Cbl-b inhibitor

Abstract

The present invention relates to an amide compound as a Cbl-b inhibitor or a pharmaceutically acceptable salt thereof. Specifically, the present invention relates to a compound as shown in general formula (I) or a pharmaceutically acceptable salt thereof. The present invention further relates to a method for preparing the compound or the pharmaceutically acceptable salt thereof. The compound of the present invention can be used for treating and / or preventing Cbl-b-mediated diseases, particularly cancers.

Description

Cbl-b inhibitors TECHNICAL FIELD

[0001] The present application relates to heterocyclic compounds or pharmaceutically acceptable salts thereof suitable for modulating or inhibiting Cbl-b activity. The present application also relates to processes for preparing the heterocyclic compounds. The present application further relates to methods for treating and / or preventing diseases mediated by the protein, in particular cancer. BACKGROUND

[0002] Cbl-b (Casitas B-lineage lymphoma proto-oncogene-b) is a RING E3 ligase, which together with Cbl and Cbl-c constitutes the Cbl family. Cbl-b protein comprises several structural regions, i.e. a N-terminal tyrosine kinase binding (TKB) domain, a helical linker (L) domain, a RING finger (RF) domain, followed by a proline rich motif (PR) and a C-terminal ubiquitin-associated domain (UBA). Cbl-b interacts with activated tyrosine kinases via its TKB domain, which leads to a conformational change upon phosphorylation of Y363 in the L domain. When Cbl-b is in the activated conformation, the masking of the TKB domain by the RF domain is relieved, which facilitates the RF domain to recruit E2 ubiquitin-conjugating enzymes and mediate ubiquitination and degradation of the substrate. The tyrosine kinases that interact with the TKB domain of Cbl-b are essential proteins for the key T cell receptor (TCR) signaling, such as ZAP70, PKC theta, PI3K, etc., and their degradation leads to termination of TCR signaling and thus inhibition of T cell activation. Cbl-b knockout mice have hyperactive T cells, which leads to enhanced adaptive and innate anti-tumor immunity. Therefore, Cbl-b plays a negative regulatory role in TCR signaling and its inhibitors are expected to be useful for immunotherapy of cancer.

[0003] DETAILED DESCRIPTION

[0004] DEFINITIONS

[0005] The following terms as used in the present application have the following meanings, unless otherwise indicated.

[0006] "C x-y " means a range of carbon atoms, wherein x and y are both integers, for example C 3-8 Cycloalkyl means a cycloalkyl group having 3 to 8 carbon atoms, i.e. a cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms. It is also to be understood that "C 3-8 " also encompasses any sub-range therein, for example C3-7 , C 3-6 , C 4-7 , C 4-6 , C 5-6 , etc.

[0007] “Alkyl” refers to a saturated straight-chain or branched-chain hydrocarbon radical containing one to twenty carbon atoms, for example, one to eight carbon atoms, one to six carbon atoms, or one to four carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, and the like.

[0008] “Cycloalkyl” refers to a saturated cyclic hydrocarbon substituent containing three to fourteen carbon ring atoms. Cycloalkyl groups can be monocarbocyclic, typically containing three to eight, three to seven, or three to six carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Cycloalkyl groups can also be bicyclic or tricyclic fused, bridged, or spiro together, such as decalinyl, bicyclo[2.2.2]octane, spiro[3.3]heptane, spiro[2.3]hexane, and the like.

[0009] “Heterocyclyl or heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic ring system, which includes three to twenty ring atoms, for example, three to fourteen, three to twelve, three to ten, three to eight, three to six, or five to six ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), with the remaining ring atoms being carbon. Preferably, three to twelve ring atoms, three to ten ring atoms, four to seven ring atoms, four to six ring atoms, wherein one to four are heteroatoms, one to three are heteroatoms, or one to two are heteroatoms are included. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperazinyl, 1,4-oxazepanyl, pyrrolidonyl, piperidonyl, 1,1-dioxidothiomorpholinyl, and the like. Polycyclic heterocyclyl groups include fused, bridged, or spiro polycyclic heterocyclyl groups, such as octahydrocyclopenta[c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, 3,8-diazabicyclo[3.2.1]octane, 3-azabicyclo[3.1.0]hexane, 5-azaspiro[2.4]heptane, 2-azaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, and the like.

[0010] "Aryl or aryl ring" means an aromatic monocyclic or fused polycyclic ring radical containing from 6 to 14 carbon atoms, preferably 6 to 10 members, e.g., phenyl and naphthyl, more preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, where the ring connected to the parent structure is the aryl ring, non-limiting examples include:

[0011] etc.

[0012] "Heteroaryl or heteroaryl ring" means a heteroaromatic system containing from 5 to 14 ring atoms, of which from 1 to 4 are selected from heteroatoms including oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 members, more preferably the heteroaryl is 5 or 6 members, e.g., furanyl, thienyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, non-limiting examples include:

[0013] etc.

[0014] "Halo" means fluoro, chloro, bromo, or iodo.

[0015] "Cyano" means -CN.

[0016] "Oxo" means =0.

[0017] "Carbonyl" means a -C(O)- group.

[0018] "Sulfonyl" means a -S(O)2- group.

[0019] "Thio" means -S-.

[0020] "Optionally" means that the event or circumstance described subsequently can, but need not, occur. For example, the description "one or more hydrogens of a phenyl group are optionally substituted with halo" includes instances in which one or more hydrogens of a phenyl group are substituted with halo and instances in which one or more hydrogens of a phenyl group are not substituted with halo.

[0021] "Substituted" means that one or more hydrogens, preferably 1 to 5, e.g., 1 to 3, hydrogens, on a group is independently replaced with a corresponding number of substituents. The substituents are placed in chemically sensible locations. For example, an amino or hydroxyl group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturated bond, e.g., an alkene. Substituents include, but are not limited to, halo, cyano, nitro, hydroxyl, amino, oxo, -SF5, C 1-4 alkyl, C 3-7cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, and the like.

[0022] "Isomers" refer to compounds having the same molecular formula but different structural arrangements of atoms. Isomers that differ in the arrangement of atoms in space are termed "stereoisomers." Stereoisomers include optical isomers, geometric isomers, and conformational isomers.

[0023] The compounds of the present application can exist in optically active or racemic forms. Optical isomers include enantiomeric and diastereomeric isomers. Enantiomeric refers to two stereoisomers which are non-superimposable mirror images of one another. A racemic mixture or racemate refers to a physical mixture of equal amounts of two enantiomeric forms. Diastereomeric refers to two or more stereoisomers which are not mirror images of one another. When a stereoisomer is referred to as an "R" or "S", it means that the absolute configuration of the compound is known. When a stereoisomer is referred to as a "(+)" or "(-)" isomer, it means that the rotation of the plane of polarized light by the compound is known, but not the absolute configuration. Methods for the preparation and resolution of optically active forms are known.

[0024] The compounds of the present application can also have different geometric isomers resulting from the orientation of substituents around a carbon-carbon double bond, a carbon-nitrogen double bond, a cycloalkyl, or a heterocyclyl. Substituents around a carbon-carbon double bond or a carbon-nitrogen bond are designated Z or E configuration, while substituents around a cycloalkyl or heterocyclyl are designated cis or trans configuration.

[0025] The compounds of the present application can also exhibit tautomerism, for example, keto-enol tautomerism.

[0026] It should be understood that the application encompasses any tautomeric or stereoisomeric form and mixtures thereof, and is not limited to only the form named or depicted in the chemical structure.

[0027] "Isotopes" mean any of the atoms of an element that vary in atomic mass due to a difference in the number of neutrons. Examples of isotopes suitable for inclusion in the compounds of the application are hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine and chlorine, examples of which are, but are not limited to 2 H(D), 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36Cl. Isotopically-labeled compounds of the application can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labeled reagent in place of the non- isotopically labeled reagent employed. Such compounds are useful in, e.g., determining biological activity, as reference standards, and as probes in assays. With reference to stable isotopes, e.g., deuterium 2 H(D), 13 C and 15 N, compounds containing such isotopes are within the scope of this application. Deuterium 2 H(D) is a preferred isotope, e.g., the hydrogen in a methyl, methylene, or methine group can be replaced by deuterium.

[0028] The compounds of the application can be administered in the form of a prodrug. By "prodrug" is meant a derivative of a biologically active compound that requires a transformation prior to being biologically active, e.g., by oxidation, reduction, hydrolysis, etc., each of which is carried out either enzymatically or without enzymatic involvement, under physiological conditions, to form the biologically active compound of the application. Examples of prodrugs are compounds in which the amino group of a compound of the application is acylated, alkylated, or phosphorylated, e.g., eicosanoylamino, alanyl-amino, pivaloyloxymethylamino, or in which the hydroxyl group is acylated, alkylated, phosphorylated, or converted into a borate, e.g., acetyloxy, palmitoyloxy, pivaloyloxy, succinoyloxy, fumaryloxy, alanyl- oxy, or in which the carboxyl group is esterified or amidated, or in which the sulfhydryl group is conjugated to a carrier molecule that selectively delivers the drug to the target and / or to the cytosol of the cell. These compounds can be prepared from the compounds of the application according to known methods.

[0029] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salts" means a salt of a compound of the present application, when the compound contains one or more acidic or basic groups, prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. Thus, a compound of the present application containing an acidic group can exist in the form of a salt, for example, an alkali metal salt, an alkaline earth metal salt, or an ammonium salt. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, or amino acids. A compound of the present application containing a basic group can exist in the form of a salt with an inorganic or organic acid. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If a compound of the present application contains both acidic and basic groups in the molecule, the present application includes, in addition to the salt forms mentioned, inner salts or betaines. Each salt can be obtained by conventional methods known to those skilled in the art, for example, by mixing a compound with an organic or inorganic acid or base in a solvent or dispersant or by exchanging anion or cation with another salt.

[0030] "Pharmaceutical composition" means a mixture of one or more compounds of the present application or pharmaceutically acceptable salts, stable isotopic derivatives, isomers, prodrugs, and mixtures thereof, with other components, such as pharmaceutically acceptable carriers and adjuvants.

[0031] Thus, reference to "a compound", "a compound of the present application", or "a compound described herein" includes all forms of the compound, such as pharmaceutically acceptable salts, stable isotopic derivatives, isomers, prodrugs, and mixtures thereof.

[0032] "Therapeutically effective amount" means an amount of a compound of the present application that is effective in inhibiting Cbl-b activity to achieve the treatment or prevention of a disease mediated thereby.

[0033] "Patient" means a mammal, especially a human.

[0034] The present application provides compounds useful as Cbl-b inhibitors. The compounds are represented by Formula (I), or prodrugs, stable isotopic derivatives, pharmaceutically acceptable salts, and isomers thereof:

[0035] wherein:

[0036] Ring A is ( represents the bond is attached to a methylene group, represents the bond is attached to a carbonyl group).

[0037] Ring B is a 5-membered heteroaromatic ring, one or two hydrogens of which are optionally replaced by C 1-6 alkyl or C 3-8 cycloalkyl, wherein one or more hydrogens of said alkyl and cycloalkyl are optionally further replaced by D or F;

[0038] L is ( denotes that the bond is attached to a phenyl or pyridyl ring, denotes that the bond is attached to ring B or methylene;

[0039] X, Y and Z 1 are each independently CH or N;

[0040] Z 2 is CR a R b or O;

[0041] Z 3 is S or O;

[0042] R 1 is H, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, -OR 21 or -NR 21 R 22 , wherein one or more hydrogens of said alkyl and cycloalkyl are optionally replaced by halogen, -OH or -OC 1-6 alkyl;

[0043] R 2 is C 1-6 alkyl or C 3-8 cycloalkyl, wherein one or more hydrogens of said alkyl and cycloalkyl are optionally replaced by R 31 ;

[0044] R 3 is H, C 1-6 alkyl or C 3-8 cycloalkyl;

[0045] R 2 and R 3 , together with the nitrogen atom to which they are attached, optionally form a 4-10 membered heterocyclic ring, wherein one or more hydrogens of said heterocyclic ring are optionally replaced by halogen, -OH, -OC 1-6 alkyl, C 1-6 alkyl, fluoroC 1- 6alkyl or C 3-8 cycloalkyl;

[0046] R 4 is H, halogen or C 1-6 alkyl;

[0047] R a , R b , R c , R d , R e and R f are each independently H, halo or C 1-6 alkyl, or R a and R b together with the carbon atom to which they are attached optionally form a C 3-6 cycloalkyl group, or R c and R d together with the carbon atom to which they are attached optionally form a C 3-6 cycloalkyl group;

[0048] R' and R" are each independently H, C 1-6 alkyl, C 3-8 cycloalkyl or 4-6 membered heterocyclyl;

[0049] R' and R" together with the carbon atom to which they are attached optionally form a C 4-6 cycloalkyl group or a 4-6 membered heterocycle containing 1 O heteroatom, one or more hydrogens of said cycloalkyl group being optionally substituted by halo, cyano, -OH, -OC 1-6 alkyl or C 1-6 alkyl, one or more hydrogens of said alkyl group being optionally further substituted by halo or cyano;

[0050] R'" is H, halo, cyano or C 1-6 alkyl;

[0051] R 21 and R 22 are each independently H, C 1-6 alkyl or C 3-8 cycloalkyl, one or more hydrogens of said alkyl or cycloalkyl group being optionally substituted by halo, cyano, -OC 1-6 alkyl or C 1-6 alkyl;

[0052] R 31 is -OH, -OC 1-6 alkyl, C 1-6 alkyl or C 3-8 cycloalkyl; and

[0053] n is 0 or 1.

[0054] In one embodiment, ring A is Z 1 is CH or N, Z 2 is CH2, CF2, C(CH3)2 or O, R c and Rd Each is independently H, F or CH3; Ring A is preferably

[0055] In one embodiment, Ring A is R f is H or CH3.

[0056] In one embodiment, Ring B is

[0057] In one embodiment, R 2 and R 3 and the nitrogen atom to which it is connected to form a 4-10 membered heterocyclic ring, including but not limited to piperidine, pyrrolidine, azaazetidine, morpholine, piperazine, Preferably, piperidine, wherein one or more hydrogen atoms of the heterocyclic ring are optionally replaced by halogen, -OH, -OC 1-6 Alkyl, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 Substituted with a cycloalkyl group.

[0058] In one embodiment, L is P is CR 41 R 42 or O, R 41 and R 42 Each is independently H, halogen, cyano, -OC 1-6 Alkyl or C 1-6 Alkyl, wherein one or more hydrogen atoms of the alkyl group are optionally replaced by halogen or cyano.

[0059] In one embodiment, L is n is 0.

[0060] In one embodiment, R 4 For H.

[0061] In some embodiments, the compound of the present invention is represented by formula (II):

[0062] in:

[0063] Ring A is

[0064] X and Z 1 Each is independently CH or N;

[0065] Z 2 CR a R b or O;

[0066] Z3 S or O;

[0067] P is CR 41 R 42 or O;

[0068] R 1 H, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, -OR 21 or -NR 21 R 22 wherein one or more hydrogens of said alkyl and cycloalkyl are optionally replaced by halogen, -OH or -OC 1-6 alkyl;

[0069] R a , R b , R c , R d , R e and R f are each independently H, halogen or C 1-6 alkyl, or R a and R b together with the carbon atom to which they are attached optionally form a C 3-6 cycloalkyl, or R c and R d together with the carbon atom to which they are attached optionally form a C 3-6 cycloalkyl;

[0070] R 21 and R 22 are each independently H, C 1-6 alkyl or C 3-8 cycloalkyl, wherein one or more hydrogens of said alkyl or cycloalkyl are optionally replaced by halogen, cyano or -OC 1-6 alkyl;

[0071] R 41 and R 42 are each independently H, halogen, cyano, -OC 1-6 alkyl or C 1-6 alkyl, wherein one or more hydrogens of said alkyl are optionally replaced by halogen or cyano;

[0072] R 43 is halogen, C 1-6 alkyl or fluoroC 1-6 alkyl;

[0073] m is an integer from 1 to 3; and

[0074] n is 0 or 1.

[0075] In one embodiment, ring A is

[0076] In one embodiment, ring A is R f is H or CH3.

[0077] In one embodiment, is

[0078] In some embodiments, the compounds of the present application are represented by Formula (III):

[0079] wherein:

[0080] ring A is

[0081] X and Y are each independently CH or N;

[0082] R 1 is H, halo, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, -OR 21 , or -NR 21 R 22 , wherein one or more hydrogens of said alkyl and cycloalkyl are optionally substituted with halo, -OH, or -OC 1-6 alkyl;

[0083] R 21 and R 22 are each independently H, C 1-6 alkyl, or C 3-8 cycloalkyl, wherein one or more hydrogens of said alkyl or cycloalkyl are optionally substituted with halo, cyano, or -OC 1-6 alkyl;

[0084] R 43 is halo, C 1-6 alkyl, or fluoroC 1-6 alkyl; and

[0085] m is an integer from 1 to 3.

[0086] In one embodiment, is

[0087] The present application also relates to the following compounds, or pharmaceutically acceptable salts, stable isotopic derivatives, isomers, prodrugs, and mixtures thereof:

[0088] The compounds of the present application are capable of effectively inhibiting the activity of Cbl-b, with an IC 50 Preferably less than 100 nM. The inhibitory effect of the compounds of the present application on the activity of Cbl-b can induce the transcriptional activation of IL-2 driven reporter gene, preferably with an EC 50 less than 100 nM.

[0089] The present application also relates to a pharmaceutical composition comprising a compound of any one of the embodiments of the present application or a pharmaceutically acceptable salt, stable isotope derivative, isomer, and prodrug thereof and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition can inhibit the activity of Cbl-b, affect its biological function, and thus achieve the effect of treating or preventing Cbl-b-mediated diseases.

[0090] The present application also provides a method for treating or preventing Cbl-b-mediated diseases, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of any one of the embodiments of the present application or a prodrug, a pharmaceutically acceptable salt, a stable isotope derivative, an isomer, a prodrug thereof, and a pharmaceutical composition thereof, wherein the Cbl-b-mediated diseases include but are not limited to tumors; the "effective amount" is an effective dose for treating diseases by improving the pathological state of the disease or alleviating the symptoms of the disease; the diseases include but are not limited to hematological tumors (such as leukemia, lymphoma, myeloma, etc.) and solid tumors (such as glioma, thyroid cancer, head and neck cancer, pancreatic cancer, lung cancer, colon cancer, liver cancer, bile duct cancer, gastric cancer, esophageal cancer, kidney cancer, prostate cancer, bladder cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, urothelial cancer, muscle cancer, bone cancer, etc.).

[0091] The present application also provides a pharmaceutical composition comprising a compound of any one of the embodiments of the present application or a prodrug, a pharmaceutically acceptable salt, a stable isotope derivative, an isomer, and at least one additional drug, wherein the additional drug includes but is not limited to a chemotherapeutic drug, a kinase inhibitor, a synthetic lethal agent, an immune and / or inflammation modulator, a neural-related disease modulator, etc.

[0092] The present application also provides a use of a compound according to any one of the embodiments of the present application, or a prodrug, a pharmaceutically acceptable salt, a stable isotope derivative, an isomer thereof, or a pharmaceutical composition according to the present application for preventing or treating a disease mediated by Cbl-b.

[0093] The present application also provides a use of a compound according to any one of the embodiments of the present application, or a prodrug, a pharmaceutically acceptable salt, a stable isotope derivative, an isomer thereof, in the manufacture of a medicament for preventing or treating a disease mediated by Cbl-b.

[0094] According to the present application, the medicament can be in any pharmaceutical dosage form, including but not limited to tablets, capsules, solutions, lyophilized preparations, injections.

[0095] The pharmaceutical preparation of the present application can be administered in the form of a dosage unit of the active ingredient in a predetermined amount. Such a unit contains 1 mg to 1000 mg of the compound of the present application, depending on the condition to be treated, the method of administration, and the age, body weight, and condition of the patient. In addition, the pharmaceutical preparation can be prepared using methods well known in the pharmaceutical field, for example, by formulating the active ingredient with one or more excipients or one or more adjuvants.

[0096] The pharmaceutical preparation of the present application can be suitable for administration by any desired suitable method, for example, oral (including buccal or sublingual) or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) methods.

[0097] The present application also provides a method for preparing the compound. The compound of the present application of general formula (I) can be prepared by the following exemplary methods and examples, but these methods and examples should not be considered as limiting the scope of the present application in any way. The compound of the present application can also be synthesized by synthetic techniques known to those skilled in the art, or by a combination of methods known in the art and the methods described in the present application. The starting materials and chemical reagents required for synthesis can be prepared according to conventional synthesis or purchased from the literature (queryable from SciFinder).

[0098] Synthetic methods

[0099] The heterocyclic compound of the present application of general formula (I) can be synthesized according to the following route: A-1 is converted to A-2 by palladium-catalyzed Suzuki coupling reaction; A-2 is obtained by hydrolysis reaction to obtain A-3; A-3 and B-1 are obtained by amidation reaction to obtain I.

[0100] The heterocyclic compound of the present application of general formula (I) can also be synthesized according to the following route: A-3 is obtained by amidation reaction to obtain A-4; A-4 and B-2 are directly obtained by palladium or copper-catalyzed cross-coupling reaction to obtain I.

[0101] Intermediates B-1 and B-2 can be synthesized according to the following route: B-11 is substituted and derivatized to obtain B-12; B-12 is hydrolyzed to obtain B-13, and then sequentially subjected to hydrazidation, cyclization and oxidation to obtain B-2; B-2 is subjected to transition metal-catalyzed amination to obtain B-1.

[0102] Intermediates B-1 can also be synthesized according to the following route: B-21 and B-22 are subjected to transition metal-catalyzed coupling to obtain B-23; B-23 is hydrolyzed to obtain B-24, and then sequentially subjected to hydrazidation, cyclization and oxidation to obtain B-26; B-26 is deprotected to obtain B-1. Examples

[0103] The starting materials of the present application can be synthesized according to methods known in the art or purchased from chemical companies such as Accela ChemBio Inc., Beijing Coupling, Bide Pharmaceutical, Zesheng Technology, Shanghai Haohong Biomedical, etc.

[0104] The structure of the compounds of the present application is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The determination of NMR uses a Bruker ASCEND-400 nuclear magnetic instrument, and the solvents used are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDC13) or deuterated methanol (CD3OD), etc., with tetramethylsilane (TMS) as the internal standard, and the chemical shift is given in units of 10 -6 (ppm). The determination of MS uses an Agilent SQD (ESI) mass spectrometer (Agilent 6120).

[0105] HPLC uses an Agilent 1260 DAD high-pressure liquid chromatograph (Poroshell 120 EC-C18, 50 x 3.0 mm, 2.7 μm column) or a Waters Arc high-pressure liquid chromatograph (Sunfirc C18, 150 x 4.6 mm, 5 μm column).

[0106] In the examples, unless otherwise specified, the reaction temperature is room temperature (20-30°C).

[0107] In the examples, unless otherwise specified, the reactions are carried out under an argon or nitrogen atmosphere. The argon or nitrogen atmosphere means that after the reaction bottle is vacuumed and filled with argon or nitrogen (repeated 3 times), a about 1L argon or nitrogen balloon is connected.

[0108] The hydrogen atmosphere means that after the reaction bottle is vacuumed and filled with hydrogen (repeated 3 times), a about 1L hydrogen balloon is connected.

[0109] Microwave reactions were performed using a CEM Discover-SP microwave reactor.

[0110] Monitoring of reaction progress in the examples was performed using an Agilent liquid chromatograph-mass spectrometer (1260 / 6120), and thin layer chromatography (TLC) can also be used. The silica gel plates used were 0.15-0.2 mm thick (Qingdao Marine GF254).

[0111] Purification of compounds was performed using column chromatography or thin layer chromatography. Column chromatography used 200-300 mesh silica gel from Qingdao Marine, and thin layer chromatography used GF254 silica gel plates from Qingdao Marine, 0.4-0.5 mm thick.

[0112] The solvent system used for column chromatography or thin layer chromatography was usually a) dichloromethane and methanol, b) petroleum ether and ethyl acetate, or as indicated in the examples. The volume ratio of solvents was adjusted according to the polarity of the compound, and a small amount of triethylamine or other acidic or basic reagent can also be added for further adjustment.

[0113] Purification of compounds was also performed using a Waters mass spectrometry guided automatic preparation system (mass spectrometer detector: SQD2, abbreviated as Prep-HPLC). According to the polarity of the compound, an appropriate acetonitrile / water (containing 0.1% trifluoroacetic acid or formic acid, or 0.05% ammonia water) gradient was used to elute a reversed-phase high-pressure column (XBridge-C18, 19x150mm, 5μm) at a flow rate of 20mL / min. In some examples, after purification using the automatic preparation system, 1N dilute hydrochloric acid was added, and then the solvent was removed under reduced pressure to obtain the hydrochloride salt.

[0114] The abbreviation DMF refers to N,N-dimethylformamide.

[0115] The abbreviation DMA refers to N,N-dimethylacetamide.

[0116] The abbreviation NMP refers to N-methylpyrrolidone.

[0117] The abbreviation THF refers to tetrahydrofuran.

[0118] The abbreviation MTBE refers to methyl tert-butyl ether.

[0119] The abbreviation DIPEA refers to N,N-diisopropylethylamine.

[0120] The abbreviation DMAP refers to p-N,N-dimethylaminopyridine.

[0121] The abbreviation LDA refers to lithium diisopropylamide.

[0122] The abbreviation LiHMDS refers to lithium hexamethyldisilazide.

[0123] The abbreviation DAST refers to diethylaminosulfur trifluoride.

[0124] The abbreviation NBS refers to N-bromosuccinimide.

[0125] The abbreviation AIBN refers to azobisisobutyronitrile.

[0126] The abbreviation HATU refers to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0127] The abbreviation Xantphos refers to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0128] The abbreviation XPhos refers to 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0129] The abbreviation BINAP refers to 1,1'-binaphthyl-2,2'-bisdiphenylphosphine.

[0130] The abbreviation TBAF refers to tetra-n-butylammonium fluoride.

[0131] The abbreviation DIAD refers to diisopropyl azodicarboxylate.

[0132] Example 1

[0133] (S)-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)benzo[c][1,2,5]thiadiazole-4-carboxamide (Compound 1)

[0134] first step

[0135] Ethyl 2-(3-(3-bromophenyl)oxetan-3-yl)acetate (1b)

[0136] Ethyl 2-(oxetane-3-ylidene)acetate 1a (5.69 g, 40 mmol), (3-bromophenyl)boronic acid (10.84 g, 54 mmol), [(COD)RhCl]2 (493 mg, 1 mmol), and potassium hydroxide (3.37 g, 60 mmol) were dissolved in 1,4-dioxane (60 mL) and water (20 mL), then stirred overnight under nitrogen. Saturated ammonium chloride solution (500 mL) was added, followed by extraction with ethyl acetate (3 x 200 mL). The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 7 / 3) to obtain the desired product 1b (11.20 g, 94%).

[0137] MS m / z(ESI):299[M+1]

[0138] Second Step

[0139] 2-(3-(3-bromophenyl)oxetan-3-yl)acetic hydrazide (1c)

[0140] Dissolve 1b (11.97 g, 40 mmol) and hydrazine hydrate (40 mL, 800 mmol) in ethanol (120 mL), then heat to 90 °C and stir overnight. After cooling to room temperature, concentrate to dryness under reduced pressure to obtain the target product 1c (11.20 g, crude). The product is used directly in the next step without further purification.

[0141] MS m / z (ESI): 285 [M+1]

[0142] Third Step

[0143] 2-(2-(3-(3-bromophenyl)oxetan-3-yl)acetyl)-N-methylhydrazine-1-carbothioamide (1d)

[0144] Dissolve 1c (11.20 g, crude, about 40 mmol) and methyl isothiocyanate (5.8 mL, 80 mmol) in THF (160 mL). After stirring for 2 hours, concentrate to dryness under reduced pressure to obtain the target product 1d (7.50 g, crude). The product is used directly in the next step without further purification.

[0145] MS m / z (ESI): 358 [M+1]

[0146] Fourth Step

[0147] 5-((3-(3-bromophenyl)oxetan-3-yl)methyl)-4-methyl-4H-1,2,4-triazole-3-thiol (1e)

[0148] Dissolve 1d (5.37 g, 15 mmol) and sodium methoxide (1.62 g, 30 mmol) in methanol (50 mL), then heat to 50 °C and stir for 3 hours. After cooling to room temperature, the filtrate is concentrated to dryness under reduced pressure, add water (40 mL) and 1 N aqueous hydrochloric acid (40 mL), and filter to obtain the target product 1e (5.10 g, crude). The product is used directly in the next step without further purification.

[0149] MS m / z (ESI): 340 [M+1]

[0150] Fifth Step

[0151] 3-((3-(3-bromophenyl)oxetan-3-yl)methyl)-4-methyl-4H-1,2,4-triazole (1f)

[0152] Dissolve 1e (5.10 g, crude, ca. 15 mmol) in water (30 mL), then add sodium nitrite (10.35 g, 150 mmol) and dilute nitric acid solution (1 N, 150 mL) at 0 °C. After stirring for 1 h, add saturated sodium bicarbonate solution (100 mL), then extract with dichloromethane (3 x 100 mL). Dry the combined organic phases over anhydrous sodium sulfate. After filtration, concentrate the filtrate to dryness under reduced pressure to obtain the target product 1f (4.00 g, crude). This product is used directly in the next reaction without further purification.

[0153] MS m / z (ESI): 308 [M+1]

[0154] Sixth step

[0155] 3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)aniline (1g)

[0156] Mix 1f (10 g, 32.45 mmol), ammonia (40 mL) and copper powder (206 mg, 3.24 mmol) in a 100 mL sealed tube, then heat to 100 °C and stir for 18 h. After cooling to room temperature, filter, dilute the filtrate with water (50 mL), then extract with methanol / dichloromethane (1 / 9) (10 x 100 mL). Dry the combined organic phases over anhydrous sodium sulfate, filter, concentrate to obtain the target product 1g (6.2 g). Purify the aqueous phase with Prep-HPLC to obtain another portion of 1g (450 mg). Combine the two portions to obtain 1g (6.65 g, 84%).

[0157] MS m / z (ESI): 245 [M+1]

[0158] Seventh step

[0159] Methyl 6-bromobenzo[c][1,2,5]thiadiazole-4-carboxylate (1i)

[0160] Dissolve methyl 2,3-diamino-5-bromobenzoate 1h (490 mg, 2 mmol) in dichloromethane (10 mL), add triethylamine (1.1 mL, 8 mmol) and thionyl chloride (290 μL, 4 mmol) at 0 °C, then warm to room temperature and stir overnight. Add brine (100 mL), then extract with ethyl acetate (100 mL). Concentrate to dryness under reduced pressure, purify the residue by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 8 / 2) to obtain the target product 1i (290 mg, 53%).

[0161] MS m / z (ESI): 273 [M+1]

[0162] Eighth step

[0163] (S)-6-((3-methylpiperidin-l-yl)methyl)benzo[c][l,2,5]thiadiazole-4-carboxylic acid methyl ester (1j)

[0164] (S)-3-methylpiperidine hydrochloride (271 mg, 2 mmol), potassium (bromomethyl)trifluoroborate (402 g, 2 mmol) and cesium carbonate (1.31 g, 4 mmol) were dissolved in THF (4 mL) and heated to 80 °C under nitrogen atmosphere and stirred for 2 hours. After cooling to room temperature, 1i (273 mg, 1 mmol), palladium acetate (45 mg, 0.2 mmol), XPhos (191 mg, 0.4 mmol) and water (0.4 mL) were added to the resulting mixture and heated to 80 °C under nitrogen protection and stirred overnight. After cooling to room temperature, water (10 mL) was added and then extracted with ethyl acetate (15 mL). The filtrate was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1 to 1 / 1) to obtain the target product 1j (225 mg, 74%).

[0165] MS m / z (ESI): 306 [M+1]

[0166] Ninth step

[0167] (S)-l-methyl-6-((3-methylpiperidin-l-yl)methyl)-lH-benzo[d][l,2,3]triazole-4-carboxylic acid (lk)

[0168] 1j (92 mg, 0.3 mmol) and lithium hydroxide monohydrate (63 mg, 1.5 mmol) were dissolved in THF (1 mL) and water (1 mL). After stirring for 1 hour, hydrogen chloride solution in 1,4-dioxane (4 M, 0.5 mL) was added and concentrated to dryness under reduced pressure to obtain the target product lk (87 mg, crude). The product was used directly in the next step reaction without further purification.

[0169] MS m / z (ESI): 292 [M+1]

[0170] Tenth step

[0171] (S)-N-(3-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-6-((3- methylpiperidin)-l-yl)methyl)benzo[c][l,2,5]thiadiazole-4-carboxamide (1)

[0172] Dissolve 1k (87 mg, 0.3 mmol) and 1g (73 mg, 0.3 mmol) in DMF (2 mL), add HATU (171 mg, 0.45 mmol) and DIPEA (262 μL, 1.5 mmol), and stir overnight. Purify with reverse-phase preparative HPLC to give the target product 1 (37 mg, 24%).

[0173] MS m / z (ESI): 518 [M+1]

[0174] 1 H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.32 (d, J = 1.2 Hz, 1H), 8.22 (s, 1H), 8.16 (d, J = 22.8 Hz, 1H), 7.74 (d, J = 9.1 Hz, 1H), 7.40 (s, 1H), 7.32 (t, J = 7.9 Hz, 1H), 6.72 (d, J = 7.8 Hz, 1H), 4.95 (d, J = 6.0 Hz, 2H), 4.87 (d, J = 6.0 Hz, 2H), 3.76 (s, 2H), 3.51 (s, 2H), 2.97 (d, J = 9.6 Hz, 3H), 2.89 - 2.75 (m, 2H), 2.00 (dd, J = 9.5, 5.6 Hz, 1H), 1.65 (dd, J = 21.3, 11.7 Hz, 4H), 1.52 (dd, J = 24.4, 12.0 Hz, 1H), 0.86 (d, J = 6.7 Hz, 1H), 0.83 (d, J = 6.4 Hz, 3H).

[0175] The following compounds were synthesized according to the procedure of Example 1, Steps 8-10, but substituting different compounds for 1i, (S)-3-methylpiperidine hydrochloride, and 1g in the procedure.

[0176] The NMR data for these compounds are as follows:

[0177] Example 2

[0178] (S)-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-6-((3- methylpiperidin)-1-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (Compound 2)

[0179] First Step

[0180] 5-bromo-2-hydrazinyl nicotinic acid methyl ester (2b)

[0181] Dissolve 5-bromo-2-chloronicotinic acid methyl ester 2a (6.27 g, 25 mmol) in dioxane (30 mL), add hydrazine hydrate (6.1 mL, 100 mmol), heat to 60 °C and stir for 4 hours. After cooling to room temperature, add water (100 mL) and filter to obtain the target product 2b (6.15 g, 99%).

[0182] MS m / z (ESI): 246 [M+1]

[0183] Second Step

[0184] 6-bromo-[l,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid methyl ester (2c)

[0185] Dissolve 2b (6.15 g, 25 mmol) in triethyl orthoformate (50 mL), add p-toluenesulfonic acid monohydrate (190 mg, 81 mmol), then heat to 100 °C and stir for 1 hour. After cooling to room temperature, filter to obtain the target product 2c (3.20 g, 50%).

[0186] MS m / z (ESI): 256 [M+1]

[0187] Third to Fifth Steps

[0188] (S)-N-(3-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-6-((3- methylpiperidin)-l-yl)methyl)-[l,2,4]triazolo[4,3-a]pyridine-8-carboxamide formate salt (2)

[0189] Synthesize 2 by following the procedure of the eighth to tenth steps in Example 1, but use 2c instead of li in the procedure.

[0190] MS m / z (ESI): 501 [M+1]

[0191] 1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 11.45 (s, 1H), 9.15 (s, 1H), 8.79 (s, 1H), 8.40 (d, J = 1.4 Hz, 1H), 8.22 (s, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.34 (dd, J = 10.2, 5.4 Hz, 2H), 6.73 (d, J = 7.7 Hz, 1H), 4.96 (d, J = 6.0 Hz, 2H), 4.87 (d, J = 6.0 Hz, 2H), 3.65 (s, 2H), 3.53 (s, 2H), 2.95 (s, 3H), 2.80 (t, J = 10.5 Hz, 2H), 1.98 (t, J = 11.1 Hz, 1H), 1.64 (ddd, J = 14.9, 12.6, 6.4 Hz, 4H), 1.49 (d, J = 12.2 Hz, 1H), 0.87 (d, J = 12.3 Hz, 1H), 0.82 (d, J = 6.3 Hz, 3H).

[0192] Example 3

[0193] (S)-N-(3-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-7-((3- methylpiperidin)-l-yl)methyl)-2,3-dihydrobenzo[b][l,4]dioxine-5-carboxamide (Compound 3)

[0194] First Step

[0195] 7-bromo-2,3-dihydrobenzo[b][l,4]dioxine-5-carboxylic acid (3b)

[0196] Dissolve 2,3-dihydrobenzo[b][l,4]dioxine-5-carboxylic acid 3a (1.80 g, 10 mmol) in concentrated sulfuric acid (40 mL), cool the resulting solution to 0 °C, then add NBS (1.96 g, 11 mmol) and warm to room temperature. After stirring for 4 hours, add an aqueous solution (400 mL), then extract with dichloromethane (3 x 100 mL). Dry the combined organic phases over anhydrous sodium sulfate, filter, then concentrate the filtrate to dryness under reduced pressure to give the target product 3b (2.59 g, crude). This product was used directly in the next reaction without further purification.

