Aryl formamide compounds, preparation methods and medical uses thereof

Abstract

A class of arylcarboxamide compounds, their preparation methods, and pharmaceutical uses. Specifically, the present invention relates to compounds represented by general formula (I), their preparation methods, and pharmaceutical compositions containing the compounds, as well as their use as P2X3 receptor antagonists, and for treating and / or preventing diseases associated with P2X3 receptor activity, such as chronic cough, pain, endometriosis, and overactive bladder. The definitions of the substituents in general formula (I) are the same as those in the specification.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to an arylcarboxamide compound, a preparation method thereof, a pharmaceutical composition containing the same, and its use as a P2X3 receptor antagonist in the treatment and / or prevention of diseases related to P2X3 receptor activity. Background Art

[0002] ATP levels are elevated in pathological settings, suggesting its crucial role in the pathogenesis of many diseases. Specifically, ATP drives and regulates a variety of sensory behaviors and related responses. The impact of ATP on sensation is particularly pronounced when the body is exposed to stimuli (e.g., ultraviolet light and chemical damage) or pathological conditions (e.g., asthma, painful bladder syndrome).

[0003] Many cell surface receptors (purinergic receptors) mediate the sensory signaling of ATP. Among them, the P2X3 receptor is the primary receptor mediating the sensory effects of ATP. The P2X3 receptor is an ATP-gated cation channel and a member of the P2X receptor family, which also includes P2X1, P2X2, P2X4, P2X5, P2X6, and P2X7. P2X3 receptors function in vivo as homotrimeric P2X3 or heterotrimeric P2X2 / 3 receptors (NeuroReport, 10, 1107–1111).

[0004] P2X3 and P2X2 / 3 receptors are mainly expressed in small and medium diameter C- and Aδ-fiber sensory neurons in dorsal root ganglia (DRG) and cranial sensory ganglia, as well as peripheral nerve endings in the receptive fields of tissues such as skin, joints and internal organs.

[0005] The P2X3 receptor is a member of the purinergic receptor family and is a non-selective ligand-gated ion channel. After being activated by ATP, it allows Na + , K + , Ca 2+ Through, especially Ca 2+ The permeability of the synaptic membrane is the most obvious, and it plays an important role in the generation and transmission of nociceptive information. When the body is injured or nerves are damaged, a large amount of ATP is released, activating the presynaptic membrane P2X3 receptors, causing a large amount of Ca 2+ The increase in intracellular calcium concentration activates protein kinase A (PKA) and protein kinase C (PKC), which leads to the phosphorylation of PKA and PKC, and at the same time promotes the release of glutamate, further activates NMDA receptors, leads to the generation of excitatory postsynaptic currents, and causes central sensitization.

[0006] Studies in various animal models have shown that P2X3 receptors play an important role in the nociception process. For example, P2X3 receptor knockout significantly reduces pain responses. P2X3 receptor antagonists have anti-nociceptive effects in various models of pain and inflammatory pain. In addition to their prominent role in nociception and acute and chronic pain, P2X3 receptors have also been shown to be involved in the pathological processes of genitourinary, gastrointestinal, and respiratory diseases, particularly overactive bladder and chronic cough. Therefore, P2X3 receptors play an important role in the pathological mechanisms of various diseases, including pain, genitourinary, gastrointestinal, and respiratory diseases, and are ideal targets for the treatment of these diseases.

[0007] P2X3 subunits not only form homotrimers, but also heterotrimers with P2X2 subunits. P2X3 and P2X2 subunits are also expressed on nerve fibers of the tongue, and receptors containing P2X3 and / or P2X2 subunits are involved in taste transmission (bitter, sweet, salty, umami, and sour). Studies have shown that P2X3 homotrimers are primarily involved in mediating nociception, while P2X2 / X3 heterotrimers are primarily involved in taste perception. Knockout animals lacking P2X2 and P2X3 subunits exhibit reduced taste and even taste loss, while P2X3 subunit knockouts show mild or no phenotypic changes (J. Physiol. 2015, 593, 1113–1125).

