Pyrazole derivatives as STING agonists

Abstract

The present invention provides novel compounds having the following general formula (I): # imgabs0 # wherein ring A, ring B, ring C, bond a, and R1 to R7 are as described herein, or a pharmaceutically acceptable salt thereof; comprising the compound; and methods of using the compounds.

Description

Technical Field

[0001] The present invention relates to organic compounds, in particular to STING agonists, which are useful for treating cancer in mammals. In particular, the present invention relates to pyrazole derivatives having STING agonist activity and their preparation; pharmaceutical compositions containing the same; and their potential use as drugs. Background Art

[0002] In the past few years, cancer immunotherapy (CIT), represented by immune checkpoint inhibitors (ICI), has rapidly emerged. The key to an effective CIT-mediated anti-tumor response depends on: T cells are initiated and activated by antigen-presenting cells, and then T cells are directed to be transported and infiltrated into the tumor mass so that they recognize and kill cancer cells (Chen DS et al. Immunity. 2013; 39). Therefore, immune checkpoint blockade has only shown a lasting response in highly immunogenic "hot" tumors, but has hardly shown efficacy in non-immunogenic "cold" tumors, which are characterized by lack of T cell infiltration and impaired T cell priming. Therefore, people's attempts have focused on promoting the conversion of "cold tumors" into "hot tumors", with the strategy of activating the innate immune system 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) serve as a key link between the innate immune system and the adaptive immune system through phagocytosis, which is used to process foreign antigens and present them on the cell surface of T cells, thereby activating T cell responses.

[0003] Stimulator of interferon genes (STING) is a four-transmembrane endoplasmic reticulum adaptor that facilitates innate immune signaling. Activation of the STING protein by its natural ligand, cyclic guanosine monophosphate (cGAMP), activates the NF-κB and IRF3 transcriptional pathways, inducing the expression of type I interferons and proinflammatory cytokines / chemokines (Ishikawa et al., Nature 2008, Quyang et al., Immunity 2012, Chen et al., Cell 2011).

[0004] STING activation has been shown to enhance immune responses and inhibit tumor growth (which is achieved by enhancing cancer antigen presentation), contributes to the priming and activation of T cells, facilitates the transport and infiltration of T cells into tumors, and promotes T cell recognition and killing of cancer cells. The first generation of intratumoral cyclic dinucleotides that have entered clinical development have only shown limited single-agent activity, mainly due to poor pharmacokinetic and physicochemical properties, i.e., low bioavailability, instability, and difficulty bypassing the plasma membrane (Leila et al., J. Clin. Med. 2020, Afsaneh et al. Cancers 2021). Summary of the Invention

[0005] The present invention relates to novel compounds of formula (I); their manufacture; medicaments based on the compounds according to the invention and their production; and the use of compounds of formula (I) as STING agonists for treating various cancers, thereby improving response rates to current immunotherapies and overcoming acquired resistance. The compounds of formula (I) exhibit excellent STING agonist activity. In addition, the compounds of formula (I) exhibit good safety and good PK properties, such as good solubility, microsomal stability, permeability, and safety margin.

[0006] One aspect of the present invention relates to compounds of formula (I),

[0007]

[0008] in

[0009] Ring A is a 5- to 12-membered monocyclic, bicyclic or tricyclic heteroaryl ring or heterocyclyl ring containing one to four heteroatoms selected from N, O and S,

[0010] R 1 、R 2 and R 3 Each of the 1-6 Alkyl, halogenated 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)2amino, C 1-6 Alkyl-S-, C 1-6 Alkyl SO2, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6Alkoxycarbonyl, carboxyl, hydroxyl, cyano, amino, halogen, acyl, carbamoyl and 5- to 8-membered monocyclic heterocyclic radicals containing one to three heteroatoms selected from N, O and S, wherein the heterocyclic radicals may be further substituted with halogen, C 1-6 Alkyl, C 1-6 Alkoxy or amino substitution;

[0011] Ring B is a 5- to 8-membered monocyclic or bicyclic heteroaryl ring or heterocyclyl ring containing one to four heteroatoms selected from N, O and S,

[0012] R 4 Not present or selected from C 1-6 Alkyl, halogenated 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)2amino, C 1-6 Alkyl-S-, C 1-6 Alkyl SO2, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkoxycarbonyl, carboxyl, hydroxy, cyano, amino, halogen, and carbamoyl;

[0013] Bond a is the bond connecting ring A and ring B;

[0014] Ring C is a 5- to 8-membered monocyclic or bicyclic heteroaryl ring or heterocyclyl ring containing one to four heteroatoms selected from N, O and S,

[0015] R 5 、R 6 and R 7 Each of the 1-6 Alkyl, halogenated 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)2amino, C 1-6 Alkyl-S-, C 1-6 Alkyl SO2, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxycarbonyl, halocarbonyl 2-6 Alkenyl, C 3-7 Cycloalkyl, C 3-7Cycloalkyl C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy C 2-6 Alkynyl, carboxyl, hydroxyl, cyano, amino, halogen, carbamoyl, cyano C 1-6 Alkyl, imidazolyl C 1-6 Alkyl, triazolyl C 1-6 Alkyl, pyridyl C 1-6 Alkyl, thiazolyl C 1-6 Alkyl and phenyl C 1-6 Alkyl, including phenyl C 1-6 The alkyl group is optionally substituted with halogen, cyano, 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 Alkoxycarbonyl substitution, or

[0016] R 5 、R 6 and R 7 The two of the alkylene groups, together with the atoms to which they are bonded, form a 5- to 6-membered ring having 0 to 2 heteroatoms selected from N, O and S;

[0017] or a pharmaceutically acceptable salt thereof.

[0018] Another aspect of the present invention relates to a method for preparing a compound of formula (I), and a compound of formula (I) or a pharmaceutically acceptable salt thereof produced according to the method.

[0019] 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.

[0020] Another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof for use as therapeutically active substances.

[0021] 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.

[0022] Another aspect of the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for treating cancer.

[0023] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for activating STING.

[0024] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for preparing a medicament for treating cancer.

[0025] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for preparing a medicament for activating STING.

[0026] 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. DETAILED DESCRIPTION

[0027] definition

[0028] 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 the invention belongs. In addition, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the present invention.

[0029] Unless otherwise indicated, the nomenclature used in this application is based on IUPAC systematic nomenclature.

[0030] The term "compound of the present invention" refers to a compound of formula (I), a compound of formula (Ia), a compound of formula (Ib), and stereoisomers, solvates, or salts (eg, pharmaceutically acceptable salts) thereof.

[0031] The term "substituent" refers to an atom or group of atoms that replaces a hydrogen atom on the parent molecule.

[0032] As used herein, the term "C 1-6 "Alkyl" alone or in combination means a saturated, linear or branched alkyl group containing 1 to 6, specifically 2 to 6 or 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc. The specific "C 1-6 "Alkyl" groups include methyl and ethyl.

[0033] The term "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0034] The term "halogenated C 1-6 "Alkyl" means an alkyl group in which at least one hydrogen atom of the alkyl group is substituted by the same or different halogen atoms, in particular fluorine atoms. 1-6 Examples of alkyl groups include monochloro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, such as difluoromethyl.

[0035] The term "heteroaryl" refers to 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, with the remaining ring atoms being 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, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl. Heteroaryl can be further substituted with halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyano, C 3-7 Cycloalkyl, (C 1-6 Alkyl)2amino or C 1-6 Alkoxy substitution.

[0036] The term "heterocyclyl" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 3 to 9 ring atoms, which contains 1, 2 or 3 heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. In specific embodiments, the heterocyclyl is a monovalent saturated monocyclic ring system of 4 to 7 ring atoms, which contains 1, 2 or 3 heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Examples of monocyclic saturated heterocyclyl are 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 are azaspiro[3.3]heptanyl, 8-aza-bicyclo[3.2.1]octanyl, quininyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, 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 are dihydrofuranyl, imidazolinyl, dihydrooxazolyl, tetrahydropyridinyl or dihydropyranyl.

[0037] The term "hydroxy C 1-6 "Alkyl" means a C 1-6 Alkyl groups, where C 1-6 At least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group.

[0038] Compound according to the present invention can exist in the form of its pharmaceutical salt.Term " pharmaceutical salt " refers to the conventional acid addition salt or base addition salt that retains the biological effectiveness and characteristic of formula (I) compound and is formed by suitable nontoxic organic acid or inorganic acid or organic base or inorganic base.Acid addition salt comprises (for example) those derived from the salt of inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from the salt of organic acid 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 salt comprises those derived from the salt of ammonium, potassium, sodium and quaternary ammonium hydroxide such as tetramethylammonium hydroxide.In order to obtain the physical and chemical stability, hygroscopicity, flowability and solubility of improved compound, chemical modification of pharmaceutical compound into salt is the well-known technology of pharmaceutical chemist. This technology is described, for example, in Bastin RJ et al., Organic Process Research & Development 2000, 4, 427-435. In particular, the sodium salt of the compound of formula (I).

[0039] 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 particular disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein. The therapeutically effective amount depends on the compound, the disease state 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 medical or veterinary doctor, and other factors.

[0040] The term "pharmaceutical composition" refers to a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with a pharmaceutically acceptable excipient for administration to a mammal (eg, a human) in need thereof.

[0041] STING agonists

[0042] The present invention relates to (i) a compound of formula (I),

[0043]

[0044] in

[0045] Ring A is a 5- to 12-membered monocyclic, bicyclic or tricyclic heteroaryl ring or heterocyclyl ring containing one to four heteroatoms selected from N, O and S,

[0046] R 1 、R 2 and R 3 Each of the1-6 Alkyl, halogenated 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)2amino, C 1-6 Alkyl-S-, C 1-6 Alkyl SO2, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkoxycarbonyl, carboxyl, hydroxyl, cyano, amino, halogen, acyl, carbamoyl and 5- to 8-membered monocyclic heterocyclic radicals containing one to three heteroatoms selected from N, O and S, wherein the heterocyclic radicals may be further substituted with halogen, C 1-6 Alkyl, C 1-6 Alkoxy or amino substitution;

[0047] Ring B is a 5- to 8-membered monocyclic or bicyclic heteroaryl ring or heterocyclyl ring containing one to four heteroatoms selected from N, O and S,

[0048] R 4 Not present or selected from C 1-6 Alkyl, halogenated 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)2amino, C 1-6 Alkyl-S-, C 1-6 Alkyl SO2, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkoxycarbonyl, carboxyl, hydroxy, cyano, amino, halogen, and carbamoyl;

[0049] Bond a is the bond connecting ring A and ring B;

[0050] Ring C is a 5- to 8-membered monocyclic or bicyclic heteroaryl ring or heterocyclyl ring containing one to four heteroatoms selected from N, O and S,

[0051] R 5 、R 6 and R 7 Each of the 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, -C(O)C 1-6 Alkyl, C1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkyl-S-, C 1-6 Alkyl SO2, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxycarbonyl, halocarbonyl 2-6 Alkenyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy C 2-6 Alkynyl, carboxyl, hydroxyl, cyano, amino, halogen, carbamoyl, cyano C 1-6 Alkyl, imidazolyl C 1-6 Alkyl, triazolyl C 1-6 Alkyl, pyridyl C 1-6 Alkyl, thiazolyl C 1-6 Alkyl and phenyl C 1-6 Alkyl, including phenyl C 1-6 The alkyl group is optionally substituted with halogen, cyano, 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 Alkoxycarbonyl substitution, or

[0052] R 5 、R 6 and R 7 The two of the alkylene groups, together with the atoms to which they are bonded, form a 5- to 6-membered ring having 0 to 2 heteroatoms selected from N, O and S;

[0053] or a pharmaceutically acceptable salt thereof.

[0054] A further embodiment of the present invention is (ii) a compound of formula (I) according to (i) or a pharmaceutically acceptable salt thereof, wherein

[0055] 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,

[0056] R 1 is a carbamoyl group,

[0057] R2 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, acyl and 5- to 8-membered monocyclic heterocyclic groups containing one to three heteroatoms selected from N, O and S, preferably R 2 C 1-6 alkyl,

[0058] R 3 Absent or halogen;

[0059] Ring B is selected from

[0060]

[0061] X 1 、X 2 and X 3 Each of is independently selected from C, N and O,

[0062] R 4 Not present or selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, amino C 1-6 Alkyl, hydroxyl C 1-6 Alkyl and carbamoyl, preferably R 4 Not present or selected from C 1-6 Alkyl and hydroxy C 1-6 alkyl;

[0063] Ring C is pyrazolyl,

[0064] R 5 Selected from C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl, halogenated 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, pyridyl C 1-6 Alkyl, thiazolyl C 1-6 Alkyl and phenyl C 1-6 Alkyl, including phenyl C 1-6 The alkyl group is optionally substituted with halogen, cyano, hydroxyl, C 1-6 Alkyl, morpholino C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 Alkoxy C 1-6 Alkyl and C 1-6 Alkoxycarbonyl substituted, and wherein phenyl C 1-6 The alkyl group is preferably optionally substituted with fluorine, cyano, methoxy, hydroxymethyl, morpholinomethyl, methoxymethyl or methoxycarbonyl, preferably R 5 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl C 1-6 Alkyl, pyridyl C 1-6 Alkyl, phenyl C 1-6 Alkyl, including phenyl C 1-6 The alkyl group is optionally substituted with halogen, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or morpholino C 1-6 Alkyl substituted, and more preferably R 5 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, pyridyl C 1-6 Alkyl and phenyl C 1-6 Alkyl, including phenyl C 1-6 The alkyl group is optionally substituted with halogen, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl or hydroxy C 1-6 Alkyl substitution;

[0065] R 6 Does not exist or is C 1-6 Alkyl, R 7 is absent or selected from hydroxy, halogen and amino, or R 6 and R 7 Together with the atoms to which they are bonded, they form a 5- to 6-membered ring containing zero to two heteroatoms selected from N, O and S, preferably R 6 C 1-6 Alkyl and R 7 It is a hydroxyl group.

[0066] A further embodiment of the present invention is (iii) a compound of formula (I) or a pharmaceutically acceptable salt thereof according to (i) or (ii), wherein

[0067] The substituted ring A is selected from

[0068] A further embodiment of the present invention is (iv) a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of (i) to (iii), wherein

[0069] The substituted ring A is selected from

[0070] R 1 is a carbamoyl group,

[0071] R 2 C 1-6 alkyl,

[0072] R 3 Absent or halogen.

[0073] A further embodiment of the present invention is (v) a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of (i) to (iii), wherein

[0074] R 1 is a carbamoyl group;

[0075] R 2 is selected from methyl, difluoromethyl, acetyl, chloro and imidazolyl;

[0076] R 3 Absent or fluorine.

[0077] A further embodiment of the present invention is (vi) a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of (i) to (v), wherein

[0078] R 1 is a carbamoyl group;

[0079] R 2 is methyl;

[0080] R 3 Absent or fluorine.

[0081] A further embodiment of the present invention is (vii) a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of (i) to (vi), wherein Ring B is selected from triazolyl, oxazolyl, oxadiazolyl and pyrimidinyl.

[0082] A further embodiment of the present invention is (viii) a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of (i) to (vii), wherein

[0083] The substituted ring B is selected from

[0084] A further embodiment of the present invention is (ix) a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of (i) to (viii), wherein

[0085] The substituted ring B is selected from

[0086] R 4 Not present or selected from C 1-6 Alkyl and hydroxy C 1-6 alkyl.

[0087] A further embodiment of the present invention is (x) a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of (i) to (viii), wherein R 4 It is absent or selected from methyl, difluoromethyl, aminomethyl, hydroxymethyl and carbamoyl.

[0088] A further embodiment of the present invention is (xi) a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of (i) to (x), wherein R 4 Absent or selected from methyl and hydroxymethyl.

[0089] A further embodiment of the present invention is (xii) a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of (i) to (xi), wherein the substituted ring C is

[0090] A further embodiment of the present invention is (xiii) a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of (i) to (xii), wherein

[0091] R 5 selected from the group consisting of 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-fluoro-propyl, 2-methoxyethyl, 3-methoxypropyl, 1-pent-3-ynyl, 5-methoxypent-3-ynyl, 2-phenylethyl, 2-(4-methoxy)ethyl ethyl, 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-pyridinyl)ethyl, 2-[4-(morpholinomethyl)phenyl]ethyl and 2-thiazol-2-ylethyl,

[0092] R 6 Not present or methyl, R 7 does not exist, is fluorine, amino or hydroxyl, or R 6 and R 7 Together with the atoms to which they are bonded, they form a 5-membered ring.

[0093] A further embodiment of the present invention is (xiv) a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of (i) to (xiii), wherein

[0094] R 5 is selected from the group consisting of propyl, butyl, cyclopropylmethyl, 3,3-difluoroallyl, 3-fluoro-propyl, 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,

[0095] R 6 is methyl,

[0096] R 7 It is a hydroxyl group.

[0097] A further embodiment of the present invention is (xv) a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of (i) or (ii), wherein

[0098] The substituted ring A is selected from

[0099] R 1 is a carbamoyl group,

[0100] R 2 C 1-6 alkyl,

[0101] R 3 Absent or halogen;

[0102] The substituted ring B is selected from

[0103] R 4 Not present or selected from C 1-6 Alkyl and hydroxy C 1-6 alkyl;

[0104] The substituted ring C is

[0105] R 5Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl C 1-6 Alkyl, pyridyl C 1-6 Alkyl, phenyl C 1-6 Alkyl, including phenyl C 1-6 The alkyl group is optionally substituted with halogen, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or morpholino C 1-6 Alkyl substitution,

[0106] R 6 C 1-6 alkyl,

[0107] R 7 It is a hydroxyl group.

[0108] A further embodiment of the present invention is (xvi) a compound of formula (I) according to (xv) or a pharmaceutically acceptable salt thereof, wherein

[0109] R 1 is a carbamoyl group,

[0110] R 2 is methyl,

[0111] R 3 Absent or fluorine;

[0112] R 4 absent or selected from methyl and hydroxymethyl;

[0113] R 5 Selected from propyl, butyl, 3-fluoro-propyl, 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]

[0114] ethyl, 2-[3-(methoxymethyl)phenyl]ethyl, 2-[4-(hydroxymethyl)phenyl]ethyl and 2-[4-

[0115] (morpholinomethyl)phenyl]ethyl,

[0116] R 6 is methyl,

[0117] R 7 It is a hydroxyl group.

[0118] A further embodiment of the present invention is (xvii) a compound of formula (I) according to (xv) or a pharmaceutically acceptable salt thereof, wherein

[0119] R 1 is a carbamoyl group,

[0120] R 2 C 1-6 alkyl,

[0121] R 3 Not present or halogen,

[0122] R 4 Not present or hydroxyl C 1-6 alkyl,

[0123] R 5 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, pyridyl C 1-6 Alkyl and phenyl C 1-6 Alkyl, including phenyl C 1-6 The alkyl group is optionally substituted with halogen, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl or hydroxy C 1-6 Alkyl substituted, preferably R 5 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl and phenyl C 1-6 Alkyl, including phenyl C 1-6 The alkyl group is optionally C 1-6 Alkoxy substitution,

[0124] R 6 C 1-6 alkyl,

[0125] R 7 It is a hydroxyl group.

[0126] A further embodiment of the present invention is (xviii) a compound of formula (I) according to (xvii) or a pharmaceutically acceptable salt thereof, wherein

[0127] R 1 is a carbamoyl group,

[0128] R 2 is methyl,

[0129] R 3 Not present or fluorine,

[0130] R 4 Not present or in the form of hydroxymethyl;

[0131] R 5Selected from propyl, butyl, 3,3-difluoropropyl, 2-(3-pyridyl)ethyl, 2-phenylethyl,

[0132] 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,

[0133] R 6 is methyl,

[0134] R 7 It is a hydroxyl group.

[0135] A further embodiment of the present invention is (xix) a compound selected from the group consisting of:

[0136] 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;

[0137] 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;

[0138] 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;

[0139] 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;

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

[0141] 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;

[0142] 4-[2-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)pyrimidin-4-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide;

[0143] 1-[2-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)pyrimidin-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide;

[0144] 1-[2-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide;

[0145] 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;

[0146] 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;

[0147] 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;

[0148] 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;

[0149] 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;

[0150] 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;

[0151] 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;

[0152] 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;

[0153] 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;

[0154] 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;

[0155] 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;

[0156] 1-[2-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0157] 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;

[0158] 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;

[0159] 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;

[0160] 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;

[0161] 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;

[0162] 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;

[0163] 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;

[0164] 1-[2-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-5-methyl-pyrrolo[2,3-c]pyridine-3-carboxamide;

[0165] 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;

[0166] 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;

[0167] 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;

[0168] 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;

[0169] 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;

[0170] 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;

[0171] 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;

[0172] 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;

[0173] 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;

[0174] 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;

[0175] 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;

[0176] 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;

[0177] 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;

[0178] 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;

[0179] 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;

[0180] 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;

[0181] 1-[3-[4-Hydroxy-5-methyl-2-[2-(4-pyridinyl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0182] 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;

[0183] 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;

[0184] 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;

[0185] 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;

[0186] 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;

[0187] 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;

[0188] 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;

[0189] 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;

[0190] 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;

[0191] 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;

[0192] 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;

[0193] 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;

[0194] 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;

[0195] 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;

[0196] 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;

[0197] 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;

[0198] 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;

[0199] 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;

[0200] 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;

[0201] 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;

[0202] 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;

[0203] 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;

[0204] 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;

[0205] 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;

[0206] 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;

[0207] 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;

[0208] 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;

[0209] 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;

[0210] 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;

[0211] 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;

[0212] 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;

[0213] 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;

[0214] 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;

[0215] 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;

[0216] 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;

[0217] 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;

[0218] 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;

[0219] 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;

[0220] 1-[2-(4-Hydroxy-5-methyl-2-propyl-pyrazol-3-yl)oxazol-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide;

[0221] 1-[2-(2-butyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide;

[0222] 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;

[0223] 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;

[0224] 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;

[0225] 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;

[0226] 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;

[0227] 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;

[0228] 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;

[0229] 8-[2-(4-Hydroxy-5-methyl-2-propyl-pyrazol-3-yl)oxazol-4-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide;

[0230] or a pharmaceutically acceptable salt thereof.

[0231] A further embodiment of the present invention is (xx) a method for preparing a compound having a structure of formula (Ia)

[0232] The method comprises one of the following steps:

[0233] (a) making the compound of formula (IIa)

[0234]

[0235] With the compound of formula (III)

[0236]

[0237] reacting in the presence of a catalyst and a base to provide a compound of formula (Ia), wherein the catalyst is preferably selected from Pd(OAc)2, CuI and Pd(dppf)Cl2, and the base is preferably selected from K2CO3, Cs2CO3 and Li2CO3;

[0238] (b) making the compound of formula (V)

[0239]

[0240] With the compound of formula (VI)

[0241]

[0242] Reaction in the presence of a catalyst and a base to provide a compound of formula (Ia), wherein the catalyst is preferably

[0243] is Pd(OAc)2, and the base is preferably selected from K2CO3, Na2CO3, Cs2CO3 and KOAc, (c) making the compound of formula (VII)

[0244]

[0245] With the compound of formula (VIII)

[0246]

[0247]

[0248] reacting in the presence of a catalyst to provide a compound of formula (Ia), wherein the catalyst is preferably selected from AgOTf and AgBF4,

[0249] (d) making a compound of formula (X)

[0250]

[0251] With the compound of formula (XI)

[0252]

[0253] reacting in the presence of a catalyst and a base to provide a compound of formula (Ia), wherein the catalyst is preferably Pd(dppf)Cl2, and the base is preferably K2CO3,

[0254] where R 1 to R 7 , A and X 1 To X 3 As defined above.

[0255] A further embodiment of the present invention is (xxi) a method for preparing a compound having a structure of formula (Ib)

[0256] The method comprises the following steps:

[0257] The compound of formula (XII)

[0258]

[0259] With the compound of formula (XIII)

[0260]

[0261] reacting in the presence of a catalyst and a base to provide a compound of formula (Ib), wherein the catalyst is preferably PPh 3 AuCl 3 , and the base is preferably selected from K 2 CO 3 , Cs 2 CO 3 and DBU,

[0262] where R 1 to R 7 and Ring A are as defined above.

[0263] A further embodiment of the present invention is (xxii) a compound of formula (I), a compound of formula (Ia), a compound of formula (Ib), or a pharmaceutically acceptable salt thereof, produced according to the method described in (xx) or (xxi).

[0264] A further embodiment of the present invention is (xxiii) a pharmaceutical composition comprising the compound according to any one of (i) to (xix) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0265] Pharmaceutical compositions and administration

[0266] The present invention also provides pharmaceutical compositions or medicines containing the compound of the present invention and treatment inert carriers, diluents or excipients, and methods for preparing such compositions and medicines using the compound of the present invention. In one example, the compound of formula (I) can be formulated as a galenical administration form by mixing with a physiologically acceptable carrier (i.e., a carrier that is nontoxic to the recipient at the dosage and concentration used) at ambient temperature under suitable pH and desired purity. The pH of the formulation depends primarily on the specific use and concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula (I) is formulated in an acetate buffer at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound can be, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

[0267] The composition is formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context 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 delivery of the agent, the method of administration, the timing of administration, and other factors known to practitioners. An "effective amount" of the compound to be administered will be influenced by such considerations and is the minimum amount necessary to activate STING-mediated type I IRF responses and pro-inflammatory cytokine production. For example, the amount may be less than an amount that is toxic to normal cells or the mammal as a whole.

[0268] In one example, the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01 to 1000 (e.g., 0.01 to 100) mg / kg of patient body weight per day, alternatively about 0.01 to 1000 (e.g., 0.1 to 20) mg / kg of patient body weight, with the initial range of the compound typically being 0.3 to 15 mg / kg / day. In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain about 1 to about 1000 (e.g., 25 to 100) mg of the compound of the invention.

[0269] The compounds of the present invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and (if necessary for local treatment) intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0270] The compounds of the present invention can be administered in any convenient administration form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components of pharmaceutical preparations, for example, diluents, carriers, pH adjusters, sweeteners, fillers and other active agents.

[0271] Typical formulations are prepared by mixing the compound of the invention with a carrier or excipient. 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 The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents, diluents and other known additives to provide an aesthetically pleasing display of the drug (e.g., a compound of the present invention or a pharmaceutical composition thereof) or to facilitate the preparation of a pharmaceutical product (e.g., a drug).

[0272] An example of a suitable oral dosage form is a tablet containing about 1 to 1000 mg (e.g., 25 mg, 50 mg, 100 mg, 250 mg, or 500 mg) of a compound of the invention compounded with 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 the PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment. Examples of aerosol formulations can be prepared by dissolving a compound of the invention (e.g., 1 to 500 mg (e.g., 5 to 400 mg)) in a suitable buffer solution (e.g., phosphate buffer), adding a penetration enhancer (e.g., a salt such as sodium chloride) if necessary. The solution can be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

[0273] Thus, embodiments include 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 and a pharmaceutically acceptable carrier or excipient.

[0274] Another embodiment includes a pharmaceutical composition comprising a compound of Formula (I) for use in treating cancer.

[0275] The following examples illustrate typical compositions of the present invention and are intended to be representative only.

[0276] Composition A

[0277] The compounds of the invention can be used as active ingredients in a manner known per se to produce tablets of the following composition:

[0278]

[0279] Composition B

[0280] The compounds of the invention can be used as active ingredients in a manner known per se to produce capsules of the following composition:

[0281]

[0282] Indications and treatments

[0283] The compounds of the present invention bind to STING and initiate a signaling cascade that induces type I interferon and other proinflammatory cytokines and / or co-stimulatory factors. Therefore, the compounds of the present invention can be used to enhance cancer antigen presentation, contribute to the priming, transport and infiltration of T cells, and promote the killing of cancer (particularly cancer cells). The compounds of the present invention can be used to enhance the innate immune response in bone marrow cells expressing STING. Alternatively, the compounds of the present invention can be used to activate T cells in tumors, which have T cells but are suppressed, for example, by upregulation of co-stimulatory molecules and the production of proinflammatory cytokines. More broadly, the compounds can be used to treat non-inflammatory (e.g., immune desert or immune rejection) cancer types by enhancing antigen presentation, T cell priming, recruitment / infiltration and tumor killing.

[0284] Another embodiment includes a method of treating cancer in a mammal in need of such treatment, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I), a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof. Cancers include, but are not limited to, sarcomas, adenocarcinomas, blastomas, and carcinomas of various organ systems, such as those affecting the pancreas, liver, lung, breast, lymphoid, stomach, gallbladder (e.g., colon), genitourinary tract (e.g., renal urothelial cells), prostate, and pharynx.

[0285] A further embodiment of the present invention is (xxiv) a compound according to the invention for use as therapeutically active substance.

[0286] A further embodiment of the present invention is (xxiv) a compound of the present invention for use in therapy or cancer.

[0287] A further embodiment of the present invention is (xxvi) use of a compound of the present invention for treating cancer.

[0288] A further embodiment of the present invention is (xxvii) use of a compound of the present invention for activating STING.

[0289] A further embodiment of the present invention is (xxviii) use of a compound of the present invention for the preparation of a medicament for the treatment of cancer.

