triisopropyl borate in Step 2. Example 62 (14 mg), LCMS (M+H) + : 502, 1 H NMR (400 MHz, DMSO-d 6 ) δ=14.13 (s, 1H), 9.57 (d, J=1.0 Hz, 1H), 9.23 (s, 1H), 8.09 - 7.99 (m, 2H), 7.83 (brs, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 4.73 (brt, J=7.2 Hz, 2H), 3.79 (s, 3H), 3.17 - 3.12 (m, 2H), 2.67 (s, 3H), 2.17 (s, 3H)

[0442] Example 63 1-(3-(1-(3,3-difluoroallyl)-4-hydroxy-3-methyl-1H-pyrazol-5-yl)-1H-1,2,4-triazol-5-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide [Chemical formula]

[0443] The title compound was prepared according to the following scheme. [Chemical formula]

[0444] 2-[4-Benzyloxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethoxy-tert-butyl-dimethyl-silane (Compound 63-a) was prepared in the same manner as the preparation of Compound 49-c, using (2-bromoethoxy)-tert-butyldimethylsilane instead of 1-bromobutane in Step 1 and using the reagent 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of triisopropyl borate in Step 3.

[0445] Step 1: 1-[5-[4-Benzyloxy-2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-methyl-pyrazol-3-yl]-1-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 63-b) To a solution of Compound 63-a (1.3 g, 2.75 mmol) dissolved in 1,4-dioxane (10 mL) and water (1 mL), 1-[5-bromo-1-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (51-d, 1.0 g, 1.69 mmol), K 2 CO 3 (1.2 g, 8.44 mmol) and Pd(dppf)Cl 2 .DCM (413 mg, 0.51 mmol) were added. The mixture was stirred at 100 °C for 12 h under N 2 atmosphere. Then it was cooled and poured into water (100 mL). The suspension was extracted with EtOAc (100 mL × 2), and the organic phase was washed with brine (20 mL × 2), dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography to obtain Compound 63-b (1.1 g). LCMS (M+H) + : 858

[0446] Step 2: 1-[5-[4-Benzyloxy-2-(2-hydroxyethyl)-5-methyl-pyrazol-3-yl]-2-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 63-c) To a solution of 1-[5-[4-benzyloxy-2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-methyl-pyrazol-3-yl]-2-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (63-b, 1.1 g, 1.28 mmol) dissolved in methanol (10 mL) was added NH 4 F (0.95 g, 25.6 mmol). The mixture was stirred at 70 °C for 1 h. The mixture was cooled, filtered and washed with MeOH (40 mL × 2). The filtrate was concentrated and purified by column chromatography to afford Compound 63-c (750 mg). LCMS (M+H) + : 744

[0447] Step 3: 1-[5-[4-Benzyloxy-5-methyl-2-(2-oxoethyl)pyrazol-3-yl]-2-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 63-d) To a solution of Compound 63-c (300 mg, 0.40 mmol) dissolved in DCM (10 mL) was added Dess-Martin periodinane (684 mg, 1.61 mmol). The mixture was stirred at 25 °C for 2 h. Then it was poured into a mixture of saturated Na 2 SO 3 solution (30 mL) and saturated NaHCO 3 solution (30 mL). The mixture was stirred for 20 min and extracted with DCM (30 mL). The organic layer was dried over Na 2 SO 4It was dried, filtered, and concentrated to obtain Compound 63-d (300 mg). LCMS (M+H) + : 742

[0448] Step 4: 1-[5-[4-Benzyloxy-2-(3,3-difluoroallyl)-5-methyl-pyrazol-3-yl]-2-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 63-e) To a solution of Compound 63-d (300 mg, 0.40 mmol) dissolved in DMF (1 mL), 2-(triphenylphosphonio)difluoroacetate (582 mg, 1.62 mmol) was added. The mixture was stirred at 80 °C for 12 hours. The mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 2). The organic phase was washed with brine (10 mL × 3) and dried over Na 2 SO 4 and concentrated. The residue was purified by prep-TLC to obtain Compound 63-e (60 mg). LCMS (M+H) + : 776

[0449] Step 5: 1-(3-(1-(3,3-Difluoroallyl)-4-hydroxy-3-methyl-1H-pyrazol-5-yl)-1H-1,2,4-triazol-5-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Example 63) To a solution of Compound 63-e (55 mg, 0.07 mmol) dissolved in HFIP (0.3 mL), MsOH (136 mg, 1.42 mmol) was added. The mixture was stirred at 50 °C for 0.5 hour. Then, the mixture was directly purified by prep-HPLC to obtain Example 63 (30 mg). LCMS (M+H) + : 416, 11H NMR (DMSO-d6, 400 MHz) δ = 14.28 (brs, 1H), 9.62 (s, 1H), 9.34 (brs, 1H), 8.05 (s, 2H), 7.78 (brs, 1H), 5.13 (brd, J = 7.6 Hz, 2H), 5.02 - 4.90 (m, 1H), 2.66 (s, 3H), 2.18 (s, 3H)

[0450] Example 64 1-[3-[4-Hydroxy-2-[2-[4-(methoxymethyl)phenyl]ethyl]-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical Structure

Chemical Structure

[0451] Step 1: Preparation of 2-[4-(methoxymethyl)phenyl]ethanol (Compound 64-a) To a solution of 2-[4-(methoxymethyl)phenyl]acetic acid (800 mg, 4.44 mmol) in THF (20 mL), LiAlH 4 (505 mg, 13.32 mmol) was added at 0 °C, and then the mixture was stirred at 60 °C for 0.5 h. The reaction mixture was added to a 1 M aqueous solution of HCl (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were dried over Na 2 SO 4 and filtered, and concentrated to obtain compound 64-a (650 mg). LCMS (M + H) + : 415, 11H NMR (400 MHz, CHLOROFORM-d) δ = 7.34 - 7.30 (m, 2H), 7.26 - 7.21 (m, 2H), 4.46 (s, 2H), 3.88 (t, J = 6.8 Hz, 2H), 3.41 (s, 3H), 2.89 (t, J = 6.4 Hz, 2H) Example 64 (30 mg), LCMS (M + H) + : 488, 1 1H NMR (400 MHz, DMSO-d6) δ = 14.16 (brs, 1H), 9.62 (d, J = 1.0 Hz, 1H), 9.23 (brs, 1H), 8.08 (s, 1H), 8.00 (brs, 1H), 7.86 (brs, 1H), 7.23 - 7.18 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 4.68 (brt, J = 7.6 Hz, 2H), 4.32 (s, 2H), 3.23 (s, 3H), 3.10 - 3.03 (brt, J = 6.8 Hz, 2H), 2.69 (s, 3H), 2.19 (s, 3H)

[0452] Example 65 1-[3-[4-Hydroxy-2-[2-[3-(methoxymethyl)phenyl]ethyl]-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical Structure

Chemical Structure

[0453] Step 1: Preparation of Methyl 2-[3-(bromomethyl)phenyl]acetate (Compound 65-a) A solution of methyl 3-methylphenylacetate (9.0 g, 54.81 mmol) in carbon tetrachloride (1 mL) was added with BPO (1.33 g, 5.48 mmol) and NBS (9.76 g, 54.81 mmol). The reaction mixture was stirred at 90 °C for 18 h under N 2 atmosphere. The reaction mixture was poured into water (100 mL) and extracted with DCM (200 mL×2). The combined organic layers were washed with brine (100 mL) and dried over Na 2 SO 4 then filtered. The filtrate was concentrated and purified by flash chromatography on silica gel to afford compound 65-a (5.0 g). LCMS (M+H) + : 243, 1 H NMR (400 MHz, DMSO-d6) δ = 7.43 - 7.29 (m, 3H), 7.27 - 7.18 (m, 1H), 4.70 (s, 2H), 3.70 (s, 2H), 3.62 (s, 3H)

[0454] Step 2: Preparation of methyl 2-[3-(methoxymethyl)phenyl]acetate (Compound 65-b) To a solution of compound 65-a (5.0 g, 20.6 mmol) in methanol (50 mL) was added NaOMe (5.0 mL, 25.0 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 18 h, poured into saturated NH 4 Cl (50 mL), and then extracted with EA (50 mL×2). The combined organic layers were washed with brine (20 mL) and dried over Na 2 SO 4 and concentrated. The residue was purified by reverse-phase column to afford compound 65-b (1.5 g). LCMS (M - CH 3 O) + : 163

[0455] Step 3: Preparation of 2-[3-(methoxymethyl)phenyl]ethanol (Compound 65-c) To a solution of compound 65-b (1.5 g, 7.7 mmol) in THF (15 mL) was added LiAlH 4(2.5M, 3.86 mL, 9.64 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour and poured into 1 N aqueous solution of HCl (20 mL). Then, it was extracted with EA (30 mL × 2). The combined organic layers were washed with brine (20 mL) and dried over Na 2 SO 4 , concentrated to obtain a residue. The residue was purified by column to obtain compound 65-c (600 mg). LCMS (M-CH 3 O) + : 135 Example 65 (32.3 mg), LCMS (M + H) + : 488, 1 H NMR (400 MHz, DMSO-d6) δ = 14.16 (brd, J = 2.6 Hz, 1H), 9.65 (d, J = 1.0 Hz, 1H), 9.47 - 8.96 (m, 1H), 8.12 (s, 1H), 8.07 (brs, 1H), 7.85 (brs, 1H), 7.20 - 7.04 (m, 4H), 4.75 - 4.65 (m, 2H), 4.17 (s, 2H), 3.09 (s, 3H), 3.07 (brs, 2H), 2.70 (s, 3H), 2.19 (s, 3H)

[0456] Example 66 1-(3-(1-(3,3-Difluoropropyl)-4-hydroxy-3-methyl-1H-pyrazol-5-yl)-1H-1,2,4-triazol-5-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical Structure

[0457] The title compound was prepared according to the following scheme.