[0197] MS m / z (ESI): 259 [M+1]

[0198] Second Step

[0199] methyl 7-bromo-2,3-dihydrobenzo[b][l,4]dioxine-5-carboxylate (3c)

[0200] To a solution of 3b (2.59 g, 10 mmol) in methanol (40 mL) was added concentrated sulfuric acid (1 mL), the resulting solution was heated to reflux and stirred for 1 h. After cooling to room temperature, it was concentrated to dryness under reduced pressure, saturated aqueous sodium chloride solution (100 mL) was added, then extracted with ethyl acetate (100 mL). The combined organic phase was concentrated to dryness under reduced pressure, the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 8 / 2) to give the target product 3c (2.50 g, 92%).

[0201] MS m / z (ESI): 273 [M+1]

[0202] Third to fifth steps

[0203] (S)-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-7-((3- methylpiperidin)-1-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxine-5-formamide (1)

[0204] Refer to the steps of the eighth to tenth steps in Example 1 for the synthesis of 3, but use 3c instead of 1i in the operation.

[0205] MS m / z (ESI): 518 [M+1]

[0206] 1 H NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 8.20 (s, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.48 (s, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.19 (s, 1H), 7.09 (s, 1H), 6.71 (d, J = 7.6 Hz, 1H), 5.04 (d, J = 9.9 Hz, 4H), 4.49 (d, J = 3.9 Hz, 2H), 4.38 (s, 2H), 4.17 (s, 2H), 3.62 (s, 2H), 3.38 (d, J = 11.8 Hz, 2H), 2.88 (s, 3H), 2.79 (t, J = 11.7 Hz, 1H), 2.52 (t, J = 11.9 Hz, 1H), 1.89 (dd, J = 29.1, 12.9 Hz, 3H), 1.74 (d, J = 13.6 Hz, 1H), 1.22 - 1.10 (m, 1H), 0.98 (d, J = 6.4 Hz, 3H).

[0207] The following compounds were synthesized according to the experimental steps of Example 3, but different compounds were used instead of 3a in the operation.

[0208] The following compounds were synthesized according to the procedure of Step two to Step five of Example 3, but different compounds were used in place of 3b and Ig in the procedure.

[0209] The NMR data of these compounds are as follows:

[0210] Example 4

[0211] (S)-3,3-dimethyl-N-(3-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-5- ((3-methylpiperidin-l-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide (Compound 5)

[0212] First Step

[0213] 3-bromo-2-((2-methylallyl)oxy)benzoic acid methyl ester (5b)

[0214] A mixture of methyl 3-bromo-2-hydroxybenzoate 5a (3.47 g, 15 mmol), 3-bromo-2- methylprop-l-ene (2.24 g, 16.5 mmol), potassium carbonate (6.23 g, 45 mmol) and acetone (60 mL) was heated to 60 °C under nitrogen protection and stirred for 1 h. After cooling to room temperature, water (100 mL) was added, followed by extraction with ethyl acetate (200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 5b (4.20 g, crude). The product was used directly in the next step without further purification.

[0215] MS m / z (ESI): 285 [M+l]

[0216] Second Step

[0217] 3,3-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester (5c)

[0218] A mixture of 5b (4.20 g, 15 mmol) was dissolved in dry toluene (60 mL), followed by the addition of AIBN (392 mg, 1.5 mmol) and Bu3SnH (6.65 g, 22.5 mmol) successively. The resulting mixture was heated to 90 °C under nitrogen atmosphere and stirred overnight. After cooling to room temperature, 10% potassium fluoride solution (100 mL) was added, stirred for 3 h, and then extracted with ethyl acetate (200 mL). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 8 / 2) to give the target product 5c (2.0 g, 65% over two steps).

[0219] MS m / z (ESI): 207 [M+1]

[0220] Third step

[0221] 5-Bromo-3,3-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester (5d)

[0222] To a solution of 5c (2.0 g, 9.7 mmol) in acetonitrile (30 mL) was added NBS (3.45 g, 19.4 mmol). The resulting solution was heated to 50 °C under nitrogen atmosphere and stirred for 3 hours. After cooling to room temperature, saturated sodium thiosulfate solution (100 mL) and sodium bicarbonate solution (100 mL) were added, followed by extraction with ethyl acetate (200 mL). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 8 / 2) to give the target product 5d (2.2 g, 80%).

[0223] MS m / z (ESI): 285 [M+1]

[0224] Third to fifth steps

[0225] (S)-3,3-Dimethyl-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-5- ((3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide formate (1)

[0226] 5 was synthesized by following the procedure of the eighth to tenth steps in Example 1, but using 5d instead of 1i in the operation.

[0227] MS m / z (ESI): 530 [M+1]

[0228] 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.55 - 8.04 (m, 2H), 7.61 (d, J = 12.6 Hz, 2H), 7.38 (s, 1H), 7.25 (dd, J = 19.8, 11.9 Hz, 2H), 6.63 (t, J = 14.3 Hz, 1H), 4.93 (s, 2H), 4.86 (s, 2H), 4.47 (s, 2H), 3.60 - 3.59 (m, 2H), 3.49 (s, 2H), 2.93 (s, 3H), 2.82 (t, J = 11.1 Hz, 2H), 2.05 (t, J = 10.6 Hz, 1H), 1.77 (t, J = 10.4 Hz, 1H), 1.64 (t, J = 11.7 Hz, 3H), 1.50 (d, J = 11.8 Hz, 1H), 1.35 (s, 6H), 0.96 - 0.86 (m, 1H), 0.82 (d, J = 6.1 Hz, 3H).

[0229] Example 5

[0230] (S)-N-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3,3- dimethyl-5-((3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide (Compound 6)

[0231] First Step

[0232] 1-(3-bromophenyl)-3,3-dimethoxycyclobutane-1-carbonitrile (6b)

[0233] To a solution of 2-(3-bromophenyl)acetonitrile 6a (19.60 g, 100 mmol) in DMF (100 mL) was added sodium hydride (60%, 8.40 g, 210 mmol) and 1,3-dibromo-2,2- dimethoxypropane (26.20 g, 100 mmol) sequentially at 0 °C. The resulting mixture was heated to 60 °C and stirred overnight. After cooling to room temperature, saturated brine (300 mL) was added, followed by extraction with ethyl acetate (3 x 200 mL). The combined organic phase was washed with saturated brine (3 x 500 mL). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give the target product 6b (14.81 g, 50%).

[0234] MS m / z (ESI): 296 [M+1]

[0235] Second Step

[0236] 1 -(3-bromophenyl)-3-oxocyclobutane-1 -carbonitrile (6c)

[0237] A mixture of 6b (12.50 g, 50 mmol), THF (100 mL) and 6N hydrochloric acid solution (100 mL) was heated to 50°C and stirred overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (300 mL) and then washed with saturated brine (300 mL). The organic phase was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 7 / 3) to give the target product 6c (10.50 g, 84%).

[0238] MS m / z (ESI): 250 [M+1]

[0239] Third step

[0240] 1 -(3-bromophenyl)-3,3-difluorocyclobutane-1 -carbonitrile (6d)

[0241] To a solution of 6c (10.00 g, 40 mmol) in dichloromethane (200 mL) was added DAST (15.8 mL, 120 mmol). After the resulting solution was stirred overnight, saturated sodium bicarbonate solution (500 mL) was added and then extracted with dichloromethane (3 x 200 mL). The combined organic phase was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give the target product 6d (6.44 g, 68%).

[0242] MS m / z (ESI): 272 [M+1]

[0243] Fourth step

[0244] 1 -(3-bromophenyl)-3,3-difluorocyclobutane-1 -carbonitrile (6d)

[0245] A mixture of 6d (6.80 g, 25 mmol), ethanol (50 mL) and sodium hydroxide solution (2N, 50 mL) was heated to 85°C and stirred overnight. After cooling to room temperature, dilute hydrochloric acid (2M, 200 mL) was added to the mixture and then extracted with dichloromethane (3 x 100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure to give the target product 6e (6.74 g, crude). This product was used directly in the next reaction without further purification.

[0246] MS m / z (ESI): 291 [M+1]

[0247] Fifth step

[0248] 2-(l-(3-bromophenyl)-3,3-difluorocyclobutane-l-carbonyl)-N-methylhydrazine-l- thioformamide (6f)

[0249] To a mixture of 6e (3.78 g, crude, about 13 mmol), N-methylhydrazine thioformamide (2.05 g, 19.5 mmol), HATU (7.41 g, 19.5 mmol) and DMF (26 mL) was added DIPEA (6.8 mL, 39 mmol). After stirring for 1 h, the reaction was used in the next step without further purification.

[0250] MS m / z (ESI): 379 [M + 1]

[0251] Sixth step

[0252] 5-(l-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-2,4-dihydro-3H-l,2,4-triazole- 3-thione (6g)

[0253] To the crude solution of 6f from the fifth step was added sodium hydroxide solution (2 N, 26 mL) and the resulting mixture was heated to 50 °C and stirred for 6 h. After cooling to room temperature, saturated aqueous ammonium chloride solution (100 mL) was added. The target product 6g (4.60 g, crude) was collected after filtration. The product was used in the next step without further purification.

[0254] MS m / z (ESI): 360 [M + 1]

[0255] Seventh step

[0256] 3-(l-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-4H-l,2,4-triazole (6h)

[0257] To a solution of 6g (4.50 g, crude, about 12.5 mmol) in dichloromethane (50 mL) was added acetic acid (7.5 mL) and hydrogen peroxide (30%, 6 mL) at 0 °C. After stirring at room temperature for 1 h, saturated sodium bicarbonate solution (200 mL) was added and then extracted with dichloromethane (3 x 100 mL). The combined organic phase was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 3 / 1) to give the target product 6h (4.09 g, 99%).

[0258] MS m / z (ESI): 328 [M + 1]

[0259] Eighth step

[0260] 3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline (6i)

[0261] A mixture of 6h (984 mg, 3 mmol), copper powder (19 mg, 0.3 mmol) and aqueous ammonia (30 mL) was heated to 100 °C and stirred overnight. After cooling to room temperature, saturated sodium bicarbonate solution (100 mL) was added, followed by filtration. The filtrate was extracted with dichloromethane (3 x 100 mL) and the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to give the target product 6i (793 mg). The product was used directly in the next step without further purification.

[0262] MS m / z (ESI): 264 [M+1]

[0263] Ninth step

[0264] To a solution of 5f (91 mg, 0.3 mmol) and 6i (79 mg, 0.3 mmol) in DMF (3 mL) was added HATU (171 mg, 0.45 mmol) and DIPEA (262 μL, 1.5 mmol). After the resulting mixture was stirred for 2 h, water (10 mL) was added, followed by extraction with ethyl acetate (3 x 20 mL). The combined organic phase was concentrated to dryness under reduced pressure and the residue was purified by reverse-phase preparative high-performance liquid chromatography to give the target product 6 (62.5 mg, 38%).

[0265] MS m / z (ESI): 550 [M+1]

[0266] 1 H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.41 (s, 1H), 7.64 (d, J = 8.7 Hz, 2H), 7.48 (s, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.30 (s, 1H), 7.09 (d, J = 7.8 Hz, 1H), 4.42 (s, 2H), 3.72 (d, J = 13.1 Hz, 2H), 3.41 (d, J = 13.4 Hz, 4H), 3.27 (s, 3H), 2.70 (t, J = 8.5 Hz, 2H), 1.83 (s, 1H), 1.60 (dd, J = 33.5, 9.7 Hz, 4H), 1.50 - 1.40 (m, 1H), 1.33 (s, 6H), 0.84 (s, 1H), 0.80 (d, J = 5.6 Hz, 3H).

[0267] The following intermediates were synthesized according to the procedure of Example 5, first step to seventh step, but substituting different compounds for 6a during the synthesis.

[0268] Example 6

[0269] (S)-N-(3-(3,3-difluoro-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)phenyl)-2,2- dimethyl-5-((3-methylpiperidin-l-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide (Compound 7)

[0270] First Step

[0271] 2,2-Dimethyl-2,3-dihydrobenzofuran-7-yl trifluoromethanesulfonate (7b)

[0272] To a solution of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol 7a (1.64 g, 10 mmol) in dichloromethane (40 mL) was added pyridine (2.0 mL, 12 mmol) and trifluoromethanesulfonic anhydride (1.2 mL, 15 mmol) at 0 °C. After stirring at room temperature for 2 h, ethyl acetate (200 mL) was added to the reaction mixture, which was then washed successively with saturated sodium bicarbonate solution (200 mL), dilute hydrochloric acid (IN, 200 mL) and saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure to give the target product 7b (2.96 g, crude). The product was used directly in the next step without further purification.

[0273] MS m / z (ESI): 297 [M+1]

[0274] Second Step

[0275] Methyl 2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate (7c)

[0276] 7b (2.96 g, crude, ca. 10 mmol), Pd(dppf)Cl2(732 mg, 1 mmol) and triethylamine (6.9 mL, 50 mmol) were dissolved in methanol (50 mL), which was then heated to 100 °C under a carbon monoxide atmosphere and stirred overnight. After cooling to room temperature, it was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 8 / 2) to give the target product 7c (1.62 g, 81%).

[0277] MS m / z (ESI): 207 [M+1]

[0278] Third Step

[0279] Methyl 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate (7d)

[0280] To a solution of 7c (919 mg, 3 mmol) in acetonitrile (15 mL) was added NBS (1.07 g, 6 mmol). After the resulting mixture was stirred for 2 h, saturated sodium thiosulfate solution (100 mL) was added, followed by extraction with ethyl acetate (100 mL). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 8 / 2) to give the target product 7d (800 mg, 94%).

[0281] MS m / z (ESI): 285 [M+1]

[0282] Fourth to sixth steps

[0283] (S)-N-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2,2- dimethyl-5-((3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide formate (7)

[0284] 7 was synthesized by referring to the procedures of the eighth to tenth steps in Example 1, but using 7d instead of 1i in the operation.

[0285] MS m / z (ESI): 550 [M+1]

[0286] 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.43 (s, 1H), 8.18 (s, 1H), 7.68 (s, 1H), 7.56 - 7.48 (m, 2H), 7.39 (t, J = 7.9 Hz, 1H), 7.33 (s, 1H), 7.09 (d, J = 7.8 Hz, 1H), 3.73 (dd, J = 26.6, 13.4 Hz, 2H), 3.48 (s, 2H), 3.38 (dd, J = 25.3, 14.0 Hz, 2H), 3.28 (s, 3H), 3.09 (s, 2H), 2.78 (t, J = 10.1 Hz, 2H), 1.94 (t, J = 10.5 Hz, 1H), 1.63 (dd, J = 19.1, 14.9 Hz, 4H), 1.52 (s, 6H), 1.48 - 1.42 (m, 1H), 0.87 (s, 1H), 0.81 (d, J = 6.2 Hz, 3H).

[0287] Example 7

[0288] N-(3-((1R,3S)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)- 3,3-dimethyl-5-(((S)-3-methylpiperidin-1-yl)methyl)-2,3,3a,7a-tetrahydrobenfuran-7- formamide (Compound 8)

[0289] First Step

[0290] 3-oxocyclobutane-1-carbonitrile (8b)

[0291] A mixture of 3-methylene cyclobutane-1-carbonitrile 8a (13.97 g, 150 mmol), ruthenium trichloride (311 mg, 1.5 mmol), sodium periodate (12.83 g, 600 mmol), dichloromethane (200 mL), acetonitrile (200 mL) and water (300 mL) was stirred for 12 h, filtered, and then extracted with dichloromethane (3 x 200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 8b (14.27 g, crude). The product was used directly in the next step without further purification.

[0292] Second Step

[0293] Methyl 2-(3-cyanocyclobutylylidene)acetate (8c)

[0294] To a solution of methyl 2-(dimethoxyphosphoryl)acetate (30.05 g, 165 mmol) in THF (600 mL) was added sodium hydride (60%, 7.20 g, 180 mmol). After stirring for 1 h, 8b (14.27 g, crude, ca. 150 mmol) was added. After stirring overnight, saturated ammonium chloride solution (500 mL) was added, and then extracted with ethyl acetate (200 mL). The separated organic phase was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 6 / 4) to give the target product 8c (17.35 g, 76%).

[0295] MS m / z (ESI): 152 [M+1]

[0296] Third Step

[0297] Methyl 2-((1R,3R)-1-(3-((tert-butoxycarbonyl)amino)phenyl)-3-cyanocyclobutyl)acetate nitrile (8d)

[0298] A mixture of 8c (15.12 g, 100 mmol), (3-((tert-butoxycarbonyl)amino)phenyl)boronic acid (30.82 g, 130 mmol), [(COD)RhCl]2(1.23 g, 2.5 mmol), potassium hydroxide (8.42 g, 150 mmol), 1,4-dioxane (250 mL) and water (125 mL) was stirred under nitrogen atmosphere overnight. Saturated ammonium chloride solution (500 mL) was added, followed by extraction with ethyl acetate (3 x 200 mL). The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 7 / 3) to give the target product 8d (9.80 g, 28%).

[0299] MS m / z (ESI): 345 [M+1]

[0300] Fourth step

[0301] 2-((1R,3R)-1-(3-((tert-butoxycarbonyl)amino)phenyl)-3-cyanocyclobutyl)acetic acid (8e)

[0302] A mixture of 8d (10.33 g, 30 mmol), lithium hydroxide (2.52 g, 60 mmol), THF (120 mL) and water (120 mL) was stirred overnight, then dilute hydrochloric acid (1 N, 200 mL) was added and extracted with ethyl acetate (3 x 100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 8e (9.91 g, crude). The product was used directly in the next step without further purification.

[0303] MS m / z (ESI): 331 [M+1]

[0304] Fifth step

[0305] (3-((1R,3R)-3-cyano-1-(2-(2-(methylthiocarbamoyl)hydrazino)-2-oxoethyl)cyclobutyl)phenyl)carbamic acid tert-butyl ester (8f)

[0306] To a mixture of 8e (9.91 g, crude, about 30 mmol), N-methylhydrazinecarbothioamide (4.57 g, 45 mmol), HATU (14.83 g, 39 mmol) and DMF (120 mL) was added DIPEA (5.2 mL, 30 mmol). The resulting mixture was stirred for 4 hours, and then used directly in the next step.

[0307] MS m / z (ESI): 418 [M+1]

[0308] Sixth step

[0309] tert-Butyl (3-((1R,3R)-3-cyano-1-((5-mercapto-4-methyl-4H-1,2,4-triazol-3- yl)methyl)cyclobutyl)phenyl)carbamate (8g)

[0310] To the reaction mixture of previous step, aqueous sodium hydroxide (1 N, 65 mL) was added, then heated to 50 °C and stirred overnight. After cooling to room temperature, dilute hydrochloric acid (1 N, 300 mL) was added to the mixture, then extracted with ethyl acetate (3 x 500 mL), the combined organic phase was washed with saturated brine (3 x 500 mL), then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to give the target product 8g (11.99 g, crude). The product was used directly in the next step without further purification.

[0311] MS m / z (ESI): 400 [M+1]

[0312] Seventh step

[0313] tert-Butyl (3-((1R,3R)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)cyclobutyl)phenyl)carbamate (8h)

[0314] To a solution of 8g (11.99 g, crude, about 30 mmol) in dichloromethane (100 mL), acetic acid (15 mL) and hydrogen peroxide (30%, 12 mL) were added at 0 °C. After the resulting mixture was stirred at room temperature for 1 h, saturated sodium bicarbonate solution (200 mL) was added, then extracted with dichloromethane (3 x 100 mL). The combined organic phase was concentrated to dryness under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 9 / 1) to give the target product 8h (11.00 g, 99%).

[0315] MS m / z (ESI): 368 [M+1]

[0316] Eighth step

[0317] (1R,3R)-3-(3-aminophenyl)-3-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)cyclobutane-1-carbonitrile (8i)

[0318] To a solution of 8h (367 mg, 30 mmol) in dichloromethane (4 mL) and trifluoroacetic acid (1 mL) was stirred at 0 °C for 4 h. Saturated sodium bicarbonate solution (10 mL) was added, followed by extraction with dichloromethane (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 8i (268 mg, crude). The product was used directly in the next step without further purification.

[0319] MS m / z (ESI): 268 [M+1]

[0320] Ninth step

[0321] N-(3-((1R,3S)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)- 3,3-dimethyl-5-(((S)-3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenzofuran-7- carboxamide (8)

[0322] To a mixture of 8i (27 mg, 0.1 mmol), 5f (30 mg, 0.1 mmol) and DMF (1 mL) was added HATU (57 mg, 0.15 mmol) and triethylamine (69 μL, 0.5 mmol). The resulting solution was stirred for 1 h, and then directly purified by prep-HPLC to give the target product 8 (1.5 mg, 3%).

[0323] MS m / z (ESI): 553 [M+1]

[0324] 1 H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.19 (s, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.53 (s, 1H), 7.33 (d, J = 6.3 Hz, 2H), 7.24 (t, J = 7.8 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 4.45 (s, 2H), 3.41 (s, 2H), 2.83 (s, 4H), 2.80 (s, 3H), 2.70 (t, J = 11.6 Hz, 3H), 2.02 - 1.94 (m, 1H), 1.85 (t, J = 10.8 Hz, 1H), 1.64 (d, J = 12.8 Hz, 1H), 1.57 (d, J = 4.6 Hz, 3H), 1.45 (d, J = 11.3 Hz, 2H), 1.29 - 1.20 (m, 6H), 0.84 (d, J = 7.0 Hz, 1H), 0.81 (d, J = 5.4 Hz, 3H).

[0325] Example 8

[0326] N-(3-((1R,3S)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)- 2,2-dimethyl-5-(((S)-3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide (Compound 9)

[0327] To a mixture of 8i (27 mg, 0.1 mmol), 7f (30 mg, 0.1 mmol) and DMF (1 mL) was added HATU (57 mg, 0.15 mmol) and triethylamine (69 μL, 0.5 mmol). The resulting solution was stirred for 1 h before it was directly purified by prep-HPLC to give the target product 9 (formate salt, 0.6 mg, 1%).

[0328] MS m / z (ESI): 553 [M+1]

[0329] 1 H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.23 (s, 1H), 8.19 (s, 1H), 7.54 (s, 2H), 7.32 (s, 1H), 7.27 (d, J = 12.7 Hz, 2H), 6.75 (d, J = 7.8 Hz, 1H), 6.60 (d, J = 38.5 Hz, 1H), 5.32 (s, 1H), 3.10 (s, 2H), 2.85 (d, J = 11.8 Hz, 6H), 2.79 (s, 7H), 2.69 (d, J = 15.2 Hz, 7H), 2.04 - 1.93 (m, 4H), 0.90 - 0.75 (m, 7H).

[0330] The following compounds were synthesized following the experimental procedure of Example 8, but substituting different compounds for 8i and 7f in the procedure.

[0331] The NMR data for these compounds are as follows:

[0332] Example 9

[0333] N-(3-((1R,3S)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)- 2,2-dimethyl-5-(((S)-3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide (Compound 9)

[0334] First Step

[0335] 2-(6-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (10b)

[0336] A mixture of 5-bromo-2,2-difluorobenzo[d][l,3]dioxole 10a (1.19 g, 5 mmol), [lr(COD)OMe]2(33 mg, 0.05 mmol), 2,2'-bipyridine (16 mg, 0.1 mmol) and pinacolborane (1.1 mL, 7.5 mmol) was heated to 80 °C under nitrogen atmosphere and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure to give the target product 10b (1.42 g, crude). The product was used directly in the next step without further purification.

[0337] MS m / z (ESI): 363 [M+1]

[0338] Second step

[0339] 6-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-carbonitrile (10c)

[0340] A mixture of 10b (1.42 g, crude, ca. 5 mmol), copper nitrate hexahydrate (2.42 g, 10 mmol), zinc cyanide (1.76 g, 15 mmol), cesium fluoride (760 mg, 5 mmol), methanol (25 mL) and water (10 mL) was heated to 100 °C and stirred for 3 h. After cooling to room temperature, saturated ammonium chloride solution (50 mL) was added to the resulting mixture, which was then extracted with dichloromethane (3 x 50 mL). The combined organic phase was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give the target product 10c (700 mg, 53%).

[0341] MS m / z (ESI): 262 [M+1]

[0342] Third step

[0343] (S)-2,2-difluoro-6-((3-methylpiperidin-l-yl)methyl)benzo[d][l,3]dioxol-4- carbonitrile (10d)

[0344] A mixture of (S)-3-methylpiperidine hydrochloride (678 mg, 5 mmol), potassium (bromomethyl)trifluoroborate (1.00 g, 5 mmol), cesium carbonate (3.26 g, 10 mmol) and THF (15 mL) was heated to 80 °C and stirred for 2 h under nitrogen atmosphere. After cooling to room temperature, 10c (655 mg, 2.5 mmol), palladium acetate (112 mg, 0.5 mmol), XPhos (478 mg, 1.0 mmol) and water (1.5 mL) were added and heated to 80 °C for overnight under nitrogen protection. After cooling to room temperature, water (10 mL) was added and then extracted with ethyl acetate (15 mL). The filtrate was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give the target product 10d (190 mg, 26%).

[0345] MS m / z (ESI): 195 [M+1]

[0346] Fourth step

[0347] (S)-2,2-difluoro-6-((3-methylpiperidin-l-yl)methyl)benzo[d][l,3]dioxole-4-carboxylic acid (10e)

[0348] A mixture of 10d (44 mg, 0.15 mmol), ethanol (0.5 mL) and 15% sodium hydroxide aqueous solution (0.5 mL) was heated to 85 °C and stirred for 2 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure to give the target product 10e (47 mg, crude). The product was used directly in the next step without further purification.

[0349] MS m / z (ESI): 314 [M+1]

[0350] Fifth step

[0351] N-(3-((lR,3S)-3-cyano-l-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-2,2-difluoro-6-(((S)-3-methylpiperidin-l-yl)methyl)benzo[d][l,3]dioxole-4-carboxamide (10)

[0352] To a solution of 10e (47 mg, 0.15 mmol) and 8i (50 mg, 0.15 mmol) in DMF (1 mL) was added HATU (86 mg, 0.225 mmol) and triethylamine (104 μL, 0.75 mmol). After stirring for 1 h, the reaction was purified by prep-HPLC to give the target product 10 (8.1 mg, 10%).

[0353] MS m / z (ESI): 563 [M+1]

[0354] 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.19 (s, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.54 (s, 1H), 7.50 (s, 1H), 7.36 (s, 1H), 7.28 (t, J = 7.8 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 3.27 - 3.26 (m, 2H), 2.90 - 2.83 (m, 4H), 2.82 (d, J = 2.0 Hz, 3H), 2.80 - 2.73 (m, 5H), 1.70 (d, J = 46.0 Hz, 5H), 1.51 (s, 2H), 0.82 (d, J = 3.7 Hz, 3H).

[0355] Example 10

[0356] N-(3-((1R,3S)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)- 3,3-difluoro-2,2-dimethyl-5-(((S)-3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenfuran-7- formamide (Compound 11)

[0357] First Step

[0358] 1-(3-bromo-2-fluoro-5-methylphenyl)-1,1-difluoro-2-methylpropan-2-ol (11b)

[0359] To a solution of ethyl 2-(3-bromo-2-fluoro-5-methylphenyl)-2,2-difluoroacetate 11a (1.56 g, 5 mmol) in THF (20 mL) was added methyl magnesium bromide in THF (3 M, 5 mL, 15 mmol) at 0 °C. After stirring at room temperature for 1 h, the mixture was added to saturated ammonium chloride solution (100 mL), then extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 11b (1.49 g, crude). The product was used directly in the next step without further purification.

[0360] MS m / z (ESI): 297 [M+1]

[0361] Second Step

[0362] 7-bromo-3,3-difluoro-2,2,5-trimethyl-2,3-dihydrobenfuran (11c)

[0363] To a solution of 11b (1.49 g, crude, about 5 mmol) in THF (25 mL) was added potassium tert-butoxide (1.40 g, 12.5 mmol). The resulting mixture was heated to 65 °C and stirred for 3 h. After cooling to room temperature, saturated sodium bicarbonate solution (100 mL) was added, followed by extraction with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 11c (1.39 g, crude). This product was used directly in the next step without further purification.

[0364] MS m / z (ESI): 277 [M + 1]

[0365] Third step

[0366] 3,3-difluoro-2,2,5-trimethyl-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester (11d)

[0367] A mixture of 11c (1.39 g, crude, about 5 mmol), Pd(dppf)Cl2(366 mg, 0.5 mmol), triethylamine (3.5 mL, 25 mmol) and methanol (25 mL) was heated to 90 °C under carbon monoxide atmosphere and stirred overnight. After cooling to room temperature, it was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 9 / 1) to give the target product 11d (1.00 g, 78%).

[0368] MS m / z (ESI): 257 [M + 1]

[0369] Fourth step

[0370] 5-(bromomethyl)-3,3-difluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester (11e)

[0371] A mixture of 11d (1.03 g, 4 mmol), NBS (1.42 g, 8 mmol), benzoyl peroxide (50 mg) and carbon tetrachloride (20 mL) was heated to 80 °C under nitrogen atmosphere and stirred overnight. After cooling to room temperature, saturated sodium thiosulfate solution (100 mL) was added, followed by extraction with dichloromethane (3 x 200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 11e (1.34 g, crude). This product was used directly in the next step without further purification.

[0372] MS m / z (ESI): 335 [M + 1]

[0373] Fifth step

[0374] (S)-3,3-difluoro-2,2-dimethyl-5-((3-methylpiperidin-l-yl)methyl)-2,3- dihydrobenzofuran-7-carboxylic acid methyl ester (11f)

[0375] To a solution of 11e (1.34 g, crude, ~ 4 mmol) and (S)-3-methylpiperidine hydrochloride (543 mg, 4 mmol) in THF (20 mL) was added triethylamine (2.8 mL, 20 mmol). After the resulting mixture was stirred for 1 h, saturated sodium bicarbonate solution (100 mL) was added, followed by extraction with ethyl acetate (100 mL). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 19 / 1 to 6 / 4) to give the target product 11f (600 mg, 43%).

[0376] MS m / z (ESI): 354 [M+1]

[0377] Sixth step

[0378] (S)-3,3-difluoro-2,2-dimethyl-5-((3-methylpiperidin-l-yl)methyl)-2,3- dihydrobenzofuran-7-carboxylic acid (11g)

[0379] A mixture of 11f (106 mg, 0.3 mmol), lithium hydroxide monohydrate (63 mg, 1.5 mmol), THF (1 mL) and water (1 mL) was stirred overnight. Concentration to dryness under reduced pressure gave the target product 11g (102 mg, 42%). The product was used directly in the next step without further purification.

[0380] MS m / z (ESI): 340 [M+1]

[0381] Seventh step

[0382] N-(3-((lR,3S)-3-cyano-l-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)- 3,3-difluoro-2,2-dimethyl-5-(((S)-3-methylpiperidin-l-yl)methyl)-2,3-dihydrobenzofuran- 7-carboxamide formate salt (11)

[0383] To a solution of 11g (102 mg, 0.3 mmol) and 8i (80 mg, 0.3 mmol) in DMF (2 mL) was added HATU (171 mg, 0.45 mmol) and triethylamine (208 μL, 1.5 mmol) successively. The resulting solution was stirred for 1 h, and then purified by prep-HPLC to give the target product 11 (36 mg, 20%).

[0384] MS m / z (ESI): 589 [M+1]

[0385] 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.82 (s, 1H), 7.69 (s, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.31 (s, 1H), 7.27 (t, J = 7.9 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 3.51 (s, 2H), 3.27 (s, 2H), 3.26 - 3.18 (m, 2H), 2.86 (dd, J = 11.9, 7.2 Hz, 2H), 2.83 (s, 3H), 2.80 (s, 1H), 2.77 - 2.70 (m, 2H), 1.91 (t, J = 10.1 Hz, 1H), 1.72 - 1.58 (m, 4H), 1.56 (s, 6H), 1.46 (d, J = 12.2 Hz, 1H), 0.87 (s, 1H), 0.82 (d, J = 6.1 Hz, 3H).

[0386] Example 11

[0387] (S)-N-(3-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-5-((3- methylpiperidin)-l-yl)methyl)-3H-spiro[benzofuran-2,l'-cyclopropane]-7-carboxamide (Compound 13)

[0388] First step

[0389] 3-bromo-2-hydroxy-5-methylbenzaldehyde (13b)

[0390] 2-bromo-4-methylphenol 13a (4.68 g, 25 mmol), magnesium chloride (7.14 g, 75 mmol), paraformaldehyde (3.00 g, 100 mmol) and triethylamine (14 mL, 100 mmol) were dissolved in acetonitrile (100 mL), heated to 80 °C and stirred overnight. After cooling to room temperature, it was concentrated to dryness under reduced pressure, the residue was added to ethyl acetate (200 mL), then washed with dilute hydrochloric acid (2N, 200 mL) and saturated brine (200 mL) in turn. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the target product 13b (5.38 g, crude). The product was used directly in the next step without further purification.

[0391] MS m / z (ESI): 589 [M+1]

[0392] Second step

[0393] 7-bromo-5-methylbenzofuran-2-carboxylic acid methyl ester (13c)

[0394] A mixture of 13b (5.38 g, crude, ca. 25 mmol), methyl 2-chloroacetate (4.2 mL, 37.5 mmol), potassium carbonate (10.37 g, 75 mmol) and DMF (100 mL) was heated to 100 °C and stirred overnight. After cooling to room temperature, saturated aqueous sodium chloride solution (200 mL) was added, followed by extraction with ethyl acetate (3 x 200 mL). After combining the organic phases, they were washed with saturated aqueous sodium chloride (3 x 200 mL), concentrated to dryness under reduced pressure and the residue purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 9 / 1) to give the target product 13c (5.03 g, 71 %).

[0395] MS m / z (ESI): 269 [M+1]

[0396] Third step

[0397] 7-bromo-5-(bromomethyl)benzofuran-2-carboxylic acid methyl ester (13d)

[0398] A mixture of 13c (4.25 g, 15 mmol), NBS (3.20 g, 18 mmol), benzoyl peroxide (50 mg) and carbon tetrachloride (70 mL) was heated to reflux and stirred overnight under a nitrogen atmosphere. After cooling to room temperature, saturated sodium thiosulfate solution (100 mL) was added, followed by extraction with dichloromethane (3 x 100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated to dryness under reduced pressure to give the target product 13d (5.43 g, crude). This product was used directly in the next reaction without further purification.

[0399] MS m / z (ESI): 347 [M+1]

[0400] Fourth step

[0401] (S)-7-bromo-5-((3-methylpiperidin-l-yl)methyl)benzofuran-2-carboxylic acid methyl ester (13e)

[0402] To a solution of 13d (5.43 g, crude, about 15 mmol) and (S)-3-methylpiperidine hydrochloride (2.03 g, 15 mmol) in THF (60 mL) was added triethylamine (10 mL, 75 mmol). After the resulting mixture was stirred for 1 h, saturated sodium bicarbonate solution (100 mL) was added, followed by extraction with ethyl acetate (100 mL). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give the target product 13e (1.00 g, 18%).

[0403] MS m / z (ESI): 366 [M+1]

[0404] Fifth step

[0405] (S)-(7-bromo-5-((3-methylpiperidin-l-yl)methyl)benzofuran-2-yl)methanol (13f)

[0406] To a solution of 13e (1.14 g, 3 mmol) in methanol (15 mL) was added sodium borohydride (227 mg, 6 mmol). The resulting mixture was heated to 50 °C and stirred for 2 h. After cooling to room temperature, saturated sodium bicarbonate solution (100 mL) was added, followed by extraction with dichloromethane (3 x 100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 13f (1.01 g, crude). The product was used directly in the next step without further purification.

[0407] MS m / z (ESI): 338 [M+1]

[0408] Sixth step

[0409] (S)-l-((7-bromo-2-(chloromethyl)benzofuran-5-yl)methyl)-3-methylpiperidine (13g)

[0410] To a solution of 13f (1.01 g, 3 mmol) in dichloromethane (15 mL) was added thionyl chloride (1.5 mL). After stirring for 1 h, saturated sodium bicarbonate solution (100 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL). Concentration to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 19 / 1 to 7 / 3) to give the target product 13g (587 mg, 55%).

[0411] MS m / z (ESI): 356 [M+1]

[0412] Seventh step

[0413] (S)-1-((7-bromo-2-methylene-2,3-dihydrobenzofuran-5-yl)methyl)-3- methylpiperidine (13h)

[0414] To a solution of chromium chloride (570 mg, 3.6 mmol) in THF (3 mL) was added lithium aluminum hydride (68 mg, 1.8 mmol) at 0 °C. The resulting mixture was stirred under nitrogen atmosphere for 15 min, then isopropanol (0.5 mL) and a solution of 13g (535 mg, 1.5 mmol) in DMF (5 mL) were added. After the resulting mixture was stirred at room temperature overnight, water (50 mL) was added, then extracted with ethyl acetate (3 x 50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, then the filtrate was concentrated to dryness under reduced pressure to give the target product 13h (483 mg, crude). The product was used in the next step without further purification.