[0008] At present, the fastest-growing research in the field of P2X3 receptor antagonists is the compound Gefapixant (AF-219) developed by Merck and Afferent (PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 115(19), 4939-4944.). This compound is a non-selective antagonist of P2X3 and P2X2 / X3 receptors. It has shown significant efficacy in a Phase II clinical study for chronic cough, but also has a side effect of taste interference. This side effect is mainly attributed to the blockade of P2X2 / 3 heterotrimers. Therefore, there is a continuous need for new or improved P2X3 receptor antagonists to develop new and more effective drugs to treat chronic cough or other diseases related to the P2X3 receptor. Summary of the Invention

[0009] After intensive research, the inventors designed and synthesized a series of substituted aryl formamide compounds and screened them for P2X3 receptor activity. The results showed that these compounds have outstanding P2X3 receptor antagonist activity and can be developed as drugs for the treatment and / or prevention of diseases related to P2X3 receptor activity.

[0010] Therefore, the object of the present invention is to provide a compound represented by general formula (I) or its meso-, racemic-, enantiomer-, diastereoisomer-, or mixture thereof, or a pharmaceutically acceptable salt thereof.

[0011]

[0012] in:

[0013] Ring A is a 5-membered heteroaryl group;

[0014] Selected from: wherein the B rings are each independently optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0015] W 1 and W 2 Each independently selected from CR 6 or N;

[0016] L 1 for

[0017] L 2 Selected from single bonds, -CO-, -O-, -S-, -SO-, -SO2- and -NR 6 -;

[0018] Every R 1 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O p R a 、-S(O) p NR a R b and-NHS(O) p R awherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

[0019] R 2 Selected from aryl and heteroaryl; the aryl and heteroaryl are each independently optionally further substituted by one or more groups selected from halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy;

[0020] R 3 selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) p R a 、-S(O) p NR a R b and-NHS(O) p R a wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxy, sulfhydryl, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) p R a 、-S(O) p NR a R b and-NHS(O) p R a One or more groups in are substituted;

[0021] R 4 and R 5each independently selected from hydrogen, alkyl, and alkoxy, wherein the alkyl and alkoxy groups are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0022] Every R 4’ and R 5’ each independently selected from hydrogen, alkyl, and alkoxy, wherein the alkyl and alkoxy groups are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0023] R 6 selected from hydrogen, halogen, hydroxy, cyano, amino, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0024] R a and R b each independently selected from hydrogen, halogen, hydroxy, cyano, amino, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0025] or R a and R b together with the atoms to which they are attached, form a cycloalkyl or heterocyclyl group, said cycloalkyl or heterocyclyl group being optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0026] p is 0, 1, or 2;

[0027] m is an integer from 1 to 4; and

[0028] n is an integer from 0 to 3.

[0029] In a preferred embodiment of the present invention, the compound represented by general formula (I) according to the present invention or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0030] Ring A is selected from pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, triazolyl and tetrazolyl, preferably pyrazolyl, thiazolyl, oxazolyl and 1,3,4-oxadiazolyl, more preferably thiazolyl.

[0031] In another preferred embodiment of the present invention, the compound represented by general formula (I) according to the present invention or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (II) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0032]

[0033] Among them, B ring, R 1 、R 2 、R 3 , L 1 , L 2 and n are as defined in the general formula (I).

[0034] In another preferred embodiment of the present invention, the compound represented by general formula (I) according to the present invention or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or its prodrug, or its pharmaceutically acceptable salt,

[0035] in,

[0036] Selected from:

[0037] wherein the B rings are each independently optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0038] Among them, W 1 、W 2 , L 2 、R 3 As defined in general formula (I).

[0039] In another preferred embodiment of the present invention, the compound represented by general formula (I) according to the present invention, or its meso-, racemic-, enantiomer-, diastereoisomer-, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0040] L 2 Selected from single bond, -(CH2) m -, -(CH)CH3-, -CO-, -SO- and -SO2-;

[0041] m is an integer of 1 to 4, preferably an integer of 1 to 3, more preferably 1 or 2.