Chemical Structure

[0458] Project 1: Preparation of 1-(3-(1-(3,3-difluoropropyl)-4-hydroxy-3-methyl-1H-pyrazol-5-yl)-1H-1,2,4-triazol-5-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Example 66) To a solution of 1-(3-(1-(3,3-difluoroallyl)-4-hydroxy-3-methyl-1H-pyrazol-5-yl)-1H-1,2,4-triazol-5-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Example 63, 20 mg, 0.05 mmol) dissolved in THF (2 mL) and EtOAc (2 mL), Pd / C (20 mg) was added under N 2 atmosphere at 20 °C. The mixture was degassed and purged with H 2 three times, and then stirred at 20 °C for 10 minutes using an H 2 balloon. The mixture was purified by prep-HPLC to obtain Example 66 (5 mg) as a yellow solid. LCMS (M+H) + : 418, 1 H NMR (DMSO-d6, 400 MHz) δ = 14.34 - 14.17 (m, 1H), 9.62 (d, J = 0.8 Hz, 1H), 9.43 - 9.20 (m, 1H), 8.15 - 7.95 (m, 2H), 7.79 (brs, 1H), 6.34 - 5.98 (m, 1H), 4.66 (t, J = 7.2 Hz, 2H), 2.67 (s, 3H), 2.43 - 2.35 (m, 2H), 2.18 (s, 3H)

[0459] Example 67 1-(2-(1-(3,3-difluoropropyl)-4-hydroxy-3-methyl-1H-pyrazol-5-yl)oxazol-4-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical formula

[0460] Step 1: Preparation of 4-(Benzyloxy)-5-bromo-1-(3,3-difluoropropyl)-3-methyl-1H-pyrazole (Compound 67-a) To a stirred mixture of 4-(benzyloxy)-5-bromo-3-methyl-1H-pyrazole (46-b, 1.50 g, 5.62 mmol), 3,3-difluoropropan-1-ol (863 mg, 8.98 mmol), and triphenylphosphine (1.91 g, 7.30 mmol) in THF (25 mL) was added diisopropyl azodicarboxylate (1.70 g, 8.42 mmol) dropwise at 0 °C. The resulting mixture was stirred at 40 °C for 4 h. Then it was cooled and slowly poured into ice / water (50 mL). The mixture was extracted with EtOAc (3 × 50 mL), the organic layer was dried and concentrated. The residue was purified by silica gel column chromatography to give Compound 67-a (800 mg). LCMS (M+H) + : 345 1 The structure was confirmed using 1H NMR and nuclear Overhauser effect spectroscopy (NOESY) (no correlation between Ha and Hb was observed). Example 67 (8.8 mg), LCMS (M+H) + : 418. 1 1H NMR (400 MHz, DMSO-d 6 ) δ = 9.54 (s, 1H), 9.19 (brs, 1H), 8.67 (s, 1H), 7.99 (s, 2H), 7.77 (s, 1H), 6.31 - 6.01 (m, 1H), 4.69 - 4.66 (m, 2H), 2.64 (s, 3H), 2.46 - 2.29 (m, 2H), 2.16 (s, 3H)

[0461] Example 68 1-[3-[4-Hydroxy-2-[2-[4-(hydroxymethyl)phenyl]ethyl]-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide [Chemical formula]

[0462] The title compound was prepared according to the following scheme.

Chemical formula

[0463] A solution of 1-[3-[4-hydroxy-2-[2-[4-(methoxymethyl)phenyl]ethyl]-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Example 64, 10 mg, 0.02 mmol) in trifluoroacetic acid (2.0 mL, 25.96 mmol) and water (0.2 mL) was stirred at 100 °C for 6 hours. The mixture was filtered and the filtrate was purified by prep-HPLC to obtain Example 68 (1.4 mg). LCMS (M+H) + : 474, 1 H NMR (400 MHz, DMSO-d 6 ) δ = 14.16 (brs, 1H), 9.63 (s, 1H), 9.22 (s, 1H), 8.06 (s, 1H), 7.98 (brs, 1H), 7.84 (brs, 1H), 7.21 - 7.16 (m, 2H), 7.15 - 7.10 (m, 2H), 4.65 (brdd, J = 7.6, 8.4 Hz, 2H), 4.41 (s, 2H), 3.08 - 3.02 (m, 2H), 2.68 (s, 3H), 2.18 (s, 3H)

[0464] Example 69 7-Fluoro-8-[3-[4-hydroxy-2-[2-(4-methoxyphenyl)ethyl]-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide

Chemical formula

[0465] Example 70 1-[3-[4-Hydroxy-2-[2-(4-methoxyphenyl)ethyl]-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

Chemical formula

[0466] Example 71 1-[3-[4-Hydroxy-2-[2-[4-(hydroxymethyl)phenyl]ethyl]-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

Chem.

[0467] The title compound was prepared according to the following scheme.

Chem.

[0468] Step 1: Preparation of [4-(2-bromoethyl)phenyl]methanol (Compound 71-a) To a solution of 4-(2-bromoethyl)benzoic acid (20.0 g, 87.3 mmol) dissolved in THF (200 mL), BH 3 .THF (1.0 M, 174.6 mL, 174.6 mmol) was added at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 2 hours. Then, it was poured into 1 N HCl (100 mL) and extracted with EA (200 mL × 2). The combined layers were washed with brine (20 mL) and dried over Na 2 SO 4 and concentrated to obtain Compound 71-a (18.0 g) as a pale yellow solid. LCMS (M+H-18) + : 197

[0469] Step 2: Preparation of [4-(2-bromoethyl)phenyl]methoxy-tert-butyl-dimethyl-silane (Compound 71-b) In DCM (100 mL), [4-(2-bromoethyl)phenyl]methanol 71-a (8.0 g, 37.2 mmol), Et 3To a solution of N (14.3 mL, 111.6 mmol) dissolved, TBSCl (8.41 g, 55.8 mmol) was added at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 18 hours. Then, it was poured into water (100 mL) and extracted with DCM (100 mL × 2). The combined layers were washed with brine (100 mL) and dried over Na 2 SO 4 and concentrated to obtain an oily substance. The residue was purified by column to obtain 71-b (8.0 g). LCMS (M+H-C 6 H 15 SiO) + : 197

[0470] Step 3: Preparation of [4-[2-[4-benzyloxy-5-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-3-methyl-pyrazol-1-yl]ethyl]phenyl]methanol (Compound 71-c) Compound 71-c was prepared in the same manner as in the preparation of Example 53, using Compound 71-b instead of 1-bromo-2-phenylethane in Step 1.

[0471] Step 4: Preparation of [4-[2-[4-benzyloxy-5-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-3-methyl-pyrazol-1-yl]ethyl]phenyl]methoxy-tert-butyl-dimethyl-silane (Compound 71-d) To a yellow solution of Compound 71-c (1.5 g, 2.9 mmol) and imidazole (400 mg, 5.9 mmol) dissolved in DCM (20 mL), TBSCl (2.96 g, 5.9 mmol) was added at 25 °C. The mixture was stirred for 2 hours and concentrated. The residue was purified by column chromatography to obtain Compound 71-d (1.2 g). LCMS (M+H) + : 624

[0472] Step 5: Preparation of 1-[5-[4-benzyloxy-2-[2-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]ethyl]-5-methyl-pyrazol-3-yl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Compound 71-e) To toluene (2 mL) were suspended compound 71-d (300 mg, 0.48 mmol), 1-bromo-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Intermediate A1, 194 mg, 0.48 mmol), Pd(OAc) 2 (32.4 mg, 0.14 mmol), PivOH (29 mg, 0.29 mmol), catacxiuma (52 mg, 0.14 mmol), K 2 CO 3 (199 mg, 1.44 mmol). The suspension was stirred at 120 °C for 12 h under N 2 atmosphere. The mixture was filtered and washed with DCM / MeOH (V / V = 20 / 1, 20 mL). The filtrate was concentrated and purified by prep-TLC to afford compound 71-e (55 mg). LCMS (M+H) + : 948

[0473] Step 6: Preparation of 1-[3-[4-hydroxy-2-[2-[4-(hydroxymethyl)phenyl]ethyl]-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Example 71) To TFA (3 mL) was dissolved compound 71-e (50.0 mg, 0.05 mmol). The solution was stirred at 60 °C for 12 h under N 2 atmosphere. The mixture was concentrated and purified by prep-HPLC to afford Example 71 (6.2 mg). LCMS (M+H) + : 474, 1 H NMR (400 MHz, DMSO-d 6 +D 2O) δ = 9.68 (s, 1H), 9.10 (s, 1H), 7.36 - 6.83 (m, 4H), 4.66 (brs, 2H), 4.41 (s, 2H), 3.04 (brt, J = 7.8 Hz, 2H), 2.50 - 2.50 (m, 3H), 2.16 (s, 3H)

[0474] Example 72 1-[3-[4-Hydroxy-5-methyl-2-[2-(3-pyridyl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

Chemical Structure

[0475] Example 72 was prepared in the same manner as the preparation of Example 53, using 2-(3-pyridyl)ethanol instead of 1-bromo-2-phenylethane in Step 1 (reaction conditions: CMBP, K 2 CO 3 toluene at 80 °C, DMF at 80 °C instead of). Example 72 (18.7 mg), LCMS (M + H) + : 445, 1 H NMR (400 MHz, DMSO + D 2 O) δ = 9.65 (s, 1H), 9.12 (s, 1H), 9.05 - 8.81 (m, 1H), 8.35 (brd, J = 3.8 Hz, 1H), 7.63 (brd, J = 7.4 Hz, 1H), 7.24 (dd, J = 4.8, 7.6 Hz, 1H), 4.69 (brt, J = 7.2 Hz, 2H), 3.09 (brt, J = 7.2 Hz, 2H), 2.49 (brs, 3H), 2.15 (s, 3H)

[0476] Example 73 7-Fluoro-8-[3-[4-hydroxy-5-methyl-2-[2-(3-pyridyl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide

Chemical Structure

[0477] Example 73 was prepared in the same manner as the preparation of Example 53, using 2-(3-pyridyl)ethanol instead of 1-bromo-2-phenylethane in Step 1 (reaction conditions: CMBP, K 2 CO 3 replaced with toluene at 80 °C, DMF at 80 °C), and using Compound 4-g instead of Intermediate A1 in Step 6. Example 73 (8.91 mg), LCMS (M+H) + : 462, 1 H NMR (400 MHz, DMSO-d 6 +D 2 O) δ = 9.56 (s, 1H), 9.17 (s, 1H), 8.34 - 8.23 (m, 2H), 7.52 (brd, J = 8.4 Hz, 1H), 7.18 (dd, J = 4.8, 7.8 Hz, 1H), 4.73 (brt, J = 7.2 Hz, 2H), 3.09 (brt, J = 7.2 Hz, 2H), 2.46 (s, 3H), 2.13 (s, 3H)

[0478] Example 74 1-(2-(4-Hydroxy-3-methyl-1-(2-(pyridin-3-yl)ethyl)-1H-pyrazol-5-yl)oxazol-4-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical Structure

Chemical Structure

[0479] Step 1. Preparation of 3-(2-(4-(benzyloxy)-5-bromo-3-methyl-1H-pyrazol-1-yl)ethyl)pyridine (Compound 74-a) To THF (8 mL), a stirred mixture of 4-(benzyloxy)-5-bromo-3-methyl-1H-pyrazole (46-b, 500 mg, 1.90 mmol), 2-(pyridin-3-yl)ethanol (345 mg, 2.80 mmol), and triphenylphosphine (638 mg, 2.40 mmol) was added diisopropyl azodicarboxylate (492 mg, 2.40 mmol) dropwise at 0 °C. The resulting mixture was stirred at 40 °C for 4 hours. The mixture was cooled and concentrated. The residue was purified by silica gel column to give compound 74-a (280 mg). LCMS (M+H) + : 372 Example 74 (15 mg). LCMS (M+H) + : 445. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.50 (s, 1H), 9.07 (brs, 1H), 8.70 (s, 1H), 8.64 (s, 2H), 8.13 (s, 1H), 8.07 (s, 2H), 7.83 (s, 1H), 7.74 (s, 1H), 4.84 - 4.81 (m, 2H), 3.35 - 3.32 (m, 2H), 2.67 (s, 3H), 2.13 (s, 3H)

[0480] Example 75 1-(2-(4-Hydroxy-1-(3-methoxyphenethyl)-3-methyl-1H-pyrazol-5-yl)oxazol-4-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical formula

[0481] Example 75 was prepared in the same manner as the preparation of Example 58, using compound 75-a instead of compound 31-h.