[0415] MS m / z (ESI): 322 [M+1]

[0416] Eighth step

[0417] (S)-1-((7-bromo-3H-spiro[benzofuran-2,1'-cyclopropane]-5-yl)methyl)-3- methylpiperidine (13i)

[0418] To a solution of 13h (183 mg, crude, ca. 1.5 mmol) in dichloroethane (10 mL) was added diethylzinc in THF (1 M, 3.8 mL, 3.75 mmol) and iodomethane (609 μL, 7.5 mmol) sequentially at 0 °C. The resulting mixture was heated to 50 °C and stirred for 2 h. After cooling to room temperature, saturated sodium bicarbonate solution (100 mL) was added, then extracted with ethyl acetate (100 mL). The organic phase was concentrated to dryness under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1 to 1 / 3) to give the target product 13i (50 mg, 10%).

[0419] MS m / z (ESI): 338 [M+1]

[0420] Ninth step

[0421] (S)-5-((3-methylpiperidin-1-yl)methyl)-3H-spiro[benzofuran-2,1'- cyclopropane]-7-carboxylic acid methyl ester (13j)

[0422] 13i (67 mg, 0.2 mmol), Pd(dppf)Cl2(29 mg, 0.04 mmol), triethylamine (139 μL, 1 mmol) and methanol (2 mL) were stirred at 80 °C under carbon monoxide environment overnight. After cooling to room temperature, it was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 19 / 1 to 7 / 3) to give the target product 13j (32 mg, 50%).

[0423] MS m / z (ESI): 316 [M+1]

[0424] Tenth step

[0425] (S)-5-((3-methylpiperidin-l-yl)methyl)-3H-spiro[benzofuran-2,l'-cyclopropane]-7-carboxylic acid (13k)

[0426] 13j (32 mg, 0.1 mmol) and lithium hydroxide monohydrate (21 mg, 0.5 mmol) were dissolved in THF (0.5 mL) and water (0.5 mL), heated to 50 °C and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure to give the target product 13k (30 mg, crude). The product was used directly in the next step reaction without further purification.

[0427] MS m / z (ESI): 302 [M+1]

[0428] Eleventh step

[0429] (S)-N-(3-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-5-((3- methylpiperidin)-l-yl)methyl)-3H-spiro[benzofuran-2,l'-cyclopropane]-7-carboxamide (13)

[0430] 13k (30 mg, crude, about 0.1 mmol) and 1g (24 mg, 0.1 mmol) were dissolved in DMF (1 mL), HATU (57 mg, 0.15 mmol) and triethylamine (70 μL, 0.5 mmol) were added, and stirred for 1 hour. Purification by reverse phase preparative high performance liquid chromatography gave the target product 13 (1.2 mg, 2%).

[0431] MS m / z (ESI): 528 [M+1]

[0432] 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.18 (d, J = 22.3 Hz, 1H), 8.15 (s, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.48 (s, 1H), 7.28 (d, J = 7.8 Hz, 2H), 6.69 (d, J = 7.2 Hz, 1H), 4.96 - 4.90 (m, 2H), 4.84 (s, 2H), 3.49 (s, 4H), 2.94 (d, J = 7.7 Hz, 3H), 2.66 (d, J = 8.6 Hz, 2H), 2.08 - 1.90 (m, 2H), 1.64 (s, 4H), 1.46 (s, 3H), 0.84 (d, J = 8.5 Hz, 4H), 0.82 (s, 3H).

[0433] Example 12

[0434] 3,3-dimethyl-N-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-(((S)-3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenfuran-7- carboxamide (Compound 16)

[0435] First Step

[0436] 1-(3-bromophenyl)-3-methylcyclobutane-1-carbonitrile (16b)

[0437] To a solution of 2-(3-bromophenyl)acetonitrile 16a (50.0 g, 255 mmol) and 1,3-dibromo-2-methylpropane (55.1 g, 255 mmol) in DMF (500 mL) was added slowly sodium hydride (60%, 20.9 g, 523 mmol) at 0 °C. The resulting mixture was heated to 60 °C under nitrogen atmosphere and stirred for 13 h. After cooling to room temperature, saturated ammonium chloride solution (500 mL) was added, followed by extraction with ethyl acetate (3 x 500 mL). The organic phase was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 9 / 1) to give the target product 16b (56 g, 88%).

[0438] MS m / z (ESI): 251 [M+1]

[0439] Second Step

[0440] 1-(3-bromophenyl)-3-methylcyclobutane-1-carbonitrile (16c)

[0441] A mixture of 16b (58 g, 232 mmol), sodium hydroxide solution (4 N, 200 mL) and ethanol (100 mL) was heated to 100 °C and stirred for 14 h. After cooling to room temperature, dilute hydrochloric acid (2 N, 200 mL) was added, followed by extraction with ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 16c (52 g, crude). This product was used directly in the next reaction without further purification.

[0442] MS m / z (ESI): 269 [M + 1]

[0443] Third Step

[0444] 2-(1-(3-bromophenyl)-3-methylcyclobutane-1-carbonyl)-N-methylhydrazine-1- thioformamide (16d)

[0445] To a solution of 16c (52.0 g, crude, ca. 193 mmol) and N-methylhydrazine thioformamide (30.5 g, 290 mmol) in DMF (500 mL) was added HATU (36 g, 95 mmol) and DIPEA (44 mL, 31.5 mmol). The resulting solution was stirred at room temperature for 1 h, and then used directly in the next reaction.

[0446] MS m / z (ESI): 356 [M + 1]

[0447] Fourth Step

[0448] 5-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol (16e)

[0449] The solution obtained in the previous step was dissolved in sodium hydroxide solution (4 N, 200 mL), heated to 50 °C and stirred overnight. After cooling to room temperature, dilute hydrochloric acid (4 N, 200 mL) was added, followed by extraction with ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 16e (59.0 g, crude). This product was used directly in the next reaction without further purification.

[0450] MS m / z (ESI): 338 [M + 1]

[0451] Fifth Step

[0452] 3-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (16f)

[0453] To a solution of 16e (20.0 g, crude) in dichloromethane (200 mL) was added dropwise hydrogen peroxide (30%, 24 mL) and acetic acid (150 mL) at 0 °C. After the resulting mixture was stirred for 1 h, saturated sodium bicarbonate solution (300 mL) was added, followed by extraction with dichloromethane (3 x 300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the target product 16f (5.50 g, 30%).

[0454] MS m / z (ESI): 306 [M+1]

[0455] Step 6

[0456] tert-Butyl (3-((lS,3S)-3-methyl-l-(4-methyl-4H-l,2,4-triazol-3- yl)cyclobutyl)phenyl)carbamate (16g)

[0457] To a solution of 16f (5.50 g, ca. 18 mmol) in 1,4-dioxane (60 mL) was added tert-butyl carbamate (2.35 g, 20 mmol), palladium acetate (1.3 g, 5.9 mmol), XPhos (4.8 g, 10.1 mmol) and cesium carbonate (11.0 g, 33.6 mmol). The resulting mixture was heated to 100 °C under nitrogen atmosphere and stirred overnight. After cooling to room temperature, saturated ammonium chloride solution (100 mL) was added, followed by extraction with dichloromethane (150 mL). The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 8 / 2) to give the target product 16g (5.5 g, 33%).

[0458] MS m / z (ESI): 343 [M+1]

[0459] Step 7

[0460] 3-((lS,3S)-3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)aniline (16h)

[0461] To a solution of 16g (750 mg, 2.2 mmol) in methanol (7 mL) was added hydrogen chloride in 1,4-dioxane (4 M, 7 mL). After the resulting solution was stirred overnight, saturated sodium bicarbonate solution (10 mL) was added, followed by extraction with ethyl acetate (3 x 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 16h (430 mg, crude). The product was used in the next step without further purification.

[0462] MS m / z (ESI): 243 [M+1]

[0463] Eighth step

[0464] 3,3-dimethyl-N-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(((S)-3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide (16)

[0465] To a mixture of 5f (30 mg, 0.1 mmol), 16h (24 mg, 0.1 mmol), HATU (57 mg, 0.15 mmol) and DMF (1 mL) was added triethylamine (69 μL, 0.5 mmol). The resulting mixture was stirred for 1 h and then purified by prep-HPLC to give the target product 16 (8.1 mg, 10%).

[0466] MS m / z (ESI): 528 [M+1]

[0467] 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.22 (s, 1H), 7.63 (s, 1H), 7.53 (d, J = 6.9 Hz, 1H), 7.42 (s, 1H), 7.25 (dd, J = 8.6, 4.7 Hz, 2H), 6.98 (s, 1H), 4.36 (s, 2H), 3.33 (s, 2H), 3.12 (d, J = 6.1 Hz, 3H), 2.74 (s, 2H), 2.63 (s, 2H), 2.47 (s, 2H), 1.96 - 1.68 (m, 2H), 1.50 (s, 3H), 1.38 (d, J = 8.6 Hz, 1H), 1.27 (d, J = 6.0 Hz, 6H), 1.17 (s, 2H), 1.01 (d, J = 5.2 Hz, 3H), 0.74 (d, J = 5.7 Hz, 3H).

[0468] The following intermediates were synthesized according to the procedure of Example 12, first step to second step, but using different compounds in place of 1,3-dibromo-2-methylpropane during the synthesis.

[0469] The following compounds were synthesized according to the procedure of Example 12, but using different compounds in place of 1,3-dibromo-2-methylpropane during the procedure.

[0470] The NMR data for the compounds are as follows:

[0471] Example 13

[0472] N-(3-((1R,3S)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)- 3,3-dimethyl-5-(((S)-3-methylpiperidin-1-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridine-7- carboxamide (Compound 17)

[0473] First Step

[0474] tert-Butyl 2-bromopyridin-3-yl carbonate (17b)

[0475] To a solution of 2-bromopyridin-3-ol 17a (3.48 g, 20 mmol) and di-tert-butyl dicarbonate (4.80 g, 22 mmol) in dichloromethane (100 mL) was added DMAP (244 mg, 2 mmol). After the resulting solution was stirred for 2 h, saturated sodium bicarbonate solution (200 mL) was added, followed by extraction with dichloromethane (3 x 100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 17b (5.48 g, crude). The product was used directly in the next step without further purification.

[0476] MS m / z (ESI): 274 [M + 1]

[0477] Second Step

[0478] tert-Butyl 2-bromo-3-hydroxyisonicotinate (17c)

[0479] To a solution of 17b (5.48 g, crude, ~ 20 mmol) in THF (100 mL) at -78 °C was added LDA in THF (2 M, 20 mL, 40 mmol). The resulting solution was stirred at room temperature overnight, saturated sodium bicarbonate solution (100 mL) was added, followed by extraction with ethyl acetate (3 x 100 mL). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give the target product 17c (2.08 g, 38%).

[0480] MS m / z (ESI): 274 [M + 1]

[0481] Third Step

[0482] tert-Butyl 2-bromo-3-((2-methylallyl)oxy)isonicotinate (17d)

[0483] A mixture of 17c (2.06 g, 7.5 mmol), 3-bromo-2-methylprop-1 -ene (1.12 g, 8.3 mmol), potassium carbonate (3.12 g, 22.5 mmol) and acetone (30 mL) was heated to reflux under nitrogen and stirred for 2 h. After cooling to room temperature, water (100 mL) was added and then extracted with ethyl acetate (200 mL). The organic phase was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 8 / 2) to give the target product 17d (1.80 g, 73%).

[0484] MS m / z (ESI): 328 [M+1 ]

[0485] Fourth step

[0486] 3,3-dimethyl-2,3-dihydrofuro[3,2-b]pyridine-7-carboxylic acid tert-butyl ester (17e)

[0487] To a solution of 17d (1.97 g, 6 mmol) in toluene (24 mL) was added AIBN (99 mg, 0.6 mmol) and Bu3SnH (2.62 g, 9 mmol). The resulting mixture was heated to 90 °C under nitrogen and stirred overnight. After cooling to room temperature, a 10% potassium fluoride solution (100 mL) was added. After stirring for 3 h, it was extracted with ethyl acetate (200 mL) and the organic phase was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1 ) to give the target product 17e (980 mg, 65%).

[0488] MS m / z (ESI): 328 [M+1 ]

[0489] Fifth step

[0490] 5-bromo-3,3-dimethyl-2,3-dihydrofuro[3,2-b]pyridine-7-carboxylic acid tert-butyl ester (17f)

[0491] To a solution of 17e (997 mg, 4 mmol) in acetonitrile (20 mL) was added NBS (1.42 g, 8 mmol). The resulting mixture was heated to 80 °C and stirred for 2 h. After cooling to room temperature, a saturated sodium thiosulfate solution (100 mL) and a sodium bicarbonate solution (100 mL) were added and then extracted with ethyl acetate (200 mL). The organic phase was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1 ) to give the target product 17f (1.05 g, 79%).

[0492] MS m / z (ESI): 328 [M+1 ]

[0493] Sixth to eighth steps

[0494] N-(3-((1 r,3S)-3-cyano-1 -((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)-3,3- dimethyl-5-(((S)-3-methylpiperidin-1 -yl)methyl)-2,3-dihydrofuro[3,2-b]pyridine-7- carboxamide (17)

[0495] Synthesis of 17 by following the procedure of Example 1, eighth to tenth steps, but substituting 17f and 8i for 1 i and 1 g in the procedure.

[0496] MS m / z (ESI): 554 [M+1 ]

[0497] 1 H NMR (400 MHz, CD3OD) δ 8.90 (s, 1H), 7.67 (s, 1H), 7.40 (s, 1H), 7.33 (s, 1H), 7.28 (s, 1H), 6.88 (d, J = 7.5 Hz, 1H), 4.60 (s, 2H), 4.32 (s, 2H), 3.47 (s, 2H), 3.43 (s, 1H), 3.36 (d, J = 12.0 Hz, 1H), 3.19 - 3.05 (m, 2H), 2.89 (dd, J = 13.5, 9.3 Hz, 7H), 2.59 (t, J = 11.8 Hz, 1H), 1.85 (s, 4H), 1.36 (s, 6H), 1.17 - 1.09 (m, 1H), 1.03 (t, J = 7.1 Hz, 1H), 0.89 (d, J = 6.4 Hz, 3H).

[0498] Example 14

[0499] N-(3-((1 r,3S)-3-cyano-1 -((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)-3,3- dimethyl-5-(((S)-3-methylpiperidin-1 -yl)methyl)-2,3-dihydrofuro[3,2-b]pyridine-7- carboxamide (17)

[0500] First step

[0501] 2-(3-bromo-2-fluoro-5-methylphenyl)-2-oxoacetic acid ethyl ester (18b)

[0502] To a solution of 2-bromo-l-fluoro-4-methylbenzene 18a (9.45 g, 50 mmol) in THF (100 mL) at -78 °C was added LDA in THF (2 M, 27.5 mL, 55 mmol). After stirring for 1 h, copper iodide (4.76 g, 25 mmol) was added to the reaction mixture. After stirring for another 5 min, ethyl 2-chloro-2-oxoacetate (6.7 mL, 60 mmol) was added to the reaction mixture. After stirring at room temperature for 1 h, saturated ammonium chloride solution (200 mL) was added, followed by extraction with ethyl acetate (3 x 100 mL). The combined organic phases were concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give the target product 18b (2.89 g, 20%).

[0503] MS m / z (ESI): 289 [M+1]

[0504] Second step

[0505] Ethyl 2-(3-bromo-2-fluoro-5-methylphenyl)-2,2-difluoroacetate (18c)

[0506] To a solution of 18b (2.89 g, 10 mmol) in dichloromethane (50 mL) was added DAST (4 mL, 30 mmol). The resulting mixture was heated to reflux and stirred for 4 h. After cooling to room temperature, saturated sodium bicarbonate solution (100 mL) was added, followed by extraction with dichloromethane (3 x 100 mL). The combined organic phases were concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 8 / 2) to give the target product 18c (2.48 g, 80%).

[0507] MS m / z (ESI): 311 [M+1]

[0508] Third step

[0509] Ethyl 2-(3-bromo-5-(bromomethyl)-2-methylphenyl)-2,2-difluoroacetate (18d)

[0510] A mixture of 18c (2.49 g, 8 mmol), NBS (2.14 g, 12 mmol), benzoyl peroxide (50 mg) and carbon tetrachloride (40 mL) was heated to 90 °C under nitrogen atmosphere and stirred overnight. After cooling to room temperature, saturated sodium thiosulfate solution (100 mL) was added, followed by extraction with dichloromethane (3 x 200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure to give the target product 18d (3.12 g, crude). The product was used in the next reaction without further purification.

[0511] MS m / z (ESI): 385 [M+1]

[0512] Fourth Step

[0513] (S)-2-(3-bromo-2-fluoro-5-((3-methylpiperidin-l-yl)methyl)phenyl)-2,2- difluoroacetic acid ethyl ester (18e)

[0514] To a solution of 18d (3.12 g, crude, about 8 mmol) and (S)-3-methylpiperidine hydrochloride (1.09 g, 8 mmol) in THF (32 mL) was added triethylamine (5.5 mL, 40 mmol). After stirring for 1 h, saturated sodium bicarbonate solution (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 x 100 mL). The combined organic phase was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give the target product 18e (1.31 g, 40%).

[0515] MS m / z (ESI): 408 [M+1]

[0516] Fifth Step

[0517] (S)-2-(3-bromo-2-fluoro-5-((3-methylpiperidin-l-yl)methyl)phenyl)-2,2- difluoroethanol-1-ol (18f)

[0518] To a solution of 18e (1.23 g, 3 mmol) in methanol (15 mL) was added sodium borohydride (227 mg, 6 mmol). After stirring for 1 h, saturated sodium bicarbonate solution (100 mL) was added to the reaction mixture, which was then extracted with dichloromethane (3 x 100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 18f (1.10 g, crude). The product was used directly in the next step without further purification.

[0519] MS m / z (ESI): 366 [M+1]

[0520] Sixth Step

[0521] (S)-1-(3-bromo-5-(2-((tert-butyldimethylsilyl)oxy)-l,l-difluoroethyl)-4- fluorobenzyl)-3-methylpiperidine (18g)

[0522] A mixture of 18f (1.10 g, crude, ~ 3 mmol), imidazole (613 mg, 9 mmol), and tert-butyldimethylsilyl chloride (678 mg, 4.5 mmol) was dissolved in dichloromethane (15 mL). After stirring for 2 h, saturated sodium bicarbonate solution (100 mL) was added, followed by extraction with dichloromethane (3 x 100 mL). The combined organic phases were concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give the target product 18g (1.21 g, 84%).

[0523] MS m / z (ESI): 460 [M + 1]

[0524] Seventh step

[0525] (S)-3-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)-2-fluoro-5-((3- methylpiperidin-1-yl)methyl)benzoic acid methyl ester (18h)

[0526] A mixture of 18g (1.20 g, 2.5 mmol), Pd(dppf)Cl2(183 mg, 0.25 mmol), triethylamine (1.7 mL, 12.5 mmol), and methanol (15 mL) was heated to 80 °C under a carbon monoxide atmosphere and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 7 / 3) to give the target product 18h (1.02 g, 89%).

[0527] MS m / z (ESI): 460 [M + 1]

[0528] Eighth step

[0529] (S)-3-(1,1-difluoro-2-hydroxyethyl)-2-fluoro-5-((3-methylpiperidin-1-yl)methyl)benzoic acid methyl ester (18i)

[0530] To a solution of 18h (115 mg, 0.25 mmol) in THF (0.5 mL) was added TBAF in THF (1 M, 5.5 mL, 40 mmol). After stirring for 1 h, saturated sodium bicarbonate solution (10 mL) was added to the mixture, followed by extraction with dichloromethane (3 x 10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 18i (86 mg, crude). This product was used directly in the next reaction without further purification.

[0531] MS m / z (ESI): 346 [M + 1]

[0532] Ninth step

[0533] (S)-3,3-difluoro-5-((3-methylpiperidin-l-yl)methyl)-2,3-dihydrobenzofuran-7- carboxylic acid methyl ester (18j)

[0534] A mixture of 18i (86 mg, crude, ~ 0.25 mmol), 18-crown-6 (66 mg, 0.25 mmol), cesium carbonate (224 mg, 0.75 mmol) and THF (2 mL) was heated to 50 °C and stirred for 1 h. After cooling to room temperature, it was filtered and the filtrate was concentrated to dryness under reduced pressure to give the target product 18j (81 mg, crude). The product was used directly in the next step without further purification.

[0535] MS m / z (ESI): 326 [M + 1]

[0536] Tenth step

[0537] (S)-3,3-difluoro-5-((3-methylpiperidin-l-yl)methyl)-2,3-dihydrobenzofuran-7- carboxylic acid (18k)

[0538] A mixture of 18j (81 mg, crude, ~ 0.25 mmol) and lithium hydroxide monohydrate (42 mg, 1 mmol) was dissolved in THF (1 mL) and water (0.25 mL). After stirring overnight, it was concentrated to dryness under reduced pressure and the residue was purified by prep-HPLC to give the target product 18k (23 mg, 42%).

[0539] MS m / z (ESI): 312 [M + 1]

[0540] Eleventh step

[0541] N-(3-((lr,3S)-3-cyano-l-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutyl)-3,3- difluoro-5-(((S)-3-methylpiperidin-l-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide (18)

[0542] To a solution of 18k (31 mg, 0.1 mmol) and 8i (28 mg, 0.1 mmol) in DMF (2 mL) was added HATU (76 mg, 0.2 mmol) and triethylamine (69 μί, 0.5 mmol). After stirring for 1 h, the reaction solution was directly purified by prep-HPLC to give the target product 18 (2.3 mg, 4%).

[0543] MS m / z (ESI): 561 [M + 1]

[0544] 1H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.61 - 7.51 (m, 1H), 7.36 (t, J = 7.9 Hz, 2H), 6.94 (d, J = 7.8 Hz, 1H), 5.01 (t, J = 15.8 Hz, 2H), 4.40 (s, 2H), 3.54 - 3.35 (m, 3H), 3.18 (dd, J = 16.4, 8.3 Hz, 1H), 3.04 - 2.95 (m, 3H), 2.93 (s, 3H), 2.65 (dd, J = 14.1, 10.0 Hz, 1H), 2.07 - 1.68 (m, 4H), 1.38 - 1.11 (m, 4H), 0.97 (t, J = 16.6 Hz, 3H).

[0545] Example 15

[0546] N-(3-((ls,3R)-3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((S)-3- methylpiperidin-l-yl)methyl)-2H-spiro[benzofuran-3,l'-cyclopropan]-7-carboxamide (Compound 19)

[0547] First Step

[0548] 2H-spiro[benzofuran-3,l'-cyclopropan]-2-one (19b)

[0549] Benzofuran-2(3H)-one 19a (6 g, 44.6 mmol), triethylamine (14 g, 132 mmol) and (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (20 g, 44.6 mmol) were dissolved in DMF (50 mL). After the resulting mixture was stirred at room temperature for 12 hours, water (200 mL) was added, followed by extraction with ethyl acetate (200 mL). The organic phase was washed with saturated brine (100 mL) once, then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 to 30%) to obtain the target product 19b (6.6 g, 91%).

[0550] Second Step

[0551] 2-[l-(hydroxymethyl)cyclopropyl]phenol (19c)

[0552] To a solution of 19b (6.6 g, 41.25 mmol) in methanol (40 mL) was added sodium borohydride (1.9 g, 50 mmol). The mixture was stirred at room temperature for 12 h, then quenched with water (4 mL). The mixture was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 to 100%) to give the target product 19c (6.1 g, 100%).

[0553] MS m / z (ESI): 147 [M+1-18]

[0554] Third Step

[0555] 2-Bromo-6-[1-(hydroxymethyl)cyclopropyl]phenol (19d)

[0556] To a solution of 19c (6 g, 36.6 mmol) and DIPEA (750 mg, 7.32 mmol) in dichloromethane (230 mL) was slowly added NBS (6 g, 34.7 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 12 h, then quenched with methanol (15 mL). The mixture was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 to 60%) to give the target product 19d (5 g, 61%).

[0557] MS m / z (ESI): 225 [M+1-18]

[0558] Fourth Step

[0559] Methyl 2-hydroxy-3-(1-(hydroxymethyl)cyclopropyl)benzoate (19e)

[0560] The mixture 19d (1.7 g, 7 mmol), triethylamine (2.1 g, 21 mmol), Pd(dppf)Cl2(500 mg, 0.7 mmol) and methanol (100 mL) were heated to 90 °C under a carbon monoxide atmosphere and stirred for 12 h. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 to 60%) to give the target product 19e (1.6 g, 103%).

[0561] MS m / z (ESI): 205 [M+1-18]

[0562] Fifth Step

[0563] Methyl 5-bromo-2-hydroxy-3-(1-(hydroxymethyl)cyclopropyl)benzoate (19f)

[0564] To a solution of 19e (2.4 g, 10.8 mmol) in acetonitrile (15 mL) was added slowly NBS (2 g, 10.8 mmol) in acetonitrile (15 mL) at 60 °C. The resulting mixture was stirred at 60 °C for 2 h, then cooled to room temperature and quenched with methanol (5 mL). The mixture was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 to 60%) to give the target product 19f (2.5 g, 81%).

[0565] MS m / z (ESI): 283 [M + 1 - 18]

[0566] Sixth step

[0567] Methyl 5-bromo-2H-spiro[benzofuran-3,1 '-cyclopropan]-7-carboxylate (19g)

[0568] A mixture of triphenylphosphine (1.08 g, 4 mmol), DIAD (810 mg, 4 mmol) and THF (20 mL) was stirred at room temperature for 20 min, then 19f (1.2 g, 4 mmol) was added. The resulting mixture was heated to 100 °C and stirred for 12 h. After cooling to room temperature, methanol (4 mL) was added, then concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 to 30%) to give the target product 19g (540 mg, 50%).

[0569] MS m / z (ESI): 283 [M + 1]

[0570] Seventh step

[0571] Methyl (S)-5-((3-methylpiperidin-1-yl)methyl)-2H-spiro[benzofuran-3,1 '- cyclopropan]-7-carboxylate (19h)

[0572] A mixture of potassium (bromomethyl)trifluoroborate (140 mg, 0.7 mmol), (S)-3- methylpiperidine hydrochloride (135 mg, 0.7 mmol), cesium carbonate (460 mg, 1.4 mmol) and THF (10 mL) was heated to 90 °C and stirred for 24 h. After cooling to room temperature, 19g (100 mg, 0.35 mmol), palladium acetate (16 mg, 0.007 mmol), XPhos (68 mg, 0.14 mmol) and water (0.1 mL) were added to the mixture, then heated to 100 °C under nitrogen atmosphere and stirred for 12 h. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 to 80%) to give the target product 19h (89 mg, 80%).

[0573] MS m / z (ESI): 316 [M+1]

[0574] Eighth Step

[0575] (S)-5-((3-methylpiperidin-l-yl)methyl)-2H-spiro[benzofuran-3,l'-cyclopropan]-7-carboxylic acid (19i)

[0576] To a solution of 19h (80 mg, 0.25 mmol) in THF (5 mL) was added water (1 mL) and lithium hydroxide monohydrate (42 mg, 1 mmol). The resulting mixture was heated to 50 °C and stirred for 12 h. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure and the residue was purified by prep-HPLC to give the target product 19i (23 mg, 30%).

[0577] MS m / z (ESI): 302 [M+1]

[0578] Ninth Step

[0579] N-(3-((l s,3R)-3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((S)-3- methylpiperidin-l-yl)methyl)-2H-spiro[benzofuran-3,l'-cyclopropan]-7-carboxamide (19)

[0580] To a solution of 19i (30 mg, 0.1 mmol), DIPEA (39 mg, 0.3 mmol) and 16h (24 mg, 0.1 mmol) in DMF (1 mL) was added HATU (46 mg, 0.12 mmol). It was stirred at room temperature for 1 h. 10 mL of water was added and then extracted with ethyl acetate (3 x 10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the target product 19 (6.8 mg, 6.5%).

[0581] MS m / z (ESI): 526 [M+1]

[0582] 1H NMR (400 MHz, CD3OD) δ 8.32 (s, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.77 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.08 (d, J = 1.9 Hz, 1H), 4.85 (s, 2H), 4.21 (s, 2H), 3.34 (s, 3H), 3.01 - 2.89 (m, 2H), 2.74 (d, J = 51.6 Hz, 2H), 2.59 (dd, J = 23.3, 13.9 Hz, 4H), 1.91 (dd, J = 30.8, 13.0 Hz, 3H), 1.77 (s, 1H), 1.25 (d, J = 15.8 Hz, 4H), 1.17 (d, J = 6.3 Hz, 5H), 1.00 (d, J = 6.5 Hz, 3H).

[0583] Example 16

[0584] N-(3-((ls,3R)-3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((S)-3- methylpiperidin-l-yl)methyl)-2H-spiro[benzofuran-3,l'-cyclopropane]-7-carboxamide (Compound 20)

[0585] First Step

[0586] 3-(3-methyl-l-(l,3,4-thiadiazol-2-yl)cyclobutyl)aniline (20a)

[0587] To a mixture of 16c (538 mg, 2 mmol), formohydrazide (180 mg, 3 mmol), HATU (1.14 g, 3 mmol) and DMF (10 mL) was added DIPEA (860 μL, 10 mmol). After the resulting mixture was stirred overnight, dilute hydrochloric acid (1 N, 100 mL) was added, followed by extraction with ethyl acetate (100 mL). The organic phase was washed successively with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to give the target product 20a (622 mg, crude). The product was used directly in the next step without further purification.

[0588] MS m / z (ESI): 311 [M + 1]

[0589] Second Step

[0590] 2-(l-(3-bromophenyl)-3-methylcyclobutyl)-l,3,4-thiadiazole (20b)

[0591] To a solution of 20a (622 mg, crude, ~ 2 mmol) in 1,4-dioxane (10 mL) was added Lawesson's reagent (1.62 g, 4 mmol), the resulting mixture was heated to 100 °C and stirred for 3 h. After cooling to room temperature, saturated sodium bicarbonate solution (100 mL) was added to the reaction mixture, which was then extracted with dichloromethane (3 x 100 mL). The combined organic phase was concentrated to dryness under reduced pressure, the residue was purified by reverse-phase preparative high-performance liquid chromatography to give the target product 20b (139 mg, 22%).

[0592] MS m / z (ESI): 309 [M+1]

[0593] Third step

[0594] tert-Butyl (3-(3-methyl-l-(l,3,4-thiadiazol-2-yl)cyclobutyl)phenyl)carbamate (20c)

[0595] A mixture of 20b (93 mg, 0.3 mmol), palladium acetate (13 mg, 0.06 mmol), XPhos (86 mg, 0.18 mmol), tert-butyl carbamate (42 mg, 0.36 mmol), cesium carbonate (147 mg, 0.45 mmol) and 1,4-dioxane (3 mL) was heated to 100 °C under nitrogen atmosphere and stirred for 1 h. After cooling to room temperature, saturated brine (50 mL) was added, which was then extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 20c (104 mg, crude). The product was used in the next step without further purification.

[0596] MS m / z (ESI): 346 [M+1]

[0597] Fourth step

[0598] 3-(3-Methyl-l-(l,3,4-thiadiazol-2-yl)cyclobutyl)phenylamine (20d)

[0599] A mixture of 20c (104 mg, crude, ~ 0.3 mmol), hydrogen chloride solution in 1,4-dioxane (4 M, 2 mL) and methanol (2 mL) was stirred overnight. Saturated brine (50 mL) was added to the mixture, which was then extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 20d (74 mg, crude). The product was used in the next step without further purification.

[0600] MS m / z (ESI): 246 [M+1]

[0601] Fifth step

[0602] (S)-3,3-dimethyl-N-(3-(3-methyl-1-(1,3,4-thiadiazol-2-yl)cyclobutyl)phenyl)-5-((3- methylpiperidin-1-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide (20)

[0603] To a solution of 20d (49 mg, 0.2 mmol) and 5f (61 mg, 0.2 mmol) in DMF (1 mL) was added HATU (76 mg, 0.2 mmol) and triethylamine (140 μL, 1 mmol). The resulting mixture was stirred for 1 h and then purified by prep-HPLC to give the target product 20 (0.9 mg, 1%).

[0604] MS m / z (ESI): 531 [M+1]

[0605] 1 H NMR (400 MHz, CD3OD) δ 9.31 (d, J = 17.3 Hz, 1H), 7.92 (s, 1H), 7.66 (d, J = 35.7 Hz, 2H), 7.52 (s, 1H), 7.45 (s, 1H), 7.35 (s, 1H), 5.36 (s, 2H), 4.61 (d, J = 4.8 Hz, 4H), 4.18 (s, 2H), 3.12 (s, 2H), 2.69 (d, J = 10.8 Hz, 3H), 2.45 (s, 2H), 2.20 (d, J = 5.4 Hz, 1H), 1.85 (s, 2H), 1.45 (d, J = 10.1 Hz, 6H), 1.42 (s, 3H), 0.99 (d, J = 5.4 Hz, 3H).

[0606] The following compounds were synthesized following the experimental procedure of Example 16, but substituting a different compound for 16c in the procedure.

[0607] The nuclear magnetic data of the compounds are as follows:

[0608] Example 17

[0609] 5-((3,3-difluoropyrrolidin-1-yl)methyl)-3,3-dimethyl-N-(3-((1s,3s)-3-methyl-1-(4- methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2,3-dihydrobenzofuran-7-carboxamide (Compound 27)

[0610] First step

[0611] 5-bromo-3,3-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid (27a)

[0612] A mixture of 5d (285 mg, 1 mmol), lithium hydroxide monohydrate (210 mg, 5 mmol), THF (2 mL) and water (2 mL) was heated to 80 °C and stirred for 1 h. After cooling to room temperature, dilute hydrochloric acid (1 N, 20 mL) was added, followed by extraction with ethyl acetate (3 x 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 27a (270 mg, crude). The product was used directly in the next reaction without further purification.

[0613] MS m / z (ESI): 271 [M+1]

[0614] Second step

[0615] 5-bromo-3,3-dimethyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-2,3-dihydrobenzofuran-7-carboxamide (27b)

[0616] To a solution of 27a (270 mg, 1 mmol) and 16h (195 mg, 0.8 mmol) in DMF (3 mL) was added HATU (570 mg, 1 mmol) and triethylamine (415 μL, 3 mmol). After stirring for 1 h, dilute hydrochloric acid (1 N, 50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (3 x 50 mL). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 8 / 2) to give the target product 27b (150 mg, 30%).

[0617] MS m / z (ESI): 495 [M+1]

[0618] Third step

[0619] 5-((3,3-difluoropyrrolidin-1-yl)methyl)-3,3-dimethyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl- 4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2,3-dihydrobenzofuran-7-carboxamide (27)

[0620] A mixture of 3,3-difluoropyrrolidine hydrochloride (43 mg, 0.3 mmol), potassium (bromomethyl)trifluoroborate (60 mg, 0.3 mmol), cesium carbonate (130 mg, 0.4 mmol) and THF (1 mL) was heated to 80 °C under nitrogen atmosphere and stirred for 2 h. After cooling to room temperature, 27b (50 mg, 0.1 mmol), palladium acetate (9 mg, 0.04 mmol), XPhos (38 mg, 0.08 mmol) and water (0.1 mL) were added and heated to 80 °C under nitrogen atmosphere and stirred overnight. After cooling to room temperature, water (10 mL) was added followed by extraction with ethyl acetate (15 mL). The organic phase was concentrated to dryness under reduced pressure and the residue was purified by prep-HPLC to give the target product 27 (3.0 mg, 6%).

[0621] MS m / z (ESI): 536 [M+1]

[0622] 1 H NMR (400 MHz, CD3OD) δ 8.67 (s, 1H), 7.84 (d, J = 1.4 Hz, 1H), 7.75 (s, 1H), 7.50 - 7.42 (m, 2H), 7.33 (dd, J = 13.8, 5.9 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 4.50 (s, 2H), 4.37 (s, 2H), 3.75 (t, J = 11.7 Hz, 2H), 3.55 (t, J = 7.6 Hz, 2H), 3.30 (s, 3H), 2.92 - 2.81 (m, 2H), 2.63 - 2.48 (m, 5H), 1.34 (s, 6H), 1.07 (d, J = 6.2 Hz, 3H).

[0623] The following compounds were synthesized following the experimental procedure of Example 17, but substituting different compounds for 3,3-difluoropyrrolidine hydrochloride in the procedure.

[0624] NMR data for the compounds are as follows:

[0625] Example 18

[0626] (S)-4,4-difluoro-N-(3-(3-methyl-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)chroman-8-carboxamide (Compound 34)

[0627] First Step

[0628] 8-bromo-6-chloro-4-dihydrochromen-8-one (34b)

[0629] To a mixture of 34a (3.6 g, 20 mmol) and concentrated sulfuric acid (20 mL) was added NBS (3.9 g, 22 mmol). After the mixture was stirred at room temperature for 3 hours, it was diluted with ice water (200 mL) and then extracted with ethyl acetate (200 mL). The organic phase was washed with saturated brine (100 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 7 / 3) to give the target product 34b (4.5 g, 86%).

[0630] MS m / z (ESI): 261, 263 [M+1]

[0631] Second step

[0632] 6-chloro-3,4-dihydro-4-oxo-2H-l-benzopyran-8-carboxylic acid methyl ester (34c)

[0633] To a mixture of 34b (1 g, 4 mmol), triethylamine (1.2 g, 12 mmol), Pd(dppf)Cl2(200 mg, 0.2 mmol) and methanol (100 mL) was continuously bubbled carbon monoxide gas at -20 °C for 1 hour. The mixture was closed and then heated to 90 °C and stirred for 5 hours. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 7 / 3) to give the target product 34c (650 mg, 67%).