[0042] In another preferred embodiment of the present invention, the compound represented by general formula (I) according to the present invention or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0043] R 3 selected from hydrogen, halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4 to 7 membered heterocyclyl, C6-C 10 aryl and 5 to 10 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4 to 7 membered heterocyclyl, C6-C 10 The aryl and 5 to 10 membered heteroaryl groups are each independently further optionally selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4 to 6 membered heterocyclyl, C6 ... 10 Aryl, 5- to 10-membered heteroaryl, -C(O)R a 、-C(O)OR a 、-S(O) p R a One or more groups in are substituted;

[0044] R a Selected from C1-C6 alkyl;

[0045] p is 1 or 2.

[0046] In another preferred embodiment of the present invention, the compound represented by general formula (I) according to the present invention or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0047] L 2Selected from single bond, -(CH2) m -and-CO-;

[0048] R 3 is selected from 4 to 6 membered heterocyclic groups, wherein the 4 to 6 membered heterocyclic groups are optionally further selected from halogen, oxo, C1-C6 alkyl, -C(O)OR a One or more groups are substituted;

[0049] R a Selected from C1-C6 alkyl;

[0050] m is 1 or 2.

[0051] In another preferred embodiment of the present invention, the compound represented by general formula (I) according to the present invention or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0052] L 2 is selected from a single bond, -CH2- and -CO-;

[0053] R 3 Selected from oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperidinyl, piperazinyl, which are optionally further selected from halogen, oxo, C1-C6 alkyl, -C(O)OR a One or more groups are substituted;

[0054] R a Selected from C1-C6 alkyl.

[0055] In another preferred embodiment of the present invention, the compound represented by general formula (I) according to the present invention or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0056] L 2 are single bonds, -CH2- and -CO-;

[0057] R 3 Selected from C3-C6 cycloalkyl, the C3-C6 cycloalkyl is optionally further substituted by one or more groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl.

[0058] In another preferred embodiment of the present invention, the compound represented by general formula (I) according to the present invention or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0059] L 2 are single bonds, -CH2- and -CO-;

[0060] R 3 phenyl or 5- to 6-membered heteroaryl, wherein the phenyl or 5- to 6-membered heteroaryl is optionally further substituted by one or more groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0061] In another preferred embodiment of the present invention, the compound represented by general formula (I) according to the present invention or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0062] L 2 is a single bond, -(CH2) m - and -(CH)CH3-;

[0063] R 3 Selected from cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl is optionally further substituted by one or more groups selected from halogen and hydroxy;

[0064] m is an integer of 1 to 4, preferably an integer of 1 to 3, more preferably 1 or 2.

[0065] In another preferred embodiment of the present invention, the compound represented by general formula (I) according to the present invention or its meso-, racemic-, enantiomer-, diastereoisomer-, or mixture thereof, or its prodrug, or its pharmaceutically acceptable salt, wherein:

[0066] L 1 for

[0067] R 4 and R 5 are each independently selected from hydrogen and C1-C6 alkyl;

[0068] Preferably, L 1 for

[0069] In another preferred embodiment of the present invention, the compound represented by the general formula (I) according to the present invention or its meso-, racemic-, enantiomer-, diastereoisomer-, or mixture thereof, or its prodrug, or its pharmaceutically acceptable salt, wherein each R 1 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C7 cycloalkyl and 5- to 7-membered heterocyclic group, preferably C1-C6 alkyl or C1-C6 haloalkyl.

[0070] In another preferred embodiment of the present invention, the compound represented by the general formula (I) according to the present invention or its meso-, racemic-, enantiomer-, diastereoisomer-, or mixture thereof, or its prodrug, or its pharmaceutically acceptable salt, wherein R 2 C6-C 10 Aryl or 5- to 10-membered heteroaryl, preferably phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, more preferably pyrimidinyl, wherein the aryl or heteroaryl is optionally further substituted by one or more groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy.

[0071] Typical compounds of the present invention include, but are not limited to:

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095] or its meso form, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt.