[0482] Compound 75-a was prepared in the same manner as the preparation of compound 74-a, using 2-(3-methoxyphenyl)ethanol instead of 2-(pyridin-3-yl)ethanol.

Chemical formula

[0483] Example 75 (8.7 mg), LCMS (M+H) + : 474. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.52 (s, 1H), 8.96 (s, 1H), 8.65 (s, 1H), 8.01 (s, 1H), 7.98 (s, 1H), 7.79 (s, 1H), 7.07 - 7.03 (m, 1H), 6.71 - 6.65 (m, 3H), 4.72 - 4.68 (m, 2H), 3.53 (s, 3H), 3.06 - 3.02 (m, 2H), 2.65 (s, 3H), 2.17 (s, 3H)

[0484] Example 76 8-[3-(2-Butyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide

Chemical Structure

[0485] Example 76 was prepared in the same manner as the preparation of Example 53, using 1-bromobutane instead of 1-bromo-2-phenylethane in Step 1 and using Compound 4-g instead of Intermediate A1 in Step 6.

[0486] Example 76 (12.3 mg), LCMS (M+H) + : 413、 1 H NMR (400 MHz, DMSO-d6) δ = 14.24 - 13.68 (m, 1H), 9.63 (s, 1H), 9.27 - 9.18 (m, 1H), 9.16 - 8.82 (m, 1H), 7.93 - 7.70 (m, 1H), 7.59 - 7.35 (m, 1H), 4.47 (t, J = 7.0 Hz, 2H), 2.48 (s, 3H), 2.14 (s, 3H), 1.75 (brt, J = 7.4 Hz, 2H), 1.34 - 1.23 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H)

[0487] Example 77 1-[3-(2-Butyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

Chemical formula

[0488] Example 77 was prepared in the same manner as the preparation of Example 53, using 1-bromobutane instead of 1-bromo-2-phenylethane in Step 1.

[0489] Example 77 (12.1 mg), LCMS (M+H) + ): 396, 1 H NMR (400 MHz, DMSO-d6) δ = 14.32 - 13.78 (m, 1H), 9.69 (d, J = 1.4 Hz, 1H), 9.10 (s, 1H), 9.08 - 8.75 (m, 1H), 8.22 - 7.79 (m, 2H), 4.46 (t, J = 6.6 Hz, 2H), 2.49 - 2.48 (m, 3H), 2.15 (s, 3H), 1.75 (brt, J = 7.4 Hz, 2H), 1.32 - 1.23 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H)

[0490] Example 78 1-(2-(4-Hydroxy-1-(4-methoxyphenethyl)-3-methyl-1H-pyrazol-5-yl)oxazol-4-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical formula

[0491] Example 78 was prepared in the same manner as the preparation of Example 58, using Compound 78-a instead of Compound 31-h.

[0492] Compound 78-a was prepared in the same manner as the preparation of compound 74-a, using 2-(4-methoxyphenyl)ethanol instead of 2-(pyridin-3-yl)ethanol. [Chemical formula]

[0493] Example 78 (2.3 mg), LCMS (M+H) + : 474. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.52 (s, 1H), 8.95 (s, 1H), 8.67 (s, 1H), 8.03 (d, J = 5.6 Hz, 1H), 7.99 (s, 1H), 7.80 (s, 1H), 7.06 (d, J = 8.4, 2H), 6.70 (d, J = 8.4, 2H), 4.67 - 4.63 (m, 2H), 3.65 (s, 3H), 3.02 - 2.98 (m, 2H), 2.66 (s, 3H), 2.17 (s, 3H)

[0494] Example 79 7-Fluoro-8-[3-(4-hydroxy-5-methyl-2-propyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide [Chemical formula]

[0495] Example 79 was prepared in the same manner as the preparation of Example 53. In step 1, 1-propanol was used instead of 1-bromo-2-phenylethane (reaction conditions: CMBP, K 2 CO 3 replaced by toluene at 80 °C, DMF at 80 °C), and in step 6, compound 4-g was used instead of intermediate A1.

[0496] Example 79 (18.4 mg), LCMS (M+H) + : 399, 11H NMR (400 MHz, DMSO-d6) δ = 14.43 - 13.53 (m, 1H), 9.70 - 9.58 (m, 1H), 9.23 (s, 1H), 9.14 - 8.81 (m, 1H), 7.87 - 7.74 (m, 1H), 7.52 - 7.39 (m, 1H), 4.43 (brt, J = 7.2 Hz, 2H), 2.48 (s, 3H), 2.16 (s, 3H), 1.85 - 1.74 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H)

[0497] Example 80 1-[3-(4-Hydroxy-5-methyl-2-propyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

Chemical Structure

[0498] Example 80 was prepared in the same manner as the preparation of Example 53, using 1-propanol instead of 1-bromo-2-phenylethane in Step 1 (reaction conditions: CMBP, K 2 CO 3 toluene at 80 °C, DMF at 80 °C instead of).

[0499] Example 80 (4.9 mg) was obtained as a yellow solid. LCMS (M+H) + : 382, 1 1H NMR (400 MHz, DMSO-d6 + D 2 O = 9.67 (s, 1H), 9.08 (s, 1H), 4.45 - 4.32 (m, 2H), 2.47 (brs, 3H), 2.14 (brs, 3H), 1.81 - 1.72 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H)

[0500] Example 81 1-[3-[4-Hydroxy-2-(5-methoxypent-3-ynyl)-5-methyl-pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide [Chemical]

[0501] Example 81 was prepared in the same manner as the preparation of Example 51, using Compound 81-b instead of 3-pentyn-1-ol in Step 1 and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of triisopropyl borate in Step 2.

[0502] Compound 81-b was prepared according to the following scheme. [Chemical]

[0503] Step 1: Preparation of tert-butyl-(5-methoxypenta-3-inoxy)-dimethyl-silane (Compound 81-a) To a solution of tert-butyl-but-3-inoxy-dimethyl-silane (5.0 g, 27.1 mmol) dissolved in THF (25 mL), N 2 Under an atmosphere, n-BuLi (13.0 mL, 32.6 mmol) was added dropwise at -78 °C. The mixture was stirred at -78 °C for 0.5 h, then bromomethyl methyl methyl ether (4.41 g, 35.3 mmol) in THF (5 mL) was added at -78 °C. The mixture was stirred at -78 °C for an additional 0.5 h. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (3 × 250 mL). The combined organic layers were washed with brine and dried over Na 2 SO 4 . It was then concentrated and purified by column chromatography to obtain Compound 81-a (5.6 g). LCMS (M+H) + : 229, 1 H NMR (400 MHz, CHLOROFORM-d) δ = 4.08 (d, J = 1.8 Hz, 2H), 3.74 (t, J = 7.2 Hz, 2H), 3.38 (s, 3H), 2.46 (d, J = 1.8 Hz, 2H), 0.91 (s, 9H), 0.08 (s, 6H)

[0504] Procedure 2: Preparation of 5-Methoxypent-3-yn-1-ol (Compound 81-b) To a solution of Compound 81-a (5.0 g, 21.9 mmol) dissolved in methanol (30 mL) was added NH 4 F (24.33 g, 656.7 mmol). The mixture was stirred at 60 °C for 1 hour. The mixture was filtered and washed with DCM (200 mL × 2). The filtrate was concentrated and purified by column chromatography to obtain Compound 81-b (2.4 g). LCMS (M+H) + : 115, 1 H NMR (400 MHz, CHLOROFORM-d) δ = 4.11 (d, J = 1.8 Hz, 2H), 3.86 - 3.62 (m, 2H), 3.39 (d, J = 1.4 Hz, 3H), 2.67 - 2.42 (m, 2H).

[0505] Example 81 (8.6 mg), LCMS (M+H) + : 436, 1 H NMR (400 MHz, DMSO-d6) δ = 14.21 (s, 1H), 9.68 (s, 1H), 9.34 - 9.18 (m, 1H), 8.06 (d, J = 5.0 Hz, 2H), 7.78 (d, J = 3.2 Hz, 1H), 4.65 (t, J = 6.8 Hz, 2H), 3.96 (s, 2H), 3.10 (s, 3H), 2.76 (t, J = 6.8 Hz, 2H), 2.66 (s, 3H), 2.18 (s, 3H)

[0506] Example 82 4-(5-(4-Hydroxy-3-methyl-1-phenethyl-1H-pyrazol-5-yl)-2H-1,2,4-triazol-3-yl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-6-carboxamide

Chemical Structure

[0507] Example 82 was prepared in the same manner as the preparation of Example 53, using Intermediate A2 instead of Intermediate A1 in Step 6.

[0508] Example 82 (8.4 mg), LCMS (M+H) + : 444 1 H NMR (400 MHz, DMSO-d 6 ) δ=15.33 - 15.16 (brs, 1H), 8.82 (brs, 1H), 8.79 (s, 2H), 8.46 (s, 1H), 7.88 (s, 1H), 7.26 - 7.15 (m, 5H), 4.70 - 4.66 (m, 2H), 4.22 (s, 3H), 3.09 - 3.05 (m, 2H), 2.16 (s, 3H)

[0509] Example 83 1-[5-(Hydroxymethyl)-2-(4-hydroxy-5-methyl-2-propyl-pyrazol-3-yl)oxazol-4-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical formula

[0510] The title compound was prepared according to the following scheme.