[0634] MS m / z (ESI): 241, 243 [M+1]

[0635] Third step

[0636] (S)-6-((3-methylpiperidin-l-yl)methyl)-4-oxochroman-8-carboxylic acid methyl ester (34d)

[0637] A mixture of potassium (bromomethyl)trifluoroborate (1.2 g, 6.2 mmol), (S)-3- methylpiperidine hydrochloride (850 mg, 6.2 mmol), cesium carbonate (5 g, 15 mmol) and THF (20 mL) was heated to 90 °C and stirred for 12 h. After cooling to room temperature, 34c (750 mg, 3.1 mmol), palladium acetate (140 mg, 0.62 mmol), XPhos (600 mg, 1.24 mmol) and water (3 mL) were added and the resulting mixture was heated to 105 °C under nitrogen atmosphere and stirred for 8 h. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 3 / 2) to give the target product 34d (180 mg, 18%).

[0638] MS m / z (ESI): 318 [M+1]

[0639] Fourth step

[0640] (S)-4,4-difluoro-6-((3-methylpiperidin-1-yl)methyl)chroman-8-carboxylic acid methyl ester (34e)

[0641] To a solution of 34d (850 mg, 2.67 mmol) in 1,4-dioxane (4 mL) was added DAST (600 mg, 3.7 mmol) slowly. The resulting mixture was heated to 80 °C and stirred for 12 h. After cooling to room temperature, saturated sodium bicarbonate solution (20 mL) was added, followed by extraction with dichloromethane (20 mL). The organic phase was washed with saturated brine (20 mL) once and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0 to 50%) to give the target product 34e (200 mg, 150%).

[0642] MS m / z (ESI): 340 [M+1]

[0643] Fifth step

[0644] (S)-4,4-difluoro-6-((3-methylpiperidin-1-yl)methyl)chroman-8-carboxylic acid (34f)

[0645] To a mixture of 34e (200 mg, 0.588 mmol), THF (12 mL) and water (3 mL) was added lithium hydroxide monohydrate (105 mg, 2.5 mmol). After stirring for 12 h, ice acetic acid was added to the mixture until pH < 7, followed by concentration to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0 to 30%) to give the target product 34f (100 mg, 51%).

[0646] MS m / z (ESI): 326 [M+1]

[0647] Sixth Step

[0648] (S)-4,4-difluoro-N-(3-(3-methyl-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl) phenyl)-6-((3-methylpiperidin-1-yl)methyl)chroman-8-carboxamide (34)

[0649] To a mixture of 34f (30 mg, 0.092 mmol), 16h (25 mg, 0.1 mmol), HATU (45 mg, 0.12 mmol) and DMF (2 mL) was added DIPEA (36 mg, 0.276 mmol). After stirring for 30 min, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by prep-HPLC to give the target product 34 (2 mg, 3.9%).

[0650] MS m / z (ESI): 550 [M+1]

[0651] 1 H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.29 (s, 1H), 7.73 - 7.49 (m, 4H), 7.38 - 7.27 (m, 1H), 7.05 (d, J = 7.6 Hz, 1H), 4.50 - 4.35 (m, 2H), 3.56 - 3.37 (m, 2H), 3.21 - 3.07 (m, 4H), 2.87 - 2.64 (m, 4H), 2.64 - 2.54 (m, 3H), 1.95 - 1.80 (m, 1H), 1.74 - 1.37 (m, 5H), 1.31 - 1.19 (m, 1H), 1.08 (d, J = 5.4 Hz, 3H), 0.92 - 0.71 (m, 4H).

[0652] Example 19

[0653] 5-((2-azaspiro[3.3]heptan-2-yl)methyl)-3,3-dimethyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl- 4H-)1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2,3-dihydrobenzofuran-7-carboxamide formate (Compound 36)

[0654] First Step

[0655] 5-(hydroxymethyl)-3,3-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester (36a)

[0656] A mixture of 5d (1.00 g, 3.5 mmol), (tributylstannyl)methanol (1.70 g, 5.2 mmol), tetrakis triphenylphosphine palladium (405 mg, 0.35 mmol) and 1,4-dioxane (15 mL) was heated to 100 °C and stirred for 4 h under nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 4 / 6) to give the target product 36a (480 mg, 55%).

[0657] MS m / z (ESI): 237 [M+1]

[0658] Second step

[0659] 5-(Iodomethyl)-3,3-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester (36b)

[0660] To a mixture of 36a (480 mg, 2.0 mmol), triphenylphosphine (800 mg, 3.0 mmol), imidazole (204 mg, 3.0 mmol) and dichloromethane (10 mL) was added iodine (760 mg, 3.0 mmol) at 0 °C. After the resulting mixture was stirred at 0 °C for 1 h, saturated sodium thiosulfate solution (15 mL) was added and then extracted with dichloromethane (3 x 20 mL). The combined organic phase was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 7 / 3) to give the target product 36b (480 mg, 55%).

[0661] MS m / z (ESI): 347 [M+1]

[0662] Third step

[0663] 5-((2-Azaspiro[3.3]heptan-2-yl)methyl)-3,3-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester (36c)

[0664] To a solution of 36b (360 mg, 1.0 mmol) in THF (10 mL) was added 2- azaspiro[3.3]heptane (134 mg, 1 mmol) and triethylamine (190 μL, 5 mmol). After stirring overnight, water (10 mL) was added and then extracted with ethyl acetate (3 x 20 mL). The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase preparative high-performance liquid chromatography to give the target product 36c (120 mg, 38%).

[0665] MS m / z (ESI): 354 [M+1]

[0666] Fourth step

[0667] 5-((2-azaspiro[3.3]heptan-2-yl)methyl)-3,3-dimethyl-2,3-dihydrobenzofuran-7- carboxylic acid (36d)

[0668] A mixture of 36c (120 mg, 0.4 mmol), lithium hydroxide monohydrate (86 mg, 2.06 mmol), THF (2 mL) and water (2 mL) was heated to 80 °C and stirred for 2 h. After cooling to room temperature, dilute hydrochloric acid (2 N, 15 mL) was added, followed by extraction with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 36d (100 mg, crude). The product was used directly in the next reaction without further purification.

[0669] MS m / z (ESI): 302 [M+1]

[0670] Fifth step

[0671] 5-((2-azaspiro[3.3]heptan-2-yl)methyl)-3,3-dimethyl-N-(3-((1s,3s)-3-methyl-1-(4- methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2,3-dihydrobenzofuran-7-carboxamide formate salt (36)

[0672] To a solution of 36d (75 mg, 2.06 mmol) and 16h (50 mg, 0.25 mmol) in DMF (3 mL) was added HATU (142 mg, 0.37 mmol) and triethylamine (173 μL, 1.25 mmol). The resulting mixture was stirred under a nitrogen atmosphere for 2 h, then water (10 mL) was added and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was concentrated to dryness under reduced pressure, and the residue was purified by prep-HPLC to give the target product (38.5 mg, 29%).

[0673] MS m / z (ESI): 526 [M+1]

[0674] 1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 8.16 (s, 1H), 7.68 (s, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 1.5 Hz, 1H), 7.41 - 7.24 (m, 2H), 7.05 (d, J = 7.7 Hz, 1H), 4.42 (s, 2H), 3.57 (s, 2H), 3.20 (d, J = 12.9 Hz, 6H), 2.80 (d, J = 3.7 Hz, 2H), 2.54 (s, 3H), 2.05 (t, J = 7.6 Hz, 4H), 1.79 - 1.71 (m, 2H), 1.33 (s, 5H), 1.23 (s, 2H), 1.08 (d, J = 5.4 Hz, 3H).

[0675] The following compounds were synthesized following the experimental procedure of Example 19, but substituting different compounds for 2-azaspiro[3.3]heptane in the procedure.

[0676] The nuclear magnetic resonance data for the compounds are as follows:

[0677] Example 20

[0678] (S)-N-(3-(3,3-difluoro-l-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)- 3,3-dimethyl-5-((3-methylpiperidin-l-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide formate (Compound 37)

[0679] First Step

[0680] (l-(3-bromophenyl)-3,3-difluorocyclobutyl)methanol (37a)

[0681] 6e (8.73 g, 30 mmol) was dissolved in borane THF solution (1 M, 120 mL). After the resulting solution was stirred overnight, methanol (100 mL) was added to quench, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give the target product 37a (8.30 g, 99%).

[0682] MS m / z (ESI): 277 [M+1]

[0683] Second Step

[0684] l-bromo-3-(3,3-difluoro-l-(iodomethyl)cyclobutyl)benzene (37b)

[0685] To a mixture of 37a (8.30 g, 30 mmol), triphenylphosphine (9.44 g, 36 mmol), imidazole (2.45 g, 36 mmol) and dichloromethane (120 mL) was added iodine (9.14 g, 36 mmol) at 0 °C. After stirring at room temperature for 2 h, the resulting mixture was added to a saturated sodium thiosulfate solution (100 mL) and then extracted with dichloromethane (3 x 100 mL). The combined organic phases were concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 8 / 2) to give the target product 37b (3.87 g, 33%).

[0686] MS m / z (ESI): 387 [M+1]

[0687] Third step

[0688] 2-(l-(3-bromophenyl)-3,3-difluorocyclobutyl)acetonitrile (37c)

[0689] To a solution of 37b (3.87 g, 10 mmol) and trimethylsilyl cyanide (2.7 mL, 20 mmol) in acetonitrile (20 mL) was added a solution of TBAF in THF (1 M, 20 mL). The resulting solution was heated to 50 °C and stirred for 2 h. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give the target product 37c (2.85 g, 99%).

[0690] MS m / z (ESI): 286 [M+1]

[0691] Fourth step

[0692] 2-(l-(3-bromophenyl)-3,3-difluorocyclobutyl)acetic acid (37d)

[0693] A mixture of 37c (2.86 g, 10 mmol), ethanol (20 mL) and a sodium hydroxide solution (2 N, 20 mL) was heated to 95 °C and stirred overnight. After cooling to room temperature, dilute hydrochloric acid (2 N, 200 mL) was added and then extracted with dichloromethane (3 x 100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure to give the target product 37d (3.05 g, crude). This product was used directly in the next reaction without further purification.

[0694] MS m / z (ESI): 305 [M+1]

[0695] Fifth step

[0696] 2-(2-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)acetyl)-N-methylhydrazine-1- thioamide (37e)

[0697] 37d (3.05 g, crude, about 10 mmol), N-methylhydrazine thioamide (1.58 g, 15 mmol) and HATU (5.70 g, 15 mmol) were dissolved in DMF (20 mL), then DIPEA (5.3 mL, 30 mmol) was added and stirred for 1 hour. The reaction solution was used directly for the next step without further purification.

[0698] MS m / z (ESI): 392 [M+1]

[0699] Sixth step

[0700] 5-((1-(3-bromophenyl)-3,3-difluorocyclobutyl)methyl)-4-methyl-4H-1,2,4-triazole-3- thiol (37f)

[0701] To the reaction solution of the crude product from the previous step, sodium hydroxide solution (2 N, 20 mL) was added, then heated to 50 °C and stirred for 6 hours. After cooling to room temperature, saturated aqueous ammonium chloride solution (100 mL) was added, and the target product 37f (3.75 g, crude) was obtained after filtration. The product was used directly for the next step without further purification.

[0702] MS m / z (ESI): 374 [M+1]

[0703] Seventh step

[0704] 3-((1-(3-bromophenyl)-3,3-difluorocyclobutyl)methyl)-4-methyl-4H-1,2,4-triazole (37g)

[0705] To a solution of 37f (3.74 g, crude, about 10 mmol) in dichloromethane (40 mL) was added acetic acid (6 mL) and hydrogen peroxide (30%, 5 mL) at 0 °C. After the mixture was warmed to room temperature and stirred for 1 hour, saturated sodium bicarbonate solution (200 mL) was added, then extracted with dichloromethane (3 x 100 mL). The combined organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 8 / 2) to obtain the target product 37g (3.13 g, 92%).

[0706] MS m / z (ESI): 342 [M+1]

[0707] Eighth step

[0708] tert-Butyl (3-(3,3-difluoro-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)carbamate (37h)

[0709] A mixture of 37g (1.03 g, 3 mmol), palladium acetate (135 mg, 0.6 mmol), XPhos (858 mg, 1.6 mmol), tert-butyl carbamate (703 mg, 6 mmol), cesium carbonate (2.93 g, 9 mmol) and 1,4-dioxane (12 mL) was heated to 110 °C and stirred overnight. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 to 8 / 2) to give the target product 37h (1.13 g, 99%).

[0710] MS m / z (ESI): 379 [M+1]

[0711] Ninth step

[0712] 3-(3,3-Difluoro-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)aniline (37i)

[0713] A mixture of 37h (1.13 g, 3 mmol), hydrogen chloride solution in 1,4-dioxane (4 M, 6 mL) and methanol (6 mL) was stirred for 1 hour. The resulting mixture was concentrated to dryness under reduced pressure to give the target product 37i (835 mg, crude). The product was used directly in the next step without further purification.

[0714] MS m / z (ESI): 279 [M+1]

[0715] Tenth step

[0716] (S)-N-(3-(3,3-Difluoro-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-3,3-dimethyl-5-((3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide formate salt (37)

[0717] To a solution of 5f (65 mg, 0.22 mmol) and 37i (60 mg, 0.22 mmol) in DMF (3 mL) was added HATU (142 mg, 0.37 mmol) and triethylamine (152 μL, 1.1 mmol). The resulting mixture was stirred under nitrogen atmosphere for 2 hours, then water (10 mL) was added and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was concentrated to dryness under reduced pressure, and the residue was purified by prep-HPLC to give the target product (27 mg, 23%).

[0718] MS m / z (ESI): 564 [M+1]

[0719] 1 H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.62 (d, J = 7.1 Hz, 1H), 7.54 (s, 1H), 7.39 - 7.29 (m, 2H), 7.25 (s, 1H), 6.66 (d, J = 7.7 Hz, 1H), 4.46 (s, 2H), 3.43 (s, 2H), 3.21 (s, 3H), 3.01 - 2.88 (m, 1H), 2.74 (s, 2H), 2.69 (d, J = 17.1 Hz, 2H), 1.98 (dd, J = 13.1, 6.9 Hz, 1H), 1.88 (d, J = 11.8 Hz, 1H), 1.62 (d, J = 36.5 Hz, 4H), 1.45 (d, J = 11.3 Hz, 2H), 1.34 (s, 6H), 0.85 (s, 2H), 0.81 (d, J = 5.7 Hz, 3H).

[0720] Example 21

[0721] 5-((2-Isopropyl-4-methylpiperazin-1-yl)methyl)-3,3-dimethyl-N-(3-((1s,3s)-3-methyl-1- (4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2,3-dihydrobenzofuran-7-carboxamide formate (Compound 39)

[0722] First Step

[0723] 3-Bromo-2-((2-methylallyl)oxy)benzonitrile (39b)

[0724] A mixture of 3-bromo-2-hydroxybenzonitrile 39a (4.95 g, 25 mmol), 3-bromo-2- methylprop-1-ene (3.71 g, 27.5 mmol), potassium carbonate (10.37 g, 75 mmol) and acetone (100 mL) was heated to reflux under nitrogen atmosphere and stirred for 4 hours. After cooling to room temperature, water (100 mL) was added, then extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, then the filtrate was concentrated to dryness under reduced pressure to give the target product 39b (6.30 g, crude). The product was used directly in the next step without further purification.

[0725] MS m / z (ESI): 564 [M+1]

[0726] Second Step

[0727] 3,3-dimethyl-2,3-dihydrobenzofuran-7-carbonitrile (39c)

[0728] To a solution of 39b (6.30 g, 25 mmol) in toluene (100 mL) was added AIBN (410 mg, 2.5 mmol) and Bu3SnH (10.91 g, 37.5 mmol). The resulting mixture was heated to 90 °C under nitrogen atmosphere and stirred overnight. After cooling to room temperature, potassium fluoride solution (10%, 100 mL) was added to the mixture and stirred for 3 hours, then extracted with ethyl acetate (200 mL). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 8 / 2) to give the target product 39c (1.35 g, 31%).

[0729] MS m / z (ESI): 174 [M+1]

[0730] Third step

[0731] 5-bromo-3,3-dimethyl-2,3-dihydrobenzofuran-7-carbonitrile (39d)

[0732] To a solution of 39c (1.21 g, 7.0 mmol) in acetonitrile (35 mL) was added NBS (2.49 g, 14 mmol). The resulting mixture was heated to 50 °C under nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature, saturated sodium thiosulfate solution (100 mL) and sodium bicarbonate solution (100 mL) were added to the mixture, then extracted with ethyl acetate (200 mL). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 8 / 2) to give the target product 39d (1.40 g, 80%).

[0733] MS m / z (ESI): 252 [M+1]

[0734] Fourth step

[0735] 5-(hydroxymethyl)-3,3-dimethyl-2,3-dihydrobenzofuran-7-carbonitrile (39e)

[0736] A mixture of 39d (1.10 g, 4.4 mmol), (tributylstannyl)methanol (2.10 g, 6.6 mmol), tetrakis(triphenylphosphine)palladium (506 mg, 0.44 mmol) and 1,4-dioxane (15 mL) was heated to 100 °C under nitrogen atmosphere and stirred for 12 hours. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 5) to give the target product 39e (650 mg, 73%).

[0737] MS m / z (ESI): 204 [M+1]

[0738] Fifth step

[0739] 5-(Iodomethyl)-3,3-dimethyl-2,3-dihydrobenzofuran-7-carbonitrile (39f)

[0740] To a mixture of 39e (605 mg, 3.0 mmol), triphenylphosphine (1.18 g, 4.5 mmol), imidazole (360 mg, 4.5 mmol) and dichloromethane (15 mL) was added iodine (1.14 g, 4.5 mmol) at 0 °C. After stirring for 1 h, saturated sodium thiosulfate solution (15 mL) was added to the mixture, which was then extracted with dichloromethane (3 x 20 mL). The combined organic phase was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give the target product 39f (680 mg, 73%).

[0741] MS m / z (ESI): 314 [M+1]

[0742] Sixth step

[0743] (S)-5-((2-Isopropyl-4-methylpiperazin-1-yl)methyl)-3,3-dimethyl-2,3- dihydrobenzofuran-7-carbonitrile (39g)

[0744] A mixture of 39f (626 mg, 2 mmol), (S)-3-isopropyl-1-methylpiperazine (430 mg, 3 mmol), cesium carbonate (1.63 g, 5 mmol) and THF (10 mL) was heated to 50 °C and stirred for 3 h. After cooling to room temperature, water (30 mL) was added, which was then extracted with ethyl acetate (3 x 30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 39g (327 mg, crude). The product was used directly in the next reaction without further purification.

[0745] MS m / z (ESI): 328 [M+1]

[0746] Seventh step

[0747] (S)-5-((2-Isopropyl-4-methylpiperazin-1-yl)methyl)-3,3-dimethyl-2,3- dihydrobenzofuran-7-carboxylic acid (39h)

[0748] A mixture of 39g (327mg, crude, ~1 mmol), lithium hydroxide monohydrate (420mg, 10 mmol), water (2.5 mL) and THF (2.5 mL) was heated to 100 °C and stirred for 4 hours. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by prep-HPLC to give the target product 39h (80mg, 23%).

[0749] MS m / z (ESI): 347 [M+1]

[0750] Eighth step

[0751] 5-((2-Isopropyl-4-methylpiperazin-1-yl)methyl)-3,3-dimethyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2,3-dihydrobenzofuran-7-carboxamide formate salt (39)

[0752] To a solution of 39h (40mg, 0.12 mmol) and 16h (56mg, 0.23 mmol) in DMF (1 mL) was added HATU (68mg, 0.18 mmol) and triethylamine (83 μL, 0.6 mmol). After the resulting mixture was stirred under nitrogen atmosphere for 2 hours, water (10 mL) was added, followed by extraction with ethyl acetate (3 x 20 mL). The combined organic phase was concentrated to dryness under reduced pressure, and the residue was purified by prep-HPLC to give the target product 39 (3.4mg, 10%).

[0753] MS m / z (ESI): 571 [M+1]

[0754] 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.37 (d, J = 27.9 Hz, 1H), 9.20 (s, 1H), 8.76 (s, 1H), 8.62 (d, J = 7.9 Hz, 1H), 8.57 (d, J = 1.4 Hz, 1H), 8.37 (dd, J = 15.1, 7.2 Hz, 1H), 8.34 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 5.48 (s, 2H), 5.06 (d, J = 13.4 Hz, 1H), 4.38 (d, J = 15.6 Hz, 3H), 4.15 (d, J = 13.3 Hz, 1H), 3.85 (d, J = 3.6 Hz, 2H), 3.71 (dd, J = 9.5, 6.1 Hz, 2H), 3.61 (d, J = 7.9 Hz, 1H), 3.44 - 3.30 (m, 1H), 3.26 (s, 2H), 3.19 (d, J = 10.9 Hz, 2H), 3.14 - 2.98 (m, 3H), 2.38 (s, 5H), 2.28 (s, 3H), 2.13 (d, J = 5.3 Hz, 3H), 2.00 - 1.90 (m, 6H), 1.07 - 1.00 (m, 1H).

[0755] The following compound was synthesized following the experimental procedure of Example 22, but substituting 16h with a different compound in the procedure.

[0756] The nuclear magnetic data of the compound are as follows:

[0757] Example 22

[0758] N-(3-(3,3-difluoro-l-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-3,3- dimethyl-5-(((l-methylcyclobutyl)amino)methyl)-2,3-dihydrobenzofuran-7-carboxamide (Compound 41)

[0759] First Step

[0760] 5-Formyl-3,3-dimethyl-2,3-dihydrobenzofuran-7-carbonitrile (41a)

[0761] A mixture of 39e (1.0 g, 4.90 mmol), manganese dioxide (8.5 g, 98 mmol) and dichloromethane (10 mL) was stirred for 2 hours, then filtered. The filtrate was concentrated to dryness under reduced pressure to give the target product 41a (900 mg, crude). The product was used directly in the next step without further purification.

[0762] MS m / z (ESI): 202 [M+1]

[0763] Second Step

[0764] 3,3-dimethyl-5-(((1-methylcyclobutyl)amino)methyl)-2,3-dihydrobenzofuran-7- carbonitrile (41b)

[0765] To a solution of 41a (360 mg, 1.78 mmol) and 1-methylcyclobutan-1-amine hydrochloride (326 mg, 2.68 mmol) in dichloromethane (5 mL) was added acetic acid (267 mg, 4.45 mmol) and sodium triacetylborohydride (1.0 g, 7.26 mmol). After the resulting mixture was stirred overnight, saturated sodium bicarbonate solution (15 mL) was added and extracted with dichloromethane (3 x 20 mL). The combined organic phase was concentrated to dryness under reduced pressure to give the target product 41b (480 mg, crude). The product was used directly in the next step without further purification.

[0766] MS m / z (ESI): 271 [M+1]

[0767] Third Step

[0768] 3,3-dimethyl-5-(((1-methylcyclobutyl)amino)methyl)-2,3-dihydrobenzofuran-7- carbonitrile (41b)

[0769] A mixture of 41b (480 mg, 1.7 mmol), sodium hydroxide solution (2 N, 5 mL) and ethanol (5 mL) was heated to 95 °C and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure and the residue was purified by reverse phase preparative high performance liquid chromatography to give the target product 41c (60 mg, 12%).

[0770] MS m / z (ESI): 290 [M+1]

[0771] Fourth Step

[0772] 5-(((tert-butoxycarbonyl)(1-methylcyclobutyl)amino)methyl)-3,3-dimethyl-2,3- dihydrobenzofuran-7-carboxylic acid (41d)

[0773] To a solution of 41c (60 mg, 0.2 mmol) and di-tert-butyl dicarbonate (0.095 mL, 0.4 mmol) in THF (2 mL) was added triethylamine (0.083 mL, 0.6 mmol) dropwise. After the resulting mixture was stirred for 2 h, dilute hydrochloric acid (2 N, 5 mL) was added, followed by extraction with ethyl acetate (3 x 10 mL). The combined organic phase was concentrated to dryness under reduced pressure, and the residue was purified by prep-HPLC to give the target product 41d (50 mg, 65%).

[0774] MS m / z (ESI): 390 [M+1]

[0775] Fifth Step

[0776] Tert-butyl ((7-((3-(3,3-difluoro-l-((4-methyl-4H-l,2,4-triazol-3- yl)methyl)cyclobutyl)phenyl)carbamoyl)-3,3-dimethyl-2,3-dihydrobenfuran-5- yl)methyl)(l-methylcyclobutyl)carbamate (41e)

[0777] To a solution of 41d (50 mg, 0.13 mmol) and 37i (50 mg, 0.13 mmol) in DMF (1 mL) was added HATU (74 mg, 0.2 mmol) and triethylamine (90 μL, 0.65 mmol). The resulting mixture was stirred under nitrogen atmosphere for 2 h, then water (10 mL) was added and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was concentrated to dryness under reduced pressure to give the target product 41e (30 mg, crude). The product was used directly in the next step without further purification.

[0778] MS m / z (ESI): 650 [M+1]

[0779] Sixth Step

[0780] N-(3-(3,3-difluoro-l-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)- 3,3-dimethyl-5-(((l-methylcyclobutyl)amino)methyl)-2,3-dihydrobenfuran-7- formamide (41)

[0781] A mixture of 41e (30 mg, 0.45 mmol), hydrogen chloride solution in 1,4-dioxane (4 M, 1 mL) and methanol (1 mL) was stirred for 1 h, then concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the target product (2.2 mg, 9%).

[0782] MS m / z (ESI): 550 [M+1]

[0783] 1 H NMR (400 MHz, CD3OD) δ 8.19 (s, 1H), 7.89 (s, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.50 (s, 1H), 7.40 - 7.29 (m, 1H), 7.24 (s, 1H), 6.80 (d, J = 7.6 Hz, 1H), 4.58 (s, 1H), 3.99 (s, 1H), 3.06 - 2.94 (m, 2H), 2.75 (d, J = 5.7 Hz, 2H), 2.32 (s, 2H), 2.24 - 2.16 (m, 1H), 2.03 (d, J = 5.9 Hz, 3H), 1.94 (d, J = 8.3 Hz, 2H), 1.59 (d, J = 11.5 Hz, 3H), 1.44 (s, 2H), 1.30 (s, 8H), 0.90 (t, J = 6.9 Hz, 1H).

[0784] The following compounds were synthesized following the experimental procedure of Example 23, but substituting different compounds for (S)-3-isopropyl-l-methylpiperazine in the procedure.

[0785] The NMR data for these compounds are as follows:

[0786] Example 23

[0787] (S)-N-(3-(3,3-difluoro-l-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-5- ((2-isopropyl-4-methylpiperazin-l-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide (Compound 42)

[0788] First Step

[0789] 7-bromo-2,3-dihydrobenzofuran-5-carbaldehyde (42b)

[0790] To a solution of 2,3-dihydrobenzofuran-5-carbaldehyde 42a (5.0 g, 33.8 mmol) in acetic acid (40 mL) was added sodium acetate (5.50 g, 41 mmol) and liquid bromine (7 mL, 67.6 mmol). After the resulting mixture was stirred for 12 h, saturated sodium thiosulfate solution (100 mL) was added, followed by extraction with ethyl acetate (300 mL). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to give the target product 42b (5.30 g, 69%).

[0791] MS m / z (ESI): 227 [M+1]

[0792] Second step

[0793] (S)-1-((7-bromo-2,3-dihydrobenzofuran-5-yl)methyl)-2-isopropyl-4- methylpiperazine (42c)

[0794] A mixture of 42b (1.2 g, 5.3 mmol), (S)-3-isopropyl-l-methylpiperazine (684 mg, 4.8 mmol), sodium triacetylborohydride (1.7 g, 7.95 mmol), triethylamine (1.45 g, 14.4 mmol) and dichloroethane (20 mL) was stirred for 12 hours, then concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give the target product 42c (1.6 g, 85%).

[0795] MS m / z (ESI): 353 [M+1]

[0796] Third step

[0797] (S)-5-((2-isopropyl-4-methylpiperazin-l-yl)methyl)-2,3-dihydrobenzofuran-7- carboxylic acid methyl ester (42d)

[0798] A mixture of 42c (1.6 g, 4.55 mmol), Pd(dppf)Cl2(330 mg, 0.455 mmol), triethylamine (1.4 g, 13.7 mmol) and methanol (25 mL) was heated to 80 °C and stirred for 12 hours under carbon monoxide atmosphere. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 3 / 1) to give the target product 42d (1.40 g, 93%).

[0799] MS m / z (ESI): 353 [M+1]

[0800] Fourth step

[0801] (S)-5-((2-isopropyl-4-methylpiperazin-l-yl)methyl)-2,3-dihydrobenzofuran-7- carboxylic acid (42e)

[0802] A mixture of 42d (550 mg, 16 mmol), lithium hydroxide monohydrate (127 mg, 3 mmol), THF (4 mL) and water (2 mL) was stirred for 12 hours, then 2N hydrochloric acid solution (20 mL) was added and extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 42e (430 mg, crude). The product was used directly in the next reaction without further purification.

[0803] MS m / z (ESI): 319 [M+1]

[0804] Fifth Step

[0805] (S)-N-(3-(3,3-difluoro-l-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-5- ((2-isopropyl-4-methylpiperazin-l-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide (42)

[0806] To a solution of 42e (25 mg, crude, ~ 0.07 mmol) in DMF (15 mL) was added HATU (20 mg, 0.07 mmol), triethylamine (21 mg, 0.21 mmol) and 37i (20 mg, 0.07 mmol) successively. After the resulting mixture was stirred for 2 h, water (20 mL) was added and extracted with ethyl acetate (20 mL). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by prep-HPLC to give the target product 42 (1.6 mg, 3.5%).

[0807] MS m / z (ESI): 579 [M+1]

[0808] 1 H NMR (400 MHz, CD3OD) δ 8.79 (d, J = 10.3 Hz, 1H), 7.75 (s, 1H), 7.51 - 7.44 (m, 2H), 7.38 - 7.00 (m, 3H), 6.86 (d, J = 7.6 Hz, 1H), 4.24 (d, J = 13.1 Hz, 1H), 3.46 (s, 4H), 3.26 (d, J = 7.3 Hz, 5H), 3.05 (dd, J = 28.5, 13.9 Hz, 6H), 2.91 (d, J = 8.7 Hz, 6H), 2.53 (d, J = 60.5 Hz, 3H), 2.28 - 1.96 (m, 1H), 1.11 - 0.98 (m, 6H).

[0809] Example 24

[0810] N-(3-(3,3-difluoro-l-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-3,3- dimethyl-5-(((4aS,7aS)-octahydro-lH-cyclopenta[b]pyrrol-1-yl)methyl)-2,3-dihydrobenzofuran- 7-carboxamide (Compound 44)

[0811] First Step

[0812] 1-(4-ethoxy-4-oxobutyl)-2-oxocyclopentane-l-carboxylic acid ethyl ester (44b)

[0813] A mixture of 2-oxocyclopentane-l-carboxylic acid ethyl ester 44a (7.80 g, 50 mmol), 4-bromobutyric acid ethyl ester (11.70 g, 60 mmol), tetrabutylammonium iodide (20.74 g, 150 mmol), potassium carbonate (1.85 g, 2.5 mmol) and THF (200 mL) was heated to reflux and stirred for 4 h. After cooling to room temperature, ethyl acetate (100 mL) was added to the mixture, which was then washed with saturated brine (100 mL). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give the target product 44b (13.51 g, 99%).

[0814] MS m / z (ESI): 271 [M+1]

[0815] Second Step

[0816] 4-(2-oxocyclopentyl)butyric acid ethyl ester (44c)

[0817] A mixture of 44b (6.76 g, 25 mmol) and 10% hydrobromic acid solution (100 mL) was heated to reflux and stirred overnight. After cooling to room temperature, saturated brine (100 mL) was added to the mixture, which was then extracted with dichloromethane (3 x 100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 44c (4.96 g, crude). The product was used directly in the next reaction without further purification.

[0818] MS m / z (ESI): 199 [M+1]

[0819] Third Step

[0820] 4-(2-oxocyclopentyl)butyric acid (44d)

[0821] A mixture of 44c (4.96 g, crude, about 25 mmol), lithium hydroxide monohydrate (4.20 g, 100 mmol), THF (50 mL) and water (50 mL) was heated to reflux and stirred for 2 h. After cooling to room temperature, dilute hydrochloric acid (1 N, 200 mL) was added to the mixture, which was then extracted with ethyl acetate (3 x 100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 44d (4.26 g, crude). The product was used directly in the next reaction without further purification.

[0822] MS m / z (ESI): 171 [M+1]

[0823] Fourth Step

[0824] tert-Butyl (3-(2-oxocyclopentyl)propyl)carbamate (44e)

[0825] A mixture of 44d (4.26 g, crude, about 25 mmol), triethylamine (6.9 mL, 50 mmol), diphenylphosphoryl azide (6.5 mL, 30 mmol) and tert-butanol (40 mL) was heated to reflux and stirred for 2 h. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure, then ethyl acetate (100 mL) was added. The resulting solution was washed successively with saturated sodium bicarbonate solution (100 mL), saturated citric acid solution (100 mL) and saturated brine (100 mL), then concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 6 / 4) to give the target product 44e (800 mg, 13%).

[0826] MS m / z (ESI): 242 [M+1]

[0827] Fifth step

[0828] 2-(3-aminopropyl)cyclopentan-1-one (44f)

[0829] 44e (724 mg, 3 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (4 M, 6 mL) and methanol (6 mL). After the resulting solution was stirred for 1 h, saturated sodium bicarbonate solution (50 mL) was added, then extracted with dichloromethane (3 x 50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, then the filtrate was concentrated to dryness under reduced pressure to give the target product 44f (424 mg, crude). This product was used directly in the next reaction without further purification.

[0830] MS m / z (ESI): 142 [M+1]

[0831] Sixth step

[0832] (4aS,7aS)-octahydro-1H-cyclopenta[b]pyridine (44g)

[0833] To a solution of 44f (424 mg, crude, about 3 mmol) in dichloroethane (15 mL) was added sodium triacetoxyborohydride (1.27 g, 6 mmol). After the resulting mixture was stirred overnight, saturated sodium bicarbonate solution (50 mL) was added, then extracted with dichloromethane (3 x 50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, then the filtrate was concentrated to dryness under reduced pressure to give the target product 44g (376 mg, crude). This product was used directly in the next reaction without further purification.

[0834] MS m / z (ESI): 126 [M+1]

[0835] Seventh to ninth steps

[0836] N-(3-(3,3-difluoro-l-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-3,3- dimethyl-5-(((4aS,7aS)-octahydro-lH-cyclopenta[b]pyrindin-l-yl)methyl)-2,3-dihydrobenfuran-7- formamide (44)

[0837] Refer to the procedure for the sixth to eighth steps in Example 21 to synthesize 44, but substitute (S)-3-isopropyl-l-methylpiperazine for 44g in the procedure.

[0838] MS m / z (ESI): 590 [M+1]

[0839] 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.23 (s, 1H), 7.89 - 7.76 (m, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.55 (dd, J = 11.0, 1.7 Hz, 1H), 7.29 (d, J = 7.9 Hz, 2H), 6.75 (d, J = 7.8 Hz, 1H), 4.52 (s, 2H), 4.15 (ddd, J = 20.7, 18.2, 12.3 Hz, 2H), 3.23 (s, 4H), 3.13 - 2.88 (m, 4H), 2.78 (s, 3H), 2.30 - 2.14 (m, 1H), 2.00 (dd, J = 14.6, 6.9 Hz, 1H), 1.86 (s, 2H), 1.82 - 1.47 (m, 6H), 1.38 (s, 6H), 1.28 (d, J = 16.8 Hz, 1H), 1.20 - 1.08 (m, 1H).

[0840] Example 25

[0841] N-(6-cyclopropyl-4-((ls,3R)-3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)pyridin-2- yl)-3,3-dimethyl-5-(((S)-3-methylpiperidin-l-yl)methyl)-2,3-dihydrobenfuran-7-carboxamide (Compound 49)

[0842] First step

[0843] Methyl 2-cyclopropyl-6-methoxyisonicotinate (49b)

[0844] To a mixture of 2-chloro-6-methoxyisonicotinic acid methyl ester 49a (5.00 g, 25 mmol), cyclopropylboronic acid (6.40 g, 75 mmol), palladium acetate (560 mg, 2.5 mmol), tricyclohexylphosphine (1.40 g, 5 mmol), potassium phosphate (15.8 g, 75 mmol), toluene (80 mL) and water (20 mL) was added sodium methoxide (2.70 g, 50 mmol). The resulting mixture was heated to 110 °C under nitrogen atmosphere and stirred for 4 h. After cooling to room temperature, water (100 mL) was added, followed by extraction with ethyl acetate (150 mL). The organic phase was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give the target product 49b (5.09 g, 99%).

[0845] MS m / z (ESI): 208 [M+1]

[0846] Second step

[0847] (2-cyclopropyl-6-methoxy-pyridin-4-yl)methanol (49c)

[0848] To a solution of 49b (5.09 g, 25 mmol) in methanol (100 mL) was added sodium borohydride (2.84 g, 75 mmol). After stirring the resulting mixture for 1 h, saturated sodium bicarbonate solution (100 mL) was added, followed by extraction with dichloromethane (3 x 100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure to give the target product 49c (4.48 g, crude). This product was used directly in the next step without further purification.