[0096] The present invention further provides a method for preparing the compound represented by general formula (I) according to the present invention or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprising the following steps:

[0097]

[0098] In the presence of a condensing agent, compound Ig and compound Ih undergo a condensation reaction under alkaline conditions to obtain a compound represented by general formula (I), wherein the reagent providing alkaline conditions is preferably DIPEA, and the condensing agent is preferably HATU;

[0099] Among them, A ring, B ring, W 1 、W 2 、R 1 、R 2 、R 3 、L 1 、L 2 , n are as defined in the general formula (I).

[0100] The present invention also provides a method for preparing the compound represented by general formula (II) according to the present invention or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, its prodrug or pharmaceutically acceptable salt, which comprises the following steps:

[0101]

[0102] In the presence of a condensing agent, compound IIg and compound IIh undergo a condensation reaction under alkaline conditions to obtain a compound represented by general formula (II), wherein the reagent providing alkaline conditions is preferably DIPEA, and the condensing agent is preferably HATU;

[0103] Among them, B ring, R 1 、R 2 、R 3 、L 1 、L2 , n are as defined in the general formula (II).

[0104] Another aspect of the present invention provides a pharmaceutical composition comprising a compound represented by general formula (I) or general formula (II) according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0105] The present invention further provides use of the compound represented by general formula (I) or general formula (II) according to the present invention, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, in the preparation of a P2X3 receptor antagonist.

[0106] The present invention further provides the use of the compound represented by general formula (I) or general formula (II) according to the present invention, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, in the preparation of a medicament for preventing and / or treating diseases related to P2X3 receptor activity.

[0107] The present invention further provides a compound represented by general formula (I) or general formula (II) according to the present invention, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a P2X3 receptor antagonist.

[0108] The present invention further provides a compound represented by general formula (I) or general formula (II) according to the present invention, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, for use in preventing and / or treating diseases related to P2X3 receptor activity.

[0109] The present invention further provides a method for preventing and / or treating diseases associated with P2X3 receptor activity, comprising administering to a subject in need thereof a preventively or therapeutically effective amount of a compound represented by general formula (I) or general formula (II) according to the present invention, or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0110] In this article, the diseases associated with P2X3 receptor activity can be: respiratory diseases including chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, pulmonary fibrosis, acute cough, chronic cough, including chronic idiopathic and chronic refractory cough, genitourinary system, gastrointestinal tract, respiratory and pain related diseases, gynecological diseases including dysmenorrhea (primary and secondary dysmenorrhea), dyspareunia, dysuria or orchitis, endometriosis and adenomyosis, endometriosis-related pain, endometriosis associated symptoms, pelvic hypersensitivity, urinary tract disease states associated with bladder outlet obstruction, urinary incontinence symptoms such as decreased bladder capacity, increased urination frequency, urge incontinence, stress incontinence or overactive bladder, benign prostatic hypertrophy, prostatic hyperplasia, prostatitis, detrusor hyperreflexia, overactive bladder and symptoms associated with overactive bladder, wherein the symptoms are particularly frequent urination, nocturia, urgency or urge incontinence, pelvic hypersensitivity, urethritis, prostatitis, prostatodynia, cystitis, especially intermittent urination cystitis, idiopathic hypersensitive bladder, epilepsy, partial and generalized seizures, gastrointestinal disorders including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), biliary colic and other biliary diseases, renal colic, diarrhea-predominant IBS, gastroesophageal reflux, gastrointestinal dilatation, Crohn's disease, neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis, Parkinson's disease, cerebral ischemia and traumatic brain injury, myocardial infarction, lipid disorders, pain-related diseases or conditions selected from hyperalgesia, allodynia, functional Gout, arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis), burning mouth syndrome, burns, migraine or cluster headaches, nerve damage, post-traumatic injury (including fractures and sports injuries), neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, cancer, trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and related neuropathies, neuropathy caused by HIV and HIV treatment, pruritus, impaired wound healing and skeletal diseases such as joint degeneration.