Chemical formula

[0511] Step 1: Preparation of 1-[2-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-5-(hydroxymethyl)oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 83-a) To a stirred mixture of ethyl 2-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-4-[3-[(2,4-dimethoxyphenyl)methylcarbamoyl]-5-methyl-pyrazolo[3,4-c]pyridin-1-yl]oxazole-5-carboxylate (Compound 58-a, 200 mg, 0.29 mmol) in THF (15 mL), LiBH 3 NMe 2(0.49 mL, 0.49 mmol) (1 M in THF) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated and purified by silica gel column chromatography to afford compound 83-a (100 mg). LCMS (M+H) + : 652

[0512] Step 2: Preparation of 1-[5-(hydroxymethyl)-2-(4-hydroxy-5-methyl-2-propyl-pyrazol-3-yl)oxazol-4-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Example 83) To HFIP (2 mL), a mixture of 1-[2-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-5-(hydroxymethyl)oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 83-a, 20 mg, 0.03 mmol) and MsOH (23 mg, 0.25 mmol) was stirred at 50 °C for 3 h under a nitrogen atmosphere. The mixture was cooled to room temperature and purified by reverse phase HPLC to afford Example 84 (3.5 mg). LCMS (M+H) + : 412, 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.52 (s, 1H), 8.90 (s, 1H), 8.12 (s, 1H), 8.03 (s, 1H), 7.78 (s, 1H), 5.51 (brs, 1H), 4.92 (s, 2H), 4.43 - 4.40 (m, 2H), 2.65 (s, 3H), 2.16 (s, 3H), 1.83 - 1.78 (m, 2H), 0.90 - 0.86 (m, 3H)

[0513] Example 84 1-[5-(4-Hydroxy-5-methyl-2-propyl-pyrazol-3-yl)-2-methyl-1,2,4-triazol-3-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical Structure

[0514] Example 84 was prepared in the same manner as the preparation of Example 48, except that in Step 1, Compound 31-h was used instead of Compound 40-b, and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of triisopropyl borate.

[0515] Example 84 (58 mg), LCMS (M+H) + : 396, 1 H NMR (400 MHz, DMSO-d6) δ = 9.59 (d, J = 1.0 Hz, 1H), 8.30 (s, 1H), 8.09 (s, 2H), 7.92 (s, 1H), 4.33 (t, J = 7.2 Hz, 2H), 4.28 (s, 3H), 2.68 (s, 3H), 2.12 (s, 3H), 1.84 - 1.71 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H)

[0516] Example 85 1-[2-(4-Hydroxy-5-methyl-2-propyl-pyrazol-3-yl)oxazol-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

Chemical formula

[0517] The title compound was prepared according to the following scheme.

Chemical formula

[0518] Step 1: Preparation of ethyl 4-[3-[(2,4-dimethoxyphenyl)methylcarbamoyl]-6-methyl-imidazo[1,5-a]pyrazin-1-yl]oxazole-5-carboxylate (Compound 85-a) To a solution of toluene (1 mL) and water (0.1 mL) dissolved with ethyl 4-bromooxazole-5-carboxylate (896 mg, 4.07 mmol) and 1-bromo-N-[(3,4-dimethylphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Intermediate A1, 1500 mg, 3.7 mmol), K 3 PO 4 (2357 mg, 11.1 mmol), B 2 Pin 2 (1880 mg, 7.4 mmol), Pd(dppf)Cl 2 (541 mg, 0.74 mmol) was added at 25 °C. The mixture was degassed and purged three times with N 2 . The mixture was heated to 80 °C and stirred for 18 hours. The mixture was concentrated and purified by flash chromatography on silica gel to obtain Compound 85-a (500 mg). LCMS (M+H) + : 466

[0519] Step 2: Preparation of ethyl 2-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-4-[3-[(2,4-dimethoxyphenyl)methylcarbamoyl]-6-methyl-imidazo[1,5-a]pyrazin-1-yl]oxazole-5-carboxylate (Compound 85-b) To toluene (1.5 mL), a mixture of ethyl 4-[3-[(2,4-dimethoxyphenyl)methylcarbamoyl]-6-methyl-imidazo[1,5-a]pyrazin-1-yl]oxazole-5-carboxylate (85-a, 200 mg, 0.43 mmol), 4-benzyloxy-5-bromo-3-methyl-1-propyl-pyrazole (31-h1 32 mg, 0.43 mmol), Pd(OAc) 2 (29 mg, 0.13 mmol), PivOH (26 mg, 0.26 mmol), catacxiuma (46 mg, 0.13 mmol), K 2 CO 3 (178 mg, 1.29 mmol) was mixed and the mixture was purged with N 2Under an atmosphere, it was stirred at 120 °C for 12 hours. The mixture was diluted with DCM (30 mL), filtered, and washed with DCM / MeOH = 10 / 1 (20 mL). The filtrate was concentrated and purified by prep-TLC to obtain compound 85-b (63 mg). LCMS (M+H) + : 694

[0520] Step 3: Preparation of 2-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-4-[3-[(2,4-dimethoxyphenyl)methylcarbamoyl]-6-methyl-imidazo[1,5-a]pyrazin-1-yl]oxazole-5-carboxylic acid (Compound 85-c) To a solution of ethyl 2-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-4-[3-[(2,4-dimethoxyphenyl)methylcarbamoyl]-6-methyl-imidazo[1,5-a]pyrazin-1-yl]oxazole-5-carboxylate (85-b, 63 mg, 0.09 mmol) dissolved in methanol (1 mL), 1N aqueous LiOH solution (1.0 mL) was added. The mixture was stirred at 20 °C for 12 hours and diluted with water (20 mL). After adjusting the pH to 5 with FA, the mixture was extracted with DCM (20 mL × 2). The combined organic phases were dried over Na 2 SO 4 and filtered, and concentrated to obtain compound 85-c (60 mg) as a crude solid, which was used directly in the next step. LCMS (M+H) + : 666

[0521] Step 4: Preparation of 1-[2-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Compound 88-d) A solution of 2-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-4-[3-[(2,4-dimethoxyphenyl)methylcarbamoyl]-6-methyl-imidazo[1,5-a]pyrazin-1-yl]oxazole-5-carboxylic acid (85-c, 60 mg, 0.09 mmol) in DMSO (1 mL) was added with AcOH (2 mg, 0.04 mmol) and Ag 2 CO 3 (10 mg, 0.04 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 2 h. The mixture was cooled and poured into water (30 mL), and the aqueous phase was extracted with EtOAc (30 mL×2). The combined organic phases were washed with brine (20 mL×3), dried over Na 2 SO 4 and concentrated to give compound 85-d (50 mg, crude). LCMS (M+H) + : 622

[0522] Step 5: Preparation of 1-[2-(4-hydroxy-5-methyl-2-propyl-pyrazol-3-yl)oxazol-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Example 85) MsOH (0.2 mL) was added to a solution of 1-[2-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (85-d, 50 mg, 0.08 mmol) in HFIP (1.0 mL). The mixture was stirred at 50 °C for 0.5 h to obtain a red solution. The mixture was directly purified by prep-HPLC to give Example 85 (11.8 mg). LCMS (M+H) + : 382, 1 H NMR (DMSO-d6, 400 MHz) δ=9.65 (d, J=1.6 Hz, 1H), 9.05 (s, 1H), 8.81 (brs, 1H), 8.63 (s, 1H), 8.07 (s, 1H), 7.87 (s, 1H), 4.46 (t, J=7.2 Hz, 2H), 2.47 (s, 3H), 2.16 (s, 3H), 1.89-1.76 (m, 2H), 0.91 (t, J=7.2 Hz, 3H)

[0523] Example 86 1-[2-(2-Butyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

Chemical Structure

[0524] Example 86 was prepared in the same manner as the preparation of Example 85, using Compound 49-b instead of Compound 31-h in Step 2.

[0525] Example 86 (1.1 mg), LCMS (M+H) + : 396, 1 H NMR (400 MHz, DMSO-d 6 +D 2 O) δ = 9.60 (s, 1H), 8.99 (s, 1H), 8.64 (s, 1H), 4.51 - 4.43 (m, 2H), 2.43 (s, 3H), 2.13 (s, 3H), 1.80 - 1.71 (m, 2H), 1.33 - 1.24 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H)

[0526] Example 87 1-[3-[4-Hydroxy-5-methyl-2-[2-[4-(morpholinomethyl)phenyl]ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

Chemical Structure

[0527] Example 87 was prepared in the same manner as the preparation of Example 53, using Compound 87-b instead of 1-bromo-2-phenylethane in Step 1 (reaction conditions: CMBP, K 2 CO 3 replaced by toluene at 80 °C, DMF at 80 °C).

[0528] Compound 87-b was prepared according to the following scheme. [Chemical Formula]

[0529] Step 1: Preparation of Methyl 2-(4-(morpholinomethyl)phenyl)acetate (Compound 87-a) To a solution of methyl 2-[4-(bromomethyl)phenyl]acetate (15.0 g, 62 mmol) dissolved in methanol (100 mL), morpholine (16.0 g, 185 mmol) was added. The mixture was stirred at 25 °C for 3 hours and concentrated. The residue was diluted with water (30 mL) and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with saturated aqueous NaCl solution (50 mL), dried over sodium sulfate, filtered, and concentrated to obtain Compound 87-a (16.0 g). LCMS (M+H) + : 250

[0530] Step 2: Preparation of 2-(4-(morpholinomethyl)phenyl)ethan-1-ol (Compound 87-b) To a solution of methyl 2-[4-(morpholinomethyl)phenyl]acetate (87-a, 16.0 g, 64 mmol) dissolved in THF (200 mL), LiAlH 4 (30.8 mL, 77 mmol) was added at 0 °C. The reaction was stirred at 0 °C for 2 hours and then quenched by the addition of water (150 mL) and 3N aqueous NaOH solution (120 mL). The aluminum salts were filtered through celite, and the filtrate was concentrated to obtain Compound 87-b (14.0 g, crude). LCMS (M+H) + : 222

[0531] Example 87 (23.7 mg), LCMS (M+H) + : 543, 1 H NMR (400 MHz, DMSO+D 2O) δ = 9.52 (s, 1H), 8.98 (s, 1H), 7.08 - 6.93 (m, 4H), 4.64 (brt, J = 6.8 Hz, 2H), 3.45 (brs, 4H), 3.27 (s, 2H), 2.95 (brt, J = 7.1 Hz, 2H), 2.43 (s, 3H), 2.19 (brs, 4H), 2.11 (s, 3H)

[0532] Example 88 1-[2-[4-Hydroxy-5-methyl-2-[2-[4-(morpholinomethyl)phenyl]ethyl]pyrazol-3-yl]oxazol-4-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical formula

[0533] Example 88 was prepared in the same manner as the preparation of Example 58, using Compound 88-a instead of Compound 31-h.

[0534] Compound 88-a was prepared in the same manner as the preparation of Compound 46-c, using Compound 87-b instead of 4-pyridineethanol in Step 3.