[0849] MS m / z (ESI): 208 [M+1]

[0850] Third step

[0851] 2-cyclopropyl-4-(iodomethyl)-6-methoxy-pyridine (49d)

[0852] To a mixture of 49c (4.48 g, crude, ca. 25 mmol), triphenylphosphine (7.87 g, 30 mmol), imidazole (2.04 g, 30 mmol) and dichloromethane (100 mL) was added iodine (7.61 g, 30 mmol). After stirring the resulting mixture for 1 h, saturated sodium thiosulfate solution (200 mL) was added, followed by extraction with dichloromethane (3 x 100 mL). The combined organic phase was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give the target product 49d (4.98 g, 69%).

[0853] MS m / z (ESI): 290 [M+1]

[0854] Fourth Step

[0855] 2-(2-cyclopropyl-6-methoxy-pyridin-4-yl)acetonitrile (49e)

[0856] To a solution of 49d (4.92 g, 17 mmol) and trimethylsilyl cyanide (4.6 mL, 34 mmol) in acetonitrile (34 mL) was added TBAF in THF (1 M, 34 mL, 34 mmol) and heated to 50 °C and stirred for 2 h. After cooling to room temperature, it was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give the target product 49e (2.89 g, 90%).

[0857] MS m / z (ESI): 189 [M+1]

[0858] Fifth Step

[0859] 1-(2-cyclopropyl-6-methoxy-pyridin-4-yl)-3-methylcyclobutane-1-carbonitrile (49f)

[0860] To a mixture of 49e (1.82 g, 15 mmol), 1,3-dibromo-2-methylpropane (3.89 g, 18 mmol) and DMF (60 mL) was added sodium hydride (1.44 g, 36 mmol). The resulting mixture was heated to 60 °C and stirred for 2 h. After cooling to room temperature, saturated sodium bicarbonate solution (100 mL) was added, followed by extraction with ethyl acetate (3 x 100 mL). The combined organic phase was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 6 / 4) to give the target product 49f (600 mg, 17%).

[0861] MS m / z (ESI): 243 [M+1]

[0862] Sixth Step

[0863] 1-(2-cyclopropyl-6-methoxy-pyridin-4-yl)-3-methylcyclobutane-1-carbonitrile (49f)

[0864] A mixture of 49f (600 mg, 2.5 mmol), sodium hydroxide (500 mg, 12.5 mmol), ethanol (5 mL) and water (5 mL) was heated to reflux and stirred overnight. After cooling to room temperature, hydrogen chloride in 1,4-dioxane (4 M, 4 mL) was added to the mixture, which was then concentrated to dryness under reduced pressure to give the target product 49g (653 mg, crude). The product was used directly in the next reaction without further purification.

[0865] MS m / z (ESI): 262 [M+1]

[0866] Seventh Step

[0867] 2-(l-(2-cyclopropyl-6-methoxy-pyridin-4-yl)-3-methyl-cyclobutane-l- carbonyl)-N-methyl-hydrazine-l-carbothioamide (49h)

[0868] To a mixture of 49g (653 mg, crude, ~ 2.5 mmol), N-methylhydrazine carbothioamide (394 mg, 3.75 mmol), HATU (1.43 g, 3.75 mmol) and DMF (10 mL) was added DIPEA (1.31 g, 7.5 mmol). The resulting solution was stirred overnight and used directly in the next step without further purification.

[0869] MS m / z (ESI): 349 [M+1]

[0870] Eighth Step

[0871] 5-(l-(2-cyclopropyl-6-methoxy-pyridin-4-yl)-3-methyl-cyclobutyl)-4-methyl- 4H-l,2,4-triazole-3-thiol (49i)

[0872] To the crude reaction solution from previous step was added sodium hydroxide solution (2 N, 10 mL) and then heated to 50 °C and stirred overnight. After cooling to room temperature, dilute hydrochloric acid (1 N, 100 mL) was added to the mixture and then extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with saturated brine (3 x 100 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to give the target product 49i (826 mg, crude). The product was used directly in the next step without further purification.

[0873] MS m / z (ESI): 331 [M+1]

[0874] Ninth Step

[0875] 2-cyclopropyl-6-methoxy-4-(3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)- cyclobutyl)-pyridine (49j)

[0876] To a solution of 49i (826 mg, crude, ca. 2.5 mmol) in dichloromethane (10 mL) was added acetic acid (1.5 mL) and 30% hydrogen peroxide solution (1.5 mL) at 0 °C. After the resulting mixture was stirred at room temperature for 1 h, saturated sodium bicarbonate solution (200 mL) was added, followed by extraction with dichloromethane (3 x 100 mL). The combined organic phase was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 to 9 / 1) to give the target product 49j (600 mg, 80%).

[0877] MS m / z (ESI): 299 [M+1]

[0878] Tenth step

[0879] 6-cyclopropyl-4-(3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)pyridin-2-ol (49k)

[0880] To a solution of 49j (597 mg, 2 mmol) in acetonitrile (10 mL) was added trimethylsilyl chloride (756 μL, 6 mmol) and sodium iodide (899 mg, 6 mmol). The resulting mixture was heated to 80 °C and stirred for 1 h. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 to 8 / 2) to give the target product 49k (588 mg, 99%).

[0881] MS m / z (ESI): 285 [M+1]

[0882] Eleventh step

[0883] 6-cyclopropyl-4-(3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl triflate (49l)

[0884] A mixture of 49k (588 mg, 2 mmol), triethylamine (1.4 mL, 10 mmol), bis(trifluoromethylsulfonyl)amide (1.07 g, 3 mmol), DMF (10 mL) and water (1 mL) was stirred overnight, then saturated sodium bicarbonate solution (100 mL) was added and extracted with ethyl acetate (100 mL). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 to 9 / 1) to give the target product 49l (600 mg, 72%).

[0885] MS m / z (ESI): 417 [M+1]

[0886] Twelfth step

[0887] (S)-3,3-dimethyl-5-((3-methylpiperidin-l-yl)methyl)-2,3-dihydrobenzofuran-7- carboxamide (49m)

[0888] To a mixture of 5f (950 mg, 3.1 mmol), ammonium chloride (845 mg, 15.7 mmol) and DMF (10 mL) was added HATU (2.30 g, 6.3 mmol) and triethylamine (4.3 mL, 37.3 mmol). After the resulting mixture was stirred for 2 hours, water (100 mL) was added, followed by extraction with ethyl acetate (3 x 50 mL). The combined organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 8 / 2) to give the target product 49m (500 mg, 53%).

[0889] MS m / z (ESI): 303 [M+1]

[0890] Thirteenth step

[0891] N-(6-cyclopropyl-4-((ls,3R)-3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)pyridin- 2-yl)-3,3-dimethyl-5-(((S)-3-methylpiperidin-l-yl)methyl)-2,3-dihydrobenzofuran-7- carboxamide bistrifluoromethanesulfonate (49)

[0892] A mixture of 49l (42 mg, 0.1 mmol), 49m (30 mg, 0.1 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol), Xantphos (23 mg, 0.04 mmol), cesium carbonate (65 mg, 0.2 mmol) and 1,4-dioxane (0.5 mL) was heated to 110 °C under nitrogen atmosphere and stirred overnight. After cooling to room temperature, it was concentrated to dryness, and the residue was purified by prep-HPLC to give the target product 49 (5.6 mg, 10%).

[0893] MS m / z (ESI): 569 [M+1]

[0894] 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.57 (s, 1H), 8.75 (s, 1H), 7.90 (d, J = 7.0 Hz, 2H), 7.62 (dd, J = 11.9, 7.1 Hz, 1H), 7.57 (d, J = 1.5 Hz, 1H), 7.13 (s, 1H), 4.59 (s, 2H), 4.28 (d, J = 4.2 Hz, 2H), 3.35 - 3.23 (m, 4H), 2.81 (dd, J = 24.8, 8.1 Hz, 3H), 2.59 (d, J = 7.3 Hz, 3H), 2.15 - 2.07 (m, 1H), 1.83 (d, J = 12.0 Hz, 2H), 1.68 (dd, J = 38.8, 12.9 Hz, 3H), 1.36 (s, 6H), 1.10 (d, J = 5.2 Hz, 3H), 1.05 (d, J = 12.9 Hz, 1H), 1.00 - 0.91 (m, 3H), 0.88 (d, J = 6.5 Hz, 3H).

[0895] The following intermediate was synthesized by following the procedure of Example 25, Step 12, but substituting a different compound for 5f in the procedure.

[0896] The following compound was synthesized by following the procedure of Example 25, Step 10, Step 11 and Step 13, but substituting a different compound for 49j in the procedure.

[0897] The nuclear magnetic resonance data for the compound is as follows:

[0898] Example 26

[0899] N-(6-ethoxy-4-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin- 2-yl)-3,3-dimethyl-5-(((S)-3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenfuran-7- formamide (Compound 50)

[0900] First Step

[0901] Ethyl 2-chloro-6-ethoxyisonicotinate (50b)

[0902] To a solution of ethyl 2,6-dichloroisonicotinate 50a (9.00 g, 37.4 mmol) in ethanol (80 mL) was added sodium ethoxide (3.06 g, 45.0 mmol). The resulting mixture was heated to 70 °C and stirred for 3 h, then cooled to 0 °C, adjusted to pH = 7 with dilute hydrochloric acid (1 N) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 5 / 1) to give the target product 50b (7.20 g, 77%).

[0903] MS m / z (ESI): 230 [M + 1]

[0904] Second step

[0905] Ethyl 2-(benzyloxy)-6-ethoxyisonicotinate (50c)

[0906] To a solution of 50b (4.00 g, 17.4 mmol) in DMF (30 mL) was added benzyl alcohol (1.88 g, 17.4 mmol). The resulting mixture was stirred for 5 min and then cooled to 0 °C, sodium hydride (766 mg, 19.2 mmol) was added and then the temperature was raised to room temperature and stirred for 4 h. To the mixture was added saturated aqueous ammonium chloride solution (30 mL) and then extracted with ethyl acetate (3 x 50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 10 / 1) to give the target product 50c (3.60 g, 69%).

[0907] MS m / z (ESI): 302 [M + 1]

[0908] Third step

[0909] (2-(benzyloxy)-6-ethoxypyridin-4-yl)methanol (50d)

[0910] To a solution of 50c (3.60 g, 12.0 mmol) in THF (50 mL) was added lithium borohydride in THF (2 M, 12.0 mL) at 0 °C. The resulting solution was heated to 70 °C and stirred for 12 h. After cooling to 0 °C, saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction solution and then extracted with ethyl acetate (3 x 60 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 4 / 1) to give the target product 50d (3.10 g, 100%).

[0911] MS m / z (ESI): 260 [M+1]

[0912] Fourth Step

[0913] 2-(benzyloxy)-6-ethoxy-4-(iodomethyl)pyridine (50e)

[0914] To a solution of 50d (3.10 g, 12.0 mmol) in dichloromethane (50 mL) were added successively imidazole (1.22 g, 17.9 mmol) and triphenylphosphine (4.70 g, 17.9 mmol). After the resulting mixture was stirred for 5 min, it was cooled to 0 °C, and then iodine (4.55 g, 17.9 mmol) was added. After the resulting mixture was stirred at room temperature for 3 h, it was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 10 / 1) to give the target product 50e (3.45 g, 78%).

[0915] MS m / z (ESI): 370 [M+1]

[0916] Fifth Step

[0917] 2-(2-(benzyloxy)-6-ethoxypyridin-4-yl)acetonitrile (50f)

[0918] To a solution of 50e (3.45 g, 9.35 mmol) in THF (40 mL) were added successively trimethylsilyl cyanide (0.93 g, 9.35 mmol) and a THF solution of TBAF (1 M, 9.5 mL) at 0 °C. After the resulting mixture was warmed to room temperature and stirred for 10 h, water (40 mL) was added, and then the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 10 / 1) to give the target product 50f (2.05 g, 82%).

[0919] MS m / z (ESI): 269 [M+1]

[0920] Sixth Step

[0921] 1-(2-(benzyloxy)-6-ethoxypyridin-4-yl)-3-methylcyclobutane-1-carbonitrile (50g)

[0922] To a solution of 50f (2.05 g, 7.64 mmol) and 1,3-dibromo-2-methylpropane (1.65 g, 7.64 mmol) in DMF (35 mL) was added sodium hydride (60%, 734 mg, 18.34 mmol) portion-wise at 0 °C. The resulting mixture was stirred at room temperature for 3 h, saturated aqueous ammonium chloride (30 mL) was added, followed by extraction with ethyl acetate (3 x 40 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 15 / 1) to give the target product 50g (1.48 g, 60%).

[0923] MS m / z (ESI): 323 [M+1]

[0924] Seventh step

[0925] 1-(2-(benzyloxy)-6-ethoxypyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid (50h)

[0926] To a solution of 50g (1.40 g, 4.34 mmol) in ethanol (44 mL) was added aqueous sodium hydroxide (44.0 mL, 2 mol / L). The resulting solution was heated to 100 °C in a sealed tube and stirred for 24 h. After cooling to room temperature, the reaction was concentrated under reduced pressure to remove ethanol. The residue was adjusted to pH = 6 with dilute hydrochloric acid (1 N) and then extracted with ethyl acetate (3 x 40 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 4 / 1) to give the target product 50h (1.21 g, 82%).

[0927] MS m / z (ESI): 342 [M+1]

[0928] Eighth step

[0929] 5-(1-(2-(benzyloxy)-6-ethoxypyridin-4-yl)-3-methylcyclobutyl)-4-methyl-2,4-dihydro- 3H-1,2,4-triazole-3-thione (50i)

[0930] To a solution of 50h (1.21 g, 3.54 mmol) in DMF (20 mL) were added N- methylhydrazinecarboxamide (559 mg, 5.32 mmol) and DIPEA (458 mg, 3.54 mmol) successively. After stirring for 10 min, HATU (1.75 g, 4.61 mmol) was added to the mixture. After stirring the resulting mixture for 2 h, an aqueous sodium hydroxide solution (2 N, 20 mL) was added at room temperature, heated to 50 °C and stirred for 13 h. After cooling to 0 °C, the reaction mixture was adjusted to pH = 6 with dilute hydrochloric acid (1 N) and then extracted with ethyl acetate (3 x 40 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 3 / 1) to give the target product 50i (1.35 g, 93%).

[0931] MS m / z (ESI): 411 [M+1]

[0932] Ninth step

[0933] 2-(benzyloxy)-6-ethoxy-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)pyridine (50j)

[0934] To a solution of 50i (700 mg, 1.71 mmol) in dichloromethane (25 mL) were added glacial acetic acid (1.54 g, 25.65 mmol) and hydrogen peroxide (30%, 582 mg, 5.13 mmol) successively at 0 °C. The resulting mixture was heated to 30 °C and stirred for 1 h, then cooled to 0 °C. The reaction mixture was adjusted to pH = 8 with saturated aqueous sodium bicarbonate solution and then extracted with dichloromethane (3 x 20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 0 to 30 / 1) to give the target product 50j (500 mg, 77%).

[0935] MS m / z (ESI): 379 [M+1]

[0936] Tenth step

[0937] 6-ethoxy-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2- ol (50k)

[0938] To a solution of 50j (250 mg, 0.66 mmol) in methanol (35 mL) was added Pd / C (20%, 50 mg). The resulting mixture was stirred under hydrogen atmosphere for 12 h, then filtered. The filtrate was concentrated to dryness under reduced pressure to give the target product 50k (190 mg, 100%). Step 10

[0939] MS m / z (ESI): 289 [M+1]

[0940] Eleventh step

[0941] 6-ethoxy-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl trifluoromethanesulfonate (50l)

[0942] To a solution of 50k (190 mg, 0.66 mmol) in dichloromethane (10 mL) was added pyridine (131 mg, 1.65 mmol) and trifluoromethanesulfonic anhydride (372 mg, 1.32 mmol) sequentially at 0 °C. The mixture was stirred at 0 °C for 2 h, then diluted with water (10 mL) and extracted with dichloromethane (3 x 15 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 0 to 50 / 1) to give the target product 50l (200 mg, 72%).

[0943] MS m / z (ESI): 421 [M+1]

[0944] Twelfth step

[0945] N-(6-ethoxy-4-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-3,3-dimethyl-5-(((S)-3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide (50)

[0946] To a solution of 49m (30 mg, 0.1 mmol) and 50l (42 mg, 0.1 mmol) in 1,4-dioxane (0.5 mL) was added tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol), Xantphos (23 mg, 0.04 mmol) and cesium carbonate (65 mg, 0.2 mmol). The resulting mixture was heated to 110 °C and stirred for 2 h. After cooling to room temperature, saturated sodium bicarbonate solution (15 mL) was added to the mixture, which was then extracted with dichloromethane (3 x 10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the target product 50 (1.2 mg, 2%).

[0947] MS m / z (ESI): 573 [M+1]

[0948] 1 H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.45 (s, 1H), 6.42 (s, 1H), 4.58 (s, 3H), 4.31 (q, J = 6.7 Hz, 2H), 3.34 (s, 2H), 2.96 (s, 1H), 2.94 - 2.88 (m, 2H), 2.72 (d, J = 7.9 Hz, 1H), 2.61 (t, J = 9.8 Hz, 2H), 2.24 - 2.08 (m, 2H), 2.03 (d, J = 5.2 Hz, 1H), 1.74 (s, 3H), 1.60 (s, 2H), 1.42 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H), 1.16 (d, J = 6.2 Hz, 3H), 0.96 (d, J = 11.5 Hz, 1H), 0.89 (d, J = 6.1 Hz, 4H).

[0949] The following intermediate was synthesized according to the procedure of Example 26, but substituting different compounds for 50d in the procedure.

[0950] The following compound was synthesized according to the procedure of Example 26, but substituting different compounds and solvents for sodium ethoxide and ethanol in the procedure.

[0951] NMR data for the compounds are as follows:

[0952] Example 27

[0953] N-(3-cyano-5-(1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-3,3- dimethyl-5-(((S)-3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide (Compound 52)

[0954] First Step

[0955] 3-bromo-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)benzonitrile

[0956] A mixture of 52a (700 mg, 1.8 mmol), zinc cyanide (105 mg, 0.9 mmol), zinc powder (117 mg, 1.8 mmol), Pd(dppf)Cl2(132 mg, 0.18 mmol) and DMF (10 mL) was heated to 110 °C under nitrogen atmosphere and stirred for 2 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was purified by prep-HPLC to give the target product 52b (150 mg, 25%).

[0957] MS m / z (ESI): 331 [M+1]

[0958] Second Step

[0959] N-(3-cyano-5-(1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-3,3- dimethyl-5-(((S)-3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide formate salt (52)

[0960] A mixture of 49m (45 mg, 0.15 mmol), 52b (50 mg, 0.15 mmol), cesium carbonate (98 mg, 0.3 mmol), Xantphos (35 mg, 0.06 mmol), Pd2(dba)3(27 mg, 0.03 mmol) and 1,4-dioxane (3 mL) was heated to 130 °C under nitrogen atmosphere and stirred for 6 h. After cooling to room temperature, the reaction was concentrated to dryness under reduced pressure and the residue was purified by prep-HPLC to give the target product 52 (48 mg, 58%).

[0961] MS m / z (ESI): 553 [M+1]

[0962] 1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 8.36 (d, J = 26.2 Hz, 1H), 8.17 - 8.02 (m, 1H), 7.85 (dd, J = 33.0, 31.3 Hz, 2H), 7.50 (t, J = 31.7 Hz, 2H), 4.57 (s, 2H), 4.07 (s, 2H), 3.33 (d, J = 5.8 Hz, 3H), 3.26 - 3.08 (m, 2H), 3.05 - 2.76 (m, 2H), 2.59 (dd, J = 32.1, 23.9 Hz, 3H), 2.32 (dd, J = 44.8, 35.5 Hz, 2H), 1.95 - 1.52 (m, 4H), 1.52 - 1.22 (m, 6H), 1.25 - 0.98 (m, 4H), 0.93 (t, J = 12.6 Hz, 3H).

[0963] The following compound was synthesized according to the procedure of Example 27, Step 2, but substituting a different compound for 52b in the procedure.

[0964] The nuclear magnetic resonance data for the compound is as follows:

[0965] Example 28

[0966] 3,3-dimethyl-N-(3-((4-methyl-4H-1,2,4-triazol-3-yl)(oxetan-3-yl)methyl)phenyl)-5-(((S)-3- methylpiperidin-1-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide (Compound 53)

[0967] First Step

[0968] 2-(3-bromophenyl)-2-(oxetan-3-yl)ethyl acetate (53b)

[0969] To a solution of ethyl 2-(3-bromophenyl)acetate 53a (6.08 g, 25 mmol) in DMF (50 mL) was added potassium tert-butoxide (3.65 g, 32.5 mmol) at 0 °C. After stirring for 30 min, 3-bromooxetane (2.6 mL, 30 mmol) was added to the mixture, which was then allowed to warm to room temperature. After stirring overnight, ethyl acetate (300 mL) was added to the mixture, which was then washed with saturated brine (3 x 200 mL). The combined organic phase was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give the target product 53b (7.47 g, 99%).

[0970] MS m / z (ESI): 299 [M + 1]

[0971] Second Step

[0972] 2-(3-bromophenyl)-2-(oxetan-3-yl)acetic acid (53c)

[0973] A mixture of 53b (7.47 g, 25 mmol), lithium hydroxide monohydrate (5.25 g, 125 mmol), THF (50 mL) and water (50 mL) was heated to 50 °C and stirred overnight. The reaction mixture was neutralized with dilute hydrochloric acid (2 N, 200 mL) and then extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 53c (6.78 g, crude). The product was used directly in the next step without further purification.

[0974] MS m / z (ESI): 271 [M+1]

[0975] Third to Eighth Steps

[0976] 3,3-dimethyl-N-(3-((4-methyl-4H-1,2,4-triazol-3-yl)(oxetan-3-yl)methyl)phenyl)-5-(((S)-3- methylpiperidin-1-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide formate salt (53)

[0977] Refer to the procedure of the third to eighth steps in Example 12 to synthesize 53, but use 53c instead of 16c in the operation.

[0978] MS m / z (ESI): 530 [M+1]

[0979] 1 H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.37 (s, 1H), 8.18 (s, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 16.5 Hz, 2H), 7.31 (t, J = 7.9 Hz, 2H), 6.98 (d, J = 7.7 Hz, 1H), 4.72 (dd, J = 14.3, 9.2 Hz, 2H), 4.54 - 4.44 (m, 2H), 4.43 (s, 2H), 4.27 (t, J = 6.3 Hz, 1H), 3.87 - 3.79 (m, 1H), 3.42 (s, 2H), 3.36 (s, 3H), 2.72 (d, J = 10.3 Hz, 2H), 1.86 (s, 1H), 1.65 (s, 1H), 1.58 (d, J = 6.4 Hz, 3H), 1.45 (d, J = 11.3 Hz, 2H), 1.33 (s, 6H), 0.81 (d, J = 5.5 Hz, 3H).

[0980] The following compounds were synthesized according to the procedure of Example 28, but substituting different compounds for 3-bromooxetane and 52b in the procedure.

[0981] The nuclear magnetic resonance data for the compounds are as follows:

[0982] Example 29

[0983] (S)-N-(4-(4-cyano-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-6- cyclopropylpyridin-2-yl)-3,3-dimethyl-5-((3-methylpiperidin-l-yl)methyl)-2,3- dihy drobenfo furan-7-carboxamide (Compound 55)

[0984] First Step

[0985] 2-bromo-5-cyanobenzoic acid (55b)

[0986] Methyl 2-bromo-5-cyanobenzoate 55a (4.80 g, 25 mmol) and LiOH H2O (4.20 g, 100 mmol) were dissolved in a mixed solvent of THF (50 mL) and water (50 mL). After stirring for 2 hours, dilute hydrochloric acid (2 N, 100 mL) was added to the mixture, which was then extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 55b (4.52 g, crude). The product was used directly in the next reaction without further purification.

[0987] MS m / z (ESI): 226, 228 [M+1]

[0988] Second Step

[0989] 2-(2-bromo-5-cyanobenzoyl)-N-methylhydrazine-1-carbothioamide (55c)

[0990] To a solution of 55b (4.52 g, crude, about 25 mmol) in DMF (50 mL) were added N-methylhydrazinecarbothioamide (2.89 g, 27.5 mmol), HATU (11.41 g, 30 mmol), and DIPEA (13 mL, 75 mmol) in sequence, and then stirred for 1 hour. The product was used directly in the next reaction without further purification.

[0991] MS m / z (ESI): 313, 315 [M+1]

[0992] Third Step

[0993] 4-bromo-3-(4-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzonitrile (55d)

[0994] To the reaction solution of the second step, saturated sodium bicarbonate solution (50 mL) was added, then heated to 80 °C and stirred for 14 hours. After cooling to room temperature, dilute hydrochloric acid (2 N, 100 mL) was added, then filtered. After collecting the precipitate and drying, the target product 55d (4.83 g, 65%) was obtained.

[0995] MS m / z (ESI): 295, 297 [M + 1]

[0996] Fourth step

[0997] 4-bromo-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile (55e)

[0998] To a solution of 55d (4.72 g, 16 mmol) in dichloromethane (60 mL) was added acetic acid (9 mL) and hydrogen peroxide solution (30%, 7.5 mL) at 0 °C. After the resulting mixture was stirred at 0 °C for 1 hour, saturated sodium bicarbonate solution (100 mL) was added, then extracted with dichloromethane (3 x 100 mL). The organic phase was dried over anhydrous sodium sulfate, then filtered. The filtrate was concentrated to dryness under reduced pressure to obtain the target product 55e (3.95 g, crude). The product was used directly in the next step without further purification.

[0999] MS m / z (ESI): 263, 265 [M + 1]

[1000] Fifth step

[1001] 4-(2,6-dichloropyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile (55f)

[1002] 55e (3.95 g, crude, about 15 mmol) was dissolved in dioxane (60 mL) and water (15 mL), then Pd(dppf)Cl2(1.10 g, 1.5 mmol), potassium carbonate (6.22 g, 45 mmol), and (2,6-dichloropyridin-4-yl)boronic acid (3.45 g, 18 mmol) were added, and stirred at 60 °C for 13 hours under nitrogen protection. After cooling to room temperature, water (100 mL) was added, then extracted with ethyl acetate (200 mL). The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 9 / 1) to obtain the target product 55f (1.64 g, 33%).

[1003] MS m / z (ESI): 330 [M+1]

[1004] Sixth step

[1005] (R)-4-(4-(1-(4-(chloromethyl)phenyl)ethyl)piperazin-1-yl)-3-fluorobenzonitrile (55g)

[1006] To a solution of 55f (1.65 g, 5 mmol) in dioxane (20 mL) and water (5 mL) was added Pd(dppf)Cl2(366 mg, 6 mmol), potassium carbonate (2.07 g, 15 mmol) and cyclopropylboronic acid (515 mg, 18 mmol), then heated to 100 °C under nitrogen atmosphere and stirred for 16 hours. After cooling to room temperature, water (100 mL) was added, then extracted with ethyl acetate (200 mL). The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 9 / 1) to give the target product 55g (1.46 g, 87%).

[1007] MS m / z (ESI): 336 [M+1]

[1008] Seventh step

[1009] (S)-N-(4-(4-cyano-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-cyclopropylpyridin-2-yl)-3,3-dimethyl-5-((3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide (55)

[1010] To a solution of 49m (30 mg, 0.1 mmol) and 55g (33 mg, 0.1 mmol) in 1,4-dioxane (0.5 mL) was added tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol), Xantphos (23 mg, 0.04 mmol) and cesium carbonate (65 mg, 0.2 mmol). The resulting mixture was heated to 110 °C under nitrogen atmosphere and stirred for 2 hours. After cooling to room temperature, saturated sodium bicarbonate solution (15 mL) was added to the mixture, then extracted with dichloromethane (3 x 10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by prep-HPLC to give the target product 55 (1.2 mg, 2%).

[1011] MS m / z (ESI): 602 [M+1]

[1012] 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.52 (s, 1H), 8.25 - 8.14 (m, 2H), 7.85 (dd, J = 14.8, 7.9 Hz, 2H), 7.73 (s, 1H), 7.56 (d, J = 1.7 Hz, 1H), 6.81 (d, J = 1.2 Hz, 1H), 4.60 (s, 2H), 4.29 (d, J = 4.7 Hz, 2H), 3.26 (d, J = 8.4 Hz, 2H), 2.89 - 2.70 (m, 2H), 2.09 - 1.92 (m, 2H), 1.73 (ddd, J = 43.9, 28.3, 14.0 Hz, 4H), 1.37 (s, 6H), 1.26 (d, J = 24.0 Hz, 3H), 1.01 - 0.90 (m, 2H), 0.91 (d, J = 5.2 Hz, 3H), 0.82 (d, J = 1.8 Hz, 2H).

[1013] The following compounds were synthesized according to the procedure of Example 29, but substituting different compounds for 49m in the procedure.

[1014] The NMR data for these compounds are as follows:

[1015] Example 30

[1016] (S)-3,3-dimethyl-N-(4-(3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)-6- (trifluoromethyl)pyridin-2-yl)-5-((3-methylpiperidin-l-yl)methyl)-2,3-dihydrobenfuran-7- carboxamide (Compound 58)

[1017] First Step

[1018] Methyl 2-methoxy-6-(trifluoromethyl)isonicotinate (58b)

[1019] To methyl 2-chloro-6-(trifluoromethyl)isonicotinate 58a (10.6 g, 44.2 mmol) in 1,4- dioxane (90 mL) was added sodium methoxide in methanol (5.4 M, 4.9 mL). The resulting mixture was heated to 120 °C and stirred overnight. After cooling to room temperature, the mixture was quenched by the addition of saturated sodium bicarbonate solution (100 mL) and then extracted with ethyl acetate (3 x 100 mL). The filtrate was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 8 / 2) to give the target product 58b (3.7 g, 36%).

[1020] MS m / z (ESI): 236 [M+l]

[1021] Second Step

[1022] (2-methoxy-6-(trifluoromethyl)pyridin-4-yl)methanol (58c)

[1023] To a solution of 58b (3.7 g, 15.7 mmol) in THF (80 mL) was added dropwise lithium borohydride in THF (2 M, 23 mL). The resulting mixture was stirred at room temperature overnight, then saturated sodium bicarbonate solution (150 mL) was added and extracted with dichloromethane (3 x 100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure to give the target product 58c (3.4 g, crude). The product was used in the next step without further purification.

[1024] MS m / z (ESI): 208 [M+1]

[1025] Third Step

[1026] 4-(iodomethyl)-2-methoxy-6-(trifluoromethyl)pyridine (58d)

[1027] To a mixture of 58c (3.4 g, crude, about 15.7 mmol), triphenylphosphine (6.4 g, 24.6 mmol), imidazole (1.7 g, 24.6 mmol) and dichloromethane (40 mL) was added iodine (6.2 g, 24.6 mmol) under ice-bath condition. The resulting mixture was stirred for 2 hours, then saturated sodium thiosulfate solution (50 mL) and saturated aqueous brine solution (50 mL) were added successively, followed by extraction with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 7 / 3) to give the target product 58d (4.9 g, 94%).

[1028] MS m / z (ESI): 318 [M+1]

[1029] Fourth Step

[1030] 2-(2-methoxy-6-(trifluoromethyl)pyridin-4-yl)acetonitrile (58e)

[1031] To a solution of 58d (4.9 g, 15.4 mmol) and trimethylsilyl cyanide (5.8 mL, 46.4 mmol) in acetonitrile (40 mL) was added dropwise TBAF in THF (1 M, 46.4 mL, 46.4 mmol). The resulting mixture was stirred for 3 hours and concentrated to dryness. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 6 / 4) to give the target product 58e (2.75 g, 76%).

[1032] MS m / z (ESI): 217 [M+1]

[1033] Fifth Step

[1034] 1 -(2-Methoxy-6-(trifluoromethyl)pyridin-4-yl)-3-methylcyclobutane-1 - carbonitrile (58f)

[1035] 58e (2.75 g, 12.7 mmol) and 1,3-dibromo-2-methylpropane (1.6 ml, 12.7 mmol) were dissolved in DMF (25 mL). After the resulting mixture was stirred at 0 °C for 1 h, sodium hydride (1.0 g, 25.4 mmol) was added slowly and stirred at 60 °C under nitrogen protection overnight. After cooling to room temperature, water (100 mL) was added to quench, followed by extraction with ethyl acetate (3 x 100 mL). The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 8 / 2) to give the target product 58f (2.0 g, 57%).

[1036] MS m / z (ESI): 271 [M+1]

[1037] Sixth Step

[1038] 1 -(2-Methoxy-6-(trifluoromethyl)pyridin-4-yl)-3-methylcyclobutane-1 - carbonitrile (58f)

[1039] To a solution of 58f (2.0 g, 7.4 mmol) in ethanol (18.5 mL) was added sodium hydroxide solution (4 N, 18.5 mL). The resulting mixture was heated to 95 °C and stirred overnight. After cooling to room temperature, dilute hydrochloric acid (2 N, 50 mL) was added to the mixture, followed by extraction with dichloromethane (150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 58g (1.9 g, crude). This product was used directly in the next reaction without further purification.

[1040] MS m / z (ESI): 290 [M+1]

[1041] Seventh Step

[1042] 2-(1 -(2-Methoxy-6-(trifluoromethyl)pyridin-4-yl)-3-methylcyclobutane-1 - carbonyl)-N-methylhydrazine-1 -carbothioamide (58h)

[1043] To a mixture of 58g (1.9 g, crude, ca. 6.6 mmol), N-methylhydrazinecarbothioamide (1.0 g, 9.9 mmol) and DMF (20 mL) was added HATU (3.0 g, 7.9 mmol) and DIPEA (3.5 mL, 12 mmol). The resulting mixture was stirred at room temperature for 2 hours, then concentrated to dryness and used directly in the next step.

[1044] MS m / z (ESI): 377 [M+1]

[1045] Eighth step

[1046] 5-(1-(2-Methoxy-6-(trifluoromethyl)pyridin-4-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol (58i)

[1047] The 58g (2.5 g, crude, ca. 6.6 mmol) from the previous step was dissolved in sodium hydroxide solution (4 N, 15 mL), heated to 50 °C and stirred overnight. After cooling to room temperature, dilute hydrochloric acid (4 N, 60 mL) was added, followed by extraction with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure to give the target product 58i (1.9 g, crude). This product was used directly in the next step without further purification.

[1048] MS m / z (ESI): 359 [M+1]

[1049] Ninth step

[1050] 2-Methoxy-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-6- (trifluoromethyl)pyridine (58j)

[1051] 58i (1.9 g, crude, ca. 6.6 mmol) was dissolved in dichloromethane solution (13 mL), cooled to 0 °C and hydrogen peroxide (30%, 1.5 mL) and acetic acid (10 mL) were added dropwise. The resulting mixture was stirred for 1 hour, saturated sodium bicarbonate solution (50 mL) was added, followed by extraction with dichloromethane (3 x 50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 8 / 2) to give the target product 58j (500 mg, 19%).

[1052] MS m / z (ESI): 327 [M+1]

[1053] Tenth step

[1054] 4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-6- (trifluoromethyl)pyridin-2-ol (58k)

[1055] To a solution of 58j (520 mg, 1.53 mmol) in acetonitrile (5 mL) was added sodium iodide (700 mg, 4.6 mmol) and trimethylsilyl chloride (580 mg, 4.6 mmol). The resulting mixture was heated to 80 °C and stirred for 4 h. The reaction was concentrated and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 to 8 / 2) to give the target product 58k (470 mg, crude).

[1056] MS m / z (ESI): 313 [M+1]

[1057] Tenth step

[1058] 4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-6- (trifluoromethyl)pyridin-2-yl trifluoromethanesulfonate (58l)

[1059] A mixture of 58k (470 mg, 1.50 mmol), bis(trifluoromethylsulfonyl)phenylamine (807 mg, 2.26 mmol), triethylamine (1 mL, 7.5 mmol) and DMF (7 mL) was stirred for 2 h, then saturated sodium bicarbonate solution (100 mL) was added and extracted with ethyl acetate (3 x 100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 to 8 / 2) to give the target product 58l (130 mg, 19.5 mmol).

[1060] MS m / z (ESI): 445 [M+1]

[1061] Twelfth step

[1062] (S)-3,3-dimethyl-N-(4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-6- (trifluoromethyl)pyridin-2-yl)-5-((3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenfuran-7- formamide (58)

[1063] To a solution of 58l (57 mg, 0.13 mmol) and 49m (30 mg, 0.1 mmol) in 1,4-dioxane (1.0 mL) was added tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol), Xantphos (23 mg, 0.04 mmol) and cesium carbonate (65 mg, 0.2 mmol). The resulting mixture was heated to 110 °C and stirred for 2 h. After cooling to room temperature, saturated sodium bicarbonate solution (15 mL) was added to the mixture, which was then extracted with dichloromethane (3 x 10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the target product 58 (17.5 mg, 30%).