[0290] A further embodiment of the present invention is (xxix) use of a compound of the present invention for the preparation of a medicament for activating STING.

[0291] A further embodiment of the present invention is (xxx) a method for treating cancer, which comprises administering an effective amount of a compound of the present invention.

[0292] A further embodiment of the present invention is (xxxi) the use according to (xxvi) or (xxviii), or the method according to (xxx), wherein the cancer is a cancer of the pancreas, liver, lung, breast, lymph, stomach, gallbladder, genitourinary tract, prostate or pharynx.

[0293] synthesis

[0294] The compounds of the present invention can be prepared by any conventional method. Suitable methods for synthesizing these compounds and their starting materials are provided in the following schemes and examples. Unless otherwise indicated, all substituents, especially ring A, X 1 To X 3 and R 1 to R 7 As defined above. Furthermore, unless otherwise specifically indicated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to one of ordinary skill in the art of organic chemistry.

[0295] The general synthetic route for preparing the compounds of the present invention is shown in Scheme 1.

[0296] Solution 1

[0297]

[0298] As depicted in Scheme 1, compounds having the structure of Formula (Ia) can be prepared via a method comprising one of the following steps:

[0299]

[0300] (a) Compound of formula (IIa)

[0301]

[0302] With the compound of formula (III)

[0303]

[0304] C—H activation in the presence of a catalyst such as Pd(OAc) 2 , CuI or Pd(dppf)Cl 2 ) and a base such as K 2 CO 3 , Cs 2 CO 3 or Li 2 CO 3 provides a compound of formula (Ia);

[0305] (b) bromide compound of formula (IV)

[0306]

[0307] After reacting with B2pin2 in the presence of a catalyst (such as Pd(dppf)Cl2, Pd2(dba)3, Pd(OAc)2 or PdCl2(PPh3)2), it can be converted into a boronate compound, which can undergo a Suzuki coupling reaction with a compound of formula (IIa) in the presence of a catalyst (such as Pd(OAc)2, Pd(dppf)Cl2, Pd2(dba)3 or Pd(PPh3)4) to obtain a compound of formula (V)

[0308]

[0309] The compound of formula (V) can also be prepared from the compound of formula (IIb)

[0310]

[0311] With the bromide compound of formula (IV)

[0312]

[0313] The Ullmann reaction is carried out in the presence of a catalyst (such as CuI) and a base (such as K3PO4 or Cs2CO3).

[0314] Compounds of formula (V) and (VI)

[0315]

[0316] C—H activation in the presence of a catalyst such as Pd(OAc) 2 and a base such as K 2 CO 3 , Na 2 CO 3 , Cs 2 CO 3 or KOAc provides a compound of formula (Ia);

[0317] (c) The bromide compound of formula (IIa) can be converted into the α-bromocarbonyl compound of formula (VII) by the following method:

[0318]

[0319] Stille coupling reaction with tributyl(1-ethoxyvinyl)tin in the presence of a catalyst (such as Pd(PPh3)2Cl2, Pd(OAc)2 or Pd(MeCN)2Cl2) and then bromination in the presence of a brominating agent (such as NBS) is performed, and then the compound of formula (VII) is reacted with the compound of formula (VIII)

[0320]

[0321] The reaction in the presence of a catalyst (such as AgOTf or AgBF4) can give a compound of formula (Ia);

[0322] (d) Dibromide compound of formula (IX)

[0323]

[0324] and a compound of formula (IIb)

[0325]

[0326] Can undergo Ullmann reaction in the presence of a catalyst (such as CuI) and a base (such as K2CO3 or K3PO4) to provide compounds of formula (X)

[0327]

[0328] It is further combined with a boride compound of formula (XI)

[0329]

[0330] The reaction proceeds via a Suzuki coupling reaction in the presence of a catalyst such as Pd(dppf)Cl2 and a base such as K2CO3 to afford compounds of formula (Ia).

[0331] As also depicted in Scheme 1, compounds having the structure of Formula (Ib) can be prepared via a method comprising the following steps:

[0332]

[0333] The bromide compound of formula (IIa) can be converted into the α,β-unsaturated carbonyl compound of formula (XII) by the following method:

[0334]

[0335] In the presence of a Pd catalyst (such as Pd (PPh 3) 4, Pd (PPh 3) 2Cl 2, Pd (dppf) Cl 2 or Pd (dppp) Cl 2) and a Cu (I) co-catalyst (such as CuI or CuBr) with tert-butyldimethyl (2-propynyloxy) silane Sonogashira coupling reaction, and then deprotection under NH 4 F and oxidation in the presence of an oxidant (such as DMP), the compound of formula (XII) and the compound of formula (XIII)

[0336]

[0337] The reaction proceeds via cyclization of the pyrimidine ring in the presence of a catalyst such as PPh 3 AuCl 3 and a base such as K 2 CO 3 , Cs 2 CO 3 or DBU to give compounds of formula (Ib).

[0338] Examples

[0339] The present invention will be more fully understood by reference to the following examples, which, however, should not be construed as limiting the scope of the invention.

[0340] The abbreviations used in this article are as follows:

[0341] ACN: acetonitrile

[0342] Ac2O: acetic anhydride

[0343] AcOH: acetic acid

[0344] AIBN: Azobisisobutyronitrile

[0345] Boc2O: di-tert-butyl dicarbonate

[0346] BnBr: benzyl bromide

[0347] BzCl: Benzoyl chloride

[0348] B2pin2: Bis(pinacol)diboron

[0349] cataCXium A: di(1-adamantyl)-n-butylphosphine

[0350] CMBP: cyanomethylenetributylphosphine

[0351] DAST: Diethylaminosulfur trifluoride

[0352] DCM: dichloromethane

[0353] DCE: dichloroethane

[0354] DIPEA or DIEA: N,N-diisopropylethylamine

[0355] DMAP: 4-dimethylaminopyridine

[0356] DMBNH2: 2,4-dimethoxybenzylamine

[0357] DMF: N,N-dimethylformamide

[0358] DMP: Dess-Martin periodine

[0359] DMSO: dimethyl sulfoxide

[0360] DPPF: 1,1'-bis(diphenylphosphino)ferrocene

[0361] EA or EtOAc: Ethyl acetate

[0362] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0363] h or hr: hours

[0364] HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol

[0365] LCMS: Liquid chromatography-mass spectrometry

[0366] LDA: lithium diisopropylamide

[0367] LiHMDS: lithium bis(trimethylsilyl)amide

[0368] mCPBA: meta-chloroperbenzoic acid

[0369] min: minutes

[0370] MeOH: methanol

[0371] MsOH: methanesulfonic acid

[0372] MTBE: Methyl tert-butyl ether

[0373] n-BuLi: n-butyllithium

[0374] NBS: N-bromosuccinamide

[0375] NIS: N-iodosuccinimide

[0376] PCy3HBF4: tri(cyclohexyl)phosphine tetrafluoroborate

[0377] PE: Petroleum ether

[0378] PivOH: 2,2-dimethylpropionic acid

[0379] PMBBr: 4-methoxybenzyl bromide

[0380] PMBNCS: 4-methoxybenzyl isothiocyanate

[0381] PMBNH2: 4-methoxybenzylamine

[0382] prep-HPLC: Preparative High Performance Liquid Chromatography

[0383] prep-TLC: Preparative Thin Layer Chromatography

[0384] PPh3: triphenylphosphine

[0385] Pd(dppf)Cl2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride

[0386] Pd(OAc)2: Palladium(II) acetate

[0387] Py: pyridine

[0388] rt: room temperature

[0389] sat.: saturated

[0390] Selective fluorine reagent 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate)

[0391] SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride

[0392] TBAF: Tetra-n-butylammonium fluoride

[0393] TBSCl: tert-Butyldimethylsilyl chloride

[0394] TEA: Trimethylamine

[0395] TFA: trifluoroacetic acid

[0396] TFAA: trifluoroacetic anhydride

[0397] TFE: 2,2,2-trifluoroethanol

[0398] Tf2O: trifluoromethanesulfonic anhydride

[0399] THF: Tetrahydrofuran

[0400] TLC: Thin layer chromatography

[0401] TMSCN: trimethylsilyl cyanide

[0402] Tol: Toluene

[0403] v / v volume ratio

[0404] General experimental conditions

[0405] Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and Quad 12 / 25 Cartridge module. ii) ISCO combi-flash chromatograph. Silica gel brand and pore size: i) KP-SIL Particle size: 40-60 μm; ii) CAS registration number: silica gel: 63231-67-4, particle size: 47-60 μm silica gel; iii) ZCX from Qingdao Ocean Chemical Co., Ltd., pore size: 200-300 or 300-400.

[0406] Intermediates and final compounds were purified by preparative HPLC on a reverse phase column using XBridge TM Prep-C18 (5 μm, OBDTM 30×100 mm) column, SunFire TM Prep-C18 (5 μm, OBD TM 30×100 mm) column, Phenomenex Synergi-C18 (10 μm, 25×150 mm) or Phenomenex Gemini-C18 (10 μm, 25×150 mm). Waters AutoP purification system (sample manager 2767, pump 2525, detectors: Micromass ZQ and UV2487, solvent systems: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water, or acetonitrile and 0.1% TFA in water). Or Gilson-281 purification system (pump 322, detector: UV156, solvent systems: 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).

[0407] LC / MS (Waters TMLC / MS spectra of the compounds were obtained using an Agilent Alliance 2795-Micromass ZQ, a Shimadzu Alliance 2020-Micromass ZQ, or an Agilent Alliance 6110-Micromass ZQ. The LC / MS conditions were as follows (run time 3 or 1.5 minutes):

[0408] Acidic conditions I: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile;

[0409] Acidic conditions II: A: 0.0375% TFA in H2O; B: 0.01875% TFA in acetonitrile;

[0410] Basic conditions I: A: 0.1% NH3·H2O solution in H2O; B: acetonitrile;

[0411] Basic conditions II: A: 0.025% NH3·H2O solution in H2O; B: acetonitrile;

[0412] Neutral conditions: A: H2O; B: acetonitrile.

[0413] Mass spectrometry (MS): Usually only ions representing the parent mass are reported. Unless otherwise stated, the mass ion quoted is the positive mass ion (MH). + .

[0414] NMR spectra were acquired using a Bruker Avance 400 MHz, 500 MHz.

[0415] Microwave-assisted reactions were performed in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under argon or nitrogen atmosphere. Unless otherwise stated, reagents were purchased from commercial suppliers as received without further purification.

[0416] Preparation Example

[0417] Intermediate A1

[0418] 1-Bromo-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

[0419]

[0420] The title compound was prepared according to the following scheme:

[0421]

[0422] Step 1: Preparation of ethyl 2-[(5-methylpyrazin-2-yl)methylamino]-2-oxo-acetate (Compound A1-b)

[0423] To a solution of 2-(aminomethyl)-5-methylpyrazine (A1-a, 7.0 g, 56.84 mmol) in THF (250 mL) was added TEA (12.63 g, 125.04 mmol), the mixture was stirred at room temperature for 1 h, then ethyl 2-chloro-2-oxo-acetate (0.22 g, 1.62 mmol) was added, and the mixture was then stirred at room temperature for 2 hours. The reaction mixture was then poured into water (100 mL) and extracted with DCM (200 mL×4). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated to give compound A1-b (10 g). LCMS (M+H) + :224.

[0424] Step 2: Preparation of ethyl 6-methylimidazo[1,5-a]pyrazine-3-carboxylate (Compound A1-c)

[0425] To a solution of P2O5 (31.79 g, 224 mmol) in POCl3 (100 mL) was added 2-[(5-methylpyrazin-2-yl)methylamino]-2-oxo-ethyl acetate (A1-b, 10 g, 44.8 mmol), and the mixture was stirred at 110 ° C for 12 hours. The mixture was then concentrated, and the residue was quenched with saturated NaHCO3 solution and extracted with EA (300 mL×3). The combined organic phases were washed with saturated NaHCO3 solution and brine, dried over anhydrous Na2SO4, and concentrated to give compound A1-c (8 g), LCMS (M+H) + :206.

[0426] Step 3: Preparation of 1-bromo-6-methyl-imidazo[1,5-a]pyrazine-3-carboxylic acid ethyl ester (Compound A1-d)

[0427] To 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 NBS (2.6 g, 14.62 mmol), and the mixture was stirred at 20 ° C for 3 hours. The mixture was then poured into water (80 mL) and extracted with EA (100 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography to obtain compound A1-d (2.9 g). LCMS (M+H) + :284.

[0428] Step 4: Preparation of 1-bromo-6-methyl-imidazo[1,5-a]pyrazine-3-carboxylic acid (Compound A1-e)

[0429] To a solution of 1-bromo-6-methyl-imidazo[1,5-a]pyrazine-3-carboxylic acid ethyl ester (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 hours. The mixture was then adjusted to pH ˜3 with HCl (12 N), the mixture was filtered, and the filter cake was dried to give compound A1-e (2.3 g). LCMS (M+H) + :256.

[0430] Step 5: Preparation of 1-bromo-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Intermediate A1)

[0431] 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) was 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 hours. The mixture was then poured into water (200 mL) and filtered, and the filter cake was dried to give Intermediate A1 (2.2 g). LCMS (M+H) + :405.

[0432] Intermediate A2

[0433] 4-Bromo-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide

[0434]

[0435] The title compound was prepared according to the following scheme:

[0436]

[0437] Step 1: Preparation of 5-formyl-1-methyl-pyrazole-4-carboxylic acid ethyl ester (Compound A2-b)

[0438] To a solution of diisopropylamine (43.89 mL, 311.34 mmol) in THF (200 mL) was added n-BuLi (2.5 M in hexane, 116.75 mL, 291.89 mmol) dropwise at -78°C, and the mixture was stirred at -78°C for 1 h. A solution of ethyl 1-methylpyrazole-4-carboxylate (A2-a, 30.0 g, 194.59 mmol) in THF (50 mL) was then added dropwise at -78°C, and the mixture was stirred for 1 h. A solution of DMF (33.07 mL, 428.1 mmol) in THF (30 mL) was then added dropwise, and the mixture was stirred at -78°C for 2 h. The mixture was poured into HCl (1 N, 400 mL) and extracted with EA (400 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography to give compound A2-b (23.5 g). LCMS (M+H) + :183.

[0439] Step 2: Preparation of 1-methyl-5-[(Z)-(2-methyl-5-oxo-oxazol-4-ylidene)methyl]pyrazole-4-carboxylic acid ethyl ester (Compound A2-c)

[0440] 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) in acetic anhydride (60 mL) was added KOAc (24.21 g, 247.01 mmol), and the mixture was stirred at 100° C. for 2 hours. The mixture was then quenched with saturated NaHCO solution (500 mL) and extracted with EA (200 mL×3). The combined organic phases were washed with brine, dried over anhydrous NaSO, and concentrated to give compound A2-c (32.0 g). LCMS (M+H) + :264.

[0441] Step 3: Preparation of 1-methyl-4-oxo-5H-pyrazolo[4,3-c]pyridine-6-carboxylic acid (Compound A2-d)

[0442] 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) was added KCO (33.6 g, 243.11 mmol) and the suspension was stirred at 70°C for 12 hours. The mixture was diluted with MTBE (500 mL) and filtered, the filter cake was washed with MTBE, and then suspended in H0 (200 mL). Concentrated HCl was added to adjust to pH 1. The mixture was then filtered and the filter cake was dried to give compound A2-d (20.0 g). LCMS (M+H) + :194.

[0443] Step 4: Preparation of 1-methyl-4-oxo-5H-pyrazolo[4,3-c]pyridine-6-carboxylic acid methyl ester (Compound A2-e)

[0444] At 0 ° C, SOCl2 (112.74 mL, 1.55 mol) was added to MeOH (400 mL), followed by 1-methyl-4-oxo-5H-pyrazolo[4,3-c]pyridine-6-carboxylic acid (A2-d, 20.0 g, 103.54 mmol), and the mixture was stirred at 60 ° C for 16 hours and then concentrated to give compound A2-e (18.9 g). LCMS (M+H) + :208.

[0445] Step 5: Preparation of methyl 1-methyl-4-(trifluoromethanesulfonyloxy)pyrazolo[4,3-c]pyridine-6-carboxylate (Compound A2-f)

[0446] 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) was added dropwise Py (22.07 mL, 273.66 mmol) and Tf2O (46.07 mL, 273.66 mmol) at 0°C, the mixture was stirred at 20°C for 1 h, and then used in the next step to obtain compound A2-f (30.9 g). LCMS (M+H) + :340.

[0447] Step 6: Preparation of 4-bromo-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxylic acid methyl ester (Compound A2-g)

[0448] To a solution of 1-methyl-4-(trifluoromethanesulfonyloxy)pyrazolo[4,3-c]pyridine-6-carboxylic acid methyl ester (A2-f, 30.9 g, 91.08 mmol) in ACN (200 mL) was added LiBr (79.11 g, 910.83 mmol), followed by the slow addition of TFA (30.44 mL, 409.87 mmol), and the mixture was stirred at 20 ° C for 16 hours. The mixture was then quenched with saturated NaHCO solution to pH> 7, and the mixture was extracted with EA (500 mL×4). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative HPLC to give compound A2-g (11.5 g). LCMS (M+H) + :270.

[0449] Step 7: Preparation of 4-bromo-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxylic acid (Compound A2-h)

[0450] To a suspension of 4-bromo-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxylic acid methyl ester (A2-g, 11.5 g, 42.58 mmol) in THF (50 mL) and water (20 mL) was added LiOH.H2O (2.66 g, 63.87 mmol), and the mixture was stirred at 20°C for 1 h. The mixture was then adjusted to pH ~ 1 with concentrated HCl, the mixture was filtered, and the filter cake was washed with water to give compound A2-h (10.55 g). LCMS (M+H) + :256.

[0451] Step 8: Preparation of 4-bromo-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Intermediate A2)

[0452] 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) was added DIPEA (15.97 g, 123.6 mmol), 2,4-dimethoxybenzylamine (7.43 mL, 49.44 mmol) and HATU (23.5 g, 61.8 mmol), and the mixture was stirred at 20° C. for 1 h. The mixture was then diluted with H 2 O (400 mL) and filtered, the filter cake was washed with H 2 O and EA, and the solid was concentrated to give intermediate A2 (15.5 g). LCMS (M+H) + :405.

[0453] Intermediate B1

[0454] 3-(4-Benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole

[0455]

[0456] The title compound was prepared according to the following scheme:

[0457]

[0458] Step 1: Preparation of N-(isopropylideneamino)ethylamine (Compound B1-b)

[0459] To a solution of ethylhydrazine dihydrochloride (B1-a, 40.0 g, 303.03 mmol) in DCM (750 mL) were added acetone (24.54 mL, 333.33 mmol) and K2CO3 (105.3 g, 757.58 mmol), and the mixture was stirred at 20° C. for 12 hours. The mixture was then filtered, the filter cake was washed with DCM, and the filtrate was concentrated to give compound B1-b (25.0 g).

[0460] Step 2: Preparation of 1-ethyl-3-methyl-pyrazole-4-carbaldehyde (Compound B1-c)

[0461] At 0 ° C, POCl (81.68 mL, 873.6 mmol) was added dropwise to DMF (100 mL), the mixture was stirred for 1 h and then cooled to -20 ° C, and then at -20 ° C, a solution of N- (isopropylideneamino) -ethylamine (B1-b, 35.0 g, 349.44 mmol) in DMF (50 mL) was added dropwise. The mixture was stirred at -20 ° C for 3 hours. The mixture was then further stirred at 80 ° C for 2 hours. The mixture was slowly poured into ice, adjusted to pH ~ 9-10 with 30% NaOH aqueous solution, and then extracted with EA (1.5 L × 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to obtain compound B1-c (26.0 g). LCMS (M+H) + :139.

[0462] Step 3: Preparation of (1-ethyl-3-methyl-pyrazol-4-yl)carboxylate (Compound B1-d)

[0463] To a solution of 1-ethyl-3-methyl-pyrazole-4-carbaldehyde (B1-c, 12.0 g, 86.85 mmol) in DCM (120 mL) was added mCPBA (35.15 g, 173.7 mmol), and the mixture was stirred at 40° C. for 1 h. The mixture was then poured into a saturated Na2SO3 solution (800 mL) and extracted with EA (400 mL×3). The combined organic phases were washed with a saturated NaHCO3 solution and brine, then dried over anhydrous Na2SO4, and concentrated to give compound B1-d (12.0 g). LCMS (M+H) + :155.

[0464] Step 4: Preparation of 1-ethyl-3-methyl-pyrazol-4-ol (Compound B1-e)

[0465] To a solution of (1-ethyl-3-methyl-pyrazol-4-yl)carboxylate (B1-d, 10.0 g, 64.86 mmol) in MeOH (100 mL) was added TEA (18.13 mL, 129.73 mmol), the mixture was stirred at room temperature for 0.5 h and then concentrated to give compound B1-e (12.0 g). LCMS (M+H) + :127.

[0466] Step 5: Preparation of 4-benzyloxy-1-ethyl-3-methyl-pyrazole (Compound B1-f)

[0467] To a solution of 1-ethyl-3-methyl-pyrazole-4-ol (B1-e, 8.0 g, 63.41 mmol) in ACN (100 mL) was added Cs2CO3 (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 h. The mixture was then 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 NaHCO3 solution and brine, dried over anhydrous Na2SO4, and concentrated, and the residue was purified by column chromatography to obtain compound B1-f (12.0 g). LCMS (M+H) + :217.

[0468] Step 6: Preparation of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxylic acid (Compound B1-g)

[0469] To a solution of 4-benzyloxy-1-ethyl-3-methyl-pyrazole (B1-f, 1.5 g, 6.94 mmol) in THF (160 mL) was added n-BuLi (2.5 M solution in hexane, 4.16 mL, 10.4 mmol) at -78°C and stirred for 1 h. CO2 (3.05 g, 69.35 mmol) was then added, the mixture was stirred at room temperature for 1 h, and then adjusted to pH ~ 7 with concentrated HCl, and then concentrated to give compound B1-g (1.8 g). LCMS (M+H) + :261.

[0470] Step 7: Preparation of isobutoxycarbonyl 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxylate (Compound B1-h)

[0471] To a solution of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxylic acid (B1-g, 1.8 g, 6.92 mmol) in DCM (20 mL) was added DIPEA (3.63 mL, 20.75 mmol) and isobutyl chloroformate (1.75 mL, 13.83 mmol), the mixture was stirred at room temperature for 2 hours and then concentrated to give compound B1-h (3.0 g). LCMS (M+H) + :361.

[0472] Step 8: Preparation of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carbohydrazide (Compound B1-i)

[0473] To a solution of hydrazine (0.59 mL, 18.94 mmol) in THF (5 mL) was added dropwise a suspension of isobutoxycarbonyl 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxylate (B1-h, 3.0 g, 8.32 mmol) in THF (30 mL) at 0° C., the mixture was stirred at room temperature for 0.5 h and then concentrated to give compound B1-i (1.6 g). LCMS (M+H) + :275.

[0474] Step 9: Preparation of 1-[(4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carbonyl)amino]-3-[(4-methoxyphenyl)methyl]thiourea (Compound B1-j)

[0475] To a solution of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carbohydrazide (B1-i, 1.6 g, 5.83 mmol) in THF (20 mL) was 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 hours. The mixture was then diluted with EA (200 mL) and filtered, the filtrate was washed with water, the organic phase was dried with anhydrous Na2SO4, and concentrated to obtain compound B1-j (3.0 g). LCMS (M+H) + :454.

[0476] 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)

[0477] 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) in water (12 mL) was added NaOH (6.0 mL, 18.0 mmol, 3N), and the mixture was stirred at 100° C. for 16 hours. The mixture was then 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, dried over anhydrous Na 2 SO 4, and concentrated to give compound B1-k (3.0 g). LCMS (M+H) + :436.

[0478] Step 11: Preparation of 3-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole (Intermediate B1)

[0479] 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) in AcOH (60 mL) was added H2O2 (15.66 g, 138.12 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was then poured into ice water (600 mL) and extracted with EA (300 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated, and the residue was purified by column chromatography to give intermediate B1 (1.02 g). LCMS (M+H) + :404.

[0480] Intermediate B2

[0481] 3-(4-Benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-1-methyl-1,2,4-triazole

[0482]

[0483] The title compound was prepared according to the following scheme:

[0484]

[0485] Step 1: Preparation of 1-[(4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carbonyl)amino]-1-methyl-thiourea (Compound B2-a)

[0486] To 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 1-amino-1-methyl-thiourea (291.8 mg, 2.77 mmol), and the mixture was stirred at 50° C. for 12 hours. The mixture was then 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 give compound B2-a (0.85 g). LCMS (M+H) + :348.

[0487] 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)

[0488] 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 hours. The mixture was then poured into water (200 mL) and extracted with EA (200 mL×3). The combined organic phases were washed with saturated NaHCO solution and brine, dried over anhydrous NaSO, and concentrated to give compound B2-b (0.75 g). LCMS (M+H) + :330.

[0489] Step 3: Preparation of 3-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-1-methyl-1,2,4-triazole (Intermediate B2)

[0490] 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 H2O2 (9.64 g, 85.02 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was then poured into ice water (200 mL) and extracted with EA (300 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated, and the residue was purified by column chromatography to give intermediate B2 (300.0 mg). LCMS (M+H) + :298.

[0491] Example 1

[0492] 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

[0493]

[0494] The title compound was prepared according to the following scheme:

[0495]

[0496] Step 1: 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-carboxylic acid ethyl ester (Compound 1-a)

[0497] To a solution of 1-bromo-6-methyl-imidazo[1,5-a]pyrazine-3-carboxylic acid ethyl ester (A1-d, 338.0 mg, 1.19 mmol) in 1,4-dioxane (1 mL) were added 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), PCy3HBF4 (145.9 mg, 0.4 mmol) and Cs2CO3 (322.2 mg, 0.99 mmol), and the mixture was stirred at 140°C for 12 hours. The mixture was then concentrated, and the residue was purified by preparative TLC to give compound 1-a (190.0 mg), LCMS (M+H): + :607.

[0498] 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)

[0499] 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) in THF (10 mL) was added NaOH (49.5 mg, 1.24 mmol) and water (2 mL), and the mixture was stirred at room temperature for 12 hours. The mixture was then dissolved in EA (30 mL) and washed with brine, and the organic layer was concentrated. The residue was dissolved in DMF (2 mL), and DIEA (67.0 mg, 0.52 mmol), NHCl (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 hours. The mixture was then concentrated, and the residue was purified by reverse phase column chromatography to give compound 1-b (50.0 mg), LCMS (M+H): + :578.

[0500] 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)

[0501] 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) in TFA (1.97 g, 17.31 mmol) was stirred at 80° C. for 0.5 h. The mixture was then purified by reverse phase column chromatography to give Example 1 (8.2 mg), LCMS (M+H) + :368. 1 H NMR (400MHz, DMSO-d6) δ = 9.69 (s, 1H), 9.10 (s, 1H), 8.00-7.82 (m, 1H), 4.48 (q, J = 6.7Hz, 2H), 2.58-2.55 (m, 3H), 2.15 (s, 3H), 1.34 (t, J = 7.0Hz, 3H).

[0502] Example 2

[0503] 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

[0504]

[0505] The title compound was prepared according to the following scheme:

[0506]

[0507] 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)

[0508] 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) were added Pd(OAc)2 (45.3 mg, 0.2 mmol), CuI (256.2 mg, 1.35 mmol), PCy3HBF4 (99.0 mg, 0.27 mmol) and Cs2CO3 (218.6 mg, 0.67 mmol), and the mixture was stirred at 140°C for 18 hours. The mixture was then concentrated, and the residue was purified by preparative TLC to give compound 2-a (190.0 mg), LCMS (M+H): + :622.

[0509] 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)

[0510] 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 hours. 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 (400MHz, DMSO-d6)δ=9.73(s,1H),9.15(s,1H),8.38(s,1H),7.97(s,1H),7.93(br s,1H),4.45(s,3H),4.45-4.40(m,2H),2.52(br s,3H),2.12(s,3H),1.33(t,J=7.2Hz,3H).

[0511] Example 3

[0512] 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

[0513]

[0514] The title compound was prepared according to the following scheme:

[0515]

[0516] Step 1: Preparation of 1-acetonyl-5-formyl-pyrrole-2-carboxylic acid methyl ester (Compound 3-b)

[0517] To a solution of 5-formyl-1H-pyrrole-2-formic acid methyl ester (3-a, 2.0 g, 13.06 mmol) in ACN (30 mL) was added 1-chloropropane-2-one (1.47 g, 15.93 mmol), Cs CO (5.19 g, 15.93 mmol) and KI (4.33 g, 26.12 mmol), and the mixture was stirred at 60 ° C for 3 hours. The mixture was then quenched with saturated NaHCO 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 SO dried, filtered and concentrated. Residue was purified by column chromatography to obtain compound 3-b (1.5 g).