Chemical formula

[0535] Example 88 (8.5 mg), LCMS (M + H) + : 543, 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.53 (d, J = 1.0 Hz, 1H), 9.16 - 8.84 (m, 1H), 8.66 (s, 1H), 8.05 (s, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 7.32 - 7.21 (m, 4H), 4.73 (brt, J = 7.4 Hz, 2H), 4.25 (s, 2H), 4.00 - 3.86 (m, 4H), 3.23 - 3.12 (m, 4H), 3.10 - 2.98 (m, 2H), 2.67 (s, 3H), 2.16 (s, 3H)

[0536] Example 89 1-[2-[4-Hydroxy-2-[2-[4-(methoxymethyl)phenyl]ethyl]-5-methyl-pyrazol-3-yl]oxazol-4-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

Chemical Structure

[0537] Example 89 was prepared in the same manner as the preparation of Example 58, using Compound 89-a instead of Compound 31-h.

[0538] Compound 89-a was prepared in Step 3 in the same manner as the preparation of Compound 46-c, using Compound 64-a instead of 4-pyridineethanol.

Chemical Structure

[0539] Example 89 (4.2 mg), LCMS (M+H) + : 488, 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.53 (d, J = 1.0 Hz, 1H), 9.04 - 8.87 (m, 1H), 8.66 (s, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.14 - 7.04 (m, 4H), 4.69 (t, J = 7.4 Hz, 2H), 4.28 (s, 2H), 3.20 (s, 3H), 3.06 (t, J = 7.4 Hz, 2H), 2.67 (s, 3H), 2.17 (s, 3H)

[0540] Example 90 1-[3-[4-Hydroxy-5-methyl-2-(2-thiazol-2-ylethyl)pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

Chemical Structure

[0541] Example 90 was prepared in the same manner as in the preparation of Example 53, using compound 90-a instead of 1-bromo-2-phenylethane in Step 1 (reaction conditions: CMBP, K 2 CO 3 replaced with toluene at 80 °C, DMF at 80 °C).

[0542] Compound 90-a was prepared according to the following scheme.

Chemical formula

[0543] Step 1: Preparation of 2-thiazol-2-ylethanol (Compound 90-a) A solution of 2-methylthiazole (5 g, 50.43 mmol) dissolved in paraformaldehyde (5 g, 50.43 mmol) was slowly heated to 140 °C and stirred for 3 hours. The reaction mixture was concentrated and purified by column chromatography to obtain compound 90-a (3 g) as a colorless oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.71 (d, J = 3.4 Hz, 1H), 7.24 (d, J = 3.4 Hz, 1H), 4.05 (t, J = 5.6 Hz, 2H), 3.25 (t, J = 5.6 Hz, 2H)

[0544] Example 90 (5.6 mg), LCMS (M+H) + : 451, 1 H NMR (400 MHz, DMSO-d6 + D 2 O) δ = 9.66 (s, 1H), 9.03 (s, 1H), 7.60 (d, J = 3.4 Hz, 1H), 7.44 (d, J = 3.4 Hz, 1H), 4.83 (brt, J = 6.8 Hz, 2H), 3.49 (brt, J = 7.0 Hz, 2H), 2.45 (s, 3H), 2.12 (s, 3H)

[0545] Example 91 8-[3-(4-Hydroxy-5-methyl-2-propyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide

Chem.

[0546] The title compound was prepared according to the following scheme.

Chem.

[0547] Step 1: Preparation of 3-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole (Compound 91-a)

[0548] Compound 91-a was prepared in Step 1 using 1-iodopropane instead of 1-bromo-2-phenylethane in the same manner as the preparation of Compound 53-e.

[0549] Step 2: Preparation of 8-[5-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (Compound 91-b) To 1,4-dioxane (3 mL) were added 3-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole (91-a, 155 mg, 0.37 mmol), 8-bromo-N-[(2,4-dimethoxyphenyl)methyl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (3-e, 150 mg, 0.37 mmol), Pd(OAc) 2 (25 mg, 0.11 mmol), CuI (141 mg, 0.74 mmol), PCy 3 HBF 4(54 mg, 0.15 mmol), Cs 2 CO 3 (120 mg, 0.37 mmol) were mixed, and the mixture was stirred at 140 °C for 18 h under a N 2 atmosphere. The mixture was cooled, filtered, and washed with DCM / MeOH (20 mL, v / v = 10 / 1). The filtrate was concentrated and purified by prep-TLC to obtain compound 91-b (100 mg). LCMS (M+H) + : 741

[0550] Step 3: Preparation of 8-[3-(4-Hydroxy-5-methyl-2-propyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (Example 91) To a solution of 8-[5-(4-Benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (91-a, 100 mg, 0.13 mmol) dissolved in HFIP (2 mL), MsOH (259 mg, 2.7 mmol) was added. The mixture was stirred at 50 °C for 0.5 h to obtain a red solution. The mixture was purified by prep-HPLC to obtain Example 91 (46.8 mg). LCMS (M+H) + : 381, 1 H NMR (DMSO-d6, 400 MHz) δ = 13.86 (s, 1H), 9.65 (s, 1H), 9.36 (s, 1H), 9.22 - 8.77 (m, 1H), 8.16 (s, 2H), 7.55 (s, 1H), 4.43 (brt, J = 6.8 Hz, 2H), 2.47 (s, 3H), 2.15 (s, 3H), 1.84 - 1.73 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H)

[0551] Example 92 1-[5-(4-Hydroxy-5-methyl-2-propyl-pyrazol-3-yl)-2-methyl-1,2,4-triazol-3-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide [Chemical formula]

[0552] The title compound was prepared according to the following scheme. [Chemical formula]

[0553] Step 1: Preparation of methyl 4-benzyloxy-5-methyl-2-propyl-pyrazole-3-carboxylate (Compound 92-a) To a solution of methyl 4-benzyloxy-3-methyl-1H-pyrazole-5-carboxylate (23-d, 2.00 g, 8.1 mmol) dissolved in toluene (10 mL), 1-propanol (585 mg, 9.7 mmol) and cyanomethylene tributylphosphorane (2550 mg, 10.5 mmol) were added. The reaction mixture was stirred at 80 °C for 12 hours. The mixture was purified by column chromatography to obtain Compound 92-a (2.0 g). LCMS (M+H) + : 289

[0554] Step 2: Preparation of 4-benzyloxy-5-methyl-2-propyl-pyrazole-3-carboxylic acid (Compound 92-b) To a solution of methyl 4-benzyloxy-5-methyl-2-propyl-pyrazole-3-carboxylate (92-a, 870 mg, 3.0 mmol) dissolved in methanol (10 mL), LiOH·H 2 O (9.0 mg, 9.0 mmol) in H 2 O (5 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. The mixture was cooled to 0 °C, adjusted to pH = 3 with 1N aqueous HCl solution, and then EtOAc (100 mL) and water (100 mL) were added. After separation, the aqueous phase was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (400 mL), dried over Na 2 SO 4 and filtered and concentrated to obtain Compound 92-b (1.6 g, crude). LCMS (M+H) +:275

[0555] Step 3: Preparation of Isobutoxycarbonyl 4-benzyloxy-5-methyl-2-propyl-pyrazole-3-carboxylate (Compound 92-c) To a solution of 4-benzyloxy-5-methyl-2-propyl-pyrazole-3-carboxylic acid (92-b, 1.5 g, 5.47 mmol) in DCM (30 mL), DIPEA (2.1 g, 16.4 mmol) and isobutyl chloroformate (1.5 g, 10.9 mmol) were added. The reaction mixture was stirred at 20 °C for 2 hours and concentrated to afford Compound 92-c (2.0 g). LCMS (M+H) + :375

[0556] Step 4: Preparation of 1-[(4-benzyloxy-5-methyl-2-propyl-pyrazole-3-carbonyl)amino]-1-methyl-thiourea (Compound 92-d) To a solution of 1-amino-1-methyl-thiourea (860 mg, 8.15 mmol) in THF (40 mL), isobutoxycarbonyl 4-benzyloxy-5-methyl-2-propyl-pyrazole-3-carboxylate (92-c, 1.5 g, 4.07 mmol) was added, and then the reaction mixture was stirred at 50 °C for 12 hours. The mixture was poured into water (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (300 mL) and brine (300 mL), and then dried over anhydrous Na 2 SO 4 . The organic layer was concentrated to afford crude Compound 92-d (2.0 g). LCMS (M+H) + :362

[0557] Step 5: Preparation of 5-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-2-methyl-1,2,4-triazole-3-thiol (Compound 92-e) To a solution of 1-[(4-benzyloxy-5-methyl-2-propyl-pyrazole-3-carbonyl)amino]-1-methyl-thiourea (92-d, 2.00 g, 5.5 mmol) in water (12 mL) was added NaOH (720 mg, 18.0 mmol). The reaction mixture was heated to 100 °C and stirred for 6 hours. The mixture was poured into water (300 ml) and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (300 mL) and brine (200 mL), and then dried over anhydrous Na 2 SO 4 . The filtered organic layer was concentrated to give compound 92-e (807 mg). LCMS (M+H) + : 344

[0558] Step 6: Preparation of 3-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-1-methyl-1,2,4-triazole (Compound 92-f) To a solution of 5-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-2-methyl-1,2,4-triazole-3-thiol (92-e, 800 mg, 2.3 mmol) in acetic acid (6 mL) was slowly added H 2 O 2 (132 mg, 11.6 mmol) at 0 °C. The reaction mixture was warmed to 20 °C and stirred for 1 hour. The mixture was poured into saturated Na 2 SO 3 aqueous solution (80 mL) and stirred at 0 °C for 30 minutes. Then it was adjusted to pH 7 - 8 with NaHCO 3 . The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by column chromatography to give compound 92-f (480 mg). LCMS (M+H) + : 312

[0559] Step 7: Preparation of 7:1-[5-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-2-methyl-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Compound 92g) To a solution of 3-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-1-methyl-1,2,4-triazole (92-f, 100 mg, 0.32 mmol) dissolved in toluene (0.5 mL), 1-bromo-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Intermediate A1, 130 mg, 0.32 mmol), catacxiuma (34 mg, 0.1 mmol), Pd(OAc) 2 (22 mg, 0.1 mmol), PivOH (20 mg, 0.19 mmol) and K 2 CO 3 (133 mg, 0.96 mmol) were added. The mixture was stirred at 120 °C for 12 hours, then filtered and washed with DCM / MeOH (20 / 1, 100 ml). The filtrate was concentrated and purified by Pre-TLC to obtain Compound 92g (80 mg). LCMS (M+H) + : 636

[0560] Step 8: Preparation of 1-[5-(4-hydroxy-5-methyl-2-propyl-pyrazol-3-yl)-2-methyl-1,2,4-triazol-3-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Example 92) A solution of 1-[5-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-2-methyl-1,2,4-triazol-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (92 g, 75 mg, 0.12 mmol) in HFIP (1 mL) was added with MsOH (226 mg, 2.36 mmol). The mixture was stirred at 50 °C for 1 hour. The reaction mixture was filtered and the filtrate was purified by prep-HPLC to obtain Example 92 (22.7 mg) as a yellow solid. LCMS (M+H) + : 396, 1 H NMR (400 MHz, DMSO-d6) δ = 9.71 (s, 1H), 9.15 (s, 1H), 8.37 (s, 1H), 7.97 (s, 1H), 7.91 (d, J = 1.4 Hz, 1H), 4.45 (s, 3H), 4.36 (t, J = 7.2 Hz, 2H), 2.51 - 2.50 (m, 3H), 2.12 (s, 3H), 1.91 - 1.70 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H)

[0561] Example 93 7-Fluoro-8-[2-(4-hydroxy-5-methyl-2-propyl-pyrazol-3-yl)oxazol-4-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide

Chemical Structure

[0562] The title compound was prepared according to the following scheme.