[1064] MS m / z (ESI): 597 [M+1]

[1065] 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (d, J = 6.4 Hz, 1H), 8.60 (s, 1H), 8.44 (s, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.62 (d, J = 1.7 Hz, 1H), 7.56 (d, J = 1.1 Hz, 1H), 4.60 (s, 3H), 4.28 (d, J = 4.5 Hz, 2H), 2.97 - 2.87 (m, 2H), 2.78 (dd, J = 22.1, 9.9 Hz, 1H), 2.70 - 2.60 (m, 3H), 1.83 (d, J = 13.9 Hz, 2H), 1.70 (dd, J = 26.8, 12.6 Hz, 2H), 1.37 (s, 7H), 1.22 (d, J = 10.6 Hz, 2H), 1.16 - 1.01 (m, 5H), 0.95 - 0.80 (m, 4H).

[1066] Example 31

[1067] (S)-N-(6-cyclopropyl-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin- 2-yl)-6-((3-methylpiperidin-1-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (Compound 59)

[1068] First Step

[1069] (R)-6-((3-methylpiperidin-1-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (59a)

[1070] To a solution of 2d (280 mg, 1.0 mmol) in methanol (5 mL) was added ammonia (7 M, 5 mL). The resulting solution was heated to 60 °C and stirred overnight. After cooling to room temperature, the reaction solution was concentrated to dryness under reduced pressure to give the target product 59a (250 mg, crude). The product was used in the next step without further purification.

[1071] MS m / z (ESI): 274 [M+1]

[1072] Second Step

[1073] (R)-N-(6-cyclopropyl-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin- 2-yl)-6-((3-methylpiperidin-1-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (59)

[1074] To a solution of 59a (30 mg, 0.11 mmol) and 49l (46 mg, 0.11 mmol) in 1,4- dioxane (1.0 mL) was added tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol), Xantphos (23 mg, 0.04 mmol) and cesium carbonate (65 mg, 0.2 mmol). The resulting mixture was heated to 110 °C under nitrogen atmosphere for 2 h. After cooling to room temperature, saturated sodium bicarbonate solution (15 mL) was added to the mixture, which was then extracted with dichloromethane (3 x 10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the target product 59 (13.6 mg, 23%).

[1075] MS m / z (ESI): 540 [M+1]

[1076] 1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 9.44 (d, J = 16.3 Hz, 1H), 8.94 (s, 1H), 8.66 (d, J = 18.4 Hz, 1H), 8.49 (s, 1H), 7.96 (s, 1H), 7.22 (s, 1H), 4.62 - 4.41 (m, 3H), 3.50 (d, J = 9.0 Hz, 1H), 3.39 (d, J = 11.8 Hz, 1H), 2.84 (d, J = 5.4 Hz, 2H), 2.61 (dd, J = 23.9, 15.1 Hz, 3H), 2.17 (s, 2H), 2.00 (dd, J = 14.6, 7.0 Hz, 1H), 1.91 - 1.54 (m, 5H), 1.23 (s, 3H), 1.12 (t, J = 8.1 Hz, 3H), 1.03 - 0.92 (m, 3H), 0.88 (d, J = 6.4 Hz, 3H).

[1077] The following intermediate was synthesized by reference to the procedure of Example 31, first step, but substituting 2d with a different compound in the procedure.

[1078] The following compound was synthesized by reference to the procedure of Example 31, but substituting 2d with a different compound in the procedure.

[1079] The nuclear magnetic data of the compound is as follows:

[1080] Example 32

[1081] (S)-N-(6-cyano-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2- yl)-3,3-dimethyl-5-((3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenfuran-7-carboxamide (Compound 63)

[1082] First Step

[1083] 2-chloro-6-methoxyisonicotinic acid (63b)

[1084] To a solution of 2,6-dichloroisonicotinic acid 63a (9.6 g, 50 mmol) in methanol (100 mL) was added sodium methoxide in methanol (30%, 27 g, 150 mmol). The resulting mixture was heated to reflux and stirred for 15 hours. After cooling to room temperature, glacial acetic acid (36 g, 600 mmol) was added to the mixture, followed by filtration. The filter cake was dried to give the target product 63b (18 g, crude). The product was used directly in the next step without further purification.

[1085] MS m / z (ESI): 188 [M+1]

[1086] Second Step

[1087] 2,6-dimethoxyisonicotinic acid (63c)

[1088] To a solution of 63b (18 g, crude, about 50 mmol) in methanol (200 mL) was added sodium methoxide in methanol (30%, 27 g, 150 mmol). The resulting mixture was heated to 135 °C in a 500 mL sealed tube and stirred for 24 h. After cooling to room temperature, glacial acetic acid (9 g, 150 mmol) was added to the mixture, which was then concentrated to dryness under reduced pressure. The residue was dissolved in 100 mL of water, and the resulting solution was directly purified by prep-HPLC to give the target product 63c (11 g).

[1089] MS m / z (ESI): 184 [M+1]

[1090] Third Step

[1091] 2,6-dimethoxy-4-hydroxymethylpyridine (63d)

[1092] To a solution of 63c (11 g, about 50 mmol) in THF (200 mL) was slowly added borane in THF (1 M, 150 mL, 150 mmol) at 0 °C, which was then heated to 70 °C and stirred for 5 h. After cooling to 0 °C, methanol (100 mL) was slowly added to the reaction solution and stirred for 1 h, which was then concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give the target product 63d (6 g, 71%).

[1093] MS m / z (ESI): 170 [M+1]

[1094] Fourth Step

[1095] 4-(iodomethyl)-2,6-dimethoxypyridine (63e)

[1096] To a mixture of 63d (6 g, 35.5 mmol), imidazole (3.6 g, 53 mmol), triphenylphosphine (14 g, 53 mmol) and dichloromethane (130 mL) was slowly added iodine (13.5 g, 53 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 3 h, which was then washed with saturated sodium sulfite (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / dichloromethane = 100 / 1 to 3 / 1) to give the target product 63e (9 g, 90%).

[1097] MS m / z (ESI): 280 [M+1]

[1098] Fifth step

[1099] 2-(2,6-dimethoxypyridin-4-yl)acetonitrile (63f)

[1100] To a mixture of 63e (9 g, 32 mmol), trimethylsilyl cyanide (6.38 g, 64 mmol) and acetonitrile (200 mL) was added slowly dropwise a solution of tetrabutylammonium fluoride in THF (1 M, 64 mL, 4 mmol) at 0 °C. The resulting solution was stirred at 0 °C for 4 h, then concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give the target product 63f (4.7 g, 83%).

[1101] MS m / z (ESI): 179 [M+1]

[1102] Sixth step

[1103] 1-(2,6-dimethoxypyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid (63h)

[1104] To a solution of 63f (4.7 g, 26.4 mmol) in DMF (30 mL) was added slowly sodium hydride (60%, 3.16 g, 79.1 mmol) at 0 °C. After the resulting mixture was stirred at 0 °C for 1 h, 1,3-dibromo-2-methylpropane (8.55 g, 39.6 mmol) was added. After the resulting mixture was stirred at 0 °C for another 2 h, it was diluted with saturated ammonium chloride solution (90 mL), then extracted with ethyl acetate (2 x 100 mL). After the combined organic phase was washed with saturated sodium chloride solution (50 mL), it was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give the target product 63g (4.2 g, 68%).

[1105] MS m / z (ESI): 233 [M+1]

[1106] Seventh step

[1107] 1-(2,6-dimethoxypyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid (63h)

[1108] To a solution of 63g (4.2 g, 18.1 mmol) in ethanol (60 mL) was added sodium hydroxide aqueous solution (2 N, 45 mL). The resulting mixture was heated to 110 °C in a sealed tube and stirred for 72 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in water (50 mL) and then adjusted to pH = 6-7 with dilute hydrochloric acid (2 N), and then concentrated to dryness under reduced pressure to give the target product 63h (10 g, crude). The product was used directly in the next step without further purification.

[1109] MS m / z (ESI): 252 [M+1]

[1110] Eighth step

[1111] 5-(1-(2,6-dimethoxypyridin-4-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3- thiol (63i)

[1112] To a mixture of 63h (10 g, crude, about 18.1 mmol), 4-methylaminothiourea (2.86 g, 27.2 mmol), DIPEA (7 g, 54.3 mmol) and DMF (60 mL) was added HATU (10.3 g, 27.2 mmol). After the resulting mixture was stirred at room temperature for 1 h, sodium hydroxide aqueous solution (2 N, 36.2 mL, 72.4 mmol) was added, and then heated to 60 °C and stirred for 15 h. After cooling to 0 °C, the mixture was adjusted to pH = 6-7 with dilute hydrochloric acid (2 N), and then extracted with ethyl acetate (2 x 100 mL). The combined organic phase was washed with saturated sodium chloride solution (50 mL), and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by prep-HPLC to give the target product 63i (4 g, 69%).

[1113] MS m / z (ESI): 321 [M+1]

[1114] Ninth step

[1115] 2,6-dimethoxy-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (63j)

[1116] To a solution of 63i (4 g, 12.5 mmol) and acetic acid (6.5 mL) in dichloromethane (80 mL) was added hydrogen peroxide (30% aqueous solution, 6 mL) at 0 °C. After the reaction mixture was stirred at 0 °C for 1 h, it was diluted with dichloromethane (100 mL) and washed with saturated sodium sulfite solution (30 mL), then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the target product 63j (2.3 g, 64%).

[1117] MS m / z (ESI): 289 [M+1]

[1118] Tenth step

[1119] 4-(3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)pyridine-2,6-diol (63k)

[1120] To a mixture of 63j (2 g, 6.9 mmol), sodium iodide (4.14 g, 27.6 mmol) and acetonitrile (80 mL) was added trimethylsilyl chloride (3 g, 27.6 mmol), then heated to 90 °C and stirred for 18 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure to give the target product 63k (10 g, crude). The product was used in the next step without further purification.

[1121] MS m / z (ESI): 261 [M+1]

[1122] Eleventh step

[1123] 4-(3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)pyridine-2,6-diol (63k)

[1124] To a mixture of 63k (10 g, crude, 6.9 mmol), triethylamine (2.1 g, 21 mmol) and DMF (20 mL) was added N-phenyl bis(trifluoromethanesulfonyl)imide (6.16 g, 17.2 mmol). After stirring for 2 h, the reaction mixture was diluted with saturated ammonium chloride (60 mL) and then extracted with ethyl acetate (2 x 100 mL). After the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 1 / 4) to give the target product 63l (2 g, 55%).

[1125] MS m / z (ESI): 525 [M+1]

[1126] Twelfth step

[1127] 6-(3,3-dimethyl-5-(((S)-3-methylpiperidin-l-yl)methyl)-2,3-dihydrobenfuran-7- carbamoyl)-4-(3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl trifluoromethanesulfonate formate salt (63m)

[1128] A mixture of 49m (91 mg, 0.3 mmol), 63l (315 mg, 0.6 mmol), cesium carbonate (195 mg, 0.6 mmol), Xantphos (69 mg, 0.12 mmol), Pd2(dba)3(55 mg, 0.06 mmol) and 1.4-dioxane (5 mL) was heated to 85 °C under nitrogen atmosphere and stirred for 20 min. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to give the target product 63m (45 mg, 22%).

[1129] MS m / z (ESI): 677 [M+1]

[1130] Thirteenth step

[1131] (S)-N-(6-cyano-4-(3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)pyridin-2- yl)-3,3-dimethyl-5-((3-methylpiperidin-l-yl)methyl)-2,3-dihydrobenfuran-7-carboxamide (63)

[1132] A mixture of 63m (45 mg, 0.066 mmol), zinc cyanide (9.4 mg, 0.08 mmol), zinc powder (4.3 mg, 0.066 mmol), Pd(dppf)Cl2(9 mg, 0.013 mmol) and DMF (2 mL) was heated to 90 °C under nitrogen atmosphere and stirred for 1 h. After cooling to room temperature, the reaction mixture was directly purified by reverse phase preparative high performance liquid chromatography to give the target product 63 (18 mg, containing 0.5 equivalent of formic acid, 49%).

[1133] MS m / z (ESI): 554 [M+1]

[1134] 1H NMR (400 MHz, CD3OD) δ 8.65 (d, J = 1.6 Hz, 1H), 8.54 (s, 0.5H), 8.37 (s, 1H), 7.85 (d, J = 1.7 Hz, 1H), 7.59 (d, J = 1.5 Hz, 1H), 7.48 (d, J = 1.7 Hz, 1H), 4.62 (s, 2H), 3.78 (s, 2H), 3.36 (d, J = 8.4 Hz, 3H), 2.99 (ddd, J = 13.6, 9.1, 8.0 Hz, 4H), 2.69 (d, J = 9.2 Hz, 2H), 2.24 (s, 1H), 1.94 (d, J = 8.5 Hz, 1H), 1.73 (t, J = 25.2 Hz, 5H), 1.43 (s, 6H), 1.18 (dd, J = 6.1, 3.6 Hz, 3H), 1.01 (dd, J = 12.2, 9.4 Hz, 1H), 0.90 (d, J = 6.4 Hz, 3H).

[1135] Example 33

[1136] N-(4-(4-cyano-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-6-cyclopropylpyridin-2-yl)-5-(((2- methoxyethyl)amino)methyl)-3,3-dimethyl-2,3-dihydrobenzofuran-7-carboxamide (Compound 64)

[1137] First Step

[1138] 5-(((2-methoxyethyl)amino)methyl)-3,3-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester (64a)

[1139] To a solution of 36b (100 mg, 0.29 mmol) in THF (5 mL) was added 2-methoxyethan-l-amine (65 mg, 1 mmol) and triethylamine (200 μL, 1.45 mmol). After the resulting mixture was stirred for 2 h, it was concentrated to dryness under reduced pressure to give the target product 64a (85 mg, crude). The product was used in the next step without further purification.

[1140] MS m / z (ESI): 294 [M+l]

[1141] Second Step

[1142] 5-(((tert-butoxycarbonyl)(2-methoxyethyl)amino)methyl)-3,3-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester (64b)

[1143] To a solution of 64a (85 mg, crude, ca. 0.29 mmol) and triethylamine (200 μL, 1.45 mmol) in dichloromethane (2 mL) was added Boc anhydride (95 mg, 0.435 mmol). After the resulting mixture was stirred for 2 h, it was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give the target product 64b (60 mg, 52%).

[1144] MS m / z (ESI): 394 [M + 1]

[1145] Third Step

[1146] ((7-((4-(4-cyano-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-6- cyclopropylpyridin-2-yl)carbamoyl))-3,3-dimethyl-2,3-dihydrobenzofuran-5-yl)methyl)(2- methoxyethyl)carbamic acid tert-butyl ester (64d)

[1147] A solution of 64b (60 mg, 0.15 mmol) was dissolved in ammonia in methanol (7 M, 2 mL). The resulting solution was heated to 60 °C and stirred overnight. After cooling to room temperature, the reaction solution was concentrated to dryness under reduced pressure to give the target product 64c (30 mg, crude). The product was used directly in the next step without further purification.

[1148] MS m / z (ESI): 394 [M + 1]

[1149] Fourth Step

[1150] ((7-((4-(4-cyano-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-6- cyclopropylpyridin-2-yl)carbamoyl))-3,3-dimethyl-2,3-dihydrobenzofuran-5-yl)methyl)(2- methoxyethyl)carbamic acid tert-butyl ester (64d)

[1151] To a solution of 64c (30 mg, ca. 0.09 mmol) and 55g (26 mg, 0.08 mmol) in 1,4- dioxane (0.5 mL) was added tris(dibenzylideneacetone)dipalladium (15 mg, 0.016 mmol), Xantphos (18.5 mg, 0.034 mmol) and cesium carbonate (52 mg, 0.16 mmol). The resulting mixture was heated to 110 °C under nitrogen atmosphere and stirred for 2 h. After cooling to room temperature, saturated sodium bicarbonate solution (15 mL) was added to the mixture, which was then extracted with dichloromethane (3 x 10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 to 9 / 1) to give the target product 64d (25 mg, 46%).

[1152] MS m / z (ESI): 678 [M+1]

[1153] Fifth Step

[1154] N-(4-(4-cyano-2-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-6- cyclopropylpyridin-2-yl)-5-(((2-methoxyethyl)amino)methyl)-3,3-dimethyl-2,3- dihydrobenzofuran-7-carboxamide (64)

[1155] To a solution of 64d (25 mg, 0.037 mmol) in methanol (0.5 mL) was added hydrogen chloride in 1,4-dioxane (4 M, 0.5 mL). After stirring overnight, the reaction solution was concentrated to dryness under reduced pressure and the residue was purified by prep-HPLC to give the target product 64 (3.0 mg, 14%).

[1156] MS m / z (ESI): 578 [M+1]

[1157] 1 H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.51 (d, J = 11.4 Hz, 1H), 8.25 - 8.15 (m, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.45 (s, 1H), 7.20 (s, 1H), 6.75 (s, 1H), 6.65 (s, 1H), 6.52 (d, J = 3.2 Hz, 1H), 5.37 - 5.26 (m, 2H), 4.53 (s, 1H), 3.40 (d, J = 14.9 Hz, 2H), 2.74 - 2.62 (m, 2H), 1.98 (dt, J = 25.6, 13.2 Hz, 3H), 1.45 (s, 2H), 1.35 (s, 2H), 1.23 (s, 9H), 0.84 (dd, J = 16.2, 9.2 Hz, 2H).

[1158] Example 34

[1159] (S)-N-(5-cyano-6'-cyclopropyl-3-(4-methyl-4H-l,2,4-triazol-3-yl)- [2,4'-bipyridin]-2'-yl)-3,3-dimethyl-5-((3-methylpiperidin-l-yl)methyl)-2,3- dihydrobenzofuran-7-carboxamide (Compound 65)

[1160] First Step

[1161] 6-amino-5-bromonicotinonitrile (65b)

[1162] To a solution of 6-aminonicotinonitrile 65a (4.95 g, 41.6 mmol) in acetonitrile (100 mL) was added NBS (8.87 g, 49.9 mmol). After stirring at room temperature for 2 h, the mixture was diluted with water (200 mL) and then extracted with ethyl acetate (3 x 200 mL). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 19 / 1) to give the target product 65b (8.23 g, 100%).

[1163] MS m / z (ESI): 198, 200 [M+1]

[1164] Second Step

[1165] Methyl 2-amino-5-cyanonate (65c)

[1166] To a solution of 65b (3.75 g, 18.9 mmol) in methanol (50 mL) was added triethylamine (5.75 g, 56.8 mmol) and Pd(dppf)Cl2(693 mg, 0.95 mmol). The mixture was sealed in a 100-mL pressure vessel and then heated to 100 °C with stirring under a carbon monoxide atmosphere (4 atm) for 5 h. Another batch of 65b (3.45 g, 17.4 mmol) was also reacted following the above procedure. After cooling to room temperature, the two batches of reaction were combined, concentrated to dryness, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 19 / 1) to give the target product 65c (5.64 g, 88%).

[1167] MS m / z (ESI): 178 [M+1]

[1168] Third Step

[1169] Methyl 2-bromo-5-cyanonate (65d)

[1170] To a solution of tert-butyl nitrite (3.88 g, 37.6 mmol) in THF (125 mL) was added copper bromide (8.39 g, 37.6 mmol) at 0 °C, then a solution of 65c (4.44 g, 25 mmol) in THF (125 mL) was added dropwise to the above mixture. The resulting mixture was warmed to room temperature and stirred for 1.5 h, then warmed to 50 °C and stirred for 2 h. After cooling to room temperature, it was concentrated to dryness under reduced pressure. The residue was dispersed in dichloromethane (200 mL) and water (200 mL), stirred for 30 min, and filtered. The filtrate was allowed to stand to separate into layers, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 4 / 1) to give the target product 65d (2.54 g, 42%).

[1171] MS m / z (ESI): 241 [M+1]

[1172] Fourth step

[1173] 2',6'-Dichloro-5-cyano-[2,4'-bipyridine]-3-carboxylic acid (65e)

[1174] A mixture of 65d (2.54 g, 10.5 mmol), (2,6-dichloropyridine-4-yl)boronic acid (2.02 g, 10.5 mmol), potassium carbonate (5.83 g, 42.2 mmol), Pd(dppf)Cl2(463 mg, 0.63 mmol), 1,4-dioxane (200 mL), and water (4 mL) was heated to 100 °C and stirred for 20 h. After cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was diluted with water (100 mL) and adjusted to pH = 3 with 1 N HCl, then extracted with ethyl acetate (3 x 200 mL). The combined organic phases were washed with saturated brine (100 mL), then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / ethyl acetate = 100 / 0 to 3 / 2) to give the target product 65e (1.04 g, 34%).

[1175] MS m / z (ESI): 294 [M+1]

[1176] Fifth step

[1177] 2',6'-Dichloro-3-(4-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-[2,4'- bipyridine]-5-carbonitrile (65f)

[1178] To a solution of 65e (1.04 g, 3.54 mmol) and N-methylhydrazinecarbothioamide (558 mg, 5.30 mmol) in NMP (7 mL) was added DIPEA (458 mg, 3.54 mmol) and HATU (1.75 g, 4.60 mmol). After stirring at room temperature for 1 h, the reaction mixture was added KHCO3(3.5 g, 35.0 mmol) and water (7 mL), then heated to 100 °C and stirred for 9 h. After cooling to room temperature, the reaction mixture was filtered, and the filter cake was washed with dichloromethane (3 x 50 mL). The combined filtrate was concentrated to dryness under reduced pressure, and the residue was dispersed in dichloromethane (200 mL) and filtered again to remove insoluble materials. The new filtrate was dried over anhydrous sodium sulfate, filtered, and the filtrate was used directly in the next step.

[1179] Sixth Step

[1180] 2',6'-Dichloro-3-(4-methyl-4H-l,2,4-triazol-3-yl)-[2,4'-bipyridine]-5-carbonitrile (65g)

[1181] The solution of 65f in dichloromethane (200 mL) in the fifth step was cooled to 0 °C, then added glacial acetic acid (5 mL) and 30% hydrogen peroxide (2 mL). After stirring at room temperature for 1 h, it was concentrated to dryness under reduced pressure, and the residue was purified by C18 column chromatography (acetonitrile / water = 5 / 95 to 3 / 7) to give the target product 65g (244 mg, 21%).

[1182] MS m / z (ESI): 331 [M + 1]

[1183] Seventh Step

[1184] 2'-Chloro-6'-cyclopropyl-3-(4-methyl-4H-l,2,4-triazol-3-yl)-[2,4'-bipyridine]-5-carbonitrile (65h)

[1185] A mixture of 65g (175 mg, 0.53 mmol), cyclopropylboronic acid (91 mg, 1.06 mmol), potassium carbonate (293 mg, 2.12 mmol), Pd(dppf)Cl2(39 mg, 0.053 mmol), 1,4-dioxane (20 mL) and water (0.5 mL) was mixed in a 30-mL microwave tube, which was purged with nitrogen to replace the air in the system. The mixture was heated to 100 °C in a microwave reactor and stirred for 2 hours. To the mixture was added again cyclopropylboronic acid (45 mg, 0.53 mmol) and Pd(dppf)Cl2(39 mg, 0.053 mmol), which was heated to 100 °C in a microwave reactor and stirred for 2 hours. After cooling to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 9 / 1) to give the target product 65h (60 mg, 34%).

[1186] MS m / z (ESI): 337 [M+1]

[1187] Eighth step

[1188] (S)-N-(5-cyano-6'-cyclopropyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-[2,4'-bipyridin]- 2'-yl)-3,3-dimethyl-5-((3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenofuran-7- formamide (65)

[1189] To a solution of 65h (17 mg, 0.05 mmol) and 49m (15 mg, 0.05 mmol) in 1,4-dioxane (2 mL) was added cesium carbonate (49 mg, 0.15 mmol), Pd2(dba)3(10 mg, 0.01 mmol) and Xantphos (12 mg, 0.02 mmol). The resulting mixture was heated to 100 °C in a microwave and stirred for 1 hour under nitrogen atmosphere. After cooling to room temperature, it was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 82 / 18), and then further purified by prep-HPLC to give the target product 65 (4.9 mg, 16%).

[1190] MS m / z (ESI): 603 [M+1]

[1191] 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.37 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.62 (s, 1H), 8.03 (d, J = 1.2 Hz, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7.38 (d, J = 1.6 Hz, 1H), 6.73 (d, J = 1.3 Hz, 1H), 4.54 (s, 2H), 3.42 (d, J = 3.2 Hz, 2H), 3.40 (s, 3H), 2.74 - 2.66 (m, 2H), 2.05 - 1.94 (m, 2H), 1.87 (d, J = 10.6 Hz, 1H), 1.61 (dd, J = 25.7, 8.9 Hz, 4H), 1.45 (d, J = 11.8 Hz, 1H), 1.35 (s, 6H), 0.95 (dt, J = 6.3, 3.9 Hz, 2H), 0.82 (d, J = 5.7 Hz, 3H), 0.76 (dt, J = 6.7, 3.9 Hz, 2H).

[1192] The following compounds were synthesized according to the procedure of Example 34, but substituting different compounds for 49m in the procedure.

[1193] The nuclear magnetic data for the compounds are as follows:

[1194] Example 35

[1195] 5-(((2-methoxyethyl)amino)methyl)-3,3-dimethyl-N-(3-((1s,3s)-3-methyl-1-(4- methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2,3-dihydrobenzofuran-7-carboxamide (Compound 67)

[1196] First Step

[1197] 5-(((2-methoxyethyl)amino)methyl)-3,3-dimethyl-2,3-dihydrobenzofuran-7-carbonitrile (67a)

[1198] To a solution of 39f (156 mg, 0.5 mmol) in DMF (1 mL) was added 2-methoxyethan-1-amine (150 mg, 2 mmol) and potassium carbonate (207 mg, 1.5 mmol). After stirring for 30 min, water (5 mL) was added to the mixture, which was then extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with brine (2 x 10 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0-9 / 1) to give the target product 67a (63 mg, 48%).

[1199] MS m / z (ESI): 261 [M+1]

[1200] Second step

[1201] 5-(((2-methoxyethyl)amino)methyl)-3,3-dimethyl-2,3-dihydrobenzofuran-7-carboxamide (67b)

[1202] To a solution of 67a (59 mg, 0.23 mmol) in THF (4 mL) was added hydrogen peroxide (30%, 4 mL) at 0 °C, followed by the slow addition of sodium hydroxide (36 mg, 0.91 mmol) in portions. After the resulting mixture was stirred at room temperature for 5 h, it was cooled to 0 °C, quenched with solid sodium bisulfite, and then adjusted to pH = 7 with dilute hydrochloric acid (2 N). The resulting mixture was concentrated to dryness under reduced pressure, and the residue was purified by prep-HPLC to give the target product 67b (43 mg, 65%).

[1203] MS m / z (ESI): 279 [M+1]

[1204] Third step

[1205] 5-(((2-methoxyethyl)amino)methyl)-3,3-dimethyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2,3-dihydrobenzofuran-7-carboxamide (77)

[1206] To a mixture of 67b (43 mg, 0.15 mmol), 16h (47 mg, 0.15 mmol) and DMA (1 mL) was added potassium phosphate (96 mg, 0.45 mmol), copper iodide (29 mg, 0.15 mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (21 mg, 0.15 mmol). The resulting mixture was heated to 110 °C under a nitrogen atmosphere using a microwave and stirred for 1 hour. After cooling to room temperature, the reaction mixture was purified using prep-HPLC to give the target product 77 (38.2 mg, 49%).

[1207] MS m / z (ESI): 504 [M+1]

[1208] 1 H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 7.80 (s, 2H), 7.55 (d, J = 7.7 Hz, 1H), 7.39 (dd, J = 18.1, 10.6 Hz, 2H), 7.12 (d, J = 6.2 Hz, 1H), 4.53 (s, 2H), 3.81 (s, 2H), 3.49 (dd, J = 8.3, 6.6 Hz, 2H), 3.44 - 3.31 (m, 6H), 2.79 (dd, J = 137.8, 27.5 Hz, 7H), 1.42 (s, 6H), 1.14 (d, J = 5.7 Hz, 3H).

[1209] The following compounds were synthesized according to the procedure of Example 35, but substituting different compounds for 2-methoxyethan-1-amine in the procedure.

[1210] The nuclear magnetic resonance data for these compounds are as follows:

[1211] Example 36

[1212] (S)-N-(5-cyano-6'-(1-hydroxycyclopropyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)- [2,4'-bipyridinyl]-2'-yl)-3,3-dimethyl-5-((3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenofuran-7-carboxamide (72)

[1213] First Step

[1214] 2-bromo-6-(1-((tert-butyldimethylsilyl)oxy)vinyl)pyridine (72b)

[1215] To a solution of 1-(6-bromopyridin-2-yl)ethan-1-one 72a (10.00 g, 50.0 mmol) in dichloromethane (100 mL) was added triethylamine (15.18 g, 150 mmol) and trimethylsilyl trifluoromethanesulfonate (14.54 g, 55.0 mmol) successively at 0 °C. After stirring at 0 °C for 1 h, the mixture was diluted with water (100 mL) and then extracted with dichloromethane (3 x 50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 20 / 1) to give the target product 72b (15.00 g, 95%).

[1216] MS m / z (ESI): 314, 316 [M+1]

[1217] Second step

[1218] 2-bromo-6-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridine (72c)

[1219] A solution of diethylzinc in toluene (64.0 mL, 127 mmol, 2 mol / L) was dissolved in dichloromethane (100 mL), then cooled to 0 °C and chloroiodomethane (44.9 g, 255 mmol) was added dropwise slowly. The resulting mixture was stirred at 0 °C for 0.5 h, then a solution of 72b (15.18 g, 150 mmol) in dichloromethane (50 mL) was added dropwise. The resulting mixture was warmed to room temperature and stirred for 12 h, then saturated aqueous ammonium chloride (100 mL) was added and then extracted with dichloromethane (3 x 80 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 100 / 1) to give the target product 72c (6.50 g, 62%).

[1220] MS m / z (ESI): 328, 330 [M+1]

[1221] Third step

[1222] 2-bromo-6-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (72d)

[1223] To a solution of 72c (2.70 g, 8.22 mmol) in MTBE (50 mL) were added sequentially bis(pinacolato)diboron (4.17 g, 16.44 mmol), methoxy(cyclooctadiene)iridium dimer (545 mg, 0.82 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (441 mg, 1.64 mmol). The resulting mixture was heated to 80 °C under nitrogen atmosphere and stirred for 12 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 100 / 1) to give the target product 72d (3.20 g, 86%).

[1224] MS m / z (ESI): 454, 456 [M+1]

[1225] Fourth Step

[1226] 2-(2-chloro-5-iodonicotinoyl)-N-methylhydrazine-1-carbothioamide (72f)

[1227] To a solution of 2-chloro-5-iodonicotinic acid 72e (5.72 g, 20.1 mmol) in DMF (40 mL) were added sequentially N-methylhydrazinecarbothioamide (5.31 g, 50.4 mmol) and DIPEA (3.91 g, 30.3 mmol). After stirring at room temperature for 10 min, HATU (8.44 g, 20.2 mmol) was added to the mixture. After stirring for 1 h, water (60 mL) was added and then filtered. The filter cake was purified by prep-HPLC to give the target product 72f (4.50 g, 60%).

[1228] MS m / z (ESI): 371 [M+1]

[1229] Fifth Step

[1230] 5-(2-chloro-5-iodopyridin-3-yl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (72g)

[1231] To a solution of 72f (4.50 g, 12.1 mmol) in NMP (15 mL) was added aqueous sodium hydroxide solution (2 N, 24 mL). The resulting mixture was heated to 80 °C and stirred for 2 h. After cooling to 0 °C, the mixture was adjusted to pH = 2 with dilute hydrochloric acid (1 N) and then extracted with ethyl acetate (3 x 30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure to give the target product 72g (3.60 g, 84%).

[1232] MS m / z (ESI): 353 [M+1]

[1233] Sixth Step

[1234] 2-chloro-5-iodo-3-(4-methyl-4H-l,2,4-triazol-3-yl)pyridine (72h)

[1235] To a solution of 72g (3.60 g, 10.2 mmol) in dichloromethane (50 mL) was added successively acetic acid (18.39 g, 306 mmol) and hydrogen peroxide (30%, 5.79 g, 51.1 mmol) at 0 °C. The resulting mixture was heated to 35 °C and stirred for 2 h, then concentrated to dryness under reduced pressure, and the residue was purified by prep-HPLC to give the desired product 72h (1.85 g, 57%).

[1236] MS m / z (ESI): 321 [M+1]

[1237] Seventh Step

[1238] 6-chloro-5-(4-methyl-4H-l,2,4-triazol-3-yl)nicotinonitrile (72i)

[1239] To a solution of 72h (1.85 g, 5.77 mmol) in DMF (40 mL) was added successively Zn(CN)2(407 mg, 3.46 mmol) and Pd(PPh3)4(1.33 g, 1.15 mmol). The resulting mixture was heated to 110 °C under nitrogen atmosphere and stirred for 3 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by prep-HPLC to give the desired product 72i (930 mg, 73%).

[1240] MS m / z (ESI): 220 [M+1]

[1241] Eighth Step

[1242] 2'-bromo-6'-(l-((tert-butyldimethylsilyl)oxy)cyclopropyl)-3-(4-methyl-4H-l,2,4- triazol-3-yl)-[2,4'-bipyridine]-5-carbonitrile (72j)

[1243] To a mixture of 72i (675 mg, 3.07 mmol), 72d (1.67 g, 3.68 mmol), 1,4-dioxane (24 mL) and water (0.3 mL) was added Pd(dppf)Cl2(251 mg, 0.31 mmol) and potassium carbonate (1.27 g, 9.21 mmol) successively. The resulting mixture was heated to 100 °C under nitrogen atmosphere and stirred for 12 h. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and then extracted with ethyl acetate (3 x 10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 3 / 1) to give the target product 72j (420 mg, 27%).

[1244] MS m / z (ESI): 511, 513 [M+1]

[1245] Ninth step

[1246] (S)-N-(6'-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-5-cyano-3-(4-methyl-4H-1,2,4-triazol-3-yl)-[2,4'-bipyridinyl]-2'-yl)-3,3-dimethyl-5-((3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenofuran-7-carboxamide (72k)

[1247] To a solution of 72j (68 mg, 0.13 mmol) and 49m (40 mg, 0.13 mmol) in DMA (3 mL) was added K3PO4(84 mg, 0.40 mmol), CuI (75 mg, 0.40 mmol) and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (56 mg, 0.40 mmol) successively. The resulting mixture was heated to 100 °C in a microwave reactor under nitrogen atmosphere and stirred for 2 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was used in the next step without purification.

[1248] MS m / z (ESI): 733 [M+1]

[1249] Tenth step

[1250] (S)-N-(5-cyano-6'-(1-hydroxycyclopropyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-[2,4'-bipyridinyl]-2'-yl)-3,3-dimethyl-5-((3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenofuran-7-carboxamide formate (72)

[1251] To a solution of 72k (82 mg, 0.13 mmol) in DMA (3 mL) was added TBAF in THF (1 M, 2 mL). After stirring for 1 h, the reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC to give the target product 72 (2.5 mg, 3.6%, contained 0.5 eq formic acid).

[1252] MS m / z (ESI): 619 [M+1]

[1253] 1 H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.38 (d, J = 2.0 Hz, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.60 (s, 1H), 8.30 (s, 0.5H, HCOOH), 7.86 (s, 1H), 7.62 (s, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 6.15 (s, 1H), 4.51 (s, 2H), 3.46 (s, 3H), 3.40 (d, J = 4.1 Hz, 2H), 2.73 - 2.65 (m, 2H), 1.85 (ddd, J = 14.1, 8.2, 3.1 Hz, 1H), 1.66 - 1.45 (m, 5H), 1.34 (s, 6H), 1.21 - 1.06 (m, 4H), 0.91 - 0.84 (m, 1H), 0.81 (d, J = 5.3 Hz, 3H).

[1254] Example 36

[1255] N-(3-cyclopropyl-5-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)-[1,2,4]triazolo[4,3- a]pyridine-8-carboxamide (Compound 73) and N-(3-cyclopropyl-5-((1r,3S)-3- methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((S)-3- methylpiperidin-1-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (Compound 74)

[1256] First step

[1257] 1-bromo-3-methoxy-5-methylbenzene (73b)

[1258] To a solution of 3-bromo-5-methylphenol 73a (7.00 g, 37.4 mmol) in acetonitrile (50 mL) were added K2CO3(15.52 g, 112 mmol) and iodomethane (13.28 g, 93.6 mmol) successively. The resulting mixture was heated to reflux and stirred for 12 h. After cooling to room temperature, it was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 50 / 1) to give the target product 73b (7.00 g, 93%).

[1259] Second step

[1260] 1 -Bromo-3-(bromomethyl)-5-methoxybenzene (73c)

[1261] To a solution of 73b (7.00 g, 34.8 mmol) in carbon tetrachloride (70 mL) were added NBS (6.82 g, 38.3 mmol) and AIBN (572 mg, 3.48 mmol) successively. The resulting mixture was heated to reflux and stirred for 12 h. After filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 50 / 1) to give the target product 73c (9.74 g, 100%).

[1262] Third step

[1263] 2-(3-Bromo-5-methoxyphenyl)acetonitrile (73d)

[1264] To a solution of 73c (9.74 g, 34.8 mmol) in acetonitrile (100 mL) were added trimethylsilyl cyanide (6.90 g, 69.6 mmol) and a solution of TBAF in THF (70 mL, 1 mol / L) successively. The resulting solution was heated to 65 °C and stirred for 12 h. After cooling to room temperature, the reaction solution was concentrated to dryness under reduced pressure, then water (100 mL) was added and extracted with ethyl acetate (3 x 80 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 3 / 1) to give the target product 73d (3.25 g, 41%).