[0518] Step 2: Preparation of methyl 3-methylpyrrolo[1,2-a]pyrazine-6-carboxylate (Compound 3-c)

[0519] To a solution of 1-acetonyl-5-formyl-pyrrole-2-carboxylic acid methyl ester (3-b, 2.07 g, 9.89 mmol) in EtOH (40 mL) was added NH4OAc (2.288 g, 29.68 mmol) and the mixture was stirred at 90°C for 2 hours. The mixture was then concentrated and diluted with water (150 mL) and extracted with EA (150 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated to give compound 3-c (2.1 g), LCMS (M+H) + :191.

[0520] Step 3: Preparation of 8-bromo-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxylic acid methyl ester (Compound 3-d)

[0521] To a solution of methyl 3-methylpyrrolo[1,2-a]pyrazine-6-carboxylate (3-c, 2.1 g, 11.04 mmol) in DMF (20 mL) was added NBS (2.36 g, 13.25 mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was then diluted with water (100 mL) and extracted with EA (120 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give compound 3-d (2.02 g). LCMS (M+H) + :269.

[0522] Step 4: Preparation of 8-bromo-N-[(2,4-dimethoxyphenyl)methyl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide (Compound 3-e)

[0523] To a solution of 8-bromo-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxylic acid methyl ester (3-d, 1.2 g, 4.46 mmol) in THF (10 mL) was added a solution of NaOH (750.0 mg, 18.75 mmol) in water (3 mL), and the mixture was stirred at 40 ° C for 12 hours. The mixture was then diluted with water (30 mL), HCl (1 N) was added to adjust to pH ~ 3, and 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 hours. The mixture was then poured into water (20 mL) and then filtered to collect the filter cake to obtain compound 3-e (252.0 mg). LCMS (M+H) + :404.

[0524] 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)

[0525] A solution of K2CO3 (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) in toluene (1 mL) was stirred at 120°C for 12 hours. The mixture was then purified by preparative TLC to give compound 3-f (32.0 mg), LCMS (M+H) + :727.

[0526] Step 6: Preparation of 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)

[0527] 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. The mixture was then purified by reverse phase column chromatography to give Example 3 (4.6 mg), LCMS (M+H) + :367. 1 H NMR (400MHz, DMSO-d6) δ = 9.64 (s, 1H), 9.36 (s, 1H), 8.17 (br s, 1H), 4.49 (br d, J = 6.8Hz, 2H), 2.47 (s, 3H), 2.15 (s, 3H), 1.35 (t, J = 7.1Hz, 3H).

[0528] Example 4

[0529] 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

[0530]

[0531] The title compound was prepared according to the following scheme:

[0532]

[0533] Step 1: Preparation of ethyl 3-fluoro-5-formyl-1H-pyrrole-2-carboxylate (Compound 4-b)

[0534] At 0 ° C, POCl (3.57 mL, 38.18 mmol) was added to a solution of DMF (3.7 mL, 47.73 mmol) in DCM (10 mL), and the mixture was stirred at 0 ° C for 15 min, and then a solution of ethyl 3-fluoro-1H-pyrrole-2-carboxylate (4-a, 3.0 g, 19.09 mmol) in DCM (5 mL) was added dropwise. The mixture was slowly poured into ice. The mixture was then adjusted to pH ~ 9-10 with a 30% aqueous NaOH solution and then extracted with EA (50 mL × 3). The combined organic phases were dried over anhydrous Na SO and concentrated. The residue was purified by column chromatography to obtain compound 4-b (1.8 g). (M+H) + :186.

[0535] Steps 2 to 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)

[0536] Similar to the preparation of compound 3-f, compound 4-h was prepared by using compound 4-b instead of 5-formyl-1H-pyrrole-2-carboxylic acid methyl ester (3-a), LCMS (M+H) + :745.

[0537] 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)

[0538] To 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 MsOH (79.91 mg, 0.83 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was then purified by reverse phase column chromatography to give Example 4 (22.0 mg). LCMS (M+H) + :385. 1 H NMR (400MHz, DMSO-d6) 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 = 6.9Hz, 2H), 2.49 (br s, 3H), 2.16 (s, 3H), 1.36 (t, J = 7.1Hz, 3H).

[0539] Example 5

[0540] 4-Acetyl-6-[3-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)-1H-1,2,4-triazol-5-yl]pyridine-2-carboxamide

[0541]

[0542] The title compound was prepared according to the following scheme:

[0543]

[0544] Step 1: Preparation of 4-bromo-2-methoxy-1-oxido-pyridin-1-ium (Compound 5-b)

[0545] 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) in portions, 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.

[0546] Step 2: Preparation of 4-bromo-6-methoxy-pyridine-2-carbonitrile (Compound 5-c)

[0547] To a solution of 4-bromo-2-methoxy-1-oxido-pyridin-1-ium (5-b, 16.0 g, 78.42 mmol) in ACN (150 mL) was added TEA (15.84 g, 156.85 mmol) and TMSCN (23.34 g, 235.27 mmol) in portions, and the mixture was stirred at 80 ° C for 12 hours under N2. The mixture was then concentrated, and the residue was poured into a saturated Na2CO3 solution (200 mL) and extracted with EA (400 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography to obtain compound 5-c (12 g), LCMS (M+H) + :213.

[0548] Step 3: Preparation of 4-acetyl-6-methoxy-pyridine-2-carbonitrile (Compound 5-d)

[0549] Under N2, to a solution of 4-bromo-6-methoxy-pyridine-2-carbonitrile (5-c, 3g, 14.08mmol) in 1,4-dioxane (30mL) was added tributyl (1-ethoxyvinyl) tin (5.23g, 14.48mmol) and Pd (PPh3) 2Cl2 (988.5mg, 1.41mmol). The mixture was stirred at 90°C for 12 hours. The mixture was then quenched with KF solution (45mL, 1N). HCl solution (60mL, 1N) was then added to the mixture and stirred at 50°C for 0.5h. The mixture was extracted with DCM (100mL), the organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography to obtain compound 5-d (1.8g). LCMS (M+H) + :177.

[0550] Step 4: Preparation of 4-acetyl-6-hydroxy-pyridine-2-carboxylic acid methyl ester (Compound 5-e)

[0551] A solution of 4-acetyl-6-methoxy-pyridine-2-carbonitrile (5-d, 1 g, 5.68 mmol) in HCl / MeOH (30 mL, 4N) was stirred at 80° C. for 12 hours and then concentrated to give compound 5-e (1.1 g). LCMS (M+H) + :196.

[0552] Step 5: Preparation of 4-acetyl-6-bromo-pyridine-2-carboxylic acid methyl ester (Compound 5-f)

[0553] To a solution of 4-acetyl-6-hydroxy-pyridine-2-carboxylic acid methyl ester (5-e, 1.1 g, 5.64 mmol) in ACN (30 mL) was added POBr 3 (4.85 g, 16.91 mmol) and the mixture was stirred at 80° C. for 2 hours. The mixture was then quenched with saturated Na 2 CO 3 solution (50 mL) and extracted with EA (50 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated to give compound 5-f (1.2 g). LCMS (M+H) + :258.

[0554] Step 6: Preparation of 4-acetyl-6-bromo-pyridine-2-carboxylic acid (Compound 5-g)

[0555] To a solution of 4-acetyl-6-bromo-pyridine-2-carboxylic acid methyl ester (5-f, 1.2 g, 4.65 mmol) in THF (10 mL) and water (3 mL) was added LiOH.H2O (780.5 mg, 18.6 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was then diluted with water (50 mL), HCl solution (1 N) was added to adjust to pH ~ 5, and the mixture was extracted with EA (50 mL x 2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated to give compound 5-g (900 mg). LCMS (M+H) + :244.

[0556] Step 7: Preparation of 4-acetyl-6-bromo-N-[(2,4-dimethoxyphenyl)methyl]pyridine-2-carboxamide (Compound 5-h)

[0557] To a solution of 4-acetyl-6-bromo-pyridine-2-carboxylic acid (5-g, 850.0 mg, 3.48 mmol) in DMF (10 mL) was added DMBNH2 (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. The mixture was then poured into water (50 mL) and extracted with EA (50 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography to obtain compound 5-h (670 mg). LCMS (M+H) + :393.

[0558] 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)

[0559] To a solution of 4-acetyl-6-bromo-N-[(2,4-dimethoxyphenyl)methyl]pyridine-2-carboxamide (5-h, 150.0 mg, 0.38 mmol) in 1,4-dioxane (3 mL) were added 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), PCy3HBF4 (56.2 mg, 0.15 mmol) and Cs2CO3 (124.0 mg, 0.38 mmol), and the mixture was stirred at 140° C. for 12 hours. The mixture was then filtered and concentrated. The residue was purified by preparative TLC to give compound 5-i (40 mg). LCMS (M+H) + :716.

[0560] 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)

[0561] 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 preparative HPLC to give Example 5 (11.8 mg), LCMS (M+H) + :356. 1 HNMR (400MHz, DMSO-d6) δ=15.4-15.0(m,1H),8.8-8.7(m,1H),8.65(d,J=1.2Hz,1H),8.46(d,J=1.6Hz,1H),8.01(br s, 1H), 4.41 (q, J = 6.8Hz, 2H), 2.77 (s, 3H), 2.13 (s, 3H), 1.31 (t, J = 7.2Hz, 3H).

[0562] Example 6

[0563] 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

[0564]

[0565] The title compound was prepared according to the following scheme:

[0566]

[0567] Step 1: Preparation of 4-imidazol-1-yl-6-methoxy-pyridine-2-carbonitrile (Compound 6-a)

[0568] To a solution of 4-bromo-6-methoxy-pyridine-2-carbonitrile (5-c, 5.0 g, 23.47 mmol) in DMSO (100 mL) was added imidazole (2.4 g, 35.21 mmol) and K2CO3 (4.87 g, 35.21 mmol), and the mixture was stirred at 100°C for 16 hours. The mixture was then poured into H2O (100 mL) and filtered, and the filter cake was dried to give compound 6-a (3.0 g, 14.99 mmol). LCMS (M+H) + :201.

[0569] Steps 2 to 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)

[0570] Similar to the preparation of Example 5, Example 6 was prepared by 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 (400MHz, DMSO-d6+D2O)δ=9.70(br s,1H),8.77(s,1H),8.52(br s,2H),7.75(br s, 1H), 4.43 (q, J = 7.1Hz, 2H), 2.14 (s, 3H), 1.30 (t, J = 7.1Hz, 3H).

[0571] Example 7

[0572] 4-[2-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)pyrimidin-4-yl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide

[0573]

[0574] The title compound was prepared according to the following scheme:

[0575]

[0576] Step 1: Preparation of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxamide (Compound 7-a)

[0577] 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) were added DIEA (7.448 g, 57.63 mmol), NH4Cl (3.08 g, 57.63 mmol) and HATU (10.96 g, 28.81 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was then concentrated. The residue was purified by column chromatography to give compound 7-a (2.5 g). LCMS (M+H) + :260.

[0578] Step 2: Preparation of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carbonitrile (Compound 7-b)

[0579] To a solution of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxamide (7-a, 2.5 g, 9.64 mmol) in DCM (50 mL) was added TEA (2.95 g, 28.92 mmol) and the mixture was cooled to -5 ° C. A solution of TFAA (2.72 mL, 19.28 mmol) in DCM (10 mL) was then added dropwise. The mixture was then stirred at room temperature for 1 h and then quenched by saturated NaHCO3 solution (800 mL). The mixture was extracted with EA (450 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography to obtain compound 7-b (1.5 g). LCMS (M+H) + :242.

[0580] Step 3: Preparation of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboximidamide (Compound 7-c)

[0581] To a suspension of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carbonitrile (compound 7-b, 1.0 g, 4.14 mmol) in THF (10 mL) was added LiHMDS (1 M solution in THF, 12.43 mL, 12.43 mmol), and the mixture was stirred at 30 ° C for 48 hours. HCl solution (3N) was then added to adjust to pH ~ 3, and the mixture was stirred at 0 ° C for 1 h. The mixture was then washed with EA. The aqueous phase was adjusted to pH ~ 14 with NaOH solution (3N) and extracted with EA (900 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated to give compound 7-c (1.2 g). LCMS (M+H) + :259.

[0582] 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)

[0583] 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) in DMF (5 mL) was added 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), and the mixture was stirred at 80° C. for 16 hours under N 2 . The mixture was then 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.

[0584] 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)

[0585] 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) in MeOH (5 mL) was added NH4F (0.6 g, 16.17 mmol), and the mixture was stirred at 60°C under N2 for 0.5 h. The mixture was then filtered and concentrated to give compound 7-e (50 mg). LCMS (M+H) + :381.

[0586] Step 6: Preparation of N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-4-(3-oxoprop-1-ynyl)pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 7-f)

[0587] 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) in DCM (2 mL) was added DMP (50.2 mg, 0.12 mmol) and the mixture was stirred at room temperature under N2 for 0.5 h. The mixture was then concentrated. The residue was purified by preparative TLC to give compound 7-f (28 mg).

[0588] Step 7: 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)

[0589] To a solution of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboximidamide (7-c, 23.8 mg, 0.09 mmol) in DCM (20 mL) was added 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), PPh3AuCl3 (39 mg, 0.1 mmol) and K2CO3 (21.2 mg, 0.15 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was then concentrated. The residue was purified by preparative TLC to give compound 7-g (45 mg). LCMS (M+H) + :619.

[0590] Step 8: Preparation of 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)

[0591] 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) in HFIP (2.0 mL) was added MsOH (62.1 mg, 0.65 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was then diluted with DMF (1 mL) and purified by reverse phase column chromatography to give Example 7 (11.2 mg). LCMS (M+H) + :379. 1 HNMR (400MHz, DMSO-d6) δ=9.34(br s,1H),9.17-9.08(m,2H),8.79(d,J=5.4Hz,1H),8.59(br s,1H),8.54(s,1H),7.87(br s, 1H), 4.65 (q, J = 7.2Hz, 2H), 4.23 (s, 3H), 2.19 (s, 3H), 1.31 (t, J = 7.2Hz, 3H).

[0592] Example 8

[0593] 1-[2-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)pyrimidin-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

[0594]

[0595] The title compound was prepared according to the following scheme:

[0596]

[0597] Example 8 was prepared similarly to the preparation of Example 7 by using Intermediate A1 instead of 4-bromo-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Intermediate A2). Example 8 (13.5 mg) was obtained. LCMS (M+H + ):379. 1 H NMR (400MHz, DMSO-d6+D2O) δ = 9.85 (d, J = 1.6Hz, 1H), 9.10 (s, 1H), 8.89 (d, J = 5.4Hz, 1H), 8.03 (d, J = 5.4Hz, 1H), 4.64 (q, J = 7.2Hz, 2H), 2.48 (br s, 3H), 2.15 (s, 3H), 1.34 (t, J = 7.2Hz, 3H).

[0598] Example 9

[0599] 1-[2-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

[0600]

[0601] The title compound was prepared according to the following scheme:

[0602]

[0603] Step 1: Preparation of 1-(1-ethoxyvinyl)-6-methyl-imidazo[1,5-a]pyrazine-3-carboxylic acid ethyl ester (Compound 9-a)

[0604] To a solution of 1-bromo-6-methyl-imidazo[1,5-a]pyrazine-3-carboxylic acid ethyl ester (A1-d, 600 mg, 2.11 mmol) and tributyl(1-ethoxyvinyl)tin (762.7 mg, 2.11 mmol) in DMF (8 mL) was added Pd(PPh 3 ) 2 Cl 2 .CH 2 Cl 2 adduct (148.2 mg, 0.21 mmol) and the mixture was stirred at 90 ° C for 12 hours under N 2 . The mixture was then quenched with 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 give compound 9a (400 mg). LCMS (M+H) + :276.

[0605] Step 2: Preparation of ethyl 1-(2-bromoacetyl)-6-methylimidazo[1,5-a]pyrazine-3-carboxylate (Compound 9-b)

[0606] At 0 ° C, to a solution of 1-(1-ethoxyvinyl)-6-methylimidazo[1,5-a]pyrazine-3-carboxylic acid ethyl ester (9-a, 400 mg, 1.45 mmol) in THF (8 mL) and water (3 mL) was added NBS (258.6 mg, 1.45 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was then 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 Na2SO4, and concentrated, and the residue was purified by column chromatography to obtain compound 9-b (250 mg). LCMS (M+H) + :326.

[0607] Step 3: Preparation of 1-(2-bromoacetyl)-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Compound 9-c)

[0608] 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 hours. The mixture was then concentrated, and the residue was dissolved in DMF (5 mL), followed by the addition of DMBNH2 (0.28 mL, 1.87 mmol), DIEA (689.5 mg, 5.33 mmol), and HATU (627.6 mg, 2.67 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was then diluted with DCM (100 mL), poured into water (60 mL), and extracted with DCM (100 mL × 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated, and the residue was purified by column chromatography to give compound 9-c (350 mg). LCMS (M+H) + :447.

[0609] 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)

[0610] 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) in EA (15 mL) were added 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), and the mixture was stirred at 70° C. for 12 hours under N2 in the dark. The mixture was then concentrated and the residue was purified by reverse phase column chromatography to give compound 9-d (100 mg), LCMS (M+H) + :608.

[0611] 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)

[0612] 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 preparative TLC to give Example 9 (3.6 mg). LCMS (M+H) + :368. 1 H NMR (400MHz, DMSO-d6) δ = 9.64 (s, 1H), 9.05 (s, 1H), 8.79 (s, 1H), 8.63 (s, 1H), 8.05 (br d,J=1.5Hz,1H),7.86(s,1H),4.55-4.49(m,2H),2.46(brs,3H),2.15(s,3H),1.39(t,J=7.0Hz,3H).

[0613] Example 10

[0614] 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

[0615]

[0616] The title compound was prepared according to the following scheme:

[0617]

[0618] Step 1: Preparation of 1-ethyl-4-[(4-methoxyphenyl)methoxy]-3-methyl-pyrazole (Compound 10-a)

[0619] To a solution of 1-ethyl-3-methyl-pyrazole-4-ol (B1-e, 25.0 g, 198.16 mmol) in DMF (300 mL) was added K2CO3 (54.7 g, 396.32 mmol) and PMBBr (59.76 g, 297.24 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was then poured into water (300 mL) and extracted with EA (300 mL×3). The combined organic phases were washed with saturated NaHCO3 solution and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography to obtain compound 10-a (10 g). LCMS (M+H) + :247.

[0620] Step 2: Preparation of 5-bromo-1-ethyl-4-[(4-methoxyphenyl)methoxy]-3-methyl-pyrazole (Compound 10-b)

[0621] To a solution of 1-ethyl-4-[(4-methoxyphenyl)methoxy]-3-methyl-pyrazole (10-a, 1.0 g, 4.06 mmol) in THF (10 mL) was added NBS (794.9 mg, 4.47 mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was then concentrated, and the residue was purified by flash column chromatography to give compound 10-b (1.11 g). LCMS (M+H) + :325.

[0622] Step 3: Preparation of ethyl 4-bromooxazole-5-carboxylate (Compound 10-d)

[0623] To a solution of ethyl oxazole-5-carboxylate (10-c, 20 g, 141.72 mmol) in THF (200 mL) and DMF (200 mL) was added LiHMDS (184.24 mL, 184.24 mmol) at -70 ° C. After stirring for 2 hours, Br2 (29.44 g, 184.24 mmol) was added dropwise. The mixture was stirred at -70 ° C for 2 hours. The mixture was then poured into a saturated NH4Cl solution (600 mL) and extracted with EA (500 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography to obtain compound 10-d (10 g), LCMS (M+H) + :220.

[0624] 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)

[0625] To a solution of ethyl 4-bromooxazole-5-carboxylate (10-d, 2.99 g, 13.57 mmol), 4-bromo-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Intermediate A2, 5.0 g, 12.34 mmol) in toluene (100 mL) and water (25 mL) was added K3PO4 (7.86 g, 37.01 mmol), B2Pin2 (6.27 g, 24.68 mmol) and Pd(dppf)Cl2 (1.81 g, 2.47 mmol), and the mixture was stirred at 80°C under N2 for 5 hours. The mixture was then concentrated and the residue was purified by flash chromatography to give compound 10-e (860 mg). LCMS (M+H) + :466.

[0626] 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)

[0627] 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), 5-bromo-1-ethyl-4-[(4-methoxyphenyl)methoxy]-3-methyl-pyrazole (10-b, 593.9 mg, 1.83 mmol) in toluene (20 mL) were added K2CO3 (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), and the mixture was stirred at 120°C under N2 for 18 h. 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.

[0628] 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)

[0629] To a solution of 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-carboxylic acid ethyl ester (10-f, 800 mg, 1.13 mmol) in THF (20 mL) and TFE (2.0 mL) was added LiBH4 (2.82 mL, 11.27 mmol) at 0 ° C. The mixture was stirred at 15 ° C. for 4 hours under N2. The mixture was then poured into saturated aqueous NH4Cl solution (20 mL) and extracted with DCM (50 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography to give compound 10-g (550 mg), LCMS (M+H) + :668.

[0630] Step 7: Preparation 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 (Compound 10-h)

[0631] 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) in DCM (10 mL) was added DMP (635.2 mg, 1.5 mmol) and the mixture was stirred at room temperature under N2 for 1 h. The mixture was then 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 give compound 10-h (250 mg), LCMS (M+H) + :666.

[0632] 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)

[0633] To a solution of DAST (3.0 mL, 29.42 mmol) in DCM (3 mL) was added dropwise 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) in DCM (6 mL) at 0 ° C. The mixture was then poured into a saturated NaHCO solution (20 mL) and extracted with DCM (20 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative TLC to give compound 10-i (20 mg), LCMS (M+H). + :688.

[0634] 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)

[0635] 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) in HFIP (0.5 mL) was added MsOH (27.9 mg, 0.29 mmol), and the mixture was stirred at room temperature for 0.5 h. The mixture was then diluted with MeOH (1 mL) and purified by reverse phase column chromatography to give Example 10 (6.5 mg). LCMS (M+H) + :418. 1 H NMR (400MHz, DMSO-d6) δ = 9.07 (s, 1H), 8.79 (s, 1H), 8.43 (s, 1H), 7.87-8.26 (m, 2H), 4.56 (q, J = 7.05Hz, 2H), 4.21 (s, 3H), 2.18 (s, 3H), 1.42 (t, J = 7.09Hz, 3H).

[0636] Example 11

[0637] 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

[0638]

[0639] The title compound was prepared according to the following scheme:

[0640]

[0641] Step 1: Preparation of 4-benzyloxy-2-ethyl-5-methyl-N-prop-2-ynyl-pyrazole-3-carboxamide (Compound 11-a)

[0642] At 0 ° C, 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) was added propargylamine (1.65 g, 29.92 mmol) dropwise, and the mixture was stirred at room temperature for 12 hours. The mixture was then concentrated and the residue was purified by column chromatography to give compound 11-a (2.4 g). LCMS (M+H) + :298.

[0643] Step 2: Preparation of (5E)-2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-5-(iodomethylene)-4H-oxazole (Compound 11-b)

[0644] To a solution of 4-benzyloxy-2-ethyl-5-methyl-N-prop-2-ynyl-pyrazole-3-carboxamide (11-a, 2.4 g, 8.07 mmol) in DCM (35 mL) was added NIS (2.72 g, 12.11 mmol), and the mixture was stirred at room temperature for 4 hours. The mixture was then concentrated to give compound 11-b (3.0 g), LCMS (M+H) + :424.

[0645] Step 3: Preparation of 2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazole-5-carbaldehyde (Compound 11-c)

[0646] Under O2, a solution of (5E)-2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-5-(iodine methylene)-4H-oxazole (11-b, 2.8 g, 6.62 mmol) in DCE (15 mL) was stirred at 80°C for 12 hours. EA (100 mL) was then added, and the mixture was washed with saturated Na2SO3 solution and brine. The organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give compound 11-c (1.0 g), LCMS (M+H) + :312.

[0647] Step 4: Preparation of (5E)-2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazole-5-carbaldehyde oxime (Compound 11-d)

[0648] To 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 NH2OH.HCl (301.3 mg, 4.34 mmol) and KOAc (474.1 mg, 5.78 mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated (<30° C.), and the residue was dissolved in water (30 mL) and then extracted with DCM (60 mL×2). The combined organic phases were concentrated to give compound 11-d (800 mg), LCMS (M+H) + :327.

[0649] Step 5: Preparation of [2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazol-5-yl]methanamine (Compound 11-e)

[0650] 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) in AcOH (20 mL) was added Zn (2.745 g, 49.03 mmol) in portions. Under N2, the mixture was stirred at room temperature for 16 hours. EA (400 mL) was added to the mixture, and then saturated Na2CO3 solution was added to adjust to pH>7. The mixture was extracted with EA (300 mL×2). The combined organic phases were concentrated to give compound 11-e (600 mg). LCMS (M+H) + :313.

[0651] 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)

[0652] To a solution of [2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazol-5-yl]methylamine (11-e, 600 mg, 1.92 mmol) in THF (15 mL) was added Boc2O (628 mg, 2.88 mmol) and TEA (582 mg, 5.76 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was then poured into water (50 mL) and extracted with EA (80 mL×3). The combined organic phases were washed with saturated NaHCO3 solution and brine, dried over anhydrous Na2SO4, and concentrated, and the residue was purified by column chromatography to obtain compound 11-f (660 mg), LCMS (M+H). + :413.

[0653] 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)

[0654] A solution of 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), K2CO3 (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), 1-bromo-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (Intermediate A1, 550.2 mg, 1.36 mmol) in toluene (25 mL) was stirred at 115°C for 12 hours. DCM (100 mL) was added, and the mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography and then by preparative TLC to give compound 11-g (27 mg), LCMS (M+H) + :737.

[0655] 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)

[0656] A solution of 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]-carbamic acid tert-butyl ester (compound 11-g, 27 mg, 0.04 mmol) in TFA (2.09 g, 18.32 mmol) was stirred at 70° C. for 2 hours. The mixture was purified by preparative HPLC to give Example 11 (4.7 mg), LCMS (M+H) + :397. 1 H NMR (400MHz, DMSO-d6+D2O) δ = 9.59 (d, J = 1.1Hz, 1H), 8.99 (s, 1H), 4.72 (s, 2H), 4.48 (q, J = 6.8Hz, 2H), 2.43 (s, 3H), 2.13 (s, 3H), 1.36 (t, J = 7.2Hz, 3H).

[0657] Example 12

[0658] 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

[0659]

[0660] The title compound was prepared according to the following scheme:

[0661]

[0662] Step 1: Preparation of 2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazole-5-carbonitrile (Compound 12-a)

[0663] To a solution of 2-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)oxazole-5-carboxaldehyde (11-c, 3.5 g, 11.24 mmol) in toluene (150 mL) was added O-diphenylphosphoryl hydroxylamine (3.93 g, 16.86 mmol), and the mixture was stirred at 100 ° C for 2 hours. The mixture was then concentrated. The residue was purified by preparative HPLC to give compound 12-a (1.2 g), LCMS (M+H) + :309.

[0664] 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)

[0665] A solution of 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), PCy3.HBF4 (95.5 mg, 0.26 mmol), Cs2CO3 (2.108 g, 0.65 mmol) in 1,4-dioxane (4 mL) was stirred at 140 ° C for 18 hours. The mixture was then concentrated. The residue was purified by preparative HPLC to give compound 12-b (70 mg). LCMS (M+H) + :633.

[0666] 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)

[0667] A solution 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 (12-b, 10 mg, 0.02 mmol) in TFA (2.0 mL) was stirred at 80° C. for 0.5 h. The mixture was then concentrated and the residue was purified by preparative HPLC to give Example 12 (1.6 mg), LCMS (M+H) + :411. 1 H NMR (400MHz, DMSO-d6)δ=10.12(br s,1H),8.78(s,1H),8.40(s,1H),8.39-8.38(m,1H),8.37(br s,1H),8.14(br s,1H),7.83(brs,1H),4.55(br d,J=6.8Hz,2H),4.20(s,3H),2.11(s,3H),1.38(t,J=7.1Hz,3H).

[0668] Example 13

[0669] 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

[0670]

[0671] The title compound was prepared according to the following scheme:

[0672]

[0673] Step 1: Preparation of ethyl 2-(2-hydroxycyclopenten-1-yl)-2-oxo-acetate (Compound 13-b)

[0674] At 0 ° C, to a solution of cyclopentanone (13-a, 10.52 mL, 118.88 mmol) in EtOH (60 mL) was added dropwise EtONa (42.37 g, 130.77 mmol), the mixture was stirred at 0 ° C for 0.5 h, then diethyl oxalate (16.15 mL, 118.88 mmol) was added dropwise, and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated (<40 ° C), the residue was poured into water (200 mL), HCl (30 mL, 1 N) was then added to adjust to pH ~ 7, and extracted with EA (500 mL × 2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated to give compound 13-b (20 g), LCMS (M+H) + :185.

[0675] Step 2: Preparation of 2-ethyl-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-carboxylic acid (Compound 13-c)

[0676] To a solution of ethyl 2-(2-hydroxycyclopenten-1-yl)-2-oxo-acetate (13-b, 15.0 g, 81.44 mmol) in EtOH (150 mL) was 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 hours. The mixture was then concentrated, and the residue was extracted with EA (200 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated to give compound 13-c (8 g), LCMS (M+H) + :181.