Chemical Structure

[0563] Step 1: Preparation of ethyl 2-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)oxazole-5-carboxylate (Compound 93-a) A solution of 4-benzyloxy-5-bromo-3-methyl-1-propyl-pyrazole (500 mg, 1.6 mmol) in THF (3 mL) was added dropwise with n-BuLi (650 μL, 1.6 mmol) at -63 °C. The reaction mixture was stirred at that temperature for 10 minutes, and ZnCl 2 (3.2 mL, 1.6 mmol) was added. Stirring was continued at that temperature for 30 minutes, and the reaction mixture was warmed to room temperature and stirred for 1 hour. The zincate solution (c = 0.23 M) was used in the next step. A mixture of ethyl 2-bromooxazole-5-carboxylate (320 mg, 1.5 mmol) and XPhos-Pd-G 3 (137 mg, 0.16 mmol) in 1,4-dioxane (6 mL) was degassed for 5 minutes. The above zincate solution was added at 20 °C, and the reaction mixture was heated to 80 °C over 90 minutes. The reaction was quenched by pouring the reaction mixture into ice water containing 2.5 mL of 1 N HCl. The mixture was extracted with EtOAc (20 mL × 3). The combined organic phases were concentrated and purified by flash silica gel chromatography to give compound 93-a (230 mg). LCMS (M+H) + : 370

[0564] Step 2: Preparation of ethyl 2-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-4-[6-[(2,4-dimethoxyphenyl)methylcarbamoyl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazin-8-yl]oxazole-5-carboxylate (Compound 93-b) To a solution of ethyl 2-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)oxazole-5-carboxylate (93-a, 230 mg, 0.62 mmol) in toluene (3 mL) were added 8-bromo-N-[(2,4-dimethoxyphenyl)methyl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (4 g, 263 mg, 0.62 mmol), potassium pivalate (131 mg, 0.93 mmol), PivOH (31 mg, 0.31 mmol) and cataCXium-A-Pd-G 3 (181 mg, 0.25 mmol). The reaction mixture was stirred under N2 Under an atmosphere, it was stirred at 120 °C for 18 hours. The mixture was filtered, and the wet cake was washed with DCM / MeOH (V / V = 20:1, 30 mL). The filtrate was concentrated and purified by prep-TLC to obtain the crude product. Then, this was purified again by reverse phase to obtain compound 93-b (40 mg). LCMS (M+H) + : 711

[0565] Step 3: Preparation of 2-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-4-[6-[(2,4-dimethoxyphenyl)methylcarbamoyl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazin-8-yl]oxazole-5-carboxylic acid (Compound 93-c) To a solution of ethyl 2-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-4-[6-[(2,4-dimethoxyphenyl)methylcarbamoyl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazin-8-yl]oxazole-5-carboxylate (93-b, 40 mg, 0.06 mmol) dissolved in methanol (4 mL) and water (2 mL), LiOH·H 2 O (12 mg, 0.28 mmol) was added. The reaction mixture was stirred at 20 °C for 12 hours. The mixture was acidified to pH = 3 - 4 with HCl (6N) and extracted with DCM (10 mL × 3). The organic layer was washed with brine and dried over Na 2 SO 4 and concentrated to obtain crude compound 93-c (33 mg). LCMS (M+H) + : 683

[0566] Step 4: Preparation of 8-[2-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)oxazol-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (Compound 93-d) To a solution of 2-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-4-[6-[(2,4-dimethoxyphenyl)methylcarbamoyl]-7-fluoro-3-methyl-pyrrolo[1,2-a]pyrazin-8-yl]oxazole-5-carboxylic acid (93-c, 33 mg, 0.05 mmol) in DMSO (1 mL), AcOH (1.2 mg, 0.02 mmol) and Ag 2 CO 3 (5.3 mg, 0.02 mmol) were added...

Claims

1. Equation (I), 【Chemistry 1】 (In the formula, Ring A is a 5-12 member monocyclic, bicyclic, or tricyclic heteroaryl or heterocyclyl ring containing 1-4 heteroatoms selected from N, O, and S. R １ 、 R ２ and R ３ each, independently, is absent or is C １～６ alkyl, halo C １～６ alkyl, hydroxyl C １～６ alkyl, amino C １～６ alkyl, -C(O)C １～６ alkyl, C １～６ alkylamino, (C １～６ alkyl) ２ amino, C １～６ alkyl-S-, C １～６ alkylSO ２ , C １～６ alkoxy, halo C １～６ alkoxy, C １～６ alkoxycarbonyl, carboxyl, hydroxyl, cyano, amino, halogen, acyl, carbamoyl, and a 5- to 8-membered monocyclic heterocyclyl containing from 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclyl may be further substituted by halogen, C １～６ alkyl, C １～６ alkoxy, or amino, Ring B is a 5-8 member monocyclic or bicyclic heteroaryl or heterocyclyl ring containing 1-4 heteroatoms selected from N, O, and S. R ４ However, it does not exist, or C １～６ Alkyl, Halo C １～６ Alkyl, Hydroxyl C １～６ Alkyl, amino C １～６ Alkyl, -C(O)C １～６ Alkyl, C １～６ Alkylamino, (C １～６ Alkyl) ２ Amino, C １～６ Alkyl-S-, C １～６ Alkyl SO ２ , C １～６ Alkoxy, Halo C １～６ Alkoxy, C １～６ Selected from alkoxycarbonyl, carboxyl, hydroxyl, cyano, amino, halogen and carbamoyl, Bond a is a bond that connects ring A and ring B. Ring C is a 5-8 member monocyclic or bicyclic heteroaryl or heterocyclyl ring containing 1-4 heteroatoms selected from N, O, and S. R ５ , R ６ and R ７ Each of these is independent, does not exist, or C １～６ Alkyl, Halo C １～６ Alkyl, Hydroxyl C １～６ Alkyl, amino C １～６ Alkyl, -C(O)C １～６ Alkyl, C １～６ Alkylamino, (C １～６ Alkyl) ２ Amino, C １～６ Alkyl-S-, C １～６ Alkyl SO ２ , C １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkyl, Halo C １～６ Alkoxy, C １～６ Alkoxycarbonyl, Halo C ２～６ Alkenil, C ３～７ Cycloalkyl, C ３～７ Cycloalkyl C １～６ Alkyl, C ２～６ Alkinyl, C １～６ Alkoxy C ２～６ Alkinyl, Carboxyl, Hydroxyl, Cyano, Amino, Halogen, Carbamoyl, Cyano C １～６ Alkyl, imidazolyl C １～６ Alkyl, Triazolyl C １～６ Alkyl, pyridinyl C １～６ Alkyl, Thiazolyl C １～６ Alkyl and phenyl C １～６ Alkyl (wherein the phenyl C １～６ Alkyl compounds include halogens, cyano, and hydroxyl C. １～６ Alkyl, Morpholino C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkyl and C １～６ Selected from (optionally substituted with alkoxycarbonyls), or R ５ , R ６ and R ７ Two of these atoms, together with the atom to which they are bonded, form a 5-6 membered ring having 0-2 heteroatoms selected from N, O, and S. Compounds thereof, or pharmaceutically acceptable salts thereof.

2. Ring A is selected from pyridyl, imidazo[1,5-a]pyradinyl, imidazo[1,5-a]pyradinyl, pyrrolo[1,2-a]pyradinyl, pyrrolo[2,3-c]pyradinyl, pyrrolo[1,2-c]pyridinyl, pyrazolo[3,4-c]pyradinyl, and 1H-pyrazolo[4,3-c]pyradinyl. R １ However, it is carbamoyl, R ２ However, C １～６ Alkyl, Halo C １～６ Selected from 5-8 membered monocyclic heterocyclines containing alkyl, halogen, acyl, and 1-3 heteroatoms selected from N, O, and S, R ３ However, it does not exist, or it is a halogen. Ring B is 【Chemistry 2】 Selected from, X １ , X ２ and X ３ Each of these is independently selected from C, N, and O. R ４ However, it does not exist, or C １～６ Alkyl, Halo C １～６ Alkyl, amino C １～６ Alkyl, hydroxy C １～６ Selected from alkyl and carbamoyl, Ring C is pyrazolyl, R ５ is C １～６ alkyl, hydroxy C １～６ alkyl, halo C １～６ alkyl, cyano C １～６ alkyl, halo C ２～６ alkenyl, C ３～７ cycloalkyl, C ３～７ cycloalkyl C １～６ alkyl, C １～６ alkoxy C １～６ alkyl, C ２～６ alkynyl, C １～６ alkoxy C ２～６ alkynyl, imidazolyl C １～６ alkyl, triazolyl C １～６ alkyl, pyridinyl C １～６ alkyl, thiazolyl C １～６ alkyl and phenyl C １～６ alkyl (wherein said phenyl C １～６ alkyl is optionally substituted by halogen, cyano, hydroxy C １～６ alkyl, morpholino C １～６ alkyl, C １～６ alkoxy, C １～６ alkoxy C １～６ alkyl and C １～６ alkoxycarbonyl) and is selected from R ６ However, it does not exist, or C １～６ It is alkyl, R ７ However, it does not exist, or is selected from hydroxyl, halogen and amino, or R ６ and R ７ The compound according to claim 1, wherein, together with the atoms to which they are bonded, they form a 5-6 membered ring containing 0-2 heteroatoms selected from N, O, and S.

3. The substituted ring A is 【Transformation 3】 A compound according to claim 1, selected from the following.

4. The substituted ring A is 【Chemistry 4】 R １ However, it is carbamoyl, R ２ However, C １～６ It is alkyl, R ３ However, it does not exist, or it is a halogen. The compound according to claim 1.

5. R １ However, it is carbamoyl, R ２ However, selected from methyl, difluoromethyl, acetyl, chloro, and imidazolyl, R ３ However, it does not exist, or it is fluoro. The compound according to claim 1.

6. R １ However, it is carbamoyl, R ２ However, it is methyl, R ３ However, it does not exist, or it is fluoro. The compound according to claim 1.