[1265] MS m / z (ESI): 226, 228 [M+1]

[1266] Fourth step

[1267] 1-(3-Bromo-5-methoxyphenyl)-3-methylcyclobutane-1-carbonitrile (73e)

[1268] To a solution of 73d (3.15 g, 13.9 mmol) and 1,3-dibromo-2-methylpropane (3.31 g, 15.3 mmol) in DMF (30 mL) was added NaH (30%, 1.23 g, 30.6 mmol) portionwise at 0 °C. After stirring at 0 °C for 4 h, the mixture was added to saturated aqueous ammonium chloride solution (30 mL) and then extracted with ethyl acetate (3 x 50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 50 / 1) to give the target product 73e (3.44 g, 88%).

[1269] MS m / z (ESI): 280, 282 [M+1]

[1270] Fifth step

[1271] 1-(3-cyclopropyl-5-methoxyphenyl)-3-methylcyclobutane-1-carbonitrile (73f)

[1272] To a mixture of 73e (3.24 g, 11.6 mmol), toluene (100 mL) and water (20 mL) was added cyclopropylpotassium trifluoroborate (3.08 g, 20.8 mmol), n-butylbis(1-adamantyl)phosphine (1.24 g, 3.47 mmol), Pd(OAc)2(389 mg, 1.73 mmol) and cesium carbonate (11.30 g, 34.7 mmol) successively. The resulting mixture was heated to 110 °C under nitrogen atmosphere and stirred for 18 h. After cooling to room temperature, water (60 mL) was added to the reaction mixture and then extracted with ethyl acetate (3 x 50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 50 / 1) to give the target product 73f (2.79 g, 100%).

[1273] MS m / z (ESI): 242 [M+1]

[1274] Sixth step

[1275] 1-(3-cyclopropyl-5-methoxyphenyl)-3-methylcyclobutane-1-carboxylic acid (73g)

[1276] To a solution of 73f (2.79 g, 11.6 mmol) in ethanol (50 mL) was added 25% aqueous potassium hydroxide solution (50 mL). The resulting mixture was heated to 110 °C in a sealed tube and stirred for 12 h. After cooling to room temperature, the reaction mixture was adjusted to pH = 4 with dilute hydrochloric acid (1 N) and then extracted with ethyl acetate (3 x 50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 3 / 1) to give the target product 73g (2.41 g, 80%).

[1277] MS m / z (ESI): 261 [M+1]

[1278] Seventh step

[1279] 2-(1-(3-cyclopropyl-5-methoxyphenyl)-3-methylcyclobutane-1-carbonyl)-N- methylhydrazine-1-carbothioamide (73h)

[1280] To a solution of 73g (2.40 g, 9.22 mmol) in DMF (40 mL) was added N- methylhydrazinecarbothioamide (1.02 g, 9.68 mmol) and DIPEA (1.19 g, 9.22 mmol) successively. After stirring at room temperature for 10 min, HATU (3.51 g, 9.22 mmol) was added to the mixture. After stirring for 1 h, water (40 mL) was added and then extracted with ethyl acetate (3 x 60 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 73h (3.20 g, 100%).

[1281] MS m / z (ESI): 348 [M+1]

[1282] Eighth step

[1283] 5-(1-(3-cyclopropyl-5-methoxyphenyl)-3-methylcyclobutyl)-4-methyl-2,4-dihydro- 3H-1,2,4-triazole-3-thione (73i)

[1284] To a solution of 73h (3.20 g, 9.22 mmol) in NMP (5 mL) was added aqueous sodium hydroxide solution (2 N, 20 mL). The resulting mixture was heated to 90 °C and stirred for 5 h. After cooling to 0 °C, it was adjusted to pH = 4 with dilute hydrochloric acid (1 N) and then extracted with ethyl acetate (3 x 30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 73i (3.03 g, 100%).

[1285] MS m / z (ESI): 330 [M+1]

[1286] Ninth step

[1287] 3-(l-(3-cyclopropyl-5-methoxyphenyl)-3-methylcyclobutyl)-4-methyl-4H-l,2,4- triazole (73j)

[1288] To a solution of 73i (3.03 g, 9.20 mmol) in dichloromethane (40 mL) was added successively acetic acid (13.81 g, 230 mmol) and hydrogen peroxide (30%, 5.21 g, 46 mmol) at 0 °C. The resulting mixture was heated to 40 °C and stirred for 1 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure and the residue was purified by prep-HPLC to give the target product 73j (2.10 g, 77%).

[1289] MS m / z (ESI): 298 [M+l]

[1290] Tenth step

[1291] 3-cyclopropyl-5-(3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)phenol (73k)

[1292] To a solution of 73j (640 mg, 2.15 mmol) in dichloromethane (15 mL) was added boron tribromide in THF (1 M, 4.3 mL) at 0 °C. After stirring at 0 °C for 1 h, the mixture was adjusted to pH = 8 with saturated aqueous sodium bicarbonate solution and then extracted with dichloromethane (3 x 15 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 20 / 1) to give the target product 73k (458 mg, 75%).

[1293] MS m / z (ESI): 284 [M+l]

[1294] Eleventh step

[1295] 3-cyclopropyl-5-(3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)phenyl trifluoromethanesulfonate (73l)

[1296] To a solution of 73k (458 mg, 1.62 mmol) in dichloromethane (10 mL) were added pyridine (256 mg, 3.24 mmol) and triflic anhydride (503 mg, 1.78 mmol) successively at 0 °C. The resulting mixture was stirred at 0 °C for 2 h, then diluted with water (20 mL) and extracted with dichloromethane (3 x 15 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 0 to 50 / 1) to give the target product 73l (490 mg, 73%).

[1297] MS m / z (ESI): 416 [M+1]

[1298] Twelfth step

[1299] N-(3-cyclopropyl-5-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)-[1,2,4]triazolo[4,3- a]pyridine-8-carboxamide (73) and N-(3-cyclopropyl-5-((1r,3S)-3-methyl-1-(4- methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)- [1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (74)

[1300] To a solution of 73l (202 mg, 0.48 mmol) and 59a (33 mg, 0.12 mmol) in 1,4- dioxane (5 mL) were added Pd2(dba)3(17 mg, 0.018 mmol), Xantphos (21 mg, 0.036 mmol) and cesium carbonate (118 mg, 0.36 mmol) successively. The resulting mixture was heated to 100 °C and stirred for 12 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 0 to 20 / 1) and prep-HPLC to give the target products 73 (16 mg, 25%) and 74 (3.2 mg, 4.9%).

[1301] Characterization data of compound 73:

[1302] MS m / z (ESI): 619 [M+1]

[1303] 1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 9.12 (s, 1H), 8.77 (s, 1H), 8.38 (s, 1H), 8.29 (s, 1H), 7.47 (s, 1H), 7.34 (s, 1H), 6.92 (s, 1H), 3.62 (s, 2H), 3.20 (s, 3H), 2.87 - 2.73 (m, 4H), 2.54 (dd, J = 11.9, 4.6 Hz, 3H), 1.97 (ddd, J = 18.3, 11.6, 7.3 Hz, 2H), 1.69 - 1.43 (m, 5H), 1.08 (d, J = 5.3 Hz, 3H), 0.98 (dt, J = 6.2, 4.3 Hz, 2H), 0.92 - 0.84 (m, 1H), 0.82 (d, J = 6.1 Hz, 3H), 0.68 (dt, J = 6.3, 4.5 Hz, 2H).

[1304] Characterization data for Compound 74:

[1305] MS m / z (ESI): 619 [M+1]

[1306] 1 H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 9.13 (s, 1H), 8.79 (s, 1H), 8.36 (s, 2H), 7.41 - 7.27 (m, 2H), 6.77 (s, 1H), 3.62 (s, 2H), 3.24 (s, 3H), 3.14 - 3.04 (m, 2H), 2.85 - 2.71 (m, 2H), 2.33 (t, J = 11.0 Hz, 1H), 2.23 (t, J = 9.9 Hz, 1H), 1.99 (dt, J = 13.0, 6.5 Hz, 3H), 1.71 - 1.41 (m, 5H), 1.10 (d, J = 6.4 Hz, 3H), 0.98 (dd, J = 13.4, 5.4 Hz, 2H), 0.87 (s, 1H), 0.84 (d, J = 7.2 Hz, 3H), 0.68 (t, J = 4.9 Hz, 2H).

[1307] The following compounds were synthesized according to the procedure of Example 36, but substituting a different compound for 59a in the procedure.

[1308] The NMR data for these compounds are as follows:

[1309] Example 37

[1310] N-(6-cyclopropyl-4-((1 r,3S)-3-fluoro-1 -(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)pyridin-2-yl)-6-(((S)-3-methylpiperidin-1 -yl)methyl)-[1,2,4]triazolo[4,3- a]pyridine-8-carboxamide (Compound 75) and N-(6-cyclopropyl-4-((1 s,3R)-3-fluoro-1 -(4- methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-6-(((S)-3-methylpiperidin-1 -yl)methyl)- [1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (Compound 76)

[1311] First Step

[1312] 5,8-Dioxaspiro[3.4]octane-2-carbonitrile (75b)

[1313] To a solution of 3-oxocyclobutane-1 -carbonitrile 75a (10 g, 105 mmol) and ethylene glycol (6.53 g, 105 mmol) in toluene (100 mL) was added p-toluenesulfonic acid (999 mg, 5.25 mmol). The reaction flask was fitted with a water separator and a condenser reflux tube, heated to 130 °C and stirred for 16 h. After cooling to room temperature, the reaction mixture was filtered, the filtrate was washed successively with saturated sodium bicarbonate (2 x 100 mL) and saturated brine (50 mL), then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to give the target product 75b (11 g, 75%).

[1314] 1 H NMR (400 MHz, CDC13) δ 3.95 - 3.87 (m, 4H), 2.93 - 2.83 (m, 1H), 2.78 - 2.68 (m, 4H).

[1315] Second Step

[1316] 2-(2,6-Dichloropyridin-4-yl)-5,8-dioxaspiro[3.4]octane-2-carbonitrile (75c)

[1317] To a solution of 75b (4.19 g, 30.1 mmol) and 2,4,6-trichloropyridine (5 g, 27.4 mmol) in THF (27 mL) was added dropwise a solution of LiHMDS in THF (1 M, 33 mL, 33 mmol) at -78 °C. After the resulting mixture was stirred at -78 °C for 30 min, it was quenched with saturated ammonium chloride solution (100 mL), then extracted with ethyl acetate (2 x 100 mL). The combined organic phase was dried over anhydrous sodium sulfate, then filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 / 100-3 / 7) to give the target product 75c (6.62 g, 85%).

[1318] MS m / z (ESI): 445 [M+1]

[1319] 1 H NMR (400 MHz, CDC13) δ 7.50 (s, 2H), 4.05 - 3.94 (m, 4H), 3.35 - 3.28 (m, 2H), 2.98 - 2.90 (m, 2H).

[1320] Third Step

[1321] 2-(2-Chloro-6-cyclopropylpyridin-4-yl)-5,8-dioxaspiro[3.4]octane-2-carbonitrile (75d)

[1322] To a solution of 75c (6.10 g, 21.4 mmol) in 1,4-dioxane (210 mL) was added cyclopropylboronic acid (2.94 g, 34.2 mmol), potassium carbonate (11.82 g, 85.6 mmol), water (30 mL) and Pd(dppf)Cl2(939 mg, 1.28 mmol). The resulting mixture was heated to 100 °C under nitrogen atmosphere and stirred for 20 h. After cooling to room temperature, the mixture was filtered, and the filtrate was allowed to stand and the aqueous layer was separated. The upper organic phase was dried over anhydrous sodium sulfate, then filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 / 100-1 / 3), then purified again by prep-HPLC to give the target product 75d (3.36 g, 54%).

[1323] MS m / z (ESI): 291 [M+1]

[1324] Fourth Step

[1325] 1-(2-Chloro-6-cyclopropylpyridin-4-yl)-3-oxocyclobutane-1-carbonitrile (75e)

[1326] To a solution of 75d (3.36 g, 11.6 mmol) in acetone (20 mL) was added dilute hydrochloric acid (4 N, 20 mL), followed by heating to 90 °C and stirring for 24 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove acetone, then adjusted to basic with saturated sodium bicarbonate solution and extracted with ethyl acetate (2 x 100 mL). The combined organic phase was dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated under reduced pressure to dryness to give the target product 75e (3.38 g).

[1327] MS m / z (ESI): 247 [M+1]

[1328] 1 H NMR (400 MHz, CDC13) δ 7.20 (d, J = 1.6 Hz, 1H), 7.17 (d, J = 1.6 Hz, 1H), 4.10 - 4.03 (m, 2H), 3.75 - 3.63 (m, 2H), 2.03 (ddt, J = 9.4, 8.0, 4.9 Hz, 1H), 1.18 - 0.99 (m, 4H).

[1329] Fifth Step

[1330] 1-(2-Chloro-6-cyclopropylpyridin-4-yl)-3-hydroxycyclobutan-1-carbonitrile (75f)

[1331] To a solution of 75e (1.6 g, 6.49 mmol) in methanol (12 mL) was added sodium borohydride (294 mg, 7.78 mmol) portionwise at 0 °C. The resulting mixture was stirred at room temperature for 5 min, then quenched with saturated ammonium chloride (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0 / 100 - 7 / 93) to give the target product 75f (1.17 g, 73%).

[1332] MS m / z (ESI): 249 [M+1]

[1333] Sixth Step

[1334] 1-(2-Chloro-6-cyclopropylpyridin-4-yl)-3-hydroxycyclobutan-1-carbonitrile (75f)

[1335] To a solution of 75f (99 mg, 0.40 mmol) in dichloromethane (5 mL) was added DAST (264 mg, 1.20 mmol). After stirring for 16 h, the dichloromethane was blown dry with nitrogen. The residue was dissolved again in dichloroethane (5 mL), then DAST (260 mg, 1.20 mmol) was added, heated to 70 °C and stirred for 1 h. After cooling to room temperature, the reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL), then extracted with dichloromethane (3 x 20 mL). The combined organic phase was dried over anhydrous sodium sulfate, then filtered. The filtrate was concentrated to dryness under reduced pressure, the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 / 100-2 / 3) to give the target product 75g (64 mg, 64%).

[1336] MS m / z (ESI): 251 [M+1]

[1337] Seventh step

[1338] 1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-fluorocyclobutan-1-ol (75g)

[1339] A mixture of 75g (142 mg, 0.57 mmol), water (4 mL) and sodium hydroxide (4 g) was heated to 130 °C and stirred for 18 h, then cooled to room temperature. The above operation was repeated once, then the two batches of reaction were mixed, adjusted to pH = 2 with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to give the target product 75h (174 mg, 100%).

[1340] MS m / z (ESI): 270 [M+1]

[1341] Eighth step

[1342] 5-(1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-fluorocyclobutyl)-4-methyl-4H-1,2,4-triazole-3- thiol (75i)

[1343] To a solution of 75h (174 mg, 0.65 mmol) and N-methylhydrazinecarboxamide (68 mg, 0.65 mmol) in DMF (4 mL) was added DIPEA (84 mg, 0.65 mmol) and HATU (247 mg, 0.65 mmol). After the resulting mixture was stirred for 5 min, it was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with water (3 x 20 mL) and saturated brine (20 mL) successively, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, the residue was dissolved in 1,4-dioxane (4 mL), and then aqueous sodium hydroxide (1 N, 6 mL) was added, heated to 80 °C and stirred for 16 h. After cooling to room temperature, it was adjusted to pH = 2 with dilute hydrochloric acid (1 N) and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with saturated brine (20 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to give the target product 75i (220 mg, 100%).

[1344] MS m / z (ESI): 339 [M+1]

[1345] Ninth step

[1346] 2-chloro-6-cyclopropyl-4-((1r,3r)-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)pyridine (75j) and 2-chloro-6-cyclopropyl-4-((1s,3s)-3-fluoro-1-(4-methyl- 4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (76j)

[1347] To a solution of 75i (220 mg, 0.65 mmol) in dichloromethane (4 mL) was added glacial acetic acid (780 mg, 13 mmol) and hydrogen peroxide (30%, 368 mg, 3.25 mmol). After the resulting mixture was stirred for 1 h, it was adjusted to pH = 8 with saturated sodium bicarbonate solution and extracted with dichloromethane (3 x 20 mL). The combined organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0 / 100-8 / 92) and then by prep-HPLC to give the target products 75j (61 mg) and 76j (58 mg).

[1348] 75j: MS m / z (ESI): 307 [M+1]

[1349] 76j: MS m / z (ESI): 307 [M+1]

[1350] Tenth step

[1351] N-(6-cyclopropyl-4-((1 r,3S)-3-fluoro-1 -(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin- 2-yl)-6-(((S)-3-methylpiperidin-1 -yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (75)

[1352] To a mixture of 75j (48 mg, 0.15 mmol), 59a (40 mg, 0.15 mmol) and 1,4-dioxane (2 mL) was added cesium carbonate (147 mg, 0.45 mmol), Pd2(dba)3(27 mg, 0.03 mmol) and Xantphos (35 mg, 0.06 mmol). The resulting mixture was heated to 110 °C in a microwave reactor and stirred for 2 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0 / 100-1 / 9) and prep-HPLC to give the target product 75 (38.8 mg, 49%).

[1353] MS m / z (ESI): 544 [M+1]

[1354] 1 H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 9.14 (d, J = 1.3 Hz, 1H), 8.80 (s, 1H), 8.41 (d, J = 1.8 Hz, 2H), 7.90 (d, J = 1.3 Hz, 1H), 7.15 (d, J = 1.5 Hz, 1H), 5.50 - 5.25 (m, 1H), 3.67 - 3.56 (m, 2H), 3.27 (s, 3H), 3.18 (ddd, J = 19.8, 9.8, 4.9 Hz, 4H), 2.77 (t, J = 9.0 Hz, 2H), 2.15 (dq, J = 7.7, 5.2 Hz, 1H), 1.94 (dd, J = 11.2, 8.8 Hz, 1H), 1.62 (ddd, J = 13.1, 10.0, 6.7 Hz, 4H), 1.54 - 1.45 (m, 1H), 1.04 - 0.92 (m, 4H), 0.88 (dd, J = 14.0, 5.3 Hz, 1H), 0.81 (d, J = 6.2 Hz, 3H).

[1355] Tenth step

[1356] N-(6-cyclopropyl-4-((1s,3R)-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)pyridin-2-yl)-6-(((S)-3-methylpiperidin-1-yl)methyl)- [1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (76)

[1357] Synthesized 76 (13.7 mg) following the procedure of tenth step, but used 76j instead of 75j in the procedure.

[1358] MS m / z (ESI): 544 [M+1]

[1359] 1 H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 9.13 (d, J = 10.1 Hz, 1H), 8.79 (d, J = 6.4 Hz, 1H), 8.46 (s, 1H), 8.40 (d, J = 6.7 Hz, 1H), 7.89 (s, 1H), 7.07 (s, 1H), 5.24 - 4.94 (m, 1H), 3.60 (s, 2H), 3.48 (s, 2H), 3.27 (s, 3H), 2.83 (dd, J = 29.5, 19.0 Hz, 4H), 2.14 (s, 1H), 1.94 (s, 1H), 1.72 - 1.37 (m, 5H), 0.97 (s, 4H), 0.81 (s, 4H).

[1360] Example 38

[1361] (S)-N-(6-cyclopropyl-4-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)pyridin-2-yl)-6-((3-methylpiperidin-1-yl)methyl)- [1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (Compound 77)

[1362] First Step

[1363] 1-(2-chloro-6-cyclopropylpyridin-4-yl)-3,3-difluorocyclobutan-1- carbonitrile (77a)

[1364] To a solution of 75e (247 mg, 1 mmol) in dichloromethane (20 mL) was added DAST (806 mg, 5 mmol). After the mixture was stirred for 20 h, saturated sodium bicarbonate (6 mL) solution was added, followed by extraction with dichloromethane (2 x 20 mL). The combined organic phase was washed with brine (10 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0-1 / 1) to give the target product 77a (202 mg, 75%).

[1365] MS m / z (ESI): 269 [M+1]

[1366] Second step

[1367] 1-(2-chloro-6-cyclopropylpyridin-4-yl)-3,3-difluorocyclobutane-1-carboxylic acid (77b)

[1368] To a solution of 77a (202 mg, 0.75 mmol) in 1,4-dioxane (0.5 mL) was added sodium hydroxide (120 mg, 3 mmol) and water (120 mg). The resulting mixture was heated to 110 °C and stirred for 6 h. After cooling to room temperature, sodium hydroxide (4 g) and water (4 g) were added to the mixture, which was heated to 110 °C and stirred for 16 h, then warmed to 130 °C and stirred for 6 h. After cooling to 0 °C, the reaction mixture was diluted with water (10 mL), then adjusted to pH = 2 with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 40 mL). The combined organic phase was dried over anhydrous sodium sulfate, then filtered. The filtrate was concentrated to dryness under reduced pressure to give the target product 77b (203 mg, 94%).

[1369] MS m / z (ESI): 288 [M+1]

[1370] Third step

[1371] 5-(1-(2-chloro-6-cyclopropylpyridin-4-yl)-3,3-difluorocyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol (77c)

[1372] To a solution of 77b (203 mg, 0.71 mmol) and N-methylhydrazinecarboxamide (75 mg, 0.71 mmol) in DMF (4 mL) was added DIPEA (92 mg, 0.71 mmol) and HATU (270 mg, 0.71 mmol) successively. After stirring for 5 min, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with water (2 x 20 mL) and saturated brine (20 mL) successively, then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, the residue was dissolved in 1,4-dioxane (4 mL), then sodium hydroxide (114 mg, 2.84 mmol) and water (2.5 mL) were added, heated to 50 °C and stirred for 20 h. After cooling to room temperature, the mixture was adjusted to pH = 2 with dilute hydrochloric acid (1 N), then extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to give the target product 77c (204 mg, 81%).

[1373] MS m / z (ESI): 357 [M+1]

[1374] Fourth step

[1375] 2-chloro-6-cyclopropyl-4-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (77d)

[1376] To a solution of 77c (204 mg, 0.57 mmol) in dichloromethane (2 mL) was added glacial acetic acid (686 mg, 11.4 mmol) and hydrogen peroxide (30%, 323 mg, 2.85 mmol) successively. After stirring for 1 h, the mixture was adjusted to pH = 8 with saturated sodium bicarbonate solution, then extracted with dichloromethane (3 x 20 mL). The combined organic phase was dried over anhydrous sodium sulfate, after filtration, the filtrate was concentrated to dryness under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0-92 / 8) to give the target product 77d (104 mg, 56%).

[1377] MS m / z (ESI): 325 [M+1]

[1378] Fifth step

[1379] (S)-N-(6-cyclopropyl-4-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (77)

[1380] To a solution of 77d (50 mg, 0.15 mmol) and 59a (42 mg, 0.15 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3(27 mg, 0.03 mmol), cesium carbonate (147 mg, 0.45 mmol) and Xantphos (35 mg, 0.06 mmol). The resulting mixture was heated to 110 °C in a microwave reactor and stirred for 2 h. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0 / 100-1 / 9) and prep-HPLC to give the target product 77 (40.9 mg, 47%).

[1381] MS m / z (ESI): 562 [M+1]

[1382] 1 H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 9.14 (s, 1H), 8.80 (s, 1H), 8.47 (s, 1H), 8.42 (s, 1H), 7.96 (d, J = 1.3 Hz, 1H), 7.15 (d, J = 1.4 Hz, 1H), 3.76 (dd, J = 26.9, 13.0 Hz, 2H), 3.68 - 3.54 (m, 2H), 3.49 - 3.43 (m, 2H), 3.31 (s, 3H), 2.77 (t, J = 9.0 Hz, 2H), 2.14 (td, J = 7.9, 4.0 Hz, 1H), 1.94 (t, J = 10.1 Hz, 1H), 1.70 - 1.39 (m, 5H), 1.05 - 0.91 (m, 4H), 0.88 (dd, J = 15.0, 4.4 Hz, 1H), 0.81 (d, J = 6.0 Hz, 3H).

[1383] Example 39

[1384] (S)-N-(6-cyclopropyl-4-(3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin- 2-yl)-6-((3-methylpiperidin-1-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (Compound 79)

[1385] First Step

[1386] 1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-hydroxycyclobutane-1-carboxylate (79a) and 1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methoxycyclobutane-1-carboxylate (79b)

[1387] To a solution of 75f (906 mg, 3.64 mmol) in methanol (7.2 mL) was added concentrated sulfuric acid (3.6 mL), heated to 80 °C and stirred for 20 h. After cooling to room temperature, ice (50 g) was added to the mixture, then adjusted to pH = 8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (3 x 100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0-0 / 100) to give the target product 79a (554 mg, 54%) and 79b (217 mg, 20%).

[1388] 79a, MS m / z (ESI): 282 [M+1]

[1389] 79b, MS m / z (ESI): 296 [M+1]

[1390] Second Step

[1391] 1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methoxycyclobutane-1-carboxylic acid (79c)

[1392] To a solution of 79b (217 mg, 0.73 mmol) in THF (6 mL) was added lithium hydroxide solution (1 M, 3 mL, 2.93 mmol). After stirring for 2 h, the resulting mixture was adjusted to pH = 3 with dilute hydrochloric acid (2 N) and then extracted with ethyl acetate (3 x 20 mL). The combined organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to dryness under reduced pressure to give the target product 79c (167 mg, 81%).

[1393] MS m / z (ESI): 282 [M+1]

[1394] Third Step

[1395] 5-(1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methoxycyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol (79d)

[1396] To a solution of 79c (167 mg, 0.59 mmol) and N-methylhydrazinecarboxamide (63 mg, 0.60 mmol) in DMF (4 mL) were added DIPEA (78 mg, 0.60 mmol) and HATU (228 mg, 0.60 mmol) successively. After stirring for 30 min, sodium hydroxide solution (2 N, 1.5 mL, 3 mmol) was added to the mixture, which was heated to 80 °C and stirred for 6 h. After the reaction mixture was cooled to room temperature, it was adjusted to pH = 3 with dilute hydrochloric acid (2 N) and then extracted with ethyl acetate (3 x 20 mL). The combined organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to dryness under reduced pressure to give the target product 79d (207 mg, 100%).

[1397] MS m / z (ESI): 387 [M+1]

[1398] Fourth step

[1399] 2-chloro-6-cyclopropyl-4-(3-methoxy-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)pyridine (79e)

[1400] To a solution of 79d (207 mg, 0.59 mmol) in dichloromethane (4 mL) were added acetic acid (885 mg, 14.75 mmol) and hydrogen peroxide (30%, 669 mg, 5.9 mmol). After the resulting mixture was stirred at room temperature for 1 h, it was adjusted to pH = 8 with saturated sodium bicarbonate solution and then extracted with dichloromethane (3 x 50 mL). The combined organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0-9 / 1) to give the target product 79e (134 mg, 71%).

[1401] MS m / z (ESI): 319 [M+1]

[1402] Fifth step

[1403] (S)-N-(6-cyclopropyl-4-(3-methoxy-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-6-((3-methylpiperidin-l-yl)methyl)-[l,2,4]triazolo[4,3-a]pyridine-8-carboxamide (79)

[1404] To a solution of 79e (134 mg, 0.42 mmol) and 59a (96 mg, 0.35 mmol) in 1,4-dioxane (4 mL) was added cesium carbonate (325 mg, 1 mmol), Pd2(dba)3(61 mg, 0.067 mmol) and Xantphos (76 mg, 0.13 mmol). The resulting mixture was heated to 100 °C in a microwave reactor and stirred for 2 h. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0-9 / 1) and prep-HPLC to give the target product 79 (58.8 mg, 30%).

[1405] MS m / z (ESI): 556 [M+1]

[1406] 1 H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 9.14 (s, 1H), 8.80 (s, 1H), 8.44 (s, 2 / 3H), 8.42 (s, 1H), 8.37 (s, 1 / 3H), 7.99 (d, J = 1.3 Hz, 1 / 3H), 7.90 (d, J = 1.2 Hz, 2 / 3H), 7.11 (d, J = 1.4 Hz, 1 / 3H), 6.98 (d, J = 1.4 Hz, 2 / 3H), 4.18 - 4.11 (m, 1 / 3H), 3.92 - 3.84 (m, 2 / 3H), 3.66 - 3.57 (m, 2H), 3.34 (d, J = 2.8 Hz, 2H), 3.26 (d, J = 2.6 Hz, 3H), 3.19 (d, J = 2.0 Hz, 3H), 3.09 - 3.02 (m, 1H), 2.82 (ddd, J = 24.9, 14.2, 7.6 Hz, 3H), 2.53 (d, J = 2.8 Hz, 1H), 2.13 (ddd, J = 10.4, 7.7, 5.0 Hz, 1H), 1.95 (dd, J = 11.3, 8.9 Hz, 1H), 1.63 (ddd, J = 13.3, 10.0, 3.9 Hz, 4H), 1.54 - 1.44 (m, 1H), 1.00 - 0.91 (m, 4H), 0.82 (d, J = 6.1 Hz, 3H).

[1407] Example 40

[1408] (S)-N-(5-cyano-6'-(1-methoxycyclopropyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)- [2,4'-bipyridinyl]-2'-yl)-3,3-dimethyl-5-((3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenofuran-7-carboxamide (Compound 80)

[1409] First Step

[1410] 1 -(6-bromopyridin-2-yl)cyclopropan-1 -ol (80a)

[1411] To a solution of 72c (3.00 g, 9.14 mmol) in THF (10 mL) was added TBAF in THF (1 M, 10 mL) dropwise. After stirring for 1 h, water (20 mL) was added to the mixture, which was then extracted with ethyl acetate (3 x 50 mL). The combined organic phase was dried over anhydrous sodium sulfate, then filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 3 / 1) to give the target product 80a (1.33 g, 68%).

[1412] MS m / z (ESI): 214, 216 [M+1]

[1413] Second Step

[1414] 2-bromo-6-(1-methoxycyclopropyl)pyridine (80b)

[1415] To a solution of 80a (1.33 g, 6.21 mmol) in THF (20 mL) was added 60% NaH (373 mg, 9.32 mmol) at 0 °C. After stirring at room temperature for 1 h, iodomethane (1.32 g, 9.32 mmol) was added to the mixture, which was stirred for 4 h. After cooling to 0 °C, saturated aqueous ammonium chloride solution (20 mL) was added to the mixture, which was then extracted with ethyl acetate (3 x 20 mL). The combined organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 25 / 1) to give the target product 80b (1.03 g, 73%).

[1416] MS m / z (ESI): 228, 230 [M+1]

[1417] Third Step

[1418] 2-bromo-6-(1-methoxycyclopropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (80c)

[1419] To a solution of 80b (1.03 g, 4.52 mmol) in MTBE (30 mL) were added sequentially bis(pinacolato)diboron (2.30 g, 9.04 mmol), methoxy(cyclooctadiene)iridium dimer (300 mg, 0.452 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (243 mg, 0.904 mmol). The resulting mixture was heated to 80 °C under nitrogen atmosphere and stirred for 18 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 100 / 1) to give the target product 80c (1.10 g, 69%).

[1420] MS m / z (ESI): 354, 356 [M+1]

[1421] Fourth Step

[1422] 2'-Bromo-6'-(1-methoxycyclopropyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)- [2,4'-bipyridine]-5-carbonitrile (80d)

[1423] To a mixture of 80c (588 g, 1.66 mmol), 72i (364 mg, 1.66 mmol), 1,4-dioxane (24 mL) and water (0.3 mL) were added sequentially Pd(dppf)Cl2(136 mg, 0.166 mmol) and potassium carbonate (688 mg, 4.98 mmol). The resulting mixture was heated to 100 °C under nitrogen atmosphere and stirred for 12 h. After cooling to room temperature, water (10 mL) was added to the mixture, which was then extracted with ethyl acetate (3 x 15 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the target product 80d (180 mg, 26%).

[1424] MS m / z (ESI): 411, 413 [M+1]

[1425] Fifth Step

[1426] (S)-N-(5-Cyano-6'-(1-methoxycyclopropyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)- [2,4'-bipyridine]-2'-yl)-3,3-dimethyl-5-((3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenzofuran-7-carboxamide (80)

[1427] To a solution of 80d (71 mg, 0.17 mmol) and 49m (50 mg, 0.16 mmol) in toluene (8 mL) were added Pd2(dba)3(23 mg, 0.025 mmol), Xantphos (29 mg, 0.050 mmol) and cesium carbonate (215 mg, 0.66 mmol) successively. The resulting mixture was heated to 110 °C under nitrogen atmosphere and stirred for 12 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the target product 80 (40 mg, 46%).

[1428] MS m / z (ESI): 633 [M+1]

[1429] 1 HNMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.39 (d, J = 1.6 Hz, 1H), 8.74 (d, J = 1.6 Hz, 1H), 8.62 (s, 1H), 8.18 (s, 1H), 7.65 (s, 1H), 7.38 (s, 1H), 7.10 (s, 1H), 4.52 (s, 2H), 3.45 (s, 3H), 3.41 (s, 2H), 3.09 (s, 3H), 2.76 - 2.65 (m, 2H), 1.92 - 1.80 (m, 1H), 1.71 - 1.41 (m, 6H), 1.34 (s, 6H), 1.18 (s, 3H), 0.92 - 0.84 (m, 1H), 0.82 (d, J = 4.8 Hz, 3H).

[1430] Example 41

[1431] (S)-N-(6-cyclopropyl-4-(3-(difluoromethoxy)-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)pyridin-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-[1,2,4]triazolo[4,3- a]pyridine-8-carboxamide (Compound 81)

[1432] First Step

[1433] 1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-(difluoromethoxy)cyclobutane-1-carboxylic acid methyl ester (81a)

[1434] To a solution of 79a (233 mg, 0.83 mmol) in dichloromethane (5 mL) was added water (2 mL), potassium acetate (815 mg, 8.30 mmol) and (bromodifluoromethyl)trimethylsilane (840 mg, 4.14 mmol). After stirring at room temperature for 4 days, potassium acetate (1 g) and (bromodifluoromethyl)trimethylsilane (1 g) were added to the reaction mixture. After stirring the resulting mixture for another 24 h, potassium acetate (1 g) and (bromodifluoromethyl)trimethylsilane (1 g) were added and stirred for 24 h. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic phases were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 4 / 1) to give the target product 81a (169 mg, 61%).

[1435] MS m / z (ESI): 332 [M+1]

[1436] Second step

[1437] 1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-(difluoromethoxy)cyclobutane-1-carboxylic acid (81b)

[1438] To a solution of 81a (169 mg, 0.51 mmol) in THF (2 mL) was added water (2 mL) and lithium hydroxide (86 mg, 2.04 mmol). After stirring the resulting mixture for 2 h, it was adjusted to pH = 2 with dilute hydrochloric acid (2 N) and then extracted with ethyl acetate (3 x 20 mL). The combined organic phases were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to dryness under reduced pressure to give the target product 81b (159 mg, 100%).

[1439] MS m / z (ESI): 318 [M+1]

[1440] Third step

[1441] 5-(1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-(difluoromethoxy)cyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol (81c)

[1442] To a solution of 81b (159 mg, 0.50 mmol) and N-methylhydrazinecarboxamide (58 mg, 0.55 mmol) in DMF (4 mL) was added DIPEA (71 mg, 0.55 mmol) and HATU (209 mg, 0.55 mmol). After stirring at room temperature for 30 min, sodium hydroxide solution (2 N, 1.5 mL, 3 mmol) was added to the mixture, which was then heated to 80 °C and stirred for 6 h. After cooling to room temperature, the reaction mixture was adjusted to pH = 3 with dilute hydrochloric acid (2 N) and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to give the target product 81c (193 mg, 100%).

[1443] MS m / z (ESI): 387 [M+1]

[1444] Fourth step

[1445] 2-chloro-6-cyclopropyl-4-(3-(difluoromethoxy)-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)pyridine (81d)

[1446] To a solution of 81c (193 mg, 0.50 mmol) in dichloromethane (4 mL) was added acetic acid (2 mL) and hydrogen peroxide (30%, 1.5 mL). After stirring at room temperature for 1 h, the reaction mixture was adjusted to pH = 8 with saturated sodium bicarbonate solution and extracted with dichloromethane (3 x 50 mL). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0-9 / 1) to give the target product 81d (142 mg, 80%).

[1447] MS m / z (ESI): 355 [M+1]

[1448] Fifth step

[1449] (S)-N-(6-cyclopropyl-4-(3-(difluoromethoxy)-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)pyridin-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-[1,2,4]triazolo[4,3- a]pyridine-8-carboxamide trifluoroacetic acid salt (81)

[1450] To a solution of 81d (142 mg, 0.40 mmol) and 59a (90 mg, 0.33 mmol) in 1,4-dioxane (4 mL) was added cesium carbonate (325 mg, 1 mmol), Pd2(dba)3(61 mg, 0.067 mmol) and Xantphos (76 mg, 0.132 mmol). The resulting mixture was heated to 100 °C in a microwave reactor and stirred for 2 h. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0-9 / 1) and prep-HPLC to give two isomers of the target product 81, 81-1 (trifluoroacetate, 42.4 mg, 18%) and 81-2 (trifluoroacetate, 51.0 mg, 22%).