[0677] Step 3: Preparation of ethyl 2-ethyl-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-carboxylate (Compound 13-d)

[0678] To a solution of 2-ethyl-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-carboxylic acid (13-c, 8.0 g, 44.4 mmol) in THF (80 mL) were added iodoethane (7.1 mL, 88.79 mmol) and K2CO3 (18.38 g, 133.19 mmol), and the mixture was stirred at 60°C for 2 hours. Water (200 mL) was added, followed by extraction with EA (300 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated, and the residue was purified by column chromatography to give compound 13-d (5.2 g). LCMS (M+H) + :209.

[0679] Steps 4 to 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)

[0680] Similar to the preparation of intermediate B1, compound 13-d was used instead of isobutyloxycarbonyl 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxylate (B1-h) to prepare compound 13-h. Compound 13-h (400 mg) was obtained. LCMS (M+H) + :324.

[0681] 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)

[0682] 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), 4-bromo-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Intermediate A2, 62.7 mg, 0.15 mmol) in toluene (5 mL) was added KCO (64.0 mg, 0.46 mmol), cataCXium A (27.7 mg, 0.08 mmol), PivOH (7.9 mg, 0.08 mmol) and Pd(OAc) (10.4 mg, 0.05 mmol). The mixture was stirred at 120° C. under N for 18 h. The mixture was then filtered, the filter cake was washed with DCM / MeOH (V / V=20 / 1), the filtrates were combined and concentrated. The residue was purified by preparative TLC to give compound 13-i (60 mg), LCMS (M+H) + :648.

[0683] 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)

[0684] 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) 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. The mixture was then diluted with ACN (1 mL) and purified by preparative HPLC to give Example 13 (13.7 mg). LCMS (M+H) + :378. 1H NMR (400MHz, DMSO-d6) δ = 15.34 (br s, 1H), 8.81 (br s,1H),8.75(d,J=0.8Hz,1H),8.46(d,J=0.6Hz,1H),7.89(brs,1H),4.66(q,J=7.1Hz,2H),4. 22(s,3H),2.90(t,J=7.1Hz,2H),2.71-2.63(m,2H),2.47-2.40(m,2H),1.42(t,J=7.1Hz,3H).

[0685] Example 14

[0686] 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

[0687]

[0688] The title compound was prepared according to the following scheme:

[0689]

[0690] Step 1: Preparation of ethyl 3-methyl-1H-pyrazole-5-carboxylate (Compound 14-b)

[0691] To a solution of ethyl 2,4-dioxopentanoate (14-a, 10 g, 63.23 mmol) in EtOH (40 mL) was added hydrazine hydrate (3.48 g, 69.55 mmol) at 0° C., the mixture was stirred at 0° C. for 1 h and then concentrated at room temperature to give compound 14-b (9.6 g). LCMS (M+H) + :155.

[0692] Step 2: Preparation of ethyl 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-1H-pyrazole-5-carboxylate (Compound 14-c)

[0693] To a solution of ethyl 3-methyl-1H-pyrazole-5-carboxylate (14-b, 9.6 g, 62.27 mmol) in DMF (50 mL) was added (3-bromopropoxy)-tert-butyldimethylsilane (31.54 g, 124.54 mmol), NaI (18.67 g, 124.54 mmol) and KCO (17.21 g, 124.54 mmol), and the mixture was stirred at 80° C. for 36 hours. The mixture was then diluted with water (800 mL) and extracted with EA (200 mL×3). The combined organic phases were washed with brine, dried over anhydrous NaSO, and concentrated, and the residue was purified by flash column chromatography to give compound 14-c (8.0 g). LCMS (M+H) + :327.

[0694] Steps 3 to 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)

[0695] Compound 14-g was prepared by using compound 14-c instead of isobutyloxycarbonyl 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxylate (B1-h) in a similar manner to the preparation of intermediate B1. Compound 14-g (1.6 g) was obtained. LCMS (M+H) + :328.

[0696] 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)

[0697] 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) in DMF (3 mL) was added imidazole (998.2 mg, 14.66 mmol) and TBSCl (1.105 g, 7.33 mmol), and the mixture was stirred at 60 ° C. for 1 h. The mixture was then concentrated and the residue was purified by flash column chromatography to give compound 14-h (600 mg). LCMS (M+H) + :442.

[0698] 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)

[0699] 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) in 1,4-dioxane (5 mL) was added 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), PCy3.HBF4 (66.7 mg, 0.18 mmol) and Cs2CO3 (147.2 mg, 0.45 mmol) and the mixture was stirred at 140°C for 16 hours. The mixture was then dissolved in DCM / MeOH (30 mL / 5 mL), filtered, and the filtrate was concentrated. The residue was purified by preparative TLC to give compound 14-i (42.0 mg), LCMS (M+H) + :766.

[0700] 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)

[0701] 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) in TFA (2.5 mL) was stirred at 70 ° C for 1.5 hours. The mixture was then concentrated, and the residue was added to MeOH (1 mL) and NH 3 .H 2 O (0.5 mL), and the suspension was stirred at room temperature for 15 min. The mixture was concentrated, and the residue was purified by preparative HPLC to give Example 14 (9.2 mg), LCMS (M+H) + :382. 1H NMR (400MHz, DMSO-d6) δ=9.72(d,J=1.34Hz,1H),9.08(s,1H),8.01-7.82(m,2H),6.62(s,1H),4.67(t,J=7.03Hz,2H),3.45(t,J=6.11Hz,2H),2.52(br s,3H),2.22(s,3H),1.98(br t,J=6.72Hz,2H).

[0702] Example 15

[0703] 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

[0704]

[0705] The title compound was prepared according to the following scheme:

[0706]

[0707] Step 1: Preparation of 2-ethyl-5-methyl-pyrazole-3-carboxylic acid ethyl ester (Compound 15-a)

[0708] To a solution of ethylhydrazine dihydrochloride (1.0 g, 7.52 mmol) in EtOH (12 mL) was added K2CO3 (2.28 g, 16.54 mmol) and ethyl 2,4-dioxopentanoate (14-a, 1.31 g, 8.27 mmol) dropwise at 0 ° C., and the mixture was stirred at room temperature for 12 hours. The mixture was then concentrated and the residue was extracted with EA (80 mL). The organic layer was washed with water, dried over anhydrous Na2SO4, filtered and concentrated to give compound 15-a (400 mg). LCMS (M+H) + :183.

[0709] Step 2: Preparation of 2-ethyl-5-methyl-pyrazole-3-carbohydrazide (Compound 15-b)

[0710] To a solution of 2-ethyl-5-methyl-pyrazole-3-carboxylic acid ethyl ester (15-a, 2.4 g, 13.17 mmol) in EtOH (30 mL) was added hydrazine hydrate (4.76 g, 80.87 mmol), the mixture was stirred at 80 ° C. for 16 hours and then concentrated to give compound 15-b (2 g), LCMS (M+H) + :169.

[0711] Step 3: Preparation of 3-(2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)-methyl]-1,2,4-triazole (Compound 15-c)

[0712] 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 h. The mixture was then concentrated. The residue was dissolved in toluene (60 mL), and 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. The mixture was then concentrated and the residue was purified by column chromatography to obtain compound 15-c (2.1 g). LCMS (M+H) + :298.

[0713] 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)

[0714] To a solution of 3-(2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole (15-c, 200 mg, 0.67 mmol) in 1,4-dioxane (2 mL) were added 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), PCy3.HBF4 (99.0 mg, 0.27 mmol) and Cs2CO3 (218.6 mg, 0.67 mmol), and the mixture was stirred at 140°C for 18 hours. The mixture was then filtered and concentrated, and the residue was purified by preparative TLC to give compound 15-d (40 mg). LCMS (M+H) + :622.

[0715] 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)

[0716] 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) in TFA (1.5 mL) was stirred at 80° C. for 1 h. The mixture was purified by preparative HPLC to give Example 15 (2.6 mg), LCMS (M+H) + :352. 1 H NMR (400MHz, DMSO-d6)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(br d,J=6.4Hz,2H),2.5(s,3H),2.23(s,3H),1.41(t,J=7.2Hz,3H).

[0717] Example 16

[0718] 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

[0719]

[0720] The title compound was prepared according to the following scheme:

[0721]

[0722] 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)

[0723] 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 a selective fluorine reagent (3.8 g, 10.76 mmol), and the mixture was stirred at 50 ° C. for 16 hours. The mixture was then concentrated and the residue was purified by column chromatography to give compound 16-a (400 mg). LCMS (M+H) + :316.

[0724] 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)

[0725] Similar to the preparation of Example 15, Example 16 was prepared by using Compound 16-a instead of 3-(2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole (15-c). Example 16 (13.2 mg) was obtained. LCMS (M+H) + :370. 1 H NMR (400MHz, DMSO-d6) δ = 9.65 (s, 1H), 9.11 (s, 1H), 7.6-8.2 (m, 2H), 4.53 (q, J = 7.2Hz, 2H), 3.31 (br s, 3H), 2.23 (s, 3H), 1.40 (t, J = 7.2Hz, 3H).

[0726] Example 17

[0727] 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

[0728]

[0729] The title compound was prepared according to the following scheme:

[0730]

[0731] Step 1: Preparation of 2-ethyl-5-methyl-pyrazole-3-formic acid methyl ester (compound 17-b) To a solution of 3-methyl-1H-pyrazole-5-formic acid methyl ester (17-a, 10.0 g, 71.36 mmol) and Cs CO (46.38 g, 142.71 mmol) in ACN (100 mL) was added iodoethane (8.56 mL, 107.04 mmol). The mixture was stirred at 80 ° C for 2 hours. The mixture was then poured into water (100 ml) and extracted with EA (100 mL × 2). The combined organic phases were washed with water and brine, dried over anhydrous Na SO dried, and concentrated. The residue was purified by flash chromatography to obtain compound 17-b (5 g). 1 H NMR (400MHz, DMSO-d6) δ = 6.64 (s, 1H), 4.42 (q, J = 7.21Hz, 2H), 3.81 (s, 3H), 2.18 (s, 3H), 1.30 (t, J = 7.19Hz, 3H).

[0732] Step 2: Preparation of 2-ethyl-5-methyl-4-nitro-pyrazole-3-carboxylic acid methyl ester (Compound 17-c)

[0733] At 0 ° C, to a solution of 2-ethyl-5-methyl-pyrazole-3-carboxylic acid methyl ester (17-b, 5 g, 29.73 mmol) in H2SO4 (23.75 mL, 445.92 mmol) was added dropwise HNO3 (15.45 mL, 311.14 mmol). The mixture was stirred at 60 ° C for 18 hours. The mixture was then poured into ice water (500 mL) and extracted with EA (300 mL×2). The combined organic phases were washed with saturated NaHCO3 solution and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash column chromatography to obtain compound 17-c (3.5 g), LCMS (M+H) + :214.

[0734] Step 3: Preparation of 4-amino-2-ethyl-5-methyl-pyrazole-3-carboxylic acid methyl ester (Compound 17-d)

[0735] To a solution of 2-ethyl-5-methyl-4-nitro-pyrazole-3-carboxylic acid methyl ester (17-c, 2.0 g, 9.38 mmol) in MeOH (40 mL) was added Pd / C (1.0 g, 9.38 mmol) and the mixture was stirred at room temperature under a H2 balloon for 16 hours. The mixture was then filtered, the filter cake was washed with MeOH, and the combined filtrate was concentrated to give compound 17-d (1.7 g). LCMS (M+H) + :184.

[0736] Step 4: Preparation of 4-benzamido-2-ethyl-5-methyl-pyrazole-3-carboxylic acid methyl ester (Compound 17-e)

[0737] To a solution of 4-amino-2-ethyl-5-methyl-pyrazole-3-carboxylic acid methyl ester (17-d, 1.4 g, 7.64 mmol) and Et3N (1.98 mL, 15.28 mmol) in DCM (30 mL) was added BzCl (0.98 mL, 8.41 mmol) at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was then concentrated. The residue was purified by flash column chromatography to give compound 17-d (2 g), LCMS (M+H) + :288.

[0738] Steps 5 to 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)

[0739] Compound 17-i was prepared similarly to the preparation of intermediate B1 by using compound 17-e instead of isobutyloxycarbonyl 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxylate (B1-h). Compound 17-i (2 g) was obtained. LCMS (M+H) + :417.

[0740] 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)

[0741] 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) in n-butanol (20 mL) was added KOH (4.29 g, 76.53 mmol), and the mixture was stirred at 130 ° C. for 16 hours. The mixture was then diluted with water (200 mL) and extracted with EA (200 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated to give compound 17-j (400 mg). LCMS (M+H) + :313.

[0742] 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), Et3N (388.0 mg, 3.84 mmol) and DMAP (15.9 mg, 0.13 mmol) in THF (0.3 mL) was added Boc2O (837.5 mg, 3.84 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was then concentrated, and the residue was purified by flash column chromatography to give Compound 17-k (250 mg). LCMS (M+H) + :513.

[0743] 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)

[0744] Example 17 was prepared similarly to the preparation of Example 14 by 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 (400MHz, DMSO-d6+D2O) δ=9.63(br s,1H),9.07(br d,J=3.4Hz,1H),4.51(br d,J=5.1Hz,2H),2.52(d,J=1.9Hz,3H),2.15-2.03(m,3H),1.31(br t,J=6.8Hz,3H).

[0745] Example 18

[0746] 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

[0747]

[0748] The title compound was prepared according to the following scheme:

[0749]

[0750] Step 1: Preparation of ethyl 2-(benzylideneamino)-2-(5-chloropyrazin-2-yl)acetate (Compound 18-b)

[0751] To a solution of 2,5-dichloropyrazine (5.0 g, 33.56 mmol) in DMF (100 mL) was added CsCO (10.94 g, 33.56 mmol) and ethyl 2-(benzylideneamino)acetate (18-a, 9.87 g, 36.92 mmol), and the mixture was stirred at room temperature for 12 hours. The mixture was then diluted with EA (900 mL) and water (1 L), the organic layer was washed with water, then dried over anhydrous NaSO, and concentrated. The residue was purified by column chromatography to obtain compound 18-b (8.0 g). LCMS (M+H) + :380.

[0752] Step 2: Preparation of (5-chloropyrazin-2-yl)methanamine (Compound 18-c)

[0753] To a solution of ethyl 2-(benzylideneamino)-2-(5-chloropyrazin-2-yl)acetate (18-b, 8.0 g, 19.52 mmol) in toluene (36 mL) was added water (12 mL) and HCl (2.0 mL, 24.0 mmol, 12 N), and the mixture was stirred at room temperature for 12 hours. The mixture was then 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), the mixture was stirred at 60° C. for 12 hours and then concentrated to give compound 18-c (4.0 g). LCMS (M+H) + :144.

[0754] Steps 3 to 7: Preparation of 1-bromo-6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-imidazo[1,5-a]pyrazine-3-carboxamide (Compound 18-h)

[0755] Compound 18-h was prepared similarly to the preparation of intermediate A1 by using compound 18-c instead of 2-(aminomethyl)-5-methylpyrazine (A1-a). Compound 18-h (360 mg) was obtained. LCMS (M+H) + :425.

[0756] 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)

[0757] Similar to the preparation of compound 3-f, compound 18-i was prepared by 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.

[0758] Step 9: Preparation of 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)

[0759] Similarly to the preparation of Example 4, Example 18 was prepared by 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). Example 18 (2.2 mg) was obtained. LCMS (M+H) + :388. 1 H NMR (400MHz, DMSO-d6) δ = 9.60 (s, 1H), 9.31 (s, 1H), 4.49 (brd, J = 7.4Hz, 2H), 2.15 (s, 3H), 1.34 (t, J = 7.2Hz, 3H).

[0760] Example 19

[0761] 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

[0762]

[0763] The title compound was prepared according to the following scheme:

[0764]

[0765] Steps 1 to 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)

[0766] Similar to the preparation of compound 2-a, compound 19-g was prepared by 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-methylpyrazine (A1-a) and 3-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-1-methyl-1,2,4-triazole (intermediate B2). Compound 19-g (120 mg) was obtained. LCMS (M+H) + :727.

[0767] 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)

[0768] 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) in HFIP (2.0 mL) was added MsOH (158.5 mg, 1.65 mmol), the mixture was stirred at room temperature for 12 hours, and then concentrated and purified by preparative HPLC to give Example 19 (12.7 mg), LCMS (M+H) + :367. 1 H NMR (400MHz, DMSO-d6) δ = 9.31 (s, 1H), 8.28 (d, J = 9.3Hz, 1H), 7.88-7.45 (m, 2H), 7.25 (br d, J=8.6Hz, 1H), 4.46 (q, J=6.8Hz, 2H), 2.36 (s, 3H), 2.14 (s, 3H), 1.33 (t, J=7.1Hz, 3H).

[0769] Example 20

[0770] 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

[0771]

[0772] The title compound was prepared according to the following scheme:

[0773]

[0774] Step 1: Preparation of ethyl 2-(6-methylpyrimidin-4-yl)acetate (Compound 20-b)

[0775] 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(PPh3)4 (2.304 g, 1.99 mmol) and then trimethylaluminum (29.91 mL, 59.81 mmol) was slowly added. The mixture was stirred at 15 ° C for 2 hours. The mixture was then poured into HCl (100 mL, 1N) and extracted with EA (50 mL). The aqueous phase was adjusted to pH ~ 9 with saturated K2CO3 solution and extracted with EA (100 mL×3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to give compound 20-b (3.0 g). LCMS (M+H) + :181.

[0776] Step 2: Preparation of ethyl 3-methylpyrrolo[1,2-c]pyrimidine-5-carboxylate (Compound 20-c)

[0777] 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), and the mixture was stirred at 65° C. for 12 hours under N 2 . The mixture was then concentrated. The residue was purified by column chromatography to give compound 20-c (2.7 g). LCMS (M+H) + :205.

[0778] Step 3: Preparation of 7-bromo-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxylic acid ethyl ester (Compound 20-d)

[0779] 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 NaHCO3 solution (500 mL) and extracted with DCM (500 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography to obtain compound 20-d (1.4 g). LCMS (M+H) + :283.

[0780] Step 4: Preparation of 7-bromo-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxylic acid (Compound 20-e)

[0781] To a solution of 7-bromo-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxylic acid ethyl ester (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 hours. Water (150 mL) was then added and washed with EA. The aqueous phase was adjusted to pH ~ 5 with HCl (1N), extracted with EA (100 mL×3), and the combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to give compound 20-e (150 mg). LCMS (M+H) + :255.

[0782] Step 5: Preparation of 7-bromo-N-[(2,4-dimethoxyphenyl)methyl]-3-methyl-pyrrolo[1,2-c]pyrimidine-5-carboxamide (Compound 20-f)

[0783] 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), DMBNH2 (0.1 mL, 0.64 mmol) and HATU (301.9 mg, 0.79 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was then poured into H2O (100 mL) and extracted with EA (150 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give compound 20-f (80 mg). LCMS (M+H) + :404.

[0784] 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)

[0785] 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) was 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), Li2CO3 (55.0 mg, 0.74 mmol) and CuI (4.7 mg, 0.02 mmol), and the mixture was stirred at 140 ° C. for 12 hours under N2. The mixture was then concentrated. The residue was purified by preparative TLC to give compound 20-g (15.0 mg). LCMS (M+H) + :727.

[0786] 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)

[0787] 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) in HFIP (0.5 mL) was added MsOH (105.7 mg, 1.1 mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was then purified by reverse phase column chromatography to give Example 20 (2.5 mg). LCMS (M+H) + :367. 1 H NMR (400MHz, DMSO-d6)δ=14.32-13.83(m,1H),10.16(s,1H),9.24-8.88(m,1H),8.05(br d,J=3.8Hz,2H),7.86-7.67(m,1H),7.18-6.98(m,1H),4.48(q,J=6.8Hz,2H),2.46(br s,3H),2.15(s,3H),1.34(t,J=7.2Hz,3H).

[0788] Example 21

[0789] 1-[2-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

[0790]

[0791] The title compound was prepared according to the following scheme:

[0792]

[0793] Step 1: Preparation of 4-benzyloxy-5-bromo-1-ethyl-3-methyl-pyrazole (Compound 21-a)

[0794] To a solution of 4-benzyloxy-1-ethyl-3-methyl-pyrazole (B1-f, 1.0 g, 4.62 mmol) in THF (10 mL) was added NBS (0.91 g, 5.09 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was then concentrated, and the residue was purified by column chromatography to give compound 21-a (1.3 g). LCMS (M+H) + :295.

[0795] Step 2: Preparation of 5-methyl-1H-pyrazolo[3,4-c]pyridine (Compound 21-c)

[0796] To a solution of 4,6-dimethylpyridin-3-amine (21-b, 10.0 g, 81.85 mmol) in AcOH (200 mL) was added a solution of NaNO2 (6.21 g, 90.04 mmol) in water (20 mL), and the mixture was stirred at 15 ° C for 12 hours. The mixture was then concentrated, diluted with water (200 mL), and then extracted with EA (200 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to obtain compound 21-c (10.0 g). LCMS (M+H) + :134.

[0797] Step 3: Preparation of 3-bromo-5-methyl-1H-pyrazolo[3,4-c]pyridine (Compound 21-d)

[0798] 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. The mixture was then 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.

[0799] Step 4: Preparation of 2-[(3-bromo-5-methyl-pyrazolo[3,4-c]pyridin-1-yl)methoxy]-ethyl-trimethyl-silane (Compound 21-e)

[0800] 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) was added Cs2CO3 (30.73 g, 94.32 mmol) and SEMCl (11.79 g, 70.74 mmol), and the mixture was stirred at 60 ° C for 2 hours. The mixture was then poured into H2O (100 mL) and extracted with EA (200 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give compound 21-e (4.0 g). LCMS (M+H) + :342.

[0801] Step 5: Preparation of 5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-c]pyridine-3-carboxylic acid methyl ester (Compound 21-f)

[0802] 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), and the mixture was stirred at 60 ° C. under CO (45 psi) for 16 hours. 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.

[0803] Step 6: Preparation of 5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-c]pyridine-3-carboxylic acid (Compound 21-g)

[0804] To a solution of 5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-c]pyridine-3-carboxylic acid methyl ester (21-f, 3.4 g, 10.58 mmol) in THF (20 mL) was added a solution of LiOH.H2O (887.7 mg, 21.15 mmol) 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 to pH ~ 4. The suspension was filtered, and the filter cake was washed with water and dried to give compound 21-g (3.2 g). LCMS (M+H) + :308.

[0805] Step 7: Preparation of N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 21-h)

[0806] 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) in DMF (60 mL) was 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 H2O (30 mL) and extracted with EA (30 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give compound 21-h (4.0 g). LCMS (M+H) + :457.

[0807] Step 8: Preparation of N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 21-i)

[0808] 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) in THF (50 mL) was added TBAF (25.0 mL, 25.0 mmol, 1 N solution in THF), and the mixture was stirred at 60 ° C for 16 hours. The mixture was then concentrated and the residue was dissolved in DCM (100 mL). Saturated NaHCO3 solution (100 mL) was then added and the mixture was extracted with DCM (100 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography to obtain compound 21-i (2.5 g). LCMS (M+H) + :327.

[0809] 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)

[0810] 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) 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), and the mixture was stirred at 120° C. for 12 hours. The mixture was then filtered and concentrated, and the residue was purified by column chromatography to give compound 21-j (200.0 mg). LCMS (M+H) + :466.

[0811] Step 10: 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 ethyl ester (Compound 21-k)

[0812] 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), 4-benzyloxy-5-bromo-1-ethyl-3-methyl-pyrazole (21-a, 200.0 mg, 0.68 mmol) in 1,4-dioxane (1 mL) were added Pd(OAc)2 (45.6 mg, 0.2 mmol), PCy3HBF4 (99.7 mg, 0.27 mmol), CuI (258.1 mg, 1.36 mmol) and Cs2CO3 (220.2 mg, 0.68 mmol), and the mixture was stirred at 140°C under N2 for 18 h. The mixture was then filtered, the filter cake was washed with DCM / MeOH (V / V=20 / 1), the filtrate was concentrated, and the residue was purified by preparative TLC to give compound 21-k (30.0 mg). LCMS (M+H) + :680.

[0813] 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 21-1)

[0814] To 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 THF / H2O / MeOH (V / V / V=1 / 1 / 1, 1 mL) was added NaOH (17.6 mg, 0.44 mmol), and the mixture was stirred at 30°C for 2 hours. HCl solution (1N) was then added to adjust to pH ~ 4, the mixture was extracted with EA (30 mL x 3), the combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give compound 21-1 (28.0 mg). LCMS (M+H) + :652.

[0815] 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)

[0816] 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 (21-1, 28.0 mg, 0.04 mmol) in DMSO (1 mL) was added AcOH (0.5 mg, 0.01 mmol) and Ag2CO3 (2.4 mg, 0.01 mmol), and the mixture was stirred at 80°C for 12 hours. The mixture was then filtered, and the filtrate was poured into water (10 mL) and extracted with EA (10 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give compound 21-m (20.0 mg). LCMS (M+H) + :608.

[0817] Step 13: Preparation of 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)

[0818] 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) 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. The mixture was then purified by reverse phase column chromatography to give Example 21 (3.5 mg). LCMS (M+H) + :368. 1 H NMR (400MHz, DMSO-d6+D2O) δ = 9.57 (s, 1H), 8.69 (s, 1H), 8.06 (s, 1H), 4.49 (q, J = 7.2Hz, 2H), 2.66 (s, 3H), 2.15 (s, 3H), 1.39 (t, J = 7.2Hz, 3H).

[0819] Example 22

[0820] 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

[0821]

[0822] The title compound was prepared according to the following scheme:

[0823]

[0824] Step 1: Preparation of 3-bromo-1-[(4-methoxyphenyl)methyl]-1,2,4-triazole (Compound 22-b)

[0825] 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) was added 3-bromo-1H-1,2,4-triazole (22-a, 5.0 g, 33.79 mmol), and the mixture was stirred at 80 ° C. for 16 hours. The mixture was then concentrated and the residue was purified by column chromatography to give compound 22-b (5.0 g). LCMS (M+H) + :268.

[0826] 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)

[0827] Compound 22-d was prepared similarly to the preparation of compound 21-k by using compound 22-b instead of ethyl 4-bromooxazole-5-carboxylate (10-d). Compound 22-d (10 mg) was obtained. LCMS (M+H) + :728.

[0828] 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)

[0829] Similar to the preparation of Example 21, Example 22 was prepared by 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. 1H NMR (400MHz, DMSO-d6+D2O) δ = 9.64 (s, 1H), 8.12 (s, 1H), 4.48 (q, J = 7.2Hz, 2H), 2.69 (s, 3H), 2.17 (s, 3H), 1.36 (t, J = 7.2Hz, 3H).

[0830] Example 23

[0831] 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

[0832]

[0833] The title compound was prepared according to the following scheme:

[0834]

[0835] Step 1: Preparation of methyl (2E)-2-[(2-ethoxy-2-oxo-ethyl)hydrazono]propionate (Compound 23-b)

[0836] To a solution of methyl 2-oxopropanoate (16.51 g, 161.71 mmol) in MeOH (250 mL) was 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 hours. H2O (80 mL) was then 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, dried over anhydrous Na2SO4, filtered and concentrated to give compound 23-b (28.5 g). LCMS (M+H) + :203.

[0837] Step 2: Preparation of 4-hydroxy-3-methyl-1H-pyrazole-5-carboxylic acid methyl ester (Compound 23-c)

[0838] To a solution of (2E)-2-[(2-ethoxy-2-oxo-ethyl)hydrazono]propionic acid methyl ester (23-b, 47.0 g, 232.43 mmol) in MeOH (470 mL) was added MeONa (139.46 mL, 697.29 mmol, 5N solution in MeOH), and the mixture was stirred at 70° C. for 16 hours. HCl (2N) was then added at 0° C. to adjust to pH ~ 7, and the mixture was then extracted with EA (500 mL×3). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered and concentrated to give compound 23-c (17.0 g). LCMS (M+H) + :157.

[0839] Step 3: Preparation of methyl 4-benzyloxy-3-methyl-1H-pyrazole-5-carboxylate (Compound 23-d)

[0840] Similar to the preparation of compound B1-f, compound 23-c and Na2CO3 were used instead of 1-ethyl-3-methyl-pyrazol-4-ol (B1-e) and Cs2CO3 to prepare compound 23-d. Compound 23-d (16.6 g) was obtained. LCMS (M+H) + :247.

[0841] Step 4: Preparation of 4-benzyloxy-2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-methyl-pyrazole-3-carboxylic acid methyl ester (Compound 23-e)

[0842] 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) was added KCO (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 hours. Additional 2-bromoethoxy-tert-butyl-dimethyl-silane (9.71 g, 40.61 mmol) and KCO (11.22 g, 81.21 mmol) were then added, and the mixture was stirred at 40° C. for another 16 hours. The mixture was then poured into water (600 mL) and extracted with EA (300 mL×3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated, and the residue was purified by column chromatography to give compound 23-e (9.0 g). LCMS (M+H) + :405.