7. The compound according to claim 1, wherein ring B is selected from triazolyl, oxazolyl, oxadiazolyl, and pyrimidinyl.

8. The substituted ring B is 【Transformation 5】 A compound according to claim 1, selected from the following.

9. The substituted ring B is 【Transformation 6】 Selected from, R ４ However, it does not exist, or C １～６ Alkyl and hydroxy C １～６ A compound according to claim 1, selected from alkyl groups.

10. R ４ The compound according to claim 1, wherein the compound is absent or selected from methyl, difluoromethyl, aminomethyl, hydroxymethyl, and carbamoyl.

11. R ４ The compound according to claim 1, wherein the compound is absent or selected from methyl and hydroxymethyl.

12. The substituted ring C, 【Transformation 7】 The compound according to claim 1.

13. R ５ However, ethyl, propyl, butyl, cyclopropyl, cyclopropylmethyl, 3,3-difluoropropyl, 3,3-difluoroallyl, 2-cyanoethyl, 3-cyanopropyl, 3-hydroxypropyl, 2-imidazole-1-ylethyl, 2-(triazole-2-yl)ethyl, 2-(triazole-1-yl)ethyl, 2-(1,2,4-triazole-4-yl)ethyl, 2-(1,2,4-triazole-1-yl)ethyl, 3-fluoropropyl, 2-methoxyethyl, 3-methoxypropyl, 1-pento-3-inyl, 5-methoxypento-3-inyl, 2-phenylethyl, 2-(4- Selected from methoxyphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-[4-(methoxymethyl)phenyl]ethyl, 2-[3-(methoxymethyl)phenyl]ethyl, 2-(4-fluorophenyl)ethyl, 2-(3-fluorophenyl)ethyl, 2-(3-cyanophenyl)ethyl, 2-(4-cyanophenyl)ethyl, 2-(4-methoxycarbonylphenyl)ethyl, 2-[4-(hydroxymethyl)phenyl]ethyl, 2-pyridine-4-ylethyl, 2-(3-pyridyl)ethyl, 2-[4-(morpholinomethyl)phenyl]ethyl, and 2-thiazole-2-ylethyl, R ６ However, it is either absent or methyl, R ７ However, it does not exist, is either fluoro, amino, or hydroxyl, or R ６ and R ７ However, together with the atoms to which they are bonded, they form a five-membered ring. The compound according to claim 1.

14. R ５ However, it is selected from propyl, butyl, cyclopropylmethyl, 3,3-difluoroallyl, 3-fluoropropyl, 3,3-difluoropropyl, 1-pento-3-inyl, 2-(3-pyridyl)ethyl, 2-phenylethyl, 2-(4-methoxyphenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(3-fluorophenyl)ethyl, 2-[4-(methoxymethyl)phenyl]ethyl, 2-[3-(methoxymethyl)phenyl]ethyl, 2-[4-(hydroxymethyl)phenyl]ethyl, and 2-[4-(morpholinomethyl)phenyl]ethyl, R ６ However, it is methyl, R ７ However, it is hydroxyl. The compound according to claim 1.

15. The substituted ring A is 【Transformation 8】 Selected from, R １ However, it is carbamoyl, R ２ However, C １～６ It is alkyl, R ３ However, it does not exist, or it is a halogen. Ring B is 【Chemistry 9】 Selected from, R ４ However, it does not exist, or C １～６ Alkyl and hydroxy C １～６ Selected from alkyl groups, The substituted ring C, 【Chemistry 10】 And, R ５ However, C １～６ Alkyl, Halo C １～６ Alkyl, Halo C ２～６ Alkenil, C ２～６ Alkinyl, C ３～７ Cycloalkyl C １～６ Alkyl, pyridinyl C １～６ Alkyl, Phenylen C １～６ Alkyl (wherein the phenyl C １～６ Alkyls are halogens, C １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkyl, Hydroxyl C １～６ Alkyl or morpholino C １～６ Selected from (arbitrarily substituted with alkyl), R ６ However, C １～６ It is alkyl, R ７ However, it is hydroxyl. The compound according to claim 1.

16. R １ However, it is carbamoyl, R ２ However, it is methyl, R ３ However, it does not exist, or it is fluoro, R ４ However, it is either absent or selected from methyl and hydroxymethyl, R ５ However, it is selected from propyl, butyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3-difluoroallyl, 1-pento-3-inyl, cyclopropylmethyl, 2-(3-pyridyl)ethyl, 2-phenylethyl, 2-(4-methoxyphenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(3-fluorophenyl)ethyl, 2-[4-(methoxymethyl)phenyl]ethyl, 2-[3-(methoxymethyl)phenyl]ethyl, 2-[4-(hydroxymethyl)phenyl]ethyl, and 2-[4-(morpholinomethyl)phenyl]ethyl, R ６ However, it is methyl, R ７ However, it is hydroxyl. The compound according to claim 15.

17. R １ However, it is carbamoyl, R ２ However, C １～６ It is alkyl, R ３ However, it does not exist, or it is a halogen. R ４ However, it is either absent or hydroxy C １～６ It is alkyl, R ５ However, C １～６ Alkyl, Halo C １～６ Alkyl, pyridinyl C １～６ Alkyl and phenyl C １～６ Alkyl (wherein the phenyl C １～６ Alkyls are halogens, C １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkyl or hydroxyl C １～６ Selected from (arbitrarily substituted with alkyl), R ６ However, C １～６ It is alkyl, R ７ However, it is hydroxyl. The compound according to claim 15.

18. R １ However, it is carbamoyl, R ２ However, it is methyl, R ３ However, it does not exist, or it is fluoro, R ４ However, it is either absent or hydroxymethyl, R ５ However, it is selected from propyl, butyl, 3,3-difluoropropyl, 2-(3-pyridyl)ethyl, 2-phenylethyl, 2-(4-methoxyphenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(3-fluorophenyl)ethyl, 2-[4-(methoxymethyl)phenyl]ethyl and 2-[4-(hydroxymethyl)phenyl]ethyl, R ６ However, it is methyl, R ７ However, it is hydroxyl. The compound according to claim 17.