[1451] 81-1, MS m / z (ESI): 592 [M+1]

[1452] 1 H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 9.72 (s, 1H), 9.42 (s, 1H), 8.93 (s, 1H), 8.63 (s, 1H), 8.53 (s, 1H), 7.89 (s, 1H), 7.28 (d, J = 1.3 Hz, 1H), 6.70 (t, J = 75.4 Hz, 1H), 4.94 (p, J = 7.5 Hz, 1H), 4.52 (q, J = 13.3 Hz, 2H), 3.51 (d, J = 13.0 Hz, 1H), 3.39 (d, J = 9.7 Hz, 1H), 3.28 (s, 3H), 3.23 - 3.15 (m, 2H), 3.15 - 3.06 (m, 2H), 2.85 (s, 1H), 2.58 (s, 1H), 2.19 (ddd, J = 12.8, 7.9, 5.0 Hz, 1H), 1.73 (ddd, J = 45.8, 27.1, 14.3 Hz, 4H), 1.13 - 0.96 (m, 5H), 0.88 (d, J = 6.5 Hz, 3H).

[1453] 81-2, MS m / z (ESI): 592 [M+1]

[1454] 1H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 9.76 (s, 1H), 9.42 (s, 1H), 8.93 (s, 1H), 8.62 (s, 1H), 8.56 (s, 1H), 7.83 (s, 1H), 7.14 (s, 1H), 6.72 (t, J = 75.5 Hz, 2H), 4.64 (dt, J = 14.6, 7.3 Hz, 1H), 4.52 (q, J = 13.2 Hz, 2H), 3.47 - 3.37 (m, 4H), 3.28 (s, 3H), 3.25 - 3.05 (m, 1H), 2.80 (dd, J = 22.7, 13.1 Hz, 3H), 2.58 (s, 1H), 2.17 (dd, J = 11.0, 6.3 Hz, 1H), 1.89 - 1.58 (m, 5H), 1.09 - 0.93 (m, 5H), 0.88 (d, J = 6.3 Hz, 3H).

[1455] Example 42

[1456] N-(3-(1-hydroxycyclopropyl)-5-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-3,3-dimethyl-5-(((S)-3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenzofuran-7-carboxamide (Compound 82)

[1457] First Step

[1458] 1-(3-bromo-5-methylphenyl)ethan-1-one (82c)

[1459] To a solution of 3-bromo-5-methylbenzaldehyde 82a (25 g, 126 mmol) in THF (200 mL) was added methylmagnesium bromide (42 mL, 126 mmol) at -78 °C. The resulting mixture was warmed to room temperature and stirred for 1 h, then saturated ammonium chloride solution (200 mL) was added and extracted with ethyl acetate (3 x 150 mL). The combined organic phase was dried over anhydrous sodium sulfate, then filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to give the target product 82b (26.5 g, 98%).

[1460] MS m / z (ESI): 197, 199 [M+1-H2O]

[1461] Second Step

[1462] 1-(3-bromo-5-methylphenyl)ethan-1-one (82c)

[1463] To a solution of 82b (26.5 g, 124 mmol) in acetonitrile (248 mL) was added IBX (41.7 g, 149 mmol) at 0 °C. The resulting mixture was heated to 80 °C and stirred for 2 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to give the target product 82c (23.9 g, 91%).

[1464] MS m / z (ESI): 213, 215 [M+1]

[1465] Third Step

[1466] 1-(3-bromo-5-(bromomethyl)phenyl)ethan-1-one (82d)

[1467] To a solution of 82c (21.2 g, 100 mmol) and AIBN (1.6 g, 10 mmol) in carbon tetrachloride (160 mL) was added NBS (19.6 g, 110 mmol). The resulting mixture was heated to 80 °C and stirred for 12 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 50 / 1 to 20 / 1) to give the target product 82d (25 g, 86%).

[1468] MS m / z (ESI): 291, 293 [M+1]

[1469] Fourth Step

[1470] 2-(3-acetyl-5-bromophenyl)acetonitrile (82e)

[1471] To a solution of 82d (20 g, 68.7 mmol) and trimethylsilyl cyanide (8.2 g, 82.5 mmol) in acetonitrile (200 mL) was added a solution of TBAF in THF (82 mL, 82 mmol). It was stirred at room temperature for 1 h. Saturated ammonium chloride solution (200 mL) was added and stirred, extracted with ethyl acetate (3 x 150 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to give the target product 82e (13.9 g, 85%).

[1472] MS m / z (ESI): 238, 240 [M+1]

[1473] Fifth Step

[1474] 1-(3-acetyl-5-bromophenyl)-3-methylcyclobutane-1-carbonitrile (82f)

[1475] To a solution of 82e (8.8 g, 37.3 mmol) and 1,3-dibromo-2-methylpropane (8.9 g, 41 mmol) in DMF (100 mL) was added NaH (60%, 4.4 g, 112 mmol) at 0 °C. After the resulting mixture was stirred at room temperature for 1 h, saturated ammonium chloride solution (200 mL) was added and stirred, then extracted with ethyl acetate (3 x 200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 50 / 1 to 20 / 1) to give the target product 82f (8.2 g, 76%).

[1476] MS m / z (ESI): 292, 294 [M+1]

[1477] Sixth step

[1478] 1-(3-bromo-5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)phenyl)-3-methylcyclobutane-1- carbonitrile (82h)

[1479] To a solution of 82f (8.2 g, 28.3 mmol) and triethylamine (8.8 g, 87.9 mmol) in dichloromethane (100 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (8.2 g, 31.1 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h, then concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) to give the target product 82g (6.6 g, 58%).

[1480] MS m / z (ESI): 406, 408 [M+1]

[1481] Seventh step

[1482] 1-(3-bromo-5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)phenyl)-3-methylcyclobutane-1- carbonitrile (82h)

[1483] To a solution of diethylzinc (33 mL, 65.5 mmol) in dichloromethane (100 mL) was added chloroiodomethane (23 g, 131 mmol) at 0 °C. After stirring at 0 °C for 1 h, a solution of 82g (6.6 g, 16.3 mmol) in dichloromethane (20 mL) was added to the mixture. After stirring for 2 h, the mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 50 / 1 to 20 / 1) to give the target product 82h (4.1 g, 45%)

[1484] MS m / z (ESI): 420 [M+1]

[1485] Eighth step

[1486] 1-(3-bromo-5-(1-hydroxycyclopropyl)phenyl)-3-methylcyclobutane-1-carboxylic acid (82i)

[1487] To a mixture of 82h (4.1 g, 9.7 mmol), ethanol (40 mL) and water (20 mL) was added potassium hydroxide (5.4 g, 97 mmol) and heated to 90 °C and stirred for 12 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 50 / 1 to 10 / 1) to give the target product 82i (1.6 g, 50%).

[1488] MS m / z (ESI): 325, 327 [M+1]

[1489] Ninth step

[1490] 2-(1-(3-bromo-5-(1-hydroxycyclopropyl)phenyl)-3-methylcyclobutane-1-carbonyl)-N- methylhydrazine-1-carbothioamide (82j)

[1491] To a mixture of 82i (1.6 g, 4.9 mmol), DIPEA (1.9 g, 14.7 mmol), 4-methylaminothioamide (775 mg, 7.38 mmol) and DMF (20 mL) was added HATU (2.1 g, 5.4 mmol). After stirring at room temperature for 1 h, water (100 mL) was added to the mixture and extracted with ethyl acetate (3 x 100 mL). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 20 / 1 to 3 / 1) to give the target product 82j (1.2 g, 55%).

[1492] MS m / z (ESI): 412 [M+1]

[1493] Tenth step

[1494] 1-(3-bromo-5-(1-(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)-3-methylcyclobutyl)phenyl)cyclopropan-1-ol (82k)

[1495] To a solution of 82j (1.2 g, 2.9 mmol) in water (10 mL) was added NaOH (350 mg, 8.7 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 12 h, then adjusted to pH = 4 with dilute hydrochloric acid (2 N). The precipitate was collected by filtration and dried in a desiccator at 50 °C to give the target product 82k (900 mg, 78%).

[1496] MS m / z (ESI): 394 [M+1]

[1497] Eleventh step

[1498] 1-(3-bromo-5-(1-(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)-3-methylcyclobutyl)phenyl)cyclopropan-1-ol (82k)

[1499] To a mixture of 82k (900 mg, 2.28 mmol), dichloromethane (35 mL) and acetic acid (6 mL) was added hydrogen peroxide (2.6 g, 22.8 mmol). The resulting mixture was stirred at room temperature for 2 h, then concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1 to 10 / 1) and then by prep-HPLC to give the target products 82l (580 mg, 67%) and 82m (160 mg, 19%).

[1500] MS m / z (ESI): 362 [M+1]

[1501] Twelfth step

[1502] N-(3-(1-hydroxycyclopropyl)-5-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3,3-dimethyl-5-(((S)-3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide formate salt (82)

[1503] A mixture of 82l (30 mg, 0.08 mmol), 49m (25.1 mg, 0.08 mmol), copper iodide (15.7 mg, 0.08 mmol), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (7.3 mg, 0.08 mmol), cesium carbonate (81 mg, 0.25 mmol) and DMF (1 mL) was heated to 100 °C in a microwave reactor under nitrogen atmosphere and stirred for 6 hours. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 20 / 1) and then by prep-HPLC to give the target product 82 (8.2 mg, 18%).

[1504] MS m / z (ESI): 584 [M+1]

[1505] 1 H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.86 (d, J = 1.7 Hz, 1H), 7.80 (d, J = 1.5 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 4.61 (s, 2H), 3.90 (s, 2H), 3.36 (s, 3H), 3.09 (d, J = 7.2 Hz, 4H), 3.01 (dd, J = 9.6, 5.4 Hz, 2H), 2.69 (s, 3H), 2.39 (s, 1H), 2.08 (d, J = 13.5 Hz, 1H), 1.81 (s, 4H), 1.47 (s, 6H), 1.25 - 1.14 (m, 5H), 1.12 - 1.02 (m, 1H), 0.96 (d, J = 6.4 Hz, 3H).

[1506] The following compounds were synthesized according to the procedure of Example 42, Step 12, but substituting different compounds for 82l and 49m in the procedure.

[1507] The NMR data for these compounds are as follows:

[1508] Example 43

[1509] N-(3-(1-methoxycyclopropyl)-5-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-3,3-dimethyl-5-(((S)-3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenzofuran-7-carboxamide (Compound 84)

[1510] First step

[1511] 3-((1s,3s)-1-(3-bromo-5-(1-methoxycyclopropyl)phenyl)-3-methylcyclobutyl)-4- methyl-4H-1,2,4-triazole (84a)

[1512] To a solution of 82l (108 mg, 0.3 mmol) in DMF (2 mL) was added NaH (60%, 14.4 mg, 0.36 mmol) at 0 °C. After the resulting mixture was stirred at 0 °C for 1 h, iodomethane (47 mg, 0.33 mmol) was added. The stirring was continued for 1 h, and then saturated ammonium chloride solution (5 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 x 30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give the target product 84a (79.2 mg, 70%).

[1513] MS m / z (ESI): 376 [M+1]

[1514] Second step

[1515] N-(3-(1-methoxycyclopropyl)-5-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-3,3-dimethyl-5-(((S)-3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenzofuran-7-carboxamide formate (84)

[1516] A mixture of 84a (30 mg, 0.08 mmol), 49m (24.2 mg, 0.08 mmol), copper iodide (15.2 mg, 0.08 mmol), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (7 mg, 0.08 mmol), cesium carbonate (78 mg, 0.24 mmol) and DMF (1 mL) was heated to 100 °C in a microwave reactor under nitrogen atmosphere and stirred for 6 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 0 to 20 / 1) and then by prep-HPLC to give the target product 84 (13 mg, 27%).

[1517] MS m / z (ESI): 598 [M+1]

[1518] 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 8.01 (s, 1H), 7.83 (d, J = 1.7 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 4.57 (s, 2H), 3.89 (s, 2H), 3.61 (s, 1H), 3.32 (s, 3H), 3.19 - 3.04 (m, 2H), 2.97 (d, J = 4.3 Hz, 2H), 2.64 (d, J = 8.6 Hz, 3H), 2.38 (t, J = 11.1 Hz, 1H), 2.10 (t, J = 10.8 Hz, 1H), 1.78 (s, 3H), 1.65 (dd, J = 18.0, 9.0 Hz, 1H), 1.43 (s, 6H), 1.17 (t, J = 5.6 Hz, 9H), 1.08 - 1.00 (m, 1H), 0.92 (d, J = 6.4 Hz, 3H).

[1519] The following compounds were synthesized according to the procedure of Example 43, but substituting different compounds for 49m in the procedure.

[1520] The nuclear magnetic data for the compounds are as follows:

[1521] Example 44

[1522] N-(6-cyclopropyl-4-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-3-methyl-6-(((S)-3-methylpiperidin-1-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (Compound 85)

[1523] First Step

[1524] tert-Butyl 2-cyano-2-(2,6-dichloropyridin-4-yl)acetate (85b)

[1525] To a solution of 2,4,6-trichloropyridine 85a (5.47 g, 30 mmol) and tert-butyl 2-cyanoacetate (5.08 g, 36 mmol) in DMF (60 mL) was added cesium carbonate (14.66 g, 45 mmol), heated to 90 °C and stirred for 2 h. After cooling to room temperature, the reaction mixture was diluted with water (200 mL) and then extracted with ethyl acetate (2 x 200 mL). The combined organic phases were washed with saturated brine (3 x 120 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 0 / 100) to give the target product 85b (10 g, 89%).

[1526] MS m / z (ESI): 287 [M+1]

[1527] Second step

[1528] 2-(2,6-dichloropyridin-4-yl)acetonitrile (85c)

[1529] To a solution of 85b (10 g, 34.8 mmol) in dichloromethane (40 mL) was added TFA (40 mL). After stirring for 2 h, the mixture was concentrated to dryness under reduced pressure and the residue was adjusted to pH = 8 with saturated sodium bicarbonate solution and then extracted with ethyl acetate (3 x 100 mL). The combined organic phases were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 3 / 7) to give the target product 85c (4.92 g, 76%).

[1530] MS m / z (ESI): 187 [M+1]

[1531] Third step

[1532] 1-(2,6-dichloropyridin-4-yl)-3-methylcyclobutane-1-carbonitrile (85d)

[1533] To a solution of 85c (2.87 g, 15.5 mmol) and 1,3-dibromo-2-methylpropane (3.98 g, 18.4 mmol) in DMF (30 mL) was added cesium carbonate (11 g, 33.8 mmol) and then heated to 60 °C and stirred for 1 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and then extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed successively with water (2 x 50 mL) and saturated brine (50 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 1 / 1) to give the target product 85d (2.36 g, 64%).

[1534] MS m / z (ESI): 241 [M+1]

[1535] Fourth Step

[1536] 1 -(2-Chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutane-1 -carbonitrile (85e)

[1537] To a solution of 85d (4.65 g, 19.3 mmol) and cyclopropylboronic acid (2.98 g, 34.7 mmol) in 1,4-dioxane (100 mL) was added water (10 mL), potassium carbonate (10.66 g, 77.2 mmol) and Pd(dppf)Cl2(847 mg, 1.16 mmol). The resulting mixture was heated to 100 °C under nitrogen atmosphere and stirred for 18 h, then cooled to room temperature and filtered. The filtrate was washed with saturated brine (20 mL), and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). All the organic phases were combined, dried over anhydrous sodium sulfate, then filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 1 / 9) to give the target product 85e (2.83 g, 59%).

[1538] MS m / z (ESI): 247 [M+1]

[1539] Fifth Step

[1540] 1 -(2-Chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutane-1 -carboxylic acid (85f)

[1541] To a solution of 85e (2.83 g, 11.5 mmol) in ethanol (1 1 mL) was added water (1 1 mL) and sodium hydroxide (3.67 g, 91.8 mmol), then heated to 1 10 °C and stirred for 12 h. After cooling to room temperature, the reaction mixture was adjusted to pH = 2 with dilute hydrochloric acid (2N). The precipitate was collected by filtration to give the target product 85f (2.89 g, 95%).

[1542] MS m / z (ESI): 266 [M+1]

[1543] Sixth Step

[1544] 2-(1 -(2-Chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutane-1 -carbonyl)-N- methylhydrazine-1 -carbothioamide (85g)

[1545] To a solution of 85f (2.89 g, 10.9 mmol) and N-methylhydrazinecarbothioamide (1.26 g, 12.0 mmol) in DMF (20 mL) was added DIPEA (1.55 g, 12.0 mmol) and HATU (4.55 g, 12.0 mmol). After the resulting mixture was stirred for 15 min, water (120 mL) was added and stirred for 30 min. The precipitate was collected by filtration to give the target product 85g (3.84 g, 100%).

[1546] MS m / z (ESI): 353 [M+1]

[1547] Seventh step

[1548] 5-(1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4- triazole-3-thiol (85h)

[1549] To a solution of 85g (3.84 g, 10.9 mmol) in 1,4-dioxane (16 mL) was added water (16 mL) and sodium hydroxide (2.61 g, 65.3 mmol), heated to 90 °C and stirred for 4 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to remove 1,4-dioxane. The residue was adjusted to pH = 2 with dilute hydrochloric acid (2 N). The precipitate was collected by filtration to give the target product 85h (3.64 g, 100%).

[1550] MS m / z (ESI): 335 [M+1]

[1551] Eighth step

[1552] 2-chloro-6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)pyridine (85i)

[1553] To a solution of 85h (3.64 g, 10.9 mmol) in dichloromethane (20 mL) was added acetic acid (9.79 g, 163 mmol). After the resulting mixture was cooled to 0 °C, hydrogen peroxide (30%, 6.16 g, 54.4 mmol) was added dropwise, then stirred at 30 °C for 30 min. After the mixture was cooled to 0 °C again, it was adjusted to pH = 8 with sodium hydroxide solution (2 N), then extracted with dichloromethane (3 x 50 mL). The combined organic phase was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0-92 / 8), then by prep-HPLC to give the target product 85i (1.34 g, 41%).

[1554] MS m / z (ESI): 303 [M+1]

[1555] Ninth step

[1556] (S)-1-((Difluoroboryl)methyl)-3-methylpiperidine (85j)

[1557] To a mixture of (S)-3-methylpiperidine hydrochloride (5.43 g, 40 mmol) and acetonitrile (200 mL) was added potassium (bromomethyl)borate (8.84 g, 44 mmol), potassium carbonate (11 g, 80 mmol) and potassium iodide (664 mg, 4 mmol). The resulting mixture was heated to 90 °C and stirred for 12 h, then cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure to give the target product 85j (6.75 g, 70%).

[1558] MS m / z (ESI): 162 [M+1]

[1559] Tenth step

[1560] 6-Bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid methyl ester (85k)

[1561] A mixture of 2b (9.98 g, 33.14 mmol) in formic acid trimethyl ester (80 mL) was heated to 125 °C and stirred for 20 h, then cooled to room temperature. The precipitate was collected by filtration and purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0-92 / 8) to give the target product 85k (5.16 g, 58%).

[1562] MS m / z (ESI): 270 [M+1]

[1563] Eleventh step

[1564] (S)-3-Methyl-6-((3-methylpiperidin-1-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine-8- carboxylic acid methyl ester (85l)

[1565] To a solution of 85k (2.45 g, 9.08 mmol) and 85j (5.97 g, 27.2 mmol) in THF (90 mL) was added water (18 mL), cesium carbonate (8.86 g, 27.2 mmol), palladium acetate (408 mg, 1.82 mmol) and XPhos (1.74 g, 3.64 mmol). The resulting mixture was heated to 80 °C under nitrogen atmosphere and stirred for 20 h. After cooling to room temperature, a second batch of palladium acetate and XPhos in the same amount as above was added to the mixture, which was heated to 80 °C and stirred for 22 h. After cooling to room temperature, a third batch of palladium acetate and XPhos was added, which was heated to 80 °C and stirred for 22 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0-4 / 1) to give the target product 85l (158 mg, 5%).

[1566] MS m / z (ESI): 303 [M+1]

[1567] Twelfth step

[1568] (S)-3-methyl-6-((3-methylpiperidin-l-yl)methyl)-[l,2,4]triazolo[4,3-a]pyridine-8- carboxamide (85m)

[1569] A mixture of 85l (158 mg, 0.52 mmol) and ammonia in methanol (7 M, 15 mL) was stirred for 16 h, and then concentrated to dryness under reduced pressure to give the target product 85m (143 mg, 95%).

[1570] MS m / z (ESI): 288 [M+1]

[1571] Thirteenth step

[1572] N-(6-cyclopropyl-4-((lS,3S)-3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)pyridin- 2-yl)-3-methyl-6-(((S)-3-methylpiperidin-l-yl)methyl)-[l,2,4]triazolo[4,3-a]pyridine-8- carboxamide hydrochloride (85)

[1573] To a solution of 85m (15 mg, 0.05 mmol) and 85i (15 mg, 0.05 mmol) in 1,4-dioxane (2 mL) was added carbonic acid (49 mg, 0.15 mmol), Pd2(dba)3(5 mg, 0.005 mmol) and Xantphos (6 mg, 0.01 mmol), then heated to 100 °C in a microwave reactor and stirred for 1 h. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified with prep-HPLC to give the target product 85 (10.3 mg, 35%).

[1574] MS m / z (ESI): 554 [M+1]

[1575] 1 H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 10.66 (s, 1H), 9.40 (d, J = 1.4 Hz, 1H), 8.91 (s, 1H), 8.59 (d, J = 1.5 Hz, 1H), 7.99 (d, J = 1.1 Hz, 1H), 7.20 (d, J = 1.4 Hz, 1H), 4.53 - 4.41 (m, 2H), 3.44 (d, J = 11.3 Hz, 1H), 3.34 (s, 1H), 3.32 (s, 3H), 2.91 - 2.75 (m, 3H), 2.68 - 2.56 (m, 3H), 2.63 (s, 3H), 2.16 (ddd, J = 13.0, 7.5, 5.5 Hz, 1H), 1.91 (s, 2H), 1.80 (s, 2H), 1.76 - 1.67 (m, 2H), 1.11 (d, J = 5.5 Hz, 3H), 1.03 - 0.95 (m, 4H), 0.86 (d, J = 6.6 Hz, 3H).

[1576] Example 45

[1577] N-(6-cyclopropyl-4-((3-(difluoromethoxy)cyclobutyl)(4-methyl-4H-1,2,4-triazol-3- yl)methyl)pyridin-2-yl)-6-(((S)-3-methylpiperidin-1-yl)methyl)-[1,2,4]triazolo[4,3- a]pyridine-8-carboxamide (Compound 86)

[1578] First step

[1579] 2-(2,6-dichloropyridin-4-yl)dimethyl propanedioate (86b)

[1580] To a solution of 2,6-dichloro-4-iodopyridine 86a (5 g, 18.3 mmol) and dimethyl malonate (3.62 g, 27.4 mmol) in 1,4-dioxane (182 mL) was added picolinic acid (899 mg, 7.30 mmol), cesium carbonate (17.85 g, 54.8 mmol) and cuprous iodide (696 mg, 3.65 mmol). The resulting mixture was heated to 50 °C under nitrogen atmosphere and stirred for 14 h. After cooling to room temperature, water (400 mL) was added to the mixture, which was then extracted with ethyl acetate (3 x 200 mL). The combined organic phase was washed with saturated brine (100 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0-7 / 3) to give the target product 86b (5.12 g, 101%).

[1581] MS m / z (ESI): 278 [M+1]

[1582] 1 H NMR (400 MHz, CDCl3) δ 7.35 (s, 2H), 4.59 (s, 1H), 3.80 (s, 6H).

[1583] Second step

[1584] 2-(2,6-dichloropyridin-4-yl)-2-(3-oxocyclobutyl)propanedioic acid dimethyl ester (86c)

[1585] To a solution of 86b (5.12 g, 18.3 mmol) and 3-bromocyclobutan-1-one (4.90 g, 32.9 mmol) in DMF (36 mL) was added NaH (60%, 1.83 g, 45.7 mmol) at 0 °C, and after stirring at room temperature for 2 h, the reaction mixture was poured into a saturated ammonium chloride solution (200 mL), which was then extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed successively with water (2 x 100 mL) and saturated brine (100 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0-4 / 1) to give the target product 86c (2.28 g, 36%).

[1586] MS m / z (ESI): 346 [M+1]

[1587] 1 H NMR (400 MHz, CDCl3) δ 7.22 (s, 2H), 3.84 (s, 6H), 3.39-3.10 (m, 5H).

[1588] Third step

[1589] 2-(2,6-dichloropyridin-4-yl)-2-(3-hydroxycyclobutyl)propanedioic acid dimethyl ester (86d)

[1590] To a solution of 86c (2.28 g, 6.59 mmol) in methanol (33 mL) was added sodium borohydride (299 mg, 7.90 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min, then quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with saturated brine (100 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to give the target product 86d (2.28 g, 100%).

[1591] MS m / z (ESI): 348 [M+1]

[1592] Fourth step

[1593] 2-(2,6-dichloropyridin-4-yl)-2-(3-hydroxycyclobutyl)propanedioic acid dimethyl ester (86d)

[1594] To a solution of 86d (2.28 g, 6.55 mmol) in DMSO (13 mL) was added water (590 mg, 32.7 mmol) and lithium chloride (555 mg, 13.1 mmol), then heated to 130 °C and stirred for 5 h. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with water (2 x 100 mL) and saturated brine (100 mL) successively, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0-1 / 1) to give the target product 86e (1.56 g, 82%).

[1595] MS m / z (ESI): 290 [M+1]

[1596] Fifth step

[1597] 2-(2,6-dichloropyridin-4-yl)-2-(3-hydroxycyclobutyl)propanedioic acid dimethyl ester (86d)

[1598] To a solution of 86e (1.56 g, 5.38 mmol) in dichloromethane (10 mL) was added water (10 mL), potassium acetate (10.56 g, 108 mmol) and (bromodifluoromethyl)trimethylsilane (5.46 g, 26.9 mmol). The resulting mixture was stirred at room temperature for 20 hours, then diluted with water (50 mL) and extracted with dichloromethane (2 x 50 mL). The combined organic phases were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 to 4 / 1) to give the target product 86f (1.44 g, 73%).

[1599] MS m / z (ESI): 340 [M+1]

[1600] Sixth step

[1601] 2-(2,6-dichloropyridin-4-yl)-2-(3-(difluoromethoxy)cyclobutyl)acetic acid (86g)

[1602] To a solution of 86f (1.44 g, 4.23 mmol) in THF (8 mL) was added water (8 mL) and lithium hydroxide (711 mg, 16.9 mmol). The mixture was stirred for 2 hours, then adjusted to pH = 3 with dilute hydrochloric acid (2 N) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to dryness under reduced pressure to give the target product 86g (1.38 g, 100%).

[1603] MS m / z (ESI): 326 [M+1]

[1604] Seventh step

[1605] 5-((2,6-dichloropyridin-4-yl)(3-(difluoromethoxy)cyclobutyl)methyl)-4-methyl-4H-1,2,4-triazole-3-thiol (86h)

[1606] To a solution of 86g (1.38 g, 4.23 mmol) and N-methylhydrazinecarboxamide (447 mg, 4.23 mmol) in DMF (6 mL) was added DIPEA (547 mg, 4.23 mmol) and HATU (1.61 g, 4.23 mmol). After the resulting mixture was stirred at room temperature for 30 min, water (60 mL) was added, followed by extraction with ethyl acetate (3 x 60 mL). The combined organic phase was washed successively with water (2 x 60 mL) and saturated brine (60 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure, the residue was dissolved in 1,4-dioxane (16 mL), then water (8 mL) and sodium hydroxide (846 mg, 21.2 mmol) were added. The resulting mixture was heated to 50 °C and stirred for 16 h, then heated to 80 °C and stirred for 3 h. After cooling to room temperature, the mixture was adjusted to pH = 4 with dilute hydrochloric acid (2 N), then extracted with ethyl acetate (3 x 50 mL). The combined organic phase was dried over anhydrous sodium sulfate, then filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0-92 / 8) to give the target product 86h (1.54 g, 92%).

[1607] MS m / z (ESI): 395 [M+1]

[1608] Eighth step

[1609] 2,6-dichloro-4-((3-(difluoromethoxy)cyclobutyl)(4-methyl-4H-1,2,4-triazol-3- yl)methyl)pyridine (86i)

[1610] To a solution of 86h (1.54 g, 3.90 mmol) in dichloromethane (40 mL) was added acetic acid (4.68 g, 77.9 mmol). After the resulting solution was cooled to 0 °C, hydrogen peroxide (30%, 2.65 g, 23.4 mmol) was added. After stirring at room temperature for 1 h, the reaction mixture was adjusted to pH = 8 with saturated sodium bicarbonate solution, then extracted with dichloromethane (3 x 50 mL). The combined organic phase was dried over anhydrous sodium sulfate, then filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by C18 column chromatography (acetonitrile / water = 10 / 90-60 / 40) to give the target product 86i (810 mg, 57%).

[1611] MS m / z (ESI): 363 [M+1]

[1612] Ninth step

[1613] 2-chloro-6-cyclopropyl-4-((3-(difluoromethoxy)cyclobutyl)(4-methyl-4H-1,2,4- triazol-3-yl)methyl)pyridine (86j)

[1614] To a solution of 86i (810 mg, 2.23 mmol) and cyclopropylboronic acid (345 mg, 4.01 mmol) in 1,4-dioxane (44 mL) was added water (5 mL), potassium carbonate (1.23 g, 8.92 mmol) and Pd(dppf)Cl2(163 mg, 0.22 mmol). The resulting mixture was heated to 100 °C under nitrogen atmosphere and stirred for 18 h. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0-9 / 1) to give the target product 86j (533 mg, 65%).

[1615] MS m / z (ESI): 369 [M+1]

[1616] Tenth step

[1617] N-(6-cyclopropyl-4-((3-(difluoromethoxy)cyclobutyl)(4-methyl-4H-1,2,4-triazol-3- yl)methyl)pyridin-2-yl)-6-(((R)-3-methylpiperidin-1-yl)methyl)-[1,2,4]triazolo[4,3- a]pyridine-8-carboxamide (86)

[1618] To a mixture of 86j (37 mg, 0.1 mmol), 59a (27 mg, 0.1 mmol) and 1,4-dioxane (4 mL) was added cesium carbonate (98 mg, 0.3 mmol), Pd2(dba)3(19 mg, 0.02 mmol) and Xantphos (24 mg, 0.04 mmol). The resulting mixture was heated to 110 °C in a microwave reactor and stirred for 1 h, then cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0-9 / 1) and then by prep-HPLC to give the target product 86 (11.8 ...

Claims

1. A compound represented by general formula (I), or a prodrug, pharmaceutically acceptable salt, stable isotope derivative, or isomer thereof: in: Ring A is ( Indicates that this bond connects the methylene group, Indicates that this bond is connected to the carbonyl group); Ring B is a 5-membered heteroaromatic ring, one or two hydrogen atoms of which are optionally replaced by C 1-6 Alkyl or C 3-8 substituted by a cycloalkyl group, wherein one or more hydrogen atoms of the alkyl group are optionally further substituted by D or F; L is ( Indicates that this bond connects the benzene ring or pyridine ring, Indicates that this bond connects ring B or methylene); X, Y, and Z 1 Each is independently CH or N; Z 2 CR a R b or O; Z 3 is S or O; R 1 H, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 21 or -NR 21 R 22 wherein one or more hydrogen atoms of the alkyl and cycloalkyl groups are optionally replaced by halogen, -OH or -OC 1-6 Alkyl substituted; R 2 C 1-6 Alkyl or C 3-8 Cycloalkyl, wherein one or more hydrogen atoms of the alkyl and cycloalkyl groups are optionally replaced by R 31 replaced by; R 3 H, C 1-6 Alkyl or C 3-8 Cycloalkyl; R 2 and R 3 and the nitrogen atom to which it is attached optionally form a 4-10 membered heterocyclic ring, wherein one or more hydrogen atoms of the heterocyclic ring are optionally replaced by halogen, -OH, -OC 1-6 Alkyl, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 substituted by cycloalkyl; R 4 is H, halogen or C 1-6 alkyl; R a 、R b 、R c 、R d 、R e and R f Each is independently H, halogen or C 1-6 Alkyl, or R a and R b and its connected carbon atoms optionally form C 3-6 Cycloalkyl, or R c and R d and its connected carbon atoms optionally form C 3-6 Cycloalkyl; R' and R" are each independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-6 membered heterocyclic group; R' and R" and the carbon atom to which they are attached optionally form a C 4-6 Cycloalkyl or a 4-6 membered heterocycle containing 1 O heteroatom, wherein one or more hydrogen atoms of the cycloalkyl group are optionally replaced by halogen, cyano, -OH, -OC 1-6 Alkyl or C 1-6 substituted by an alkyl group, wherein one or more hydrogen atoms of the alkyl group are optionally further substituted by a halogen or a cyano group; R'' is H, halogen, cyano or C 1-6 alkyl; R 21 and R 22 Each is independently H, C 1-6 Alkyl or C 3-8 Cycloalkyl, wherein one or more hydrogen atoms of the alkyl or cycloalkyl group are optionally replaced by halogen, cyano, -OC 1-6 Alkyl or C 1-6 Alkyl substituted; R 31 -OH, -OC 1-6 Alkyl, C 1-6 Alkyl or C 3-8 cycloalkyl; and n is 0 or 1.

2. The compound according to claim 1, or its prodrug, pharmaceutically acceptable salt, stable isotope derivative and isomer, wherein ring A is Z 1 CH or N, Z 2 is CH2, CF2, C(CH3)2 or O, R c and R d Each is independently H, F or CH3, R f is H or CH3.

3. The compound according to any one of claims 1 to 2, or a prodrug, a pharmaceutically acceptable salt, a stable isotope derivative, and an isomer thereof, wherein ring B is R 2 and R 3 and the nitrogen atom to which it is connected optionally form a 4-10 membered heterocyclic ring, including but not limited to piperidine, pyrrolidine, azaazetidine, morpholine, piperazine, Preferably, piperidine, wherein one or more hydrogen atoms of the heterocyclic ring are optionally replaced by halogen, -OH, -OC 1-6 Alkyl, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 substituted with a cycloalkyl group.

4. The compound according to any one of claims 1 to 3, or a prodrug, pharmaceutically acceptable salt, stable isotope derivative, and isomer thereof, which is a compound represented by general formula (II): in: Ring A is X and Z 1 Each is independently CH or N; Z 2 CR a R b or O; Z 3 is S or O; P is CR 41 R 42 or O; R 1 H, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 21 or -NR 21 R 22 wherein one or more hydrogen atoms of the alkyl and cycloalkyl groups are optionally replaced by halogen, -OH or -OC 1-6 Alkyl substituted; R a 、R b 、R c 、R d 、R e and R f Each is independently H, halogen or C 1-6 Alkyl, or R a and R b and its connected carbon atoms optionally form C 3-6 Cycloalkyl, or R c and R d and its connected carbon atoms optionally form C 3-6 Cycloalkyl; R 21 and R 22 Each is independently H, C 1-6 Alkyl or C 3-8 Cycloalkyl, wherein one or more hydrogen atoms of the alkyl or cycloalkyl group are optionally replaced by halogen, cyano or -OC 1-6 Alkyl substituted; R 41 and R 42 Each is independently H, halogen, cyano, -OC 1-6 Alkyl or C 1-6 an alkyl group, wherein one or more hydrogen atoms of the alkyl group are optionally substituted with halogen or cyano; R 43 Halogen, C 1-6 Alkyl or fluorinated C 1-6 alkyl; m is an integer from 1 to 3; and n is 0 or 1.

5. The compound according to any one of claims 1 to 4, or a prodrug, a pharmaceutically acceptable salt, a stable isotope derivative, and an isomer thereof, wherein ring A is R f is H or CH3.

6. The compound according to any one of claims 1 to 3, or a prodrug, pharmaceutically acceptable salt, stable isotope derivative, and isomer thereof, which is a compound represented by general formula (III): in: Ring A is X and Y are each independently CH or N; R 1 H, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 21 or -NR 21 R 22 wherein one or more hydrogen atoms of the alkyl and cycloalkyl groups are optionally replaced by halogen, -OH or -OC 1-6 Alkyl substituted; R 21 and R 22 Each is independently H, C 1-6 Alkyl or C 3-8 Cycloalkyl, wherein one or more hydrogen atoms of the alkyl or cycloalkyl group are optionally replaced by halogen, cyano or -OC 1-6 Alkyl substituted; R 43 Halogen, C 1-6 Alkyl or fluorinated C 1-6 alkyl; and m is an integer from 1 to 3.

7. The compound according to any one of claims 1 to 6, or a prodrug, a pharmaceutically acceptable salt, a stable isotope derivative, and an isomer thereof, wherein for 8. The compound according to claim 1 or its prodrug, pharmaceutically acceptable salt, stable isotope derivative and isomer is selected from:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or its prodrug, pharmaceutically acceptable salt, stable isotope derivative, isomer and one or more pharmaceutically acceptable carriers or excipients.

10. A method for preventing or treating a disease mediated by Cbl-b, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 8, or a prodrug, pharmaceutically acceptable salt, stable isotope derivative, isomer thereof, or the pharmaceutical composition according to claim 9, wherein the disease mediated by Cbl-b includes but is not limited to tumors.

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