[0843] Steps 5 to 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)

[0844] Compound 23-i was prepared by using compound 23-e instead of isobutyloxycarbonyl 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxylate (B1-h) in analogy to the preparation of intermediate B1. Compound 23-i (3.6 g) was obtained. LCMS (M+H) + :420.

[0845] 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)

[0846] 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) in DCM (100 mL) was added imidazole (3.9 g, 57.21 mmol) and TBSCl (4.31 g, 28.61 mmol), and the mixture was stirred at 60 ° C. for 1 h. The mixture was then concentrated and the residue was purified by column chromatography to give compound 23-j (2.0 g). LCMS (M+H) + :534.

[0847] Step 10: Preparation 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-dimethoxy-phenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Compound 23-k)

[0848] Similar to the preparation of compound 1-a, compound 23-j and intermediate A2 were used instead of 1-bromo-6-methyl-imidazo[1,5-a]pyrazine-3-carboxylic acid ethyl ester (A1-d) and 3-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)-methyl]-1,2,4-triazole (intermediate B1) to prepare compound 23-k. Compound 23-k (150 mg) was obtained. LCMS (M+H) + :858.

[0849] Step 11: Preparation 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 (Compound 23-1)

[0850] 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) in MeOH (4 mL) was added NH4F (232.5 mg, 6.12 mmol), and the mixture was stirred at 60° C. for 12 hours. The mixture was then concentrated, and the residue was purified by column chromatography to give compound 23-1 (120 mg). LCMS (M+H) + :744.

[0851] Step 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)

[0852] 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 (23-1, 33 mg, 0.04 mmol) and CMBP (0.07 mL, 0.22 mmol) in anhydrous toluene (1.5 mL) was added imidazole (15.1 mg, 0.22 mmol), and the mixture was stirred at 60° C. for 12 hours. The mixture was then concentrated, and the residue was purified by column chromatography to give compound 23-m (10 mg). LCMS (M+H) + :794.

[0853] Step 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)

[0854] Example 23 was prepared by using compound 23-m in analogy to the preparation of Example 21 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 23 (2.5 mg) was obtained. LCMS (M+H) + :434. 1 H NMR (400MHz, DMSO-d6) 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 = 4.4Hz, 2H), 4.69 (d, J = 4.4Hz, 2H), 4.24 (s, 3H), 2.11 (s, 3H).

[0855] Example 24

[0856] 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

[0857]

[0858] The title compound was prepared according to the following scheme:

[0859]

[0860] 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)

[0861] 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 (23-1, 200 mg, 0.27 mmol) in DCM (5 mL) was added DMP (228.1 mg, 0.54 mmol) at 0° C., and the mixture was stirred at 30° C. for 1 h. Saturated Na2SO3 solution (50 mL) and saturated NaHCO3 solution (100 mL) were then added to the mixture at 0° C. The mixture was extracted with DCM (100 mL×3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated, and the residue was purified by preparative TLC to give compound 24-a (100 mg). LCMS (M+H) + :742.

[0862] 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)

[0863] 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) in EtOH (3 mL) was added (cyanomethyl)triphenylphosphonium chloride (91.13 mg, 0.27 mmol), and then at 0 ° C. A solution of TEA (0.06 mL, 0.4 mmol) in EtOH (3 mL) was added dropwise to the mixture. The mixture was stirred at 30 ° C for 3 hours. The mixture was then purified by preparative TLC to obtain compound 24-b (80 mg). LCMS (M+H) + :765.

[0864] 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)

[0865] To 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 Pd / C (300 mg) under N2, and the mixture was stirred at room temperature under H2 (15 psi) for 2 hours. The mixture was then purified by preparative TLC to give compound 24-c (50 mg). LCMS (M+H) + :677.

[0866] 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)

[0867] 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. The mixture was then purified by reverse phase column chromatography to give Example 24 (2.2 mg). LCMS (M+H) + :407. 1 H NMR (400MHz, DMSO-d6)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).

[0868] Example 25

[0869] 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

[0870]

[0871] The title compound was prepared according to the following scheme:

[0872]

[0873] 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)

[0874] 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) was added Py (565 mg, 7.15 mmol) and Ms2O (830.5 mg, 4.77 mmol) at 0°C. The mixture was stirred at room temperature for 1 h. H2O (20 mL) was then added to the mixture, and the mixture was extracted with DCM (100 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give compound 25-a (1.0 g). LCMS (M+H) + :498.

[0875] Step 2: Preparation of 3-[4-benzyloxy-5-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-3-methyl-pyrazol-1-yl]propionitrile (Compound 25-b)

[0876] To 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 NaCN (760 mg, 15.51 mmol), and the mixture was stirred at 60 ° C for 18 hours. Saturated NaHCO 3 solution (50 mL) was then added to the mixture, and the mixture was extracted with DCM (50 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4, filtered and concentrated, and the residue was purified by column chromatography to obtain compound 25-b (330.0 mg). LCMS (M+H) + :429.

[0877] 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)

[0878] Similar to the preparation of compound 3-f, compound 25-b and intermediate A2 were used 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) to prepare compound 25-c. Compound 25-c (120 mg) was obtained. LCMS (M+H) + :753.

[0879] 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)

[0880] Similarly to the preparation of Example 24, Example 25 was prepared by 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 (400MHz, DMSO-d6) δ = 15.39 (s, 1H), 8.87 (s, 2H), 8.47 (s, 1H), 8.15 (s, 1H), 7.88 (br d, J = 1.2Hz, 1H), 4.75 (br t, J=6.6Hz, 2H), 4.23 (s, 3H), 3.09 (t, J=6.6Hz, 2H), 2.16 (s, 3H).

[0881] Example 26

[0882] 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

[0883]

[0884] The title compound was prepared according to the following scheme:

[0885]

[0886] Step 1: Preparation of ethyl 1-bromo-6-(bromomethyl)imidazo[1,5-a]pyrazine-3-carboxylate (Compound 26-a)

[0887] To a solution of 1-bromo-6-methyl-imidazo[1,5-a]pyrazine-3-carboxylic acid ethyl ester (A1-d, 1.9 g, 6.69 mmol) in CCl4 (40 mL) were added 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 hours. The mixture was then concentrated and the residue was purified by column chromatography to give compound 26-a (2.1 g). LCMS (M+H) + :362.

[0888] Step 2: Preparation of ethyl 1-bromo-6-(hydroxymethyl)imidazo[1,5-a]pyrazine-3-carboxylate (Compound 26-b)

[0889] 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 hours. Water (100 mL) was then added to the mixture, and the mixture was extracted with EA (50 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give compound 26-b (1.6 g). LCMS (M+H) + :300.

[0890] Step 3: Preparation of 1-bromo-6-formyl-imidazo[1,5-a]pyrazine-3-carboxylic acid ethyl ester (Compound 26-c)

[0891] 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. The mixture was then filtered, the filter cake was washed with DCM, the filtrate was concentrated, and the residue was purified by column chromatography to give compound 26-c (1.0 g). LCMS (M+H) + :298.

[0892] Step 4: Preparation of ethyl 1-bromo-6-(difluoromethyl)imidazo[1,5-a]pyrazine-3-carboxylate (Compound 26-d)

[0893] At 0 ° C, to a solution of 1-bromo-6-formyl-imidazo[1,5-a]pyrazine-3-carboxylic acid ethyl ester (26-c, 1.0 g, 3.35 mmol) in DCM (20 mL) was added DAST (1.62 g, 10.06 mmol) dropwise, and the mixture was stirred at room temperature for 1 h. Saturated NaHCO3 solution (100 mL) was then added to the mixture, and the mixture was extracted with DCM (100 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated, and the residue was purified by column chromatography to obtain compound 26-d (650 mg). LCMS (M+H) + :320.

[0894] Steps 5 to 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)

[0895] Example 26 was prepared similarly to Example 5 by using Compound 26-d instead of 4-acetyl-6-bromo-pyridine-2-carboxylic acid methyl ester (5-f). Example 26 (17.1 mg) was obtained. LCMS (M+H) + :404. 1 H NMR (400MHz, DMSO-d6+D2O) δ = 9.78 (s, 1H), 9.53 (s, 1H), 7.15 (t, J = 54.4Hz, 1H), 4.56-4.39 (m, 2H), 2.15 (s, 3H), 1.34 (t, J = 7.0Hz, 3H).

[0896] Example 27

[0897] 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

[0898]

[0899] The title compound was prepared according to the following scheme:

[0900]

[0901] Step 1: Preparation of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carboxamide (Compound 27-a)

[0902] 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), NH4Cl (616.5 mg, 11.53 mmol) and HATU (2.19 g, 5.76 mmol), and the mixture was stirred at 50°C for 2 hours. The mixture was then concentrated and the residue was purified by reverse phase column chromatography to give compound 27-a (850 mg). LCMS (M+H) + :260.

[0903] Step 2: Preparation of 4-benzyloxy-2-ethyl-5-methyl-pyrazole-3-carbonitrile (Compound 27-b)

[0904] 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 a solution of 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. NaHCO 3 solution (5%, 100 mL) was then 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, filtered and concentrated, and the residue was purified by column chromatography to give compound 27-b (0.5 g). LCMS (M+H) + :242.

[0905] Step 3: Preparation of 4-benzyloxy-2-ethyl-N-hydroxy-5-methyl-pyrazole-3-carboximidamide (Compound 27-c)

[0906] 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. The mixture was then extracted with EA (150 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated, and the residue was purified by column chromatography to obtain compound 27-c (450 mg). LCMS (M+H) + :275.

[0907] Step 4: Preparation of 3-(4-benzyloxy-2-ethyl-5-methyl-pyrazol-3-yl)-1,2,4-oxadiazole (Compound 27-d)

[0908] To a solution of 4-benzyloxy-2-ethyl-N-hydroxy-5-methyl-pyrazole-3-carboximidamide (27-c, 0.4 g, 1.46 mmol) 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. NaHCO 3 solution (5%, 100 mL) was then added to the mixture, and the mixture was extracted with EA (150 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, and the residue was purified by column chromatography to obtain compound 27-d (350 mg). LCMS (M+H) + :285.

[0909] 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)

[0910] 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) in toluene (5 mL) was added 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), PPh3 (36.9 mg, 0.14 mmol) and AgOAc (350.3 mg, 2.11 mmol), and the mixture was stirred at 120 ° C. for 12 hours. The mixture was then concentrated and the residue was purified by preparative TLC to give compound 27-e (18 mg). LCMS (M+H) + :608.

[0911] 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)

[0912] Similar to the preparation of Example 21, Example 27 was prepared by 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 (400MHz, DMSO-d6+D2O) δ = 10.11 (s, 1H), 8.43 (s, 1H), 8.17 (s, 1H), 4.39 (d, J = 6.8Hz, 2H), 2.54 (s, 3H), 2.15 (s, 3H), 1.34 (t, J = 7.2Hz, 3H).

[0913] Example 28

[0914] 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

[0915]

[0916] The title compound was prepared according to the following scheme:

[0917]

[0918] Step 1: Preparation of tributyl-[2-ethyl-4-[(4-methoxyphenyl)methoxy]-5-methyl-pyrazol-3-yl]stannane (Compound 28-a)

[0919] 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) was added dropwise n-BuLi (6.5 mL, 16.24 mmol, 2.5 N solution in hexane) at -78 ° C., and the mixture was stirred at -78 ° C. for 1 h. Tributyltin chloride (5.7 g, 17.51 ​​mmol) was then added to the mixture at -78 ° C., and the mixture was stirred at room temperature for 3 hours. The mixture was then poured into water (100 mL), and HCl (1 N) was added to adjust to pH ~ 5. The mixture was extracted with DCM (50 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated, and the residue was purified by column chromatography to obtain compound 28-a (3.7 g). LCMS (M+H) + :537.

[0920] Step 2: Preparation of ethyl 2-(1-ethyl-4-((4-methoxybenzyl)oxy)-3-methyl-1H-pyrazol-5-yl)oxazole-5-carboxylate (Compound 28-b)

[0921] 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(PPh3)2Cl2 (0.32 g, 0.45 mmol), and the mixture was stirred at 110°C for 18 hours. The mixture was then filtered and washed with EA. The filtrate was concentrated and the residue was purified by column chromatography to give compound 28-b (720 mg). LCMS (M+H) + :386.

[0922] Step 3: Preparation of 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-carboxylic acid ethyl ester (Compound 28-c)

[0923] 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) were added 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), and the mixture was stirred at 120° C. for 12 hours. The mixture was then diluted with DCM / MeOH (V / V=10 / 1, 20 mL), filtered and concentrated, and the residue was purified by preparative TLC to give compound 28-c (30 mg). LCMS (M+H) + :727.

[0924] Steps 4 to 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)

[0925] Similar to the preparation of Example 21, Example 28 was prepared by using Compound 28-c instead 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 ethyl ester (21-k). Example 28 (3.7 mg) was obtained. LCMS (M+H) + :385. 1 H NMR (400MHz, DMSO-d6) δ = 9.55 (s, 1H), 9.15 (s, 1H), 8.77 (br s,1H),8.58(s,1H),7.79(s,1H),7.41(s,1H),4.50(q,J=6.8Hz,2H),2.45(s,3H),2.15(s,3H),1.37(t,J=7.2Hz,3H).

[0926] Example 29

[0927] 1-[2-(2-ethyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-5-methyl-pyrrolo[2,3-c]pyridine-3-carboxamide

[0928]

[0929] The title compound was prepared according to the following scheme:

[0930]

[0931] Step 1: Preparation of (E)-N,N-dimethyl-2-(2-methyl-5-nitro-4-pyridyl)ethyleneamine (Compound 29-b)

[0932] To a solution of 2,4-dimethyl-5-nitro-pyridine (29-a, 20.0 g, 131.45 mmol) in DMF (400 mL) was added DMF-DMA (32.29 g, 271.0 mmol), and the mixture was stirred at 100 ° C. for 2 hours. The mixture was then purified by column chromatography to give compound 29-b (24.0 g). LCMS (M+H) + :208.

[0933] Step 2: Preparation of 1-hydroxy-5-methyl-pyrrolo[2,3-c]pyridine (Compound 29-c) Under H2 (15 psi), a mixture of (E)-N,N-dimethyl-2-(2-methyl-5-nitro-4-pyridyl)ethyleneamine (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. The mixture was then filtered through celite and concentrated to give Compound 29-c (20.0 g). LCMS (M+H) + :149.

[0934] Step 3: Preparation of 5-methyl-1H-pyrrolo[2,3-c]pyridine (Compound 29-d)

[0935] Under H2 (15 psi), 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 hours. The mixture was then filtered through celite and concentrated, and the residue was purified by reverse phase column chromatography to give compound 29-d (10.0 g). LCMS (M+H) + :133.

[0936] Step 4: Preparation of 3-bromo-5-methyl-1H-pyrrolo[2,3-c]pyridine (Compound 29-e)

[0937] 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 hours. The mixture was then filtered and concentrated to give compound 29-e (3.0 g). LCMS (M+H) + :211.

[0938] Step 5: Preparation of 5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid methyl ester (Compound 29-f)

[0939] 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-dicyclohexylphosphoniumpropyl)phosphonium; ditetrafluoroborate (DCPP, 3.48 g, 5.69 mmol) and K2CO3 (5.88 g, 42.64 mmol), and the mixture was stirred at 80°C under CO (50 Psi) for 12 hours. 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.

[0940] Step 6: Preparation of 5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (Compound 29-g)

[0941] 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 / H2O / MeOH (V / V / V=1 / 1 / 1, 30 mL) was added NaOH (4.21 g, 105.15 mmol), and the mixture was stirred at 60°C for 12 hours. The mixture was then purified by reverse phase column chromatography to give compound 29-g (1.7 g). LCMS (MH) - :175.

[0942] Step 7: Preparation of N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (Compound 29-h)

[0943] Compound 29-h was prepared by using compound 29-g instead of 5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-c]pyridine-3-carboxylic acid (21-g) in a manner similar to the preparation of compound 21-h. Compound 29-h (1.1 g) was obtained. LCMS (MH) - :324.

[0944] 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)

[0945] Example 29 was prepared by using compound 29-h in place of N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (21-i) in analogy to the preparation of Example 21. Example 29 (2.9 mg) was obtained. LCMS (M+H) + :367. 1 H NMR(400MHz,DMSO-d6+D2O)δ9.29(s,1H),9.03(s,1H),8.79(s,1H),8.39(s, 1H), 4.44 (q, J = 7.0Hz, 2H), 2.73 (s, 3H), 2.13 (s, 3H), 1.34 (t, J = 7.2Hz, 3H).

[0946] Example 30

[0947] 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

[0948]

[0949] The title compound was prepared according to the following scheme:

[0950]

[0951] Steps 1 to 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)

[0952] Compound 30-b was prepared similarly to the preparation of compound 25-d by using compound 4-g instead of 4-bromo-N-[(2,4-dimethoxyphenyl)methyl]-1-methyl-pyrazolo[4,3-c]pyridine-6-carboxamide (Intermediate A2). Compound 30-b (16 mg) was obtained. LCMS (M+H) + :680.

[0953] 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)

[0954] Similar to the preparation of Example 21, Example 30 was prepared by 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 (400MHz, DMSO-d6)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(br t,J=6.6Hz,2H),3.11(t,J=6.6Hz,2H),2.48(s,3H),2.18(s,3H).

[0955] Example 31

[0956] 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

[0957]

[0958] The title compound was prepared according to the following scheme:

[0959]

[0960] Step 1: Preparation of 3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carbaldehyde (Compound 31-b)

[0961] At 0 ° C, to a mixture of NaH (871.9 mg, 21.8 mmol) in THF (15 mL) was added dropwise a solution of 3-methyl-1H-pyrazole-4-carboxaldehyde (32-a, 2.0 g, 18.16 mmol) in THF (15 mL), and the mixture was stirred at 0 ° C for 30 min. Then SEMCl (4.54 g, 27.25 mmol) was added dropwise to the mixture. The mixture was stirred at room temperature for 16 hours. The mixture was then poured into water (50 mL) and extracted with EA (50 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography to obtain compound 32-b (3.8 g). LCMS (M+H) + :241.

[0962] Steps 2 to 4: Preparation of 2-[(4-benzyloxy-3-methyl-pyrazol-1-yl)methoxy]ethyl-trimethyl-silane (Compound 31-e)

[0963] Compound 31-e was prepared similarly to the preparation of compound B1-f by using compound 31-b instead of 1-ethyl-3-methyl-pyrazole-4-carbaldehyde (B1-c). Compound 31-e (3.13 g) was obtained. LCMS (M+H) + :319.

[0964] Step 5: Preparation of 4-benzyloxy-3-methyl-1H-pyrazole (Compound 31-f)

[0965] 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) was added TFA (14.8 g, 129.8 mmol), and the mixture was stirred at room temperature for 12 hours. The mixture was then concentrated, and the residue was dissolved in DCM (10 mL). Saturated NaHCO3 solution was then added to adjust to pH~8. The mixture was then extracted with DCM (50 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography to obtain compound 31-f (1.2 g). LCMS (M+H) + :189.

[0966] Step 6: Preparation of 4-benzyloxy-3-methyl-1-propyl-pyrazole (Compound 31-g)

[0967] To a solution of 4-benzyloxy-3-methyl-1H-pyrazole (31-f, 500 mg, 2.66 mmol) in DMF (10 mL) was added 1-iodopropane (903.1 mg, 5.31 mmol) and Cs2CO3 (2.59 g, 7.97 mmol), and the mixture was stirred at 80°C for 16 hours. The mixture was then diluted with water (10 mL) and extracted with EA (30 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to obtain compound 31-g (450 mg). LCMS (M+H) + :231.

[0968] Step 7: Preparation of 4-benzyloxy-5-bromo-3-methyl-1-propyl-pyrazole (Compound 31-h)

[0969] Compound 31-h was prepared similarly to compound 21-a by 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.

[0970] 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)

[0971] Under N2, a solution of 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-h, 72.2 mg, 0.23 mmol), Pd(OAc)2 (10.5 mg, 0.05 mmol), CuI (14.3 mg, 0.14 mmol), PPh3 (33.5 mg, 0.09 mmol) and K2CO3 (96.7 mg, 0.7 mmol) in toluene (3 mL) was stirred at 120° C. for 12 hours. The mixture was then diluted with DCM (10 mL) and filtered. The filtrate was concentrated and the residue was purified by preparative TLC to give compound 31-i (10 mg). LCMS (M+H) + :742.

[0972] 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)

[0973] Similarly to the preparation of Example 21, Example 31 was prepared by 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). Example 31 (1.7 mg) was obtained. LCMS (M+H) + :382. 1H NMR (400MHz, DMSO-d6) δ = 14.20 (br s, 1H), 9.64 (s, 1H), 9.20 (s, 1H), 8.06 (s, 2H), 7.78 (br s,1H),4.43(t,J=6.8Hz,2H),2.67(s,3H),2.18(s,3H),1.86-1.75(m,2H),0.87(t,J=7.2Hz,3H).

[0974] Example 32

[0975] 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

[0976]

[0977] Example 32 was prepared similarly to the preparation of Example 31 by using bromomethylcyclopropane instead of 1-iodopropane. Example 32 (3.4 mg) was obtained. LCMS (M+H) + :394. 1 H NMR (400MHz, DMSO-d6) δ = 9.61 (s, 1H), 8.04-7.95 (m, 2H), 7.70 (br s,1H),4.37(d,J=6.8Hz,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).

[0978] Example 33

[0979] 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

[0980]

[0981] The title compound was prepared according to the following scheme:

[0982]

[0983] Step 1: Preparation of 4-benzyloxy-1-cyclopropyl-3-methyl-pyrazole (Compound 33-a)

[0984] To a solution of 4-benzyloxy-3-methyl-1H-pyrazole (31-f, 500 mg, 2.66 mmol) in 1,4-dioxane (20 mL) were added 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 hours under O2. The mixture was then diluted with water (50 mL) and extracted with EA (30 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography to obtain compound 33-a (540 mg). LCMS (M+H) + :229.

[0985] Steps 2 to 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)

[0986] Example 33 was prepared similarly to Example 31 by using compound 33-a instead of 4-benzyloxy-3-methyl-1-propyl-pyrazole (31-g). Example 33 (1.5 mg) was obtained. LCMS (M+H) + :380. 1 H NMR (400MHz, DMSO-d6) δ = 14.31 (br s, 1H), 9.67 (d, J = 1.2Hz, 1H), 9.15 (br s, 1H), 8.10-8.00 (m, 2H), 7.77 (br s,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).

[0987] Example 34

[0988] 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

[0989]

[0990] The title compound was prepared according to the following scheme:

[0991]

[0992] 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)

[0993] 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 (22.1 mg, 0.08 mmol) in DMF (1 mL) was added 2-chloro-2,2-difluoro-sodium acetate (16.1 mg, 0.11 mmol) and the mixture was stirred at 100 ° C for 12 hours. Water (50 mL) was then added to the mixture and extracted with EA (50 mL×3). The combined organic phases were washed with water, dried over anhydrous Na SO , filtered and concentrated. The residue was purified by preparative TLC to give compound 34-a (12 mg). LCMS (M+H) + :776.

[0994] Step 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)

[0995] Similar to the preparation of Example 21, Example 34 was prepared by 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). Example 34 (1.3 mg) was obtained. LCMS (M+H) + :416. 1 H NMR (400 MHz, methanol-d4) δ = 8.86 (s, 1H), 8.43 (s, 1H), 5.26 (br d, J = 7.6 Hz, 2H), 4.90 (s, 1H), 4.23 (s, 3H), 2.25 (s, 3H).

[0996] Example 35

[0997] 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

[0998]

[0999] Example 35 was prepared similarly to the preparation of Example 23 by using 1,2,3-triazole instead of imidazole. Example 35 (7.1 mg) was obtained. LCMS (M+H) + :435. 1 H NMR (400MHz, DMSO-d6) δ = 15.33 (br s, 1H), 8.90-8.86 (m, 2H), 8.46 (s, 1H), 8.05 (br s, 1H), 7.87 (br s,1H),7.66(s,2H),4.98(t,J=6.2Hz,2H),4.87(t,J=6.2Hz,2H),4.22(s,3H),2.12(s,3H).

[1000] Example 36

[1001] 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

[1002]

[1003] Example 36 was prepared similarly to the preparation of Example 23 by using 1,2,3-triazole instead of imidazole. Example 36 (5.1 mg) was obtained. LCMS (M+H) + :435. 1 H NMR(400MHz,DMSO-d6)δ=15.32(br s,1H),8.86(s,2H),8.46(s,1H),8.08(s,1H),7.8-7.9(m,2H),7.57(s,1H ), 4.96 (t, J = 5.2Hz, 2H), 4.86 (t, J = 5.2Hz, 2H), 4.23 (s, 3H), 2.12 (s, 3H).

[1004] Example 37

[1005] 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

[1006]

[1007] The title compound was prepared according to the following scheme:

[1008]

[1009] 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)

[1010] 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) was added Pd / C (10 mg), and the mixture was stirred at 30° C. under a balloon of H 2 for 12 hours. The mixture was then purified by reverse phase column chromatography to give Example 37 (2.9 mg). LCMS (M+H) + :418. 1 H NMR (400MHz, DMSO-d6) δ = 15.39 (s, 1H), 8.86 (d, J = 1.6Hz, 1H), 8.83 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.87 (d, J = 2. 6Hz,1H),6.34-6.00(m,1H),4.64(t,J=7.4Hz,2H),4.22(s,3H),2.53-2.52(m,1H),2.46-2.45(m,1H),2.15(s,3H).

[1011] Example 38

[1012] 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

[1013]

[1014] The title compound was prepared according to the following scheme:

[1015]

[1016] 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)

[1017] Compound 38-a was prepared similarly to the preparation of compound 23-m by using 1,2,4-triazole instead of imidazole. The residue was purified by preparative TLC (DCM / MeOH=30 / 1), and the minor spot (Rf=0.25) was defined as compound 38-a (10 mg) without further structural conformation. LCMS (M+H) + :795.

[1018] 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)

[1019] Similar to the preparation of Example 21, Example 38 was prepared by 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). Example 38 (2.0 mg) was obtained. LCMS (M+H) + :435. 1 H NMR(400MHz, DMSO-d6)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=5.8Hz,2H),4.63(t,J=5.8Hz,2H),2.97(d,J=4.4Hz,3H),2.09(s,3H).

[1020] Example 39

[1021] 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

[1022]

[1023] The title compound was prepared according to the following scheme:

[1024]

[1025] 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)

[1026] Compound 39-a was prepared similarly to the preparation of compound 23-m by using 1,2,4-triazole instead of imidazole. The residue was purified by preparative TLC (DCM / MeOH=30 / 1), and the main spot (Rf=0.3) was defined as compound 39-a (20 mg) without further structural conformation. LCMS (M+H) + :795.

[1027] 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)

[1028] Similar to the preparation of Example 21, Example 39 was prepared by 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 (400MHz, DMSO-d6) δ = 15.33 (s, 1H), 8.90-8.82 (m, 2H), 8.47 (s, 1H), 8.24 (s, 1H), 8.05 (br s,1H),7.89-7.85(m,1H),7.83(s,1H),4.91(t,J=6.2Hz,2H),4.66(t,J=6.2Hz,2H),4.23(s,3H),2.13(s,3H).

[1029] Example 40

[1030] 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

[1031]

[1032] The title compound was prepared according to the following scheme:

[1033]

[1034] Step 1: Preparation of 4-benzyloxy-3-methyl-1-(2-phenylethyl)pyrazole (Compound 40-a)

[1035] To a solution of 4-benzyloxy-3-methyl-1H-pyrazole (31-f, 500 mg, 2.66 mmol) in DMF (4 mL) was added CsCO (2596 mg, 7.97 mmol) and 1-bromo-2-phenylethane (1.09 mL, 7.97 mmol). The mixture was stirred at 100 ° C for 12 hours. 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 x 2). The combined organic layer was dried over NaSO and concentrated to obtain a residue, which was purified via preparative TLC to obtain 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).

[1036] Step 2: Preparation of 4-benzyloxy-5-bromo-3-methyl-1-(2-phenylethyl)pyrazole (Compound 40-b)

[1037] To a solution of compound 40-a (500.0 mg, 1.71 mmol) in THF (5 mL) was added NBS (365 mg, 2.05 mmol). The mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated and purified by preparative TLC to give compound 40-b (450.0 mg). LCMS (M+H) + :371. 1H 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).

[1038] Step 3: Preparation of 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)

[1039] Under N2 atmosphere, a mixture of 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), PPh3(56 mg, 0.22 mmol), K2CO3(223 mg, 1.62 mmol) in toluene (10 mL) was stirred at 120 ° C for 12 hours. The reaction mixture was diluted with DCM (10 mL) and filtered. The filtrate was concentrated and purified by preparative TLC to give compound 40-c (10 mg). LCMS (M+H) + :804.

[1040] 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)

[1041] A solution of compound 40-c (10 mg, 0.01 mmol) and MsOH (12 mg, 0.12 mmol) in HFIP (0.3 mL) was stirred at 30° C. for 3 hours. The reaction mixture was purified by HPLC to give Example 40 (1.8 mg). LCMS (M+H) + :444, 1H NMR (400MHz, 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=7.4Hz,2H),3.09-3.05(m,2H),2.67(s,3H),2.18(s,3H).