19. 1-[3-(2-ethyl-4-hydroxy-5-methylpyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-6-methylimidazo[1,5-a]pyrazine-3-carboxamide, 1-[5-(2-ethyl-4-hydroxy-5-methylpyrazole-3-yl)-2-methyl-1,2,4-triazole-3-yl]-6-methylimidazo[1,5-a]pyrazine-3-carboxamide, 8-[3-(2-ethyl-4-hydroxy-5-methylpyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, 8-[3-(2-ethyl-4-hydroxy-5-methylpyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-7-fluoro-3-methylpyrrolo[1,2-a]pyrazine-6-carboxamide, 4-Acetyl-6-[3-(2-ethyl-4-hydroxy-5-methyl-pyrazole-3-yl)-1H-1,2,4-triazole-5-yl]pyridine-2-carboxamide, 6-[3-(2-ethyl-4-hydroxy-5-methylpyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-4-imidazole-1-ylpyridine-2-carboxamide, 4-[2-(2-ethyl-4-hydroxy-5-methylpyrazole-3-yl)pyrimidine-4-yl]-1-methylpyrazolo[4,3-c]pyridine-6-carboxamide, 1-[2-(2-ethyl-4-hydroxy-5-methylpyrazole-3-yl)pyrimidine-4-yl]-6-methylimidazo[1,5-a]pyrazine-3-carboxamide, 1-[2-(2-ethyl-4-hydroxy-5-methylpyrazole-3-yl)oxazole-4-yl]-6-methylimidazo[1,5-a]pyrazine-3-carboxamide, 4-[5-(difluoromethyl)-2-(2-ethyl-4-hydroxy-5-methylpyrazole-3-yl)oxazole-4-yl]-1-methylpyrazolo[4,3-c]pyridine-6-carboxamide, 1-[5-(aminomethyl)-2-(2-ethyl-4-hydroxy-5-methylpyrazole-3-yl)oxazole-4-yl]-6-methylimidazo[1,5-a]pyrazine-3-carboxamide, 4-(6-carbamoyl-1-methylpyrazolo[4,3-c]pyridine-4-yl)-2-(2-ethyl-4-hydroxy-5-methylpyrazole-3-yl)oxazole-5-carboxamide, 4-[3-(2-ethyl-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide, 1-[3-[2-(3-hydroxypropyl)-5-methylpyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-6-methylimidazo[1,5-a]pyrazine-3-carboxamide, 1-[3-(2-ethyl-5-methyl-pyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-[3-(2-ethyl-4-fluoro-5-methyl-pyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-[3-(4-amino-2-ethyl-5-methyl-pyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 6-Chloro-1-[3-(2-ethyl-4-hydroxy-5-methyl-pyrazole-3-yl)-1H-1,2,4-triazole-5-yl]imidazo[1,5-a]pyrazine-3-carboxamide, 1-[3-(2-ethyl-4-hydroxy-5-methylpyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-6-methylimidazo[1,5-a]pyridine-3-carboxamide, 7-[3-(2-ethyl-4-hydroxy-5-methylpyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxamide, 1-[2-(2-ethyl-4-hydroxy-5-methylpyrazole-3-yl)oxazole-4-yl]-5-methylpyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-(2-ethyl-4-hydroxy-5-methylpyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-5-methylpyrazolo[3,4-c]pyridine-3-carboxamide, 4-[3-[4-hydroxy-2-(2-imidazole-1-ylethyl)-5-methyl-pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide, 4-[3-[2-(3-cyanopropyl)-4-hydroxy-5-methylpyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-1-methylpyrazolo[4,3-c]pyridine-6-carboxamide, 4-[3-[2-(2-cyanoethyl)-4-hydroxy-5-methylpyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-1-methylpyrazolo[4,3-c]pyridine-6-carboxamide, 6-(difluoromethyl)-1-[3-(2-ethyl-4-hydroxy-5-methylpyrazole-3-yl)-1H-1,2,4-triazole-5-yl]imidazo[1,5-a]pyrazine-3-carboxamide, 7-[3-(2-ethyl-4-hydroxy-5-methylpyrazole-3-yl)-1,2,4-oxadiazole-5-yl]-3-methylpyrrolo[1,2-c]pyrimidine-5-carboxamide, 8-[2-(2-ethyl-4-hydroxy-5-methylpyrazole-3-yl)oxazole-4-yl]-7-fluoro-3-methylpyrrolo[1,2-a]pyrazine-6-carboxamide, 1-[2-(2-ethyl-4-hydroxy-5-methylpyrazole-3-yl)oxazole-4-yl]-5-methylpyrrolo[2,3-c]pyridine-3-carboxamide, 8-[3-[2-(2-cyanoethyl)-4-hydroxy-5-methylpyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-7-fluoro-3-methylpyrrolo[1,2-a]pyrazine-6-carboxamide, 1-[3-(4-hydroxy-5-methyl-2-propyl-pyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[2-(cyclopropylmethyl)-4-hydroxy-5-methylpyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-5-methylpyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-(2-cyclopropyl-4-hydroxy-5-methylpyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-5-methylpyrazolo[3,4-c]pyridine-3-carboxamide, 4-[3-[2-(3,3-difluoroaryl)-4-hydroxy-5-methylpyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-1-methylpyrazolo[4,3-c]pyridine-6-carboxamide, 4-[3-[4-hydroxy-5-methyl-2-[2-(triazole-2-yl)ethyl]pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide, 4-[3-[4-hydroxy-5-methyl-2-[2-(triazole-1-yl)ethyl]pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide, 4-[3-[2-(3,3-difluoropropyl)-4-hydroxy-5-methylpyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-1-methylpyrazolo[4,3-c]pyridine-6-carboxamide, 4-[3-[4-hydroxy-5-methyl-2-[2-(1,2,4-triazole-4-yl)ethyl]pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide, 4-[3-[4-hydroxy-5-methyl-2-[2-(1,2,4-triazole-1-yl)ethyl]pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide, 1-[3-[4-hydroxy-5-methyl-2-(2-phenylethyl)pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[2-(3-fluoropropyl)-4-hydroxy-5-methylpyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-5-methylpyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[4-hydroxy-2-(2-methoxyethyl)-5-methyl-pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-(2-butyl-4-hydroxy-5-methylpyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-5-methylpyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[4-hydroxy-2-(3-methoxypropyl)-5-methylpyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-5-methylpyrazolo[3,4-c]pyridine-3-carboxamide, 4-[3-(4-hydroxy-5-methyl-2-pento-3-inylpyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-1-methylpyrazolo[4,3-c]pyridine-6-carboxamide, 1-[3-[4-hydroxy-5-methyl-2-[2-(4-pyridyl)ethyl]pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[4-hydroxy-5-methyl-2-[2-(3-pyridyl)ethyl]pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[5-[4-hydroxy-5-methyl-2-(2-phenylethyl)pyrazole-3-yl]-2-methyl-1,2,4-triazole-3-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[5-(2-butyl-4-hydroxy-5-methylpyrazole-3-yl)-2-methyl-1,2,4-triazole-3-yl]-5-methylpyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[4-hydroxy-2-[2-(4-methoxyphenyl)ethyl]-5-methyl-pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-(4-hydroxy-5-methyl-2-pento-3-inylpyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-5-methylpyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[2-[2-(4-fluorophenyl)ethyl]-4-hydroxy-5-methyl-pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[4-hydroxy-5-methyl-2-(2-phenylethyl)pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-[3-[4-hydroxy-2-[2-(3-methoxyphenyl)ethyl]-5-methyl-pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-(3-(1-(3-fluorophenethyl)-4-hydroxy-3-methyl-1H-pyrazole-5-yl)-1H-1,2,4-triazole-5-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[2-[2-(2-fluorophenyl)ethyl]-4-hydroxy-5-methyl-pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 7-Fluoro-8-[3-[4-hydroxy-5-methyl-2-(2-phenylethyl)pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, 1-(2-(4-hydroxy-3-methyl-1-propyl-1H-pyrazole-5-yl)oxazole-4-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-(2-(1-butyl-4-hydroxy-3-methyl-1H-pyrazole-5-yl)oxazole-4-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[2-[2-(3-cyanophenyl)ethyl]-4-hydroxy-5-methylpyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-5-methylpyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[2-[2-(4-cyanophenyl)ethyl]-4-hydroxy-5-methyl-pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, Methyl 4-[2-[5-[5-(3-carbamoyl-5-methyl-pyrazolo[3,4-c]pyridine-1-yl)-1H-1,2,4-triazole-3-yl]-4-hydroxy-3-methyl-pyrazole-1-yl]ethyl]benzoate, 1-(3-(1-(3,3-difluoroaryl)-4-hydroxy-3-methyl-1H-pyrazole-5-yl)-1H-1,2,4-triazole-5-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[4-hydroxy-2-[2-[4-(methoxymethyl)phenyl]ethyl]-5-methyl-pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[4-hydroxy-2-[2-[3-(methoxymethyl)phenyl]ethyl]-5-methyl-pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-(3-(1-(3,3-difluoropropyl)-4-hydroxy-3-methyl-1H-pyrazole-5-yl)-1H-1,2,4-triazole-5-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-(2-(1-(3,3-difluoropropyl)-4-hydroxy-3-methyl-1H-pyrazole-5-yl)oxazole-4-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[4-hydroxy-2-[2-[4-(hydroxymethyl)phenyl]ethyl]-5-methyl-pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 7-Fluoro-8-[3-[4-Hydroxy-2-[2-(4-methoxyphenyl)ethyl]-5-methyl-pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, 1-[3-[4-hydroxy-2-[2-(4-methoxyphenyl)ethyl]-5-methyl-pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-[3-[4-hydroxy-2-[2-[4-(hydroxymethyl)phenyl]ethyl]-5-methylpyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-6-methylimidazo[1,5-a]pyrazine-3-carboxamide, 1-[3-[4-hydroxy-5-methyl-2-[2-(3-pyridyl)ethyl]pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 7-Fluoro-8-[3-[4-hydroxy-5-methyl-2-[2-(3-pyridyl)ethyl]pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, 1-(2-(4-hydroxy-3-methyl-1-(2-(pyridine-3-yl)ethyl)-1H-pyrazole-5-yl)oxazole-4-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-(2-(4-hydroxy-1-(3-methoxyphenethyl)-3-methyl-1H-pyrazole-5-yl)oxazole-4-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, 8-[3-(2-butyl-4-hydroxy-5-methylpyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-7-fluoro-3-methylpyrrolo[1,2-a]pyrazine-6-carboxamide, 1-[3-(2-butyl-4-hydroxy-5-methylpyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-6-methylimidazo[1,5-a]pyrazine-3-carboxamide, 1-(2-(4-hydroxy-1-(4-methoxyphenethyl)-3-methyl-1H-pyrazole-5-yl)oxazole-4-yl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, 7-Fluoro-8-[3-(4-hydroxy-5-methyl-2-propyl-pyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, 1-[3-(4-hydroxy-5-methyl-2-propyl-pyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-[3-[4-hydroxy-2-(5-methoxypento-3-inyl)-5-methyl-pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 4-(5-(4-hydroxy-3-methyl-1-phenethyl-1H-pyrazole-5-yl)-2H-1,2,4-triazole-3-yl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-6-carboxamide, 1-[5-(hydroxymethyl)-2-(4-hydroxy-5-methyl-2-propyl-pyrazole-3-yl)oxazole-4-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[5-(4-hydroxy-5-methyl-2-propyl-pyrazole-3-yl)-2-methyl-1,2,4-triazole-3-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[2-(4-hydroxy-5-methyl-2-propyl-pyrazole-3-yl)oxazole-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-[2-(2-butyl-4-hydroxy-5-methylpyrazole-3-yl)oxazole-4-yl]-6-methylimidazo[1,5-a]pyrazine-3-carboxamide, 1-[3-[4-hydroxy-5-methyl-2-[2-[4-(morpholinomethyl)phenyl]ethyl]pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 1-[2-[4-hydroxy-5-methyl-2-[2-[4-(morpholinomethyl)phenyl]ethyl]pyrazole-3-yl]oxazole-4-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[2-[4-hydroxy-2-[2-[4-(methoxymethyl)phenyl]ethyl]-5-methyl-pyrazole-3-yl]oxazole-4-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide, 1-[3-[4-hydroxy-5-methyl-2-(2-thiazole-2-ylethyl)pyrazole-3-yl]-1H-1,2,4-triazole-5-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 8-[3-(4-hydroxy-5-methyl-2-propyl-pyrazole-3-yl)-1H-1,2,4-triazole-5-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, 1-[5-(4-hydroxy-5-methyl-2-propyl-pyrazole-3-yl)-2-methyl-1,2,4-triazole-3-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide, 7-Fluoro-8-[2-(4-hydroxy-5-methyl-2-propyl-pyrazole-3-yl)oxazole-4-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, 8-[2-(4-hydroxy-5-methyl-2-propyl-pyrazole-3-yl)oxazole-4-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide, A compound selected from, or a pharmaceutically acceptable salt thereof.

20. Equation (Ia) 【Chemistry 11】 A method for preparing a compound having the structure, comprising the following steps: (a) Equation (IIa) 【Chemistry 12】 The compound of formula (III) 【Chemistry 13】 A step of reacting a compound with a catalyst and a base to obtain a compound of formula (Ia), wherein the catalyst is preferably Pd(OAc) ２ , CuI, and Pd(dppf)Cl ２ Selected from, the base is preferably K ２ CO ３ , Cs ２ CO ３ , and Li ２ CO ３ The process selected from (b) Formula (V) 【Chemistry 14】 The compound of formula (VI) 【Chemistry 15】 A step of reacting a compound with a catalyst and a base to obtain a compound of formula (Ia), wherein the catalyst is preferably Pd(OAc) ２ The base is preferably K ２ CO ３ Na ２ CO ３ , Cs ２ CO ３ and a process selected from KOAc, (c) Formula (VII), 【Chemistry 16】 The compound of formula (VIII) 【Chemistry 17】 A step of reacting a compound with a catalyst in the presence of a catalyst to obtain a compound of formula (Ia), wherein the catalyst is preferably AgOTf and AgBF ４ The process selected from (d) Formula (X) [Chemistry 18] The compound of formula (XI) 【Chemistry 19】 A step of reacting a compound with a catalyst and a base to obtain a compound of formula (Ia), wherein the catalyst is preferably Pd(dppf)Cl ２ The base is preferably K ２ CO ３ The process (In the formula, R １ ~R ７ and ring A is as described in any one of claims 1 to 18, X １ ~X ３ A method comprising one of the following (as described in claim 2).

21. Formula (Ib), 【Chemistry 20】 A method for preparing a compound having the structure, comprising the following steps: Equation (XII) 【Chemistry 21】 The compound of formula (XIII) 【Chemistry 22】 A step of reacting a compound with a catalyst and a base to obtain a compound of formula (Ib), wherein the catalyst is preferably PPh ３ AuCl ３ The base is preferably K ２ CO ３ , Cs ２ CO ３ and processes selected from DBU (In the formula, R １ A method comprising (where R7 and ring A are as described in any one of claims 1 to 18).

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

23. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

24. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

25. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for the treatment of cancer.

26. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for the activation of STING.

27. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for preparing a medicament for the treatment of cancer.

28. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for preparing a pharmacopoeia for the activation of STING.

29. A method for treating cancer, comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19.

30. The use according to claim 25, wherein the cancer is a cancer of the pancreas, liver, lung, breast, lymphatic system, stomach, biliary tract / intestine, urogenital tract, prostate, or pharynx.

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