[1042] Example 41

[1043] 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

[1044]

[1045] Similar to the preparation of Example 40, Example 41 was prepared by using Compound 41-c instead of Compound 40-b.

[1046] Compound 41-c was prepared according to the following scheme:

[1047]

[1048] 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)

[1049] To a solution of 4-benzyloxy-3-methyl-1H-pyrazole (31-f, 500 mg, 2.66 mmol) in acetonitrile (5 mL) was added CsCO (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. The mixture was then filtered and concentrated. The residue was purified by preparative TLC to obtain compound 41-a (250 mg) and compound 41-b (150 mg).

[1050] Compound 41-a, LCMS (M+H) + :249. 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).

[1051] Compound 41-b, LCMS (M+H) + :249. 1 H 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).

[1052] Step 2: Preparation of 4-benzyloxy-5-bromo-1-(3-fluoropropyl)-3-methyl-pyrazole (Compound 41-c)

[1053] 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 h. 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.

[1054] Example 41 (2.4 mg), LCMS (M+H) + :400, 1 H NMR (400MHz, DMSO-d6) δ=14.37-14.11(m,1H),9.64(d,J=1.0Hz,1H),9.44-9.15(m,1H),8.08(s,2H),7.80(br s, 1H), 4.60 (t, J = 7.0Hz, 2H), 4.54 (t, J = 5.8Hz, 1H), 4.42 (t, J = 5.8Hz, 1H), 2.68 (s, 3H), 2.23-2.13 (m, 5H).

[1055] Example 42

[1056] 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

[1057]

[1058] Example 42 was prepared similarly to the preparation of Example 40 by using 2-bromoethyl methyl ether instead of 1-bromo-2-phenylethane in Step 1.

[1059] Example 42, LCMS (M+H) + :398, 1 H NMR(400MHz,DMSO-d6)δ=14.23(br s,1H),9.63(s,1H),9.30-9.08(m,1H),8.08(s,2H),7.79(s,1H),4.64(t,J =5.6Hz,2H),3.70(t,J=5.8Hz,2H),3.18(s,3H),2.67(s,3H),2.17(s,3H).

[1060] Example 43

[1061] 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

[1062]

[1063] Similar to the preparation of Example 40, 1-bromobutane was used instead of 1-bromo-2-benzene in step 1.

[1064] Example 43 was prepared using 1,2-dimethylethane.

[1065] Example 43 (1.5 mg), LCMS (M+H) + :396, 1 H NMR (400MHz, DMSO-d6)δ=14.20(br s,1H),9.64(br s,1H),9.19(br s,1H),8.05(s,2H),7.78(br s,1H),4.47(br t,J=7.2Hz,2H),2.67(s,3H),2.18(s,3H),1.82-1.72(m,2H),1.32-1.26(m,2H),0.87(br t,J=7.2Hz,3H).

[1066] Example 44

[1067] 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

[1068]

[1069] Example 44 was prepared similarly to the preparation of Example 40 by using 1-bromo-3-methoxypropane instead of 1-bromo-2-phenylethane in Step 1.

[1070] Example 44 (11.7 mg), LCMS (M+H) + :412, 1 H NMR (400MHz, DMSO-d6) δ = 9.65 (s, 1H), 8.01 (s, 2H), 7.78-7.67 (m, 1H), 7.22-6.84 (m, 1H), 4.53 (t,J=7.0Hz,2H),3.29-3.29(m,2H),3.18(s,3H),2.65(s,3H),2.15(s,3H),2.05-1.96(m,2H).

[1071] Example 45

[1072] 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

[1073]

[1074] The title compound was prepared according to the following scheme:

[1075]

[1076] Step 1: Preparation of 4-benzyloxy-5-methyl-2-pent-3-ynyl-pyrazole-3-carboxylic acid methyl ester (Compound 45-a)

[1077] To a solution of methyl 4-benzyloxy-3-methyl-1H-pyrazole-5-carboxylate (1.5 g, 6.09 mmol) in toluene (15 mL) was added CMBP (7.36 g, 30.46 mmol) and 3-pentyn-1-ol (2.81 mL, 30.46 mmol), and the mixture was stirred at 80 ° C for 12 hours. The reaction 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.

[1078] Step 2: Preparation of 4-benzyloxy-5-methyl-2-pent-3-ynyl-pyrazole-3-carbohydrazide (Compound 45-b)

[1079] To a solution of compound 45-a (1.8 g, 5.76 mmol) in methanol (20 mL) was added hydrazine hydrate (2.94 g, 57.63 mmol) at room temperature. The mixture was then stirred at 80° C. for 4 hours. The mixture was concentrated to give compound 45-b (1.8 g). LCMS (M+H) + :313.

[1080] 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)

[1081] 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) was added 4-methoxybenzyl isothiocyanate (1.95 g, 10.88 mmol) at room temperature. The mixture was stirred for 12 hours and concentrated to afford compound 45-c (2.3 g). LCMS (M+H) + :492.

[1082] Step 4: Preparation of 5-(4-benzyloxy-5-methyl-2-pent-3-ynyl-pyrazol-3-yl)-4-[(4-methoxyphenyl)methyl]-1,2,4-triazole-3-thiol (Compound 45-d)

[1083] A yellow solution of compound 45-c (2.3 g, 4.68 mmol) in 3N NaOH (25 mL) was stirred at 100 ° C for 3 h. The mixture was washed with EA (3 x 900 mL). The combined organic layers were washed with water (3 x 800 mL) and brine (1050 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was purified by column chromatography to give compound 45-d (2.0 g). LCMS (M+H) + :474.

[1084] 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)

[1085] To a solution of compound 45-d (2.5 g, 5.28 mmol) in acetic acid (8 mL) was slowly added H2O2 (11.27 g, 99.44 mmol), and the mixture was then stirred at room temperature for 1 h. The reaction mixture was poured into a saturated aqueous solution of Na2SO3 (200 mL) and extracted with ethyl acetate (3 x 250 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to obtain compound 45-e (1.2 g). LCMS (M+H) + :442.

[1086] 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)

[1087] Under N2, to a solution of compound 45-e (100 mg, 0.23 mmol) in 1,4-dioxane (2 mL) was added 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), PCy3HBF4(33 mg, 0.09 mmol) and Cs2CO3(73 mg, 0.23 mmol), and the mixture was stirred at 140°C for 12 hours. The mixture was added to DCM / MeOH (30 mL / 6 mL) and filtered. The filtrate was evaporated and purified via preparative TLC to obtain compound 45-f (20 mg). LCMS (M+H) + :766.

[1088] 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)

[1089] Under N2 atmosphere, 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 hours. The reaction mixture was purified by reverse phase HPLC to obtain Example 45 (5.5 mg). LCMS (M+H) + :406,1 H NMR (400MHz, 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=7.4Hz,2H),4.23(s,3H),2.63(d,J=5.6Hz,2H),2.14(s,3H),1.73(s,3H).

[1090] Example 46

[1091] 1-[3-[4-Hydroxy-5-methyl-2-[2-(4-pyridinyl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide

[1092]

[1093] The title compound was prepared according to the following scheme:

[1094]

[1095] Step 1: Preparation of 4-(benzyloxy)-5-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Compound 46-a)

[1096] 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) in portions. Under a nitrogen atmosphere, the resulting mixture was stirred at 60 ° C. for 2 h. 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.

[1097] Step 2: Preparation of 4-(benzyloxy)-5-bromo-3-methyl-1H-pyrazole (Compound 46-b)

[1098] 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 solution in THF) dropwise. Under a nitrogen atmosphere, the resulting mixture was stirred at 80 ° C for 15 h. 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.

[1099] Step 3: Preparation of 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)

[1100] To a solution of compound 46-b (500 mg, 1.87 mmol) in toluene (5 mL) was added CMBP (1353 mg, 5.62 mmol) and 4-pyridineethanol (691 mg, 5.62 mmol). The mixture was stirred at 80° C. for 12 hours. The mixture was concentrated and purified via preparative NPLC (Welch Ultimate XB-SiOH 250*70*10 μm, hexane-EtOH (0.1% FA, 10% to 50%)) to obtain compound 46-c (250 mg) and compound 46-d (300 mg).

[1101] 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).

[1102] Compound 46-d, LCMS (M+H) + :372, 1 H NMR (400MHz, chloroform-d) δ = 8.53 (br d,J=5.3Hz,2H),7.37(s,5H),7.08(d,J=5.9Hz,2H),4.93(s,2H),4.15(t,J=7.0Hz,2H),3.17(t,J=6.8Hz,2H),1.68(s,3H).

[1103] 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)

[1104] Under N2 atmosphere, 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), PPh3(38 mg, 0.15 mmol), K2CO3(121 mg, 0.88 mmol) in toluene (3 mL) was stirred at 120 ° C for 12 hours. The reaction mixture was diluted with DCM (10 mL) and filtered. The filtrate was concentrated and purified via preparative TLC to give compound 46-e (35 mg). LCMS (M+H) + :805.

[1105] Step 5: Preparation of 1-[3-[4-hydroxy-5-methyl-2-[2-(4-pyridinyl)ethyl]pyrazol-3-yl]-1H-1,2,4-triazol-5-yl]-5-methyl-pyrazolo[3,4-c]pyridine-3-carboxamide (Example 46)

[1106] 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) in HFIP (1.0 mL) was added MsOH (120 mg, 0.88 mmol). The mixture was stirred at 60° C. for 2 hours and purified via reverse phase HPLC to give Example 46 (11.2 mg). LCMS (M+H) + :445, 1H NMR (400MHz, DMSO-d6) δ=14.30-14.11(m,1H),9.57(d,J=1.0Hz,1H),9.45-9.23(m,1H),8.65(d,J=6.4Hz,2H),8.07(s,2H),7.85(br s,1H),7.79(br d, J=5.8Hz, 2H), 4.84 (br t, J=7.2Hz, 2H), 3.38 (br t, J=7.0Hz, 2H), 2.68 (s, 3H), 2.16 (s, 3H).

[1107] Example 47

[1108] 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

[1109]

[1110] Example 47 was prepared similarly to the preparation of Example 46 by using 3-(2-hydroxyethyl)pyridine instead of 4-pyridineethanol in Step 3.

[1111] Example 47 (6.9 mg), LCMS (M+H) + :445, 1 H NMR (400MHz, DMSO-d6) δ = 9.65 (s, 1H), 8.87 (br s, 1H), 8.46 (br s, 1H), 8.37 (br d, J = 4.4Hz, 1H), 8.06 (s, 1H), 7.81 (br s, 1H), 7.69 (br d, J=7.6Hz, 1H), 7.25 (dd, J=4.6, 7.8Hz, 1H), 4.70 (br t, J=7.4Hz, 2H), 3.10 (br t, J=7.4Hz, 2H), 2.67 (s, 3H), 2.16 (s, 3H).

[1112] Example 48

[1113] 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

[1114]

[1115] The title compound was prepared according to the following scheme:

[1116]

[1117] Step 1: Preparation of [4-benzyloxy-5-methyl-2-(2-phenylethyl)pyrazol-3-yl]boronic acid (Compound 48-a)

[1118] At -78 ° C under N2 atmosphere, 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) was added dropwise n-BuLi (2.5 M, 0.15 mL, 0.36 mmol). The mixture was stirred at -78 ° C for 1 h, and 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 NH4Cl aqueous solution (50 ml) and extracted with EA (3 x 60 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to obtain compound 48-a (80.0 mg). LCMS (M+H) + :337.

[1119] 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)

[1120] To N-(2,4-dimethoxybenzyl)-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (21-i, 800mg, 2.45mmol), 3,5-dibromo-1-methyl-1,2,4-triazole (1.76g, 7.35mmol) in DMF (15.0mL) was added copper (I) iodide (233mg, 1.23mmol), 1,10-phenanthroline (441mg, 2.45mmol) and potassium carbonate (846mg, 6.13mmol) in batches. The resulting mixture was stirred at 100°C for 16 hours. The mixture was cooled and diluted with ice water (60mL) and extracted with EtOAc (3x 80mL). The combined organic layer was washed with brine (150mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain compound 48-b (415 mg). LCMS (M+H) + :485.

[1121] 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)

[1122] 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) in 1,4-dioxane (3 mL) and water (0.3 mL) was added KCO (280 mg, 2.04 mmol) and Pd(dppf)Cl (56 mg, 0.07 mmol). Under N atmosphere, the mixture was stirred at 100 ° C for 12 hours. The mixture was concentrated and purified via preparative TLC to obtain compound 48-c (30 mg). LCMS (M+H) + :698.

[1123] 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)

[1124] A solution of compound 48-c (20 mg, 0.03 mmol) and MsOH (1.0 mL, 0.29 mmol) in HFIP (2.0 mL) was stirred at 30° C. for 3 hours. The reaction mixture was purified via reverse phase HPLC to obtain Example 48 (10 mg). LCMS (M+H) + :458, 1 H NMR (400MHz, DMSO-d6) δ = 9.58 (s, 1H), 8.29 (br s,1H),8.07(s,1H),8.05(s,1H),7.91(s,1H),7.25-7.11(m,5H),4.58(t,J =7.6Hz,2H),4.29(s,3H),3.04(t,J=7.8Hz,2H),2.68(s,3H),2.14(s,3H).

[1125] Example 49

[1126] 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

[1127]

[1128] Example 49 was prepared similarly to the preparation of Example 48 by using Compound 49-c instead of Compound 40-b in Step 1.

[1129] Compound 49-c was prepared according to the following scheme:

[1130]

[1131] Step 1: Preparation of 4-benzyloxy-1-butyl-3-methyl-pyrazole (Compound 49-a)

[1132] To a solution of 4-benzyloxy-3-methyl-1H-pyrazole (31-f, 0.5 g, 2.66 mmol) in DMF (5 mL) was added CsCO (2.6 g, 7.97 mmol) and 1-bromobutane (1.09 g, 7.97 mmol). The mixture was stirred at 100 ° C for 12 hours. The reaction mixture was cooled and diluted with EtOAc (20 mL) and water (20 mL). The two phases were separated and the aqueous phase was extracted with EtOAc (300 mL x 2). All organic layers were combined, dried over NaSO and concentrated to obtain compound 49-a (400 mg). LCMS (M+H) + :245.

[1133] Step 2: Preparation of 4-benzyloxy-5-bromo-1-butyl-3-methyl-pyrazole (Compound 49-b)

[1134] To a solution of compound 49-a (900 mg, 3.68 mmol) in THF (10 mL) was added NBS (786 mg, 4.42 mmol). The mixture was stirred at 20 ° C for 1 h. The reaction mixture was concentrated and purified via preparative TLC to give 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).

[1135] Step 3: Preparation of (4-benzyloxy-2-butyl-5-methyl-pyrazol-3-yl)boronic acid (Compound 49-c)

[1136] At -78 ° C under N2 atmosphere, to a solution of compound 49-b (46 mg, 0.14 mmol) in THF (2 mL) was added dropwise n-BuLi (2.5 M, 0.09 mL, 0.21 mmol). The mixture was stirred at -78 ° C for 0.5 h. Triisopropyl borate (160 mg, 0.2 mL, 0.85 mmol) was then added. The mixture was warmed to 25 ° C and stirred for 0.5 h, then poured into NH4Cl aqueous solution (50 ml) and extracted with EA (3 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated to give compound 49-c (50.0 mg). LCMS (M+H) + :289.

[1137] Example 49, LCMS (M+H) + :410, 1 H NMR (400MHz, DMSO-d6) δ = 9.59 (d, J = 0.8Hz, 1H), 8.31 (s, 1H), 8.10 (s, 2H), 7.92 (s, 1H), 4.37 (t, J = 7.2Hz, 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 = 7.2Hz, 3H).

[1138] Example 50

[1139] 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

[1140]

[1141] Example 50 was prepared similarly to the preparation of Example 40 by using 4-methoxyphenethyl instead of 1-bromo-2-phenylethane in Step 1.

[1142] Example 50 (3.2 mg), LCMS (M+H) + :474, 1H NMR (400MHz, DMSO-d6) δ = 14.16 (dd, J = 2.6, 4.0Hz, 1H), 9.62 (s, 1H), 9.32-9.15 (m, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.88 (br s,1H),7.15(d,J=8.6Hz,2H),6.73(d,J=8.6Hz,2H),4.66-4.58(m,2H),3.67(s,3H),3.00(d,J=6.8Hz,2H),2.68(s,3H),2.18(s,3H).

[1143] Example 51

[1144] 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

[1145]

[1146] The title compound was prepared according to the following scheme:

[1147]

[1148] Step 1: Preparation of 4-benzyloxy-5-bromo-3-methyl-1-pent-3-ynyl-pyrazole (Compound 51-a)

[1149] 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). Under a N2 balloon, the mixture was stirred at 80°C for 16 hours. The mixture was concentrated and purified via preparative TLC to give compound 51-a (140 mg). LCMS (M+H) + :332.

[1150] Step 2: Preparation of (4-benzyloxy-5-methyl-2-pent-3-ynyl-pyrazol-3-yl)boronic acid (Compound 51-b)

[1151] At -70 ° C under N2 atmosphere, 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 dropwise n-BuLi (2.5 M, 0.14 mL, 0.36 mmol). The mixture was stirred at -70 ° C for 1 h, and 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 hours. At 0 ° C, the reaction mixture was poured into a saturated aqueous solution of NH4Cl (10 ml) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to obtain crude compound 51-b (60.0 mg). LCMS (M+H) + :299.

[1152] Step 3: Preparation of 3,5-dibromo-1-[(4-methoxyphenyl)methyl]-1,2,4-triazole (Compound 51-c)

[1153] Under N2 balloon, 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), DIEA (43.7 mL, 264 mmol) in MeCN (200 mL) was stirred at 80 ° C. for 16 hours. The mixture was concentrated and purified by column chromatography to give compound 51-c (30 g). LCMS (M+H) + :346, 1 H NMR (400MHz, 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).

[1154] 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)

[1155] To 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) in DMF (30 mL) was added CuI (0.59 g, 3.06 mmol), 1-N,2-N-dimethylcyclohexane-1,2-diamine (435 mg, 3.06 mmol) and K PO (6.5 g, 30.64 mmol). Under N , the mixture was stirred at 120 ° C for 12 hours. The reaction mixture was poured into ice water (1000 mL) and extracted with ethyl acetate (3 x 500 mL). The organic layer was washed with water (2 x 500 mL) and brine (2 x 500 mL). The combined organic layer was dried over Na SO , filtered and concentrated. The residue was triturated with ethyl acetate (30 mL) and filtered to give compound 51-d (4.8 g). LCMS (M+H) + :592, 1 H NMR (400MHz, DMSO-d6) δ = 9.45 (s, 1H), 9.06 (t, J = 5.6Hz, 1H), 8.01 (s, 1H), 7.28 (d, J = 8.4Hz, 2H), 7.16 (d, J = 8.4Hz, 1H), 6.79 (d, J = 8. 4Hz,2H),6.58(s,1H),6.47(d,J=8.2Hz,1H),5.89(s,2H),4.49(d,J=5.6Hz,2H),3.80(s,3H),3.74(s,3H),3.68(s,3H),2.64(s,3H).

[1156] 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)

[1157] To a solution of compound 51-d (80 mg, 0.14 mmol) in 1,4-dioxane (5 mL) and water (0.500 mL) were added compound 51-b (60 mg, 0.2 mmol), K2CO3 (93 mg, 0.68 mmol) and Pd(dppf)Cl2.DCM (33 mg, 0.04 mmol). Under an N2 atmosphere, the mixture was stirred at 100°C for 12 hours. 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.

[1158] 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)

[1159] To a solution of compound 51-e (90 mg, 0.12 mmol) in HFIP (2 mL) was added MsOH (112 mg, 1.18 mmol) at 25° C. The mixture was stirred at 25° C. for 1 h to give a red solution. The mixture was purified by reverse phase column to give Example 51 (8 mg). LCMS (M+H) + :406.1, 1 H NMR (400MHz, 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 (br t,J=6.8Hz,2H),2.67(s,3H),2.64-2.58(m,2H),2.18(s,3H),1.61(s,3H).

[1160] Example 52

[1161] 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

[1162]

[1163] Example 52 was prepared similarly to the preparation of Example 51 by using 1-(2-bromoethyl)-4-fluorobenzene instead of 3-pentyn-1-ol in Step 1.

[1164] Example 52 (18.12 mg), LCMS (M+H) + :462, 1 H NMR (400MHz, DMSO-d6) δ = 9.60 (s, 1H), 8.03 (s, 1H), 7.99 (br s, 1H), 7.82 (br s,1H),7.27(dd,J=5.6,8.4Hz,2H),6.98(t,J=8.8Hz,2H),4.73-4.59(m,2H),3.06(br t,J=7.6Hz,2H),2.67(s,3H),2.17(s,3H).

[1165] Example 53

[1166] 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

[1167]

[1168] The title compound was prepared according to the following scheme:

[1169]

[1170] Step 1: Preparation of methyl 4-benzyloxy-5-methyl-2-(2-phenylethyl)pyrazole-3-carboxylate (Compound 53-a)

[1171] To a solution of methyl 4-benzyloxy-3-methyl-1H-pyrazole-5-carboxylate (23-d, 2.0 g, 8.12 mmol) in DMF (20 mL) was added 1-bromo-2-phenylethane (2.25 g, 1.66 mL, 12.18 mmol) and K2CO3 (3.37 g, 24.36 mmol). The mixture was stirred at 80 ° C for 12 hours and then concentrated. The residue was purified by column chromatography to obtain compound 53-a (1.7 g). LCMS (M+H) + :351, 1 H 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).

[1172] Step 2: Preparation of 4-benzyloxy-5-methyl-2-(2-phenylethyl)pyrazole-3-carbohydrazide (Compound 53-b)

[1173] To a solution of compound 53-a (1.5 g, 4.28 mmol) in methanol (15 mL) was added hydrazine hydrate (2.19 g, 42.81 mmol) at 25°C. The mixture was then stirred at 80°C for 4 hours. The mixture was concentrated to give compound 53-b (1.4 g). LCMS (M+H) + :351.

[1174] Step 3: Preparation of 1-[[4-benzyloxy-5-methyl-2-(2-phenylethyl)pyrazole-3-carbonyl]amino]-3-[(4-methoxyphenyl)methyl]thiourea (Compound 53-c)

[1175] To a yellow solution of compound 53-b (1.5 g, 4.28 mmol) and DIPEA (2.12 mL, 12.84 mmol) in THF (20 mL) was added 4-methoxybenzyl isothiocyanate (1.53 g, 8.56 mmol) at 25°C. The mixture was then stirred at 30°C for 3 hours. The mixture was concentrated to obtain compound 53-c (2.2 g). LCMS (M+H) + :530.

[1176] 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)

[1177] A yellow solution of 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 x 100 mL). The organic layer was washed with water (3 x 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.

[1178] 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)

[1179] To a solution of compound 53-d (1.3 g, 2.54 mmol) in acetic acid (4 mL) was slowly added H2O2 (2.91 g, 25.68 mmol) and then stirred at 25 ° C for 1 h. The reaction mixture was poured into a saturated solution of Na2SO3 (300 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4 and concentrated. The residue was purified by column chromatography to obtain compound 53-e (1.0 g). LCMS (M+H) + :480.

[1180] 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)

[1181] 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) in 1,4-dioxane (2 mL) was added Pd(OAc)2 (14 mg, 0.06 mmol), Cs2CO3 (67 mg, 0.21 mmol), PCy3HBF4 (30 mg, 0.08 mmol), CuI (79 mg, 0.42 mmol) and compound 53-e (0.1 g, 0.21 mmol) in a single portion. The mixture was stirred at 140 ° C. for 12 hours in a sealed tube. (The reaction was set up in a glove box). The mixture was concentrated and purified via preparative TLC to give compound 53-f (60 mg). LCMS (M+H) + :804.

[1182] 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)

[1183] 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 hours. The reaction mixture was purified by reverse phase HPLC to obtain Example 53 (18.0 mg). LCMS (M+H) + :444, 1 H NMR (400MHz, DMSO-d6) δ = 14.17-13.83 (m, 1H), 9.68 (d, J = 1.4Hz, 1H), 9.32-8.79 (m, 2H), 8.21-7. 80(m,2H),7.29-7.11(m,5H),4.69(d,J=1.8Hz,2H),3.13-2.99(m,2H),2.50(s,3H),2.16(s,3H).

[1184] Example 54

[1185] 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

[1186]

[1187] Example 54 was prepared analogously to the preparation of Example 51 by using 1-(2-bromo-ethyl)-3-methoxy-benzene instead of 3-pentyn-1-ol in Step 1.

[1188] Example 54 (6.9 mg), LCMS (M+H) + :474, 1 H NMR (400MHz, DMSO-d6) δ = 14.17 (br s, 1H), 9.63 (d, J = 1.2Hz, 1H), 9.34-9.15 (m, 1H), 8.08 (s, 1H), 7.98 (br d,J=0.9Hz,1H),7.85(brs,1H),7.09(t,J=7.8Hz,1H),6.79(d,J=7.6Hz,1H),6.75-6.67(m,2H),4.69(br t,J=7.6Hz,2H),3.56(s,3H),3.10-3.00(m,2H),2.68(s,3H),2.19(s,3H).

[1189] Example 55

[1190] 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

[1191]

[1192] Example 55 was prepared similarly to the preparation of Example 51 by using Compound 55-b instead of Compound 51-b in Step 5.

[1193] Compound 55-b was prepared according to the following scheme:

[1194]

[1195] Step 1: Preparation of 4-(benzyloxy)-5-bromo-1-(3-fluorophenethyl)-3-methyl-1H-pyrazole (Compound 55-a)

[1196] To a solution of 4-benzyloxy-5-bromo-3-methyl-1H-pyrazole (46-b, 400.0 mg, 1.5 mmol) in DMF (1 mL) was added CsCO (1463.7 mg, 4.49 mmol) and 1-(2-bromoethyl)-3-fluoro-benzene (912 mg, 4.49 mmol). The mixture was stirred at 100 ° C for 12 hours. The reaction mixture was diluted with H O (50 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine, dried over Na SO and concentrated. The residue was purified by column chromatography and preparative HPLC to obtain compound 55-a (130 mg). LCMS (M+H) + :389, 1 HNMR (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 (br d, 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).

[1197] 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)

[1198] At -78 ° C under N2 atmosphere, to 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) was dropwise added n-BuLi (2.5 M, 0.12 mL, 0.31 mmol). The mixture was stirred at -78 ° C for 1 h, then slowly warmed to 20 ° C and stirred for 1 h. At 0 ° C, the mixture was poured into a saturated aqueous solution of NH4 Cl (10 ml) and extracted with EtOAc (3 x 10 mL). The organic layer was washed with salt water and dried over anhydrous Na2SO4 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.

[1199] Example 55 (18 mg), LCMS (M+H) + :462, 1H NMR (400MHz, DMSO-d6)δ=14.16(br s,1H),9.61(s,1H),9.24(br s,1H),8.08(s,1H),7.99(br s,1H),7.83(br s,1H),7.25-7.14(m,1H),7.07-6.92(m,3H),4.70(br t,J=7.6Hz,2H),3.10(br t,J=7.6Hz,2H),2.68(s,3H),2.17(s,3H).

[1200] Example 56

[1201] 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

[1202]

[1203] Example 56 was prepared similarly to the preparation of Example 51 by using 2-fluorophenethyl alcohol instead of 3-pentyn-1-ol in Step 1 and using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of triisopropyl borate in Step 2.

[1204] Example 56 (35.3 mg), LCMS (M+H + ):462, 1 H NMR (400MHz, DMSO-d6)δ=14.35-13.88(m,1H),9.63(s,1H),9.03(s,1H),8.11(s,1H),8.02(s,1H),7.81(s,1H) ,7.29-7.15(m,2H),7.04-6.92(m,2H),4.72(t,J=6.8Hz,2H),3.11(t,J=6.8Hz,2H),2.69(s,3H),2.17(s,3H).

[1205] Example 57

[1206] 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

[1207]

[1208] Similar to the preparation of Example 53, Example 57 was prepared by using Compound 4-g instead of Intermediate A1 in Step 6.

[1209] Example 57 (7.9 mg), LCMS (M+H) + :461, 1 H NMR (400MHz, DMSO-d6)δ=14.37-13.69(m,1H),9.63(s,1H),9.22(s,1H),9.21-8.78(m,1H),7.92-7.74(m,1H ),7.56-7.37(m,1H),7.23-7.16(m,5H),4.69(t,J=7.6Hz,2H),3.08-3.02(m,2H),2.49(s,3H),2.16(s,3H).

[1210] Example 58

[1211] 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

[1212]

[1213] The title compound was prepared according to the following scheme:

[1214]

[1215] 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)

[1216] To a stirred mixture of 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) in 1,4-dioxane (8 mL) was added 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). The resulting mixture was stirred at 140 ° C for 16 hours under a nitrogen atmosphere. The mixture was cooled and concentrated. The residue was purified by silica gel column chromatography to obtain compound 58-a (40 mg). LCMS (M+H) + :694.

[1217] 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)

[1218] To a stirred mixture of ethyl compound 58-a (35 mg, 0.05 mmol) in THF (1 mL) and methanol (1 mL) was added a solution of sodium hydroxide (22 mg, 0.55 mmol) in water (1 mL) dropwise at 0° C. The resulting mixture was stirred at 25° C. for 16 hours and then acidified to pH=5 with HCl (1.0 M aqueous solution) at 0° C. The suspension was filtered and the wet cake was dried to give compound 58-b (25 mg). LCMS (M+H) + :666.

[1219] 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)

[1220] To a stirred mixture of compound 58-b (20 mg, 0.03 mmol) in DMSO (4 mL) was added acetic acid (0.5 mg, 0.01 mmol) and silver carbonate (2.1 mg, 0.01 mmol). Under a nitrogen atmosphere, the resulting mixture was stirred at 85 ° C for 3 hours. The mixture was poured into ice / water (10 mL) and extracted with EtOAc (3 x 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.

[1221] 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)

[1222] 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). Under a nitrogen atmosphere, the resulting mixture was stirred at 50 ° C for 5 hours. The mixture was cooled to room temperature. The residue was purified via reverse phase flash chromatography to give Example 58 (5.7 mg) as a white solid. LCMS (M+H)+ :382. 1 H NMR(400MHz, DMSO-d6)δ=9.57(s,1H),8.99(s,1H),8.66(s,1H),8.00(s,2H),7.78(s,1 H),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).

[1223] Example 59

[1224] 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

[1225]

[1226] Example 59 was prepared similarly to the preparation of Example 58 by using Compound 49-b instead of Compound 31-h.

[1227] Example 59 (3.0 mg), LCMS (M+H) + :396, 1 H NMR (400MHz, DMSO-d6) δ = 9.55 (s, 1H), 9.01 (br s,1H),8.66(s,1H),8.00(s,2H),7.78(s,1H),4.49-4.46(m,2H),2.65(s, 3H),2.16(s,3H),1.81-1.77(m,2H),1.33-1.31(m,2H),0.91-0.87(m,3H).

[1228] Example 60

[1229] 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

[1230]

[1231] Example 60 was prepared similarly to the preparation of Example 51 by using 3-(2-hydroxyethyl)benzonitrile instead of 3-pentyn-1-ol in Step 1 and using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of triisopropyl borate in Step 2.

[1232] Example 60 (30 mg), LCMS (M+H)+ :469, 1 H NMR (400MHz, DMSO-d6)δ=14.12(br s,1H),9.60(s,1H),9.25(br s,1H),8.06(s,1H),8.03(br s,1H),7.80(br s,1H),7.61-7.55(m,2H),7.53(br d, J=7.8Hz, 1H), 7.36 (t, J=7.8Hz, 1H), 4.75 (br t, J=7.2Hz, 2H), 3.16 (brt, J=7.2Hz, 2H), 2.68 (s, 3H), 2.18 (s, 3H).

[1233] Example 61

[1234] 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

[1235]

[1236] Example 61 was prepared similarly to the preparation of Example 51 by using 4-(2-hydroxyethyl)benzonitrile instead of 3-pentyn-1-ol in Step 1 and using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of triisopropyl borate in Step 2.

[1237] Example 61 (17.6 mg), LCMS (M+H) + :469, 1 H NMR (400MHz, DMSO-d6) δ = 14.14 (s, 1H), 9.57 (d, J = 1.0Hz, 1H), 9.42-9.15 (m, 1H), 8.06 (s, 2H), 7.86 (s, 1H), 7.61 (d, J=8.2Hz, 2H), 7.42 (d, J=8.2Hz, 2H), 4.72 (t, J=7.2Hz, 2H), 3.17 (t, J=7.2Hz, 2H), 2.68 (s, 3H), 2.16 (s, 3H).

[1238] Example 62

[1239] 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

[1240]

[1241] Example 62 was prepared similarly to the preparation of Example 51 by using methyl 4-(2-hydroxyethyl)benzoate instead of 3-pentyn-1-ol in Step 1 and using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of triisopropyl borate in Step 2.

[1242] Example 62 (14 mg), LCMS (M+H) + :502, 1 H NMR (400MHz, DMSO-d6) δ = 14.13 (s, 1H), 9.57 (d, J = 1.0Hz, 1H), 9.23 (s, 1H), 8.09-7.99 (m, 2H), 7.83 (br s,1H),7.72(d,J=8.4Hz,2H),7.32(d,J=8.0Hz,2H),4.73(br t,J=7.2Hz,2H),3.79(s,3H),3.17-3.12(m,2H),2.67(s,3H),2.17(s,3H).

[1243] Example 63

[1244] 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

[1245]

[1246] The title compound was prepared according to the following scheme:

[1247]

[1248] Analogously to the preparation of compound 49-c, 2-[4-benzyloxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyrazol-1-yl]ethoxy-tert-butyl-dimethyl-silane (compound 63-a) was prepared by 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.

[1249] 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)

[1250] To a solution of compound 63-a (1.3 g, 2.75 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added 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), KCO (1.2 g, 8.44 mmol) and Pd(dppf)Cl.DCM (413 mg, 0.51 mmol). Under N atmosphere, the mixture was stirred at 100 ° C for 12 hours. It was then cooled and poured into water (100 mL). The suspension was extracted with EtOAc (100 mL x 2). The organic phase was washed with brine (20 mL x 2), dried over NaSO and concentrated. The residue was purified by column chromatography to give compound 63-b (1.1 g). LCMS (M+H) + :858.

[1251] 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)

[1252] 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) in methanol (10 mL) was added NH4F (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 x 2). The filtrate was concentrated and purified by column chromatography to give compound 63-c (750 mg). LCMS (M+H) + :744.

[1253] 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)

[1254] To a solution of compound 63-c (300 mg, 0.40 mmol) in DCM (10 mL) was added Dess-Martin periodinane (684 mg, 1.61 mmol). The mixture was stirred at 25 ° C for 2 hours. It was then poured into a mixture of saturated Na2SO3 solution (30 mL) and saturated NaHCO3 solution (30 mL). The mixture was stirred for 20 min and extracted with DCM (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give compound 63-d (300 mg). LCMS (M+H) + :742.

[1255] 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)

[1256] To a solution of compound 63-d (300 mg, 0.40 mmol) in DMF (1 mL) was added 2-(triphenylphosphine) difluoroacetate (582 mg, 1.62 mmol). The mixture was stirred at 80 ° C for 12 hours. The mixture was poured into water (30 mL) and extracted with EtOAc (30 mL x 2), and the organic phase was washed with brine (10 mL x 3), dried over Na2SO4, and concentrated. The residue was purified via preparative TLC to obtain compound 63-e (60 mg). LCMS (M+H) + :776.

[1257] 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)

[1258] To a solution of compound 63-e (55 mg, 0.07 mmol) in HFIP (0.3 mL) was added MsOH (136 mg, 1.42 mmol). The mixture was stirred at 50 ° C for 0.5 h. The mixture was then directly purified via preparative HPLC to give Example 63 (30 mg). LCMS (M+H) + :416, 1 H NMR(DMSO-d6,400MHz)δ=14.28(br s,1H),9.62(s,1H),9.34(br s,1H),8.05(s,2H),7.78(br s,1H),5.13(br d,J=7.6Hz,2H),5.02-4.90(m,1H),2.66(s,3H),2.18(s,3H).

[1259] Example 64

[1260] 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

[1261]

[1262] Similar to the preparation of Example 51, Example 64 was prepared by using Compound 64-a instead of 3-pentyn-1-ol in Step 1 and using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of triisopropyl borate in Step 2.

[1263] Compound 64-a was prepared according to the following scheme:

[1264]

[1265] Step 1: Preparation of 2-[4-(methoxymethyl)phenyl]ethanol (Compound 64-a)

[1266] To a solution of 2-[4-(methoxymethyl)phenyl]acetic acid (800 mg, 4.44 mmol) in THF (20 mL) was added LiAlH4 (505 mg, 13.32 mmol) at 0°C, and 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 x 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated to give compound 64-a (650 mg). LCMS (M+H) + :415, 1H 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).

[1267] Example 64 (30 mg), LCMS (M+H) + :488, 1 H NMR (400MHz, DMSO-d6) δ=14.16(br s,1H),9.62(d,J=1.0Hz,1H),9.23(br s,1H),8.08(s,1H),8.00(br s,1H),7.86(br s,1H),7.23-7.18(d,J=8.0Hz,2H),7.11(d,J=8.0Hz,2H),4.68(br t,J=7.6Hz,2H),4.32(s,2H),3.23(s,3H),3.10-3.03(br t,J=6.8Hz,2H),2.69(s,3H),2.19(s,3H).

[1268] Example 65

[1269] 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

[1270]

[1271] Similar to the preparation of Example 51, Example 65 was prepared by using Compound 65-c instead of 3-pentyn-1-ol in Step 1 and using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of triisopropyl borate in Step 2.

[1272] Compound 65-c was prepared according to the following scheme:

[1273]

[1274] Step 1: Preparation of methyl 2-[3-(bromomethyl)phenyl]acetate (Compound 65-a)

[1275] To a solution of methyl 3-methylphenylacetate (9.0 g, 54.81 mmol) in carbon tetrachloride (1 mL) was added BPO (1.33 g, 5.48 mmol) and NBS (9.76 g, 54.81 mmol). Under N2, the reaction mixture was stirred at 90 ° C for 18 hours. The reaction mixture was poured into water (100 mL) and extracted with DCM (200 mL x 2). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and purified via flash chromatography on silica gel to obtain compound 65-a (5.0 g). LCMS (M+H) + :243, 1 H NMR (400MHz, 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).

[1276] Step 2: Preparation of methyl 2-[3-(methoxymethyl)phenyl]acetate (Compound 65-b)

[1277] At 0 ° C, NaOMe (5.0 mL, 25.0 mmol) was added to a solution of compound 65-a (5.0 g, 20.6 mmol) in methanol (50 mL). The reaction mixture was stirred at 25 ° C for 18 hours and poured into a saturated NH4Cl solution (50 mL), which was then extracted with EA (50 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified via a reverse phase column to obtain compound 65-b (1.5 g). LCMS (M-CH3O) + :163.

[1278] Step 3: Preparation of 2-[3-(methoxymethyl)phenyl]ethanol (Compound 65-c)

[1279] At 0 ° C, to a solution of compound 65-b (1.5 g, 7.7 mmol) in THF (15 mL) was added LiAlH4 (2.5 M, 3.86 mL, 9.64 mmol). The reaction mixture was stirred at 0 ° C for 1 h and poured into a 1N aqueous solution of HCl (20 mL). It was then extracted with EA (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated to obtain a residue. The residue was purified via column to obtain compound 65-c (600 mg). LCMS (M-CH3O) + :135.

[1280] Example 65 (32.3 mg), LCMS (M+H) + :488, 1 H NMR (400MHz, DMSO-d6) δ = 14.16 (br d, J = 2.6Hz, 1H), 9.65 (d, J = 1.0Hz, 1H), 9.47-8.96 (m, 1H), 8.12 (s, 1H), 8.07 (br s, 1H), 7.85 (br s,1H),7.20-7.04(m,4H),4.75-4.65(m,2H),4.17(s,2H),3.09(s,3H),3.07(br s,2H),2.70(s,3H),2.19(s,3H).

[1281] Example 66

[1282] 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

[1283]

[1284] The title compound was prepared according to the following scheme:

[1285]

[1286] Step 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)

[1287] 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) in THF (2 mL) and EtOAc (2 mL) was added Pd / C (20 mg) at 20° C. under N2 atmosphere. The mixture was degassed and purged with H2 three times, then stirred with H2 balloon at 20° C. for 10 min. The mixture was purified via preparative HPLC to give Example 66 (5 mg) as a yellow solid. LCMS (M+H) + :418, 1H NMR (DMSO-d6, 400MHz) δ = 14.34-14.17 (m, 1H), 9.62 (d, J = 0.8Hz, 1H), 9.43-9.20 (m, 1H), 8.15-7.95 (m, 2H), 7.79 (br s,1H),6.34-5.98(m,1H),4.66(t,J=7.2Hz,2H),2.67(s,3H),2.43-2.35(m,2H),2.18(s,3H).

[1288] Example 67

[1289] 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

[1290]

[1291] Example 67 was prepared similarly to the preparation of Example 58 by using Compound 67-a instead of Compound 31-h.

[1292] Compound 67-a was prepared according to the following scheme:

[1293]

[1294] Step 1: Preparation of 4-(benzyloxy)-5-bromo-1-(3,3-difluoropropyl)-3-methyl-1H-pyrazole (Compound 67-a)

[1295] At 0 ° C, to a stirred mixture of 4- (benzyloxy) -5- bromo -3- methyl -1H- pyrazole (46-b, 1.50 g, 5.62 mmol), 3,3- difluoropropane -1- alcohol (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. The resulting mixture was stirred at 40 ° C for 4 hours. It was then cooled and slowly poured into ice / water (50 mL). The mixture was extracted with EtOAc (3 x 50 mL), and the organic layer was dried and concentrated. The residue was purified via silica gel column chromatography to obtain compound 67-a (800 mg). LCMS (M + H) + :345.The structure is used 1 The results were confirmed by H NMR and nuclear Overhauser effect spectroscopy (NOESY) (no correlation between Ha and Hb was observed).

[1296] Example 67 (8.8 mg), LCMS (M+H) +:418. 1 H NMR (400MHz, DMSO-d6) δ = 9.54 (s, 1H), 9.19 (br s,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).

[1297] Example 68

[1298] 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

[1299]

[1300] The title compound was prepared according to the following scheme:

[1301]

[1302] 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 via preparative HPLC to give Example 68 (1.4 mg), LCMS (M+H) + :474, 1 H NMR (400MHz, DMSO-d6)δ=14.16(br s,1H),9.63(s,1H),9.22(s,1H),8.06(s,1H),7.98(br s,1H),7.84(br s,1H),7.21-7.16(m,2H),7.15-7.10(m,2H),4.65(br dd,J=7.6,8.4Hz,2H),4.41(s,2H),3.08-3.02(m,2H),2.68(s,3H),2.18(s,3H).

[1303] Example 69

[1304] 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

[1305]

[1306] Similar to the preparation of Example 53, Example 69 was prepared by using 4-methoxyphenethyl bromide instead of 1-bromo-2-phenylethane in Step 1 and using Compound 4-g instead of Intermediate A1 in Step 6.

[1307] Example 69 (6.2 mg), LCMS (M+H) + :491, 1 H NMR(400MHz, DMSO-d6)δ=14.19-13.59(m,1H),9.61(s,1H),9.22(s,1H),9.19-8.91(m,1H),7.93-7.69(m,1H),7.60-7.37(m,1H) ,7.10(d,J=8.6Hz,2H),6.76(d,J=8.6Hz,2H),4.69-4.62(m,2H),3.68(s,3H),3.00-2.95(m,2H),2.49-2.48(m,3H),2.16(s,3H).

[1308] Example 70

[1309] 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

[1310]

[1311] Example 70 was prepared analogously to the preparation of Example 53 by using 4-methoxyphenethyl instead of 1-bromo-2-phenylethane in Step 1.

[1312] Example 70 (20 mg), LCMS (M+H) + :474.3, 1H NMR (400MHz, DMSO-d6+D2O) δ = 9.57 (s, 1H), 9.02 (s, 1H), 7.00 (d, J = 8.4Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 4.60 (t, J = 7.2 Hz, 2H), 3.59 (s, 3H), 2.91 (t, J = 7.2 Hz, 2H), 2.45 (s, 3H), 2.12 (s, 3H).

[1313] Example 71

[1314] 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

[1315]

[1316] The title compound was prepared according to the following scheme:

[1317]

[1318] Step 1: Preparation of [4-(2-bromoethyl)phenyl]methanol (Compound 71-a)

[1319] At 0 ° C, to a solution of 4- (2- bromoethyl) benzoic acid (20.0 g, 87.3 mmol) in THF (200 mL) was added BH .THF (1.0 M, 174.6 mL, 174.6 mmol). The reaction mixture was warmed to 25 ° C and stirred for 2 hours. It was then poured into 1N HCl (100 mL) and extracted with EA (200 mL x 2). The combined layer was washed with brine (20 mL), dried over Na SO and concentrated to give compound 71-a (18.0 g) as a light yellow solid. LCMS (M+H-18) + :197.

[1320] Step 2: Preparation of [4-(2-bromoethyl)phenyl]methoxy-tert-butyl-dimethyl-silane (Compound 71-b)

[1321] At 0 ° C, to [4- (2- bromoethyl) phenyl] methanol 71-a (8.0 g, 37.2 mmol), Et3N (14.3 mL, 111.6 mmol) in DCM (100 mL) was added TBSCl (8.41 g, 55.8 mmol). The reaction mixture was warmed to 25 ° C and stirred for 18 hours. It was then poured into water (100 mL) and extracted with DCM (100 mL x 2). The combined layer was washed with brine (100 mL), dried over Na2SO4, and concentrated to obtain an oil. The residue was purified via column to obtain 71-b (8.0 g). LCMS (M+H-C6H 15 SiO) + :197.

[1322] 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)

[1323] Similar to the preparation of Example 53, compound 71-c was prepared by using compound 71-b instead of 1-bromo-2-phenylethane in step 1.

[1324] 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)

[1325] To a yellow solution of compound 71-c (1.5 g, 2.9 mmol) and imidazole (400 mg, 5.9 mmol) in DCM (20 mL) was added TBSCl (2.96 g, 5.9 mmol) at 25°C. The mixture was stirred for 2 hours and concentrated. The residue was purified by column chromatography to give compound 71-d (1.2 g). LCMS (M+H) + :624.

[1326] 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)

[1327] Under N2 atmosphere, a suspension of 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), K2CO3 (199 mg, 1.44 mmol) in toluene (2 mL) was stirred at 120 ° C for 12 hours. The mixture was filtered and washed with DCM / MeOH (V / V=20 / 1, 20 mL). The filtrate was concentrated and purified by preparative TLC to give compound 71-e (55 mg). LCMS (M+H) + :948.

[1328] 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)

[1329] Under N2 atmosphere, a solution of compound 71-e (50.0 mg, 0.05 mmol) in TFA (3 mL) was stirred at 60 ° C for 12 hours. The mixture was concentrated and purified by preparative HPLC to give Example 71 (6.2 mg). LCMS (M+H) + :474, 1 H NMR (400MHz, DMSO-d6+D2O)δ=9.68(s,1H),9.10(s,1H),7.36-6.83(m,4H),4.66(br s,2H),4.41(s,2H),3.04(br t,J=7.8Hz,2H),2.50-2.50(m,3H),2.16(s,3H).

[1330] Example 72

[1331] 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

[1332]

[1333] Similar to the preparation of Example 53, Example 72 was prepared by using 2-(3-pyridyl)ethanol instead of 1-bromo-2-phenylethane in Step 1 (reaction conditions: CMBP, toluene 80°C instead of K2CO3, DMF 80°C).

[1334] Example 72 (18.7 mg), LCMS (M+H) + :445, 1 H NMR (400MHz, DMSO+D2O) δ = 9.65 (s, 1H), 9.12 (s, 1H), 9.05-8.81 (m, 1H), 8.35 (br d, J = 3.8Hz, 1H), 7.63 (br d, J=7.4Hz, 1H), 7.24 (dd, J=4.8, 7.6Hz, 1H), 4.69 (br t, J=7.2Hz, 2H), 3.09 (br t, J=7.2Hz, 2H), 2.49 (br s, 3H), 2.15 (s, 3H).

[1335] Example 73

[1336] 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

[1337]

[1338] Similar to the preparation of Example 53, Example 73 was prepared by using 2-(3-pyridyl)ethanol instead of 1-bromo-2-phenylethane in Step 1 (reaction conditions: CMBP, toluene 80°C instead of K2CO3, DMF 80°C) and using compound 4-g instead of intermediate A1 in Step 6.

[1339] Example 73 (8.91 mg), LCMS (M+H) + :462, 1 H NMR (400MHz, DMSO-d6+D2O) δ=9.56(s,1H),9.17(s,1H),8.34-8.23(m,2H),7.52(br d,J=8.4Hz,1H),7.18(dd,J=4.8,7.8Hz,1H),4.73(br t,J=7.2Hz,2H),3.09(br t,J=7.2Hz,2H),2.46(s,3H),2.13(s,3H).

[1340] Example 74

[1341] 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

[1342]

[1343] Example 74 was prepared similarly to the preparation of Example 58 by using Compound 74-a instead of Compound 31-h.

[1344] Compound 74-a was prepared according to the following scheme:

[1345]

[1346] Step 1. Preparation of 3-(2-(4-(benzyloxy)-5-bromo-3-methyl-1H-pyrazol-1-yl)ethyl)pyridine (Compound 74-a)

[1347] To 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) in THF (8 mL) 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 via silica gel column to obtain compound 74-a (280 mg). LCMS (M+H) + :372.

[1348] Example 74 (15 mg). LCMS (M+H) + :445. 1 H NMR (400MHz, DMSO-d6) δ = 9.50 (s, 1H), 9.07 (br s,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).

[1349] Example 75

[1350] 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

[1351]

[1352] Example 75 was prepared similarly to the preparation of Example 58 by using Compound 75-a instead of Compound 31-h.

[1353] Similar to the preparation of compound 74-a, compound 75-a was prepared by using 2-(3-methoxyphenyl)ethanol instead of 2-(pyridin-3-yl)ethanol.

[1354]

[1355] Example 75 (8.7 mg), LCMS (M+H) + :474. 1 H NMR (400MHz, DMSO-d6)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).

[1356] Example 76

[1357] 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

[1358]

[1359] Similar to the preparation of Example 53, Example 76 was prepared by using 1-bromobutane instead of 1-bromo-2-phenylethane in Step 1 and using Compound 4-g instead of Intermediate A1 in Step 6.

[1360] Example 76 (12.3 mg), LCMS (M+H) + :413, 1H NMR (400MHz, 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=7.0Hz,2H),2.48(s,3H),2.14(s,3H),1.75(br t,J=7.4Hz,2H),1.34-1.23(m,2H),0.87(t,J=7.4Hz,3H).

[1361] Example 77

[1362] 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

[1363]

[1364] Example 77 was prepared analogously to the preparation of Example 53 by using 1-bromobutane instead of 1-bromo-2-phenylethane in Step 1.

[1365] Example 77 (12.1 mg), LCMS (M+H) + ):396, 1 H NMR (400MHz, DMSO-d6) δ = 14.32-13.78 (m, 1H), 9.69 (d, J = 1.4Hz, 1H), 9.10 (s, 1H), 9.08-8.7 5(m,1H),8.22-7.79(m,2H),4.46(t,J=6.6Hz,2H),2.49-2.48(m,3H),2.15(s,3H),1.75(br t,J=7.4Hz,2H),1.32-1.23(m,2H),0.86(t,J=7.4Hz,3H).

[1366] Example 78

[1367] 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

[1368]

[1369] Example 78 was prepared similarly to the preparation of Example 58 by using Compound 78-a instead of Compound 31-h.

[1370] Compound 78-a was prepared similarly to the preparation of compound 74-a by using 2-(4-methoxyphenyl)ethanol instead of 2-(pyridin-3-yl)ethanol.

[1371]

[1372] Example 78 (2.3 mg), LCMS (M+H) + :474. 1 H NMR (400MHz, DMSO-d6) δ = 9.52 (s, 1H), 8.95 (s, 1H), 8.67 (s, 1H), 8.03 (d, J = 5.6Hz, 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).

[1373] Example 79

[1374] 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

[1375]

[1376] Similar to the preparation of Example 53, Example 79 was prepared by using 1-propanol instead of 1-bromo-2-phenylethane in Step 1 (reaction conditions: CMBP, toluene 80°C instead of K2CO3, DMF 80°C) and using compound 4-g instead of intermediate A1 in Step 6.

[1377] Example 79 (18.4 mg), LCMS (M+H) + :399, 1 H NMR (400MHz, 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(br t,J=7.2Hz,2H),2.48(s,3H),2.16(s,3H),1.85-1.74(m,2H),0.88(t,J=7.4Hz,3H).

[1378] Example 80

[1379] 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

[1380]

[1381] Similar to the preparation of Example 53, Example 80 was prepared by using 1-propanol instead of 1-bromo-2-phenylethane in Step 1 (reaction conditions: CMBP, toluene 80° C. instead of K 2 CO 3 , DMF 80° C.).

[1382] Example 80 (4.9 mg) was obtained as a yellow solid. LCMS (M+H) + :382, 1 H NMR (400MHz, DMSO-d6+D2O=9.67(s,1H),9.08(s,1H),4.45-4.32(m,2H),2.47(br s,3H),2.14(br s,3H),1.81-1.72(m,2H),0.83(t,J=7.4Hz,3H).

[1383] Example 81

[1384] 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

[1385]

[1386] Similar to the preparation of Example 51, Example 81 was prepared by using Compound 81-b instead of 3-pentyn-1-ol in Step 1 and using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of triisopropyl borate in Step 2.

[1387] Compound 81-b was prepared according to the following scheme:

[1388]

[1389] Step 1: Preparation of tert-butyl-(5-methoxypent-3-ynyloxy)-dimethyl-silane (Compound 81-a)

[1390] At -78 ° C under N2 atmosphere, to a solution of tert-butyl-but-3-ynyloxy-dimethyl-silane (5.0 g, 27.1 mmol) in THF (25 mL) was added dropwise n-BuLi (13.0 mL, 32.6 mmol). The mixture was stirred at -78 ° C for 0.5 h, and then a solution of bromomethyl methyl ether (4.41 g, 35.3 mmol) in THF (5 mL) was added at -78 ° C. The mixture was stirred for another 0.5 h at -78 ° C. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (3 x 250 mL). The combined organic layers were washed with brine and dried over Na2SO4. 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).

[1391] Step 2: Preparation of 5-methoxypent-3-yn-1-ol (Compound 81-b)

[1392] To a solution of compound 81-a (5.0 g, 21.9 mmol) in methanol (30 mL) was added NH4F (24.33 g, 656.7 mmol). The mixture was stirred at 60 ° C for 1 h. The mixture was filtered and washed with DCM (200 mL x 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).

[1393] Example 81 (8.6 mg), LCMS (M+H) + :436, 1H NMR (400MHz, DMSO-d6) δ = 14.21 (s, 1H), 9.68 (s, 1H), 9.34-9.18 (m, 1H), 8.06 (d, J = 5.0Hz, 2H), 7.78 (d, J = 3. 2Hz, 1H), 4.65 (t, J = 6.8Hz, 2H), 3.96 (s, 2H), 3.10 (s, 3H), 2.76 (t, J = 6.8Hz, 2H), 2.66 (s, 3H), 2.18 (s, 3H).

[1394] Example 82

[1395] 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

[1396]

[1397] Example 82 was prepared similarly to the preparation of Example 53 by using Intermediate A2 instead of Intermediate A1 in Step 6.

[1398] Example 82 (8.4 mg), LCMS (M+H) + :444. 1 H NMR (400MHz, DMSO-d6) δ = 15.33-15.16 (brs, 1H), 8.82 (br s, 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).

[1399] Example 83

[1400] 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

[1401]

[1402] The title compound was prepared according to the following scheme:

[1403]

[1404] 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)

[1405] 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) was added LiBH3NMe2 (0.49 mL, 0.49 mmol) (1 M solution in THF) dropwise at 0 ° C. The reaction was stirred at 25 ° C. for 1 h. The mixture was concentrated and purified by silica gel column chromatography to give compound 83-a (100 mg). LCMS (M+H) + :652.

[1406] 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)

[1407] 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) in HFIP (2 mL) was stirred at 50° C. under nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature and purified via reverse phase HPLC to give Example 84 (3.5 mg). LCMS (M+H) + :412, 1 H NMR (400MHz, DMSO-d6) δ = 9.52 (s, 1H), 8.90 (s, 1H), 8.12 (s, 1H), 8.03 (s, 1H), 7.78 (s, 1H), 5.51 (br s,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).

[1408] Example 84

[1409] 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

[1410]

[1411] Similar to the preparation of Example 48, Example 84 was prepared by using Compound 31-h instead of Compound 40-b and using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of triisopropyl borate in Step 1.

[1412] Example 84 (58 mg), LCMS (M+H) + :396, 1 H NMR (400MHz, DMSO-d6) δ = 9.59 (d, J = 1.0Hz, 1H), 8.30 (s, 1H), 8.09 (s, 2H), 7.92 (s, 1H), 4.33 (t ,J=7.2Hz,2H),4.28(s,3H),2.68(s,3H),2.12(s,3H),1.84-1.71(m,2H),0.85(t,J=7.4Hz,3H)

[1413] Example 85

[1414] 1-[2-(4-Hydroxy-5-methyl-2-propyl-pyrazol-3-yl)oxazol-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

[1415]

[1416] The title compound was prepared according to the following scheme:

[1417]

[1418] 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)

[1419] At 25 ° C, to a solution of ethyl 4-bromooxazole-5-carboxylate (896 mg, 4.07 mmol), 1-bromo-N-[(3,4-dimethylphenyl)methyl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide (intermediate A1, 1500 mg, 3.7 mmol) in toluene (1 mL) and water (0.1 mL) was added K3PO4 (2357 mg, 11.1 mmol), B2Pin2 (1880 mg, 7.4 mmol) and Pd(dppf)Cl2 (541 mg, 0.74 mmol). The mixture was degassed and purged with N2 three times. The mixture was heated to 80 ° C and stirred for 18 hours. The mixture was concentrated and purified via flash chromatography on silica gel to obtain compound 85-a (500 mg). LCMS (M+H) + :466.

[1420] Step 2: 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 ethyl ester (Compound 85-b)

[1421] Under N2 atmosphere, a mixture of 4-[3-[(2,4-dimethoxyphenyl)methylcarbamoyl]-6-methyl-imidazo[1,5-a]pyrazin-1-yl]oxazole-5-carboxylic acid ethyl ester (85-a, 200 mg, 0.43 mmol), 4-benzyloxy-5-bromo-3-methyl-1-propyl-pyrazole (31-h, 132 mg, 0.43 mmol), Pd(OAc)2 (29 mg, 0.13 mmol), PivOH (26 mg, 0.26 mmol), catacxiuma (46 mg, 0.13 mmol), K2CO3 (178 mg, 1.29 mmol) in toluene (1.5 mL) was stirred at 120°C for 12 hours. The mixture was diluted with DCM (30 mL), filtered and washed with water DCM / MeOH = 10 / 1 (20 mL). The filtrate was concentrated and purified by preparative TLC to give compound 85-b (63 mg). LCMS (M+H) + :694.

[1422] 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)

[1423] 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) in methanol (1 mL) was added 1N LiOH aqueous solution (1.0 mL). The mixture was stirred at 20 ° C for 12 hours and diluted with water (20 mL). After the pH was adjusted to 5 with FA, the mixture was extracted with DCM (20 mL x 2). The combined organic phases were dried over Na SO , filtered and concentrated to give compound 85-c (60 mg) as a crude solid, which was used directly in the next step. LCMS (M+H) + :666.

[1424] 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)

[1425] To 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 AcOH (2 mg, 0.04 mmol) and AgCO (10 mg, 0.04 mmol) at 25 ° C. The reaction was stirred at 80 ° C for 2 hours. The mixture was cooled and poured into water (30 mL), and the aqueous phase was extracted with EtOAc (30 mL x 2). The combined organic phases were washed with brine (20 mL x 3), dried over NaSO and concentrated to give compound 85-d (50 mg, crude). LCMS (M+H) + :622.

[1426] 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)

[1427] 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) was added MsOH (0.2 mL). The mixture was stirred at 50 ° C for 0.5 h to give a red solution. The mixture was directly purified via preparative HPLC to give Example 85 (11.8 mg). LCMS (M+H) + :382, 1 H NMR (DMSO-d6, 400MHz) δ = 9.65 (d, J = 1.6Hz, 1H), 9.05 (s, 1H), 8.81 (br s,1H),8.63(s,1H),8.07(s,1H),7.87(s,1H),4.46(t,J=7.2Hz,2H),2.47(s,3H),2.16(s,3H),1.89-1.76(m,2H),0.91(t,J=7.2Hz,3H).

[1428] Example 86

[1429] 1-[2-(2-Butyl-4-hydroxy-5-methyl-pyrazol-3-yl)oxazol-4-yl]-6-methyl-imidazo[1,5-a]pyrazine-3-carboxamide

[1430]

[1431] Similar to the preparation of Example 85, Example 86 was prepared by using Compound 49-b instead of Compound 31-h in Step 2.

[1432] Example 86 (1.1 mg), LCMS (M+H) + :396, 1 H NMR(400MHz, DMSO-d6+D2O)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=7.2Hz,3H).

[1433] Example 87

[1434] 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

[1435]

[1436] Similar to the preparation of Example 53, Example 87 was prepared by using Compound 87-b instead of 1-bromo-2-phenylethane in Step 1 (reaction conditions: CMBP, toluene 80° C. instead of K 2 CO 3 , DMF 80° C.).

[1437] Compound 87-b was prepared according to the following scheme:

[1438]

[1439] Step 1: Preparation of methyl 2-(4-(morpholinomethyl)phenyl)acetate (Compound 87-a)

[1440] To a solution of methyl 2-[4-(bromomethyl)phenyl]acetate (15.0 g, 62 mmol) in methanol (100 mL) was added morpholine (16.0 g, 185 mmol). The mixture was stirred at 25 ° C for 3 hours and concentrated. The residue was treated with water (30 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with saturated aqueous NaCl solution (50 mL), dried over sodium sulfate, filtered and concentrated to give compound 87-a (16.0 g). LCMS (M+H) + :250.

[1441] Step 2: Preparation of 2-(4-(morpholinomethyl)phenyl)ethan-1-ol (Compound 87-b)

[1442] To a solution of methyl 2-[4-(morpholinomethyl)phenyl]acetate (87-a, 16.0 g, 64 mmol) in THF (200 mL) was added LiAlH4 (30.8 mL, 77 mmol) at 0°C. The reaction was stirred at 0°C for 2 hours and then quenched by adding water (150 mL) and 3N NaOH aqueous solution (120 mL). The aluminum salt was filtered through celite and the filtrate was concentrated to give compound 87-b (14.0 g, crude). LCMS (M+H) + :222.

[1443] Example 87 (23.7 mg), LCMS (M+H) + :543, 1H NMR (400MHz, DMSO+D2O) δ = 9.52 (s, 1H), 8.98 (s, 1H), 7.08-6.93 (m, 4H), 4.64 (br t, J = 6.8Hz, 2H), 3.45 (br s, 4H), 3.27 (s, 2H), 2.95 (br t,J=7.1Hz,2H),2.43(s,3H),2.19(br s,4H),2.11(s,3H).

[1444] Example 88

[1445] 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

[1446]

[1447] Example 88 was prepared similarly to the preparation of Example 58 by using Compound 88-a instead of Compound 31-h.

[1448] Similar to the preparation of compound 46-c, compound 88-a was prepared by using compound 87-b instead of 4-pyridineethanol in step 3.

[1449]

[1450] Example 88 (8.5 mg), LCMS (M+H) + :543, 1 H NMR (400MHz, DMSO-d6) δ = 9.53 (d, J = 1.0Hz, 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 (br t,J=7.4Hz,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).

[1451] Example 89

[1452] 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

[1453]

[1454] Example 89 was prepared similarly to the preparation of Example 58 by using Compound 89-a instead of Compound 31-h.

[1455] Similar to the preparation of compound 46-c, compound 89-a was prepared by using compound 64-a instead of 4-pyridineethanol in step 3.

[1456]

[1457] Example 89 (4.2 mg), LCMS (M+H) + :488, 1 H NMR (400MHz, DMSO-d6) δ = 9.53 (d, J = 1.0Hz, 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=7.4Hz,2H),4.28(s,2H),3.20(s,3H),3.06(t,J=7.4Hz,2H),2.67(s,3H),2.17(s,3H).

[1458] Example 90

[1459] 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

[1460]

[1461] Similar to the preparation of Example 53, Example 90 was prepared by using Compound 90-a instead of 1-bromo-2-phenylethane in Step 1 (reaction conditions: CMBP, toluene 80° C. instead of K 2 CO 3 , DMF 80° C.).

[1462] Compound 90-a was prepared according to the following scheme:

[1463]

[1464] Step 1: Preparation of 2-thiazol-2-ylethanol (Compound 90-a)

[1465] A solution of 2-methylthiazole (5 g, 50.43 mmol) 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 give compound 90-a (3 g) as a colorless oil. 1H 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).

[1466] Example 90 (5.6 mg), LCMS (M+H) + :451, 1 H NMR (400MHz, DMSO-d6+D2O) δ = 9.66 (s, 1H), 9.03 (s, 1H), 7.60 (d, J = 3.4Hz, 1H), 7.44 (d, J = 3.4Hz, 1H), 4.83 (br t, J = 6.8Hz, 2H), 3.49 (br t,J=7.0Hz,2H),2.45(s,3H),2.12(s,3H).

[1467] Example 91

[1468] 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

[1469]

[1470] The title compound was prepared according to the following scheme:

[1471]

[1472] 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)

[1473] Similar to the preparation of compound 53-e, compound 91-a was prepared by using 1-iodopropane instead of 1-bromo-2-phenylethane in step 1.

[1474] 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)

[1475] Under N2 atmosphere, a mixture of 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), PCy3HBF4 (54 mg, 0.15 mmol), Cs2CO3 (120 mg, 0.37 mmol) in 1,4-dioxane (3 mL) was stirred at 140°C for 18 hours. The mixture was cooled, filtered and washed with DCM / MeOH (20 mL, v / v=10 / 1). The filtrate was concentrated and purified by preparative TLC to give compound 91-b (100 mg). LCMS (M+H) + :741.

[1476] 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)

[1477] 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) in HFIP (2 mL) was added MsOH (259 mg, 2.7 mmol). The mixture was stirred at 50 ° C for 0.5 h to give a red solution. The mixture was purified via preparative HPLC to give Example 91 (46.8 mg). LCMS (M+H) + :381, 1 H NMR (DMSO-d6, 400MHz) 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 (br t,J=6.8Hz,2H),2.47(s,3H),2.15(s,3H),1.84-1.73(m,2H),0.86(t,J=7.4Hz,3H).

[1478] Example 92

[1479] 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

[1480]

[1481] The title compound was prepared according to the following scheme:

[1482]

[1483] Step 1: Preparation of 4-benzyloxy-5-methyl-2-propyl-pyrazole-3-carboxylic acid methyl ester (Compound 92-a)

[1484] To a solution of methyl 4-benzyloxy-3-methyl-1H-pyrazole-5-carboxylate (23-d, 2.00 g, 8.1 mmol) in toluene (10 mL) was added 1-propanol (585 mg, 9.7 mmol) and cyanomethylenetributylphosphine (2550 mg, 10.5 mmol). The reaction was stirred at 80 ° C for 12 hours. The mixture was purified by column chromatography to give compound 92-a (2.0 g). LCMS (M+H) + :289.

[1485] Step 2: Preparation of 4-benzyloxy-5-methyl-2-propyl-pyrazole-3-carboxylic acid (Compound 92-b)

[1486] To a solution of 4-benzyloxy-5-methyl-2-propyl-pyrazole-3-carboxylic acid methyl ester (92-a, 870 mg, 3.0 mmol) in methanol (10 mL) was added a solution of LiOH.H2O (9.0 mg, 9.0 mmol) in H2O (5 mL). The reaction was stirred at 25 ° C for 2 hours. The mixture was cooled to 0 ° C and adjusted to pH = 3 with 1N HCl aqueous solution, then EtOAc (100 mL) and water (100 mL) were added. After separation, the aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered and concentrated to give compound 92-b (1.6 g, crude). LCMS (M+H) + :275.

[1487] Step 3: Preparation of isobutoxycarbonyl 4-benzyloxy-5-methyl-2-propyl-pyrazole-3-carboxylate (Compound 92-c)

[1488] 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) was added DIPEA (2.1 g, 16.4 mmol) and isobutyl chloroformate (1.5 g, 10.9 mmol). The reaction was stirred at 20 ° C for 2 hours and concentrated to give compound 92-c (2.0 g). LCMS (M+H) + :375.

[1489] Step 4: Preparation of 1-[(4-benzyloxy-5-methyl-2-propyl-pyrazole-3-carbonyl)amino]-1-methyl-thiourea (Compound 92-d)

[1490] To a solution of 1-amino-1-methyl-thiourea (860 mg, 8.15 mmol) in THF (40 mL) was added isobutoxycarbonyl 4-benzyloxy-5-methyl-2-propyl-pyrazole-3-carboxylate (92-c, 1.5 g, 4.07 mmol) and the reaction was stirred at 50 ° C for 12 hours. The mixture was poured into water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with saturated NaHCO3 aqueous solution (300 mL) and brine (300 mL) and then dried over anhydrous Na2SO4. The organic layer was concentrated to give crude compound 92-d (2.0 g). LCMS (M+H) + :362.

[1491] 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)

[1492] 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 was heated to 100 ° C and stirred for 6 hours. The mixture was poured into water (300 ml) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with saturated NaHCO3 aqueous solution (300 mL) and brine (200 mL), then dried over anhydrous Na2SO4. The filtered organic layer was concentrated to give compound 92-e (807 mg). LCMS (M+H) + :344.

[1493] Step 6: Preparation of 3-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)-1-methyl-1,2,4-triazole (Compound 92-f)

[1494] 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 H2O2 (132 mg, 11.6 mmol) at 0°C. The reaction was warmed to 20°C and stirred for 1 h. The mixture was poured into a saturated aqueous Na2SO3 solution (80 mL) and stirred at 0°C for 30 min. The pH was then adjusted to 7-8 with NaHCO3. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to obtain compound 92-f (480 mg). LCMS (M+H) + :312.

[1495] Step 7: Preparation 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 (Compound 92-g)

[1496] 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) in toluene (0.5 mL) was added 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 K2CO3 (133 mg, 0.96 mmol). The mixture was stirred at 120°C for 12 hours and then filtered and washed with DCM / MeOH (20 / 1, 100 ml). The filtrate was concentrated and purified by preparative TLC to give compound 92-g (80 mg). LCMS (M+H) + :636.

[1497] 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)

[1498] To 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 MsOH (226 mg, 2.36 mmol). The mixture was stirred at 50 ° C for 1 h. The reaction mixture was filtered and the filtrate was purified via preparative HPLC to give Example 92 (22.7 mg) as a yellow solid. LCMS (M+H) + :396, 1 H NMR (400MHz, DMSO-d6) δ = 9.71 (s, 1H), 9.15 (s, 1H), 8.37 (s, 1H), 7.97 (s, 1H), 7.91 (d, J = 1.4Hz, 1H), 4.45 (s,3H),4.36(t,J=7.2Hz,2H),2.51-2.50(m,3H),2.12(s,3H),1.91-1.70(m,2H),0.85(t,J=7.4Hz,3H).

[1499] Example 93

[1500] 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

[1501]

[1502] The title compound was prepared according to the following scheme:

[1503]

[1504] Step 1: Preparation of 2-(4-benzyloxy-5-methyl-2-propyl-pyrazol-3-yl)oxazole-5-carboxylic acid ethyl ester (Compound 93-a)

[1505] At -63 ° C, to a solution of 4-benzyloxy-5-bromo-3-methyl-1-propyl-pyrazole (31-h, 500 mg, 1.6 mmol) in THF (3 mL) was added n-BuLi (650 μL, 1.6 mmol) dropwise. The reaction was stirred at this temperature for 10 min and ZnCl2 (3.2 mL, 1.6 mmol) was added. Stirring was continued at this temperature for 30 min, the reaction was warmed to room temperature and stirred for 1 h. 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-G3 (137 mg, 0.16 mmol) in 1,4-dioxane (6 mL) was degassed for 5 min. The above zincate solution was added at 20 ° C and the reaction was heated to 80 ° C for 90 min. The reaction was quenched by pouring into ice water containing 2.5 mL of 1N 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.

[1506] Step 2: 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 ethyl ester (Compound 93-b)

[1507] 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) was 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-G3 (181 mg, 0.25 mmol). Under an N2 atmosphere, the reaction 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 via preparative TLC to give the crude product. It was then purified again via reverse phase to give compound 93-b (40 mg). LCMS (M+H) + :711.

[1508] 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)

[1509] 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) in methanol (4 mL) and water (2 mL) was added LiOH.H2O (12 mg, 0.28 mmol). The reaction 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 x 3). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give crude compound 93-c (33 mg). LCMS (M+H) + :683.

[1510] 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)

[1511] 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]pyrazine-8-yl]oxazole-5-carboxylic acid (93-c, 33 mg, 0.05 mmol) in DMSO (1 mL) was added AcOH (1.2 mg, 0.02 mmol) and AgCO (5.3 mg, 0.02 mmol) at 20 ° C. The reaction was stirred at 80 ° C for 2 hours. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (20 mL x 3), dried over NaSO, filtered and concentrated to give crude compound 93-d (25 mg). LCMS (M+H) + :639.

[1512] Step 5: Preparation of 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 (Example 93)

[1513] To a solution 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 (93-d, 25 mg, 0.04 mmol) in HFIP (1 mL) was added MsOH (113 mg, 1.17 mmol). The reaction was stirred at 50 °C for 2 hours to give a red solution. The mixture was filtered and the filtrate was purified via preparative HPLC to give Example 93 (13.2 mg). LCMS (M+H) + :399. 1 H NMR (400MHz, DMSO-d6) δ = 9.56 (d, J = 1.2Hz, 1H), 9.14 (s, 1H), 8.83 (br s,1H),8.57(s,1H),7.91-7.69(m,1H),7.52-7.30(m,1H),4.44(t,J=7.2H z, 2H), 2.45 (s, 3H), 2.14 (s, 3H), 1.87-1.74 (m, 2H), 0.90 (t, J = 7.2Hz, 3H).

[1514] Example 94

[1515] 8-[2-(4-Hydroxy-5-methyl-2-propyl-pyrazol-3-yl)oxazol-4-yl]-3-methyl-pyrrolo[1,2-a]pyrazine-6-carboxamide

[1516]

[1517] Similar to the preparation of Example 93, Example 94 was prepared by using Compound 3-e instead of Compound 4-g in Step 2.

[1518] Example 94 (43.8 mg), LCMS (M+H) + :381. 1 H NMR (DMSO-d6, 400MHz) δ = 9.51 (d, J = 1.2Hz, 1H), 9.31 (s, 1H), 8.75-8.62 (s, 2H), 8.22-8.05 (m, 1H), 7.99 (s, 1H) ,7.54-7.51(m,1H),4.44(t,J=7.2Hz,2H),2.46(s,3H),2.14(s,3H),1.84-1.74(m,2H),0.88(t,J=7.2Hz,3H).

[1519] Biological Examples

[1520] 1.THP1-dual reporter gene assay (Agonist_THP1_EC 50 )

[1521] This is used to evaluate the effect of compounds on THP1-Dual TM A cellular reporter gene assay for agonism of the interferon regulatory factor (IRF) pathway in THP1-Dual cells (InvivoGen, catalog number thpd-nfis). TM The cells are derived from the human THP-1 monocytic cell line by stably integrating the lucia luciferase gene (a novel secreted luciferase reporter gene) under the control of the ISG54 (interferon-stimulated gene) minimal promoter combined with five interferon (IFN)-stimulated response elements. TM The cells allow the study of IRF pathways by assessing Lucia luciferase activity. TM Lucia luciferase protein can be easily measured in cell culture supernatants when luciferase is expressed in the presence of luciferase inhibitor (InvivoGen, catalog number: rep-qlcg-500).

[1522] Compounds were tested for agonism and cytotoxicity on the IRF pathway in THP1-Dual cells by measuring luminescence and OD 450 on an Envision microplate reader after 20 to 24 hours of compound treatment.

[1523] On the day of the experiment, 30 μL of assay medium (RPMI 1640, 2 mM L-glutamine, 25 mM HEPES, 10% heat-inactivated fetal bovine serum) was dispensed into a white 384-well plate (Grenier, catalog number: 781098) containing serially diluted compounds (final 1% DMSO) transferred by an Echo550 machine. Immediately thereafter, 30 μL of cell suspension (approximately 33,000 cells, 1.1 × 10 6 cells / mL) for incubation at 37°C, 5% CO2 for 20 to 24 hours. After incubation, 10 μL of cell supernatant was transferred to a proxiplate 384-plus plate for IRF detection, and then 10 μL of QUANTI-Luc TMGold solution was added to the plate and the measurement was immediately continued. To detect cell viabi...

Claims

1. A compound of formula (I), in Ring A is a 5- to 12-membered monocyclic, bicyclic or tricyclic heteroaryl ring or heterocyclyl ring containing one to four heteroatoms selected from N, O and S, R 1 , R 2 and R 3 Each of which is independently absent or selected from C 1-6 Alkyl, halogenated 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)2amino, C 1-6 Alkyl-S-, C 1-6 Alkyl SO2, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkoxycarbonyl, carboxyl, hydroxyl, cyano, amino, halogen, acyl, carbamoyl, and a 5- to 8-membered monocyclic heterocyclic group containing one to three heteroatoms selected from N, O and S, wherein the heterocyclic group may be further substituted by halogen, C 1-6 Alkyl, C 1-6 Alkoxy or amino substitution; Ring B is a 5- to 8-membered monocyclic or bicyclic heteroaryl ring or heterocyclyl ring containing one to four heteroatoms selected from N, O and S, R 4 Not present or selected from C 1-6 Alkyl, halogenated 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)2amino, C 1-6 Alkyl-S-, C 1-6 Alkyl SO2, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkoxycarbonyl, carboxyl, hydroxy, cyano, amino, halogen and carbamoyl; Bond a is the bond connecting ring A and ring B; Ring C is a 5- to 8-membered monocyclic or bicyclic heteroaryl ring or heterocyclyl ring containing one to four heteroatoms selected from N, O and S, R 5 , R 6 and R 7 Each of which is independently absent or selected from C 1-6 Alkyl, halogenated 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)2amino, C 1-6 Alkyl-S-, C 1-6 Alkyl SO2, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxycarbonyl, halocarbonyl 2-6 Alkenyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy C 2-6 Alkynyl, carboxyl, hydroxyl, cyano, amino, halogen, carbamoyl, cyano 1-6 Alkyl, imidazolyl C 1-6 Alkyl, triazolyl C 1-6 Alkyl, pyridyl C 1-6 Alkyl, thiazolyl C 1-6 Alkyl and phenyl C 1-6 Alkyl, wherein the phenyl C 1-6 The alkyl group is optionally substituted with halogen, cyano, hydroxyl 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 substituted, or R 5 , R 6 and R 7 The two of the two together with the atoms to which they are bonded form a 5- to 6-membered ring having 0 to 2 heteroatoms selected from N, O and S; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, 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 a carbamoyl group, R 2 Selected from C 1-6 Alkyl, halogenated C 1-6 alkyl, halogen, acyl and 5- to 8-membered monocyclic heterocyclic radicals containing one to three heteroatoms selected from N, O and S, R 3 Absent or halogen; Ring B is selected from X 1 , X 2 and X 3 Each of is independently selected from C, N and O, R 4 Not present or selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, amino C 1-6 Alkyl, hydroxyl C 1-6 Alkyl and carbamoyl groups; Ring C is pyrazolyl, R 5 Selected from C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl, halogenated 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, pyridyl C 1-6 Alkyl, thiazolyl C 1-6 Alkyl and phenyl C 1-6 Alkyl, wherein the phenyl C 1-6 The alkyl group is optionally substituted with halogen, cyano, hydroxyl 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 substitution, R 6 Does not exist or is C 1-6 Alkyl, R 7 is absent or is selected from hydroxy, halogen and amino, or R 6 and R 7 Together with the atoms to which they are bound they form a 5- to 6-membered ring containing zero to two heteroatoms selected from N, O and S.

3. The compound according to claim 1 or claim 2, wherein The substituted ring A is selected from 4. A compound according to any one of claims 1 to 3, wherein The substituted ring A is selected from R 1 is a carbamoyl group, R 2 C 1-6 alkyl, R 3 Absent or halogen.

5. The compound according to any one of claims 1 to 3, wherein R 1 is a carbamoyl group; R 2 is selected from methyl, difluoromethyl, acetyl, chloro and imidazolyl; R 3 Absent or fluorine.

6. A compound according to any one of claims 1 to 5, wherein R 1 is a carbamoyl group; R 2 is methyl; R 3 Absent or fluorine.

7. A compound according to any one of claims 1 to 6, wherein Ring B is selected from the group consisting of triazolyl, oxazolyl, oxadiazolyl and pyrimidinyl.

8. A compound according to any one of claims 1 to 7, wherein The substituted ring B is selected from 9. A compound according to any one of claims 1 to 8, wherein The substituted ring B is selected from R 4 Not present or selected from C 1-6 Alkyl and hydroxyl C 1-6 alkyl.

10. A compound according to any one of claims 1 to 8, wherein R 4 It is absent or selected from methyl, difluoromethyl, aminomethyl, hydroxymethyl and carbamoyl.

11. A compound according to any one of claims 1 to 10, wherein R 4 Absent or selected from methyl and hydroxymethyl.

12. A compound according to any one of claims 1 to 11, wherein The substituted ring C is 13. A compound according to any one of claims 1 to 12, wherein R 5 selected from the group consisting of 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-fluoro-propyl, 2-methoxyethyl, 3-methoxypropyl, 1-pent-3-ynyl, 5-methoxypent-3-ynyl, 2-phenylethyl, 2-(4-methoxy)ethyl, 2-(1,2,4-triazol-1-yl ... ethyl, 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-pyridinyl)ethyl, 2-[4-(morpholinomethyl)phenyl]ethyl and 2-thiazol-2-ylethyl, R 6 Not present or methyl, R 7 does not exist, is fluorine, amino or hydroxyl, or R 6 and R 7 Together with the atoms to which they are bonded they form a 5-membered ring.

14. A compound according to any one of claims 1 to 13, wherein R 5 is selected from the group consisting of propyl, butyl, cyclopropylmethyl, 3,3-difluoroallyl, 3-fluoro-propyl, 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 Methyl, R 7 It is hydroxyl.

15. The compound according to claim 1 or 2, wherein The substituted ring A is selected from R 1 is a carbamoyl group, R 2 C 1-6 alkyl, R 3 Absent or halogen; The substituted ring B is selected from R 4 Not present or selected from C 1-6 Alkyl and hydroxyl C 1-6 alkyl; The substituted ring C is R 5 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl C 1-6 Alkyl, pyridyl C 1-6 Alkyl, phenyl C 1-6 Alkyl, wherein the phenyl C 1-6 The alkyl group is optionally substituted with halogen, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or morpholino C 1-6 Alkyl substitution, R 6 C 1-6 alkyl, R 7 It is hydroxyl.

16. The compound according to claim 15, wherein R 1 is a carbamoyl group, R 2 Methyl, R 3 Absent or fluorine; R 4 absent or selected from methyl and hydroxymethyl; R 5 is selected from the group consisting of propyl, butyl, 3-fluoro-propyl, 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 Methyl, R 7 It is hydroxyl.

17. The compound according to claim 15, wherein R 1 is a carbamoyl group, R 2 C 1-6 alkyl, R 3 Absent or halogen, R 4 Not present or hydroxyl C 1-6 alkyl, R 5 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, pyridyl C 1-6 Alkyl and phenyl C 1-6 Alkyl, wherein the phenyl C 1-6 The alkyl group is optionally substituted with halogen, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl or hydroxyl C 1-6 Alkyl substitution, R 6 C 1-6 alkyl, R 7 It is hydroxyl.

18. The compound according to claim 17, wherein R 1 is a carbamoyl group, R 2 Methyl, R 3 Absent or fluorine; R 4 Not present or 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, R 6 Methyl, R 7 It is hydroxyl.

19. A compound selected from: 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-methyl-imidazo[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-pyridinyl)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-pyridinyl)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; 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]benzoic acid methyl ester; 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-pyridinyl)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; or a pharmaceutically acceptable salt thereof.

20. A method for preparing a compound having a structure of formula (Ia) The method comprises one of the following steps: (a) making the compound of formula (IIa) With the compound of formula (III) reacting in the presence of a catalyst and a base to provide a compound of formula (Ia), wherein the catalyst is preferably selected from Pd(OAc)2, CuI and Pd(dppf)Cl2, and the base is preferably selected from K2CO3, Cs2CO3 and Li2CO3; (b) making the compound of formula (V) With the compound of formula (VI) reacting in the presence of a catalyst and a base to provide a compound of formula (Ia), wherein the catalyst is preferably Pd(OAc)2, and the base is preferably selected from K2CO3, Na2CO3, Cs2CO3 and KOAc, (c) making the compound of formula (VII) With the compound of formula (VIII) reacting in the presence of a catalyst to provide a compound of formula (Ia), wherein the catalyst is preferably selected from AgOTf and AgBF4, (d) making a compound of formula (X) With the compound of formula (XI) reacting in the presence of a catalyst and a base to provide a compound of formula (Ia), wherein the catalyst is preferably Pd(dppf)Cl2, and the base is preferably K2CO3, wherein R 1 To R 7 and Ring A is as defined in any one of claims 1 to 18, X 1 To X 3 As defined in claim 2.

21. A method for preparing a compound having a structure of formula (Ib) The method comprises the following steps: The compound of formula (XII) With the compound of formula (XIII) reacting in the presence of a catalyst and a base to provide a compound of formula (Ib), wherein the catalyst is preferably PPh3AuCl3, and the base is preferably selected from K2CO3, Cs2CO3 and DBU, Where R 1 To R 7 and Ring A is as defined in any one of claims 1 to 18.

22. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, produced according to the method of claim 20 or 21.

23. 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 excipient.

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

25. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for use in therapy or cancer.

26. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for treating cancer.

27. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for activating STING.

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

29. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for activating STING.

30. A method for treating cancer, the method comprising administering an effective amount of a compound as defined in any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

31. The use according to claim 26 or 28, or the method according to claim 30, wherein the cancer is a cancer of the pancreas, liver, lung, breast, lymph, stomach, biliary tract, genitourinary tract, prostate or pharynx.

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