[0111] According to conventional methods in the field of the present invention, the compound represented by general formula (I) of the present invention can form a pharmaceutically acceptable acid addition salt with an acid. The acid includes inorganic acids and organic acids, and is particularly preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.

[0112] According to conventional methods in the field of the present invention, the compound represented by general formula (I) of the present invention can form a pharmaceutically acceptable basic addition salt with a base. The base includes inorganic bases and organic bases. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide, etc.

[0113] In addition, the present invention also includes prodrugs of the compounds represented by general formula (I) of the present invention. The prodrugs described in the present invention are derivatives of the compounds represented by general formula (I), which may have weak activity or even no activity themselves, but after administration, are converted into the corresponding biologically active form under physiological conditions (e.g., through metabolism, solvolysis, or other means).

[0114] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions and may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as microcrystalline cellulose, croscarmellose sodium, corn starch, or alginic acid; binders such as starch, gelatin, polyvinyl pyrrolidone, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. These tablets may be uncoated or may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release over a longer period of time. For example, water-soluble taste masking substances such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending substances such as ethylcellulose, cellulose acetate butyrate may be used.

[0115] Oral preparations may also be provided in hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oily vehicle such as peanut oil, liquid paraffin or olive oil.

[0116] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersants or wetting agents, which may be naturally occurring phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyethylene oxide sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene oxide dehydrated sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, for example ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.

[0117] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. Oil suspensions can contain thickeners such as beeswax, hard paraffin or cetyl alcohol. The above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

[0118] Dispersible powders and granules suitable for preparing aqueous suspensions can be provided with the active ingredient and a dispersant or wetting agent, a suspending agent, or one or more preservatives for mixing by the addition of water. Suitable dispersants or wetting agents and suspending agents are as described above. Other excipients such as sweeteners, flavorings, and coloring agents may also be added. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

[0119] The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. Emulsions can also contain sweeteners, flavorings, preservatives, and antioxidants. Syrups and elixirs prepared with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose can be used. Such preparations can also contain demulcents, preservatives, colorants, and antioxidants.

[0120] The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. For example, the active ingredient may be dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerol to form a microemulsion. The injection or microemulsion may be injected into the patient's bloodstream via local, bolus injection. Alternatively, the solution or microemulsion may be administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device may be used.

[0121] The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. Such suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in a nontoxic, parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. Furthermore, sterile fixed oils may conveniently be used as solvents or suspending media. For this purpose, any blended fixed oil, including synthetic mono- or diglycerides, may be used. Furthermore, fatty acids, such as oleic acid, may also be used to prepare injectable formulations.

[0122] The compounds of this invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thereby dissolves and releases the drug in the rectum. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and mixtures of fatty acid esters of polyethylene glycol.

[0123] It is well known to those skilled in the art that the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health condition, the patient's behavior, the patient's diet, the time of administration, the route of administration, the rate of excretion, the combination of drugs, etc. In addition, the optimal treatment method, such as the mode of treatment, the daily dosage of the general formula compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment protocols.

[0124] The present invention may contain a compound represented by general formula (I), and a pharmaceutically acceptable salt, hydrate, or solvate thereof as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to form a composition, and then prepared into a clinically acceptable dosage form. The derivatives of the present invention may be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions. The compounds of the present invention may be used as the sole active ingredient or in combination with other drugs for treating diseases related to P2X3 receptor activity. Combination therapy is achieved by administering the individual therapeutic components simultaneously, separately, or sequentially.

[0125] Detailed Description of the Invention

[0126] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0127] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-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, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-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, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0128] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

[0129] The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, for example, ethynyl, propynyl, butynyl, etc. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0130] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0131] The term "spiroalkyl" refers to a polycyclic group having a carbon atom (called a spiro atom) shared between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spiroalkyl group is divided into a single spiroalkyl group, a double spiroalkyl group or a multi-spiroalkyl group, preferably a single spiroalkyl group and a double spiroalkyl group. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl group. Non-limiting examples of spiroalkyl groups include:

[0132]

[0133] The term "fused cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0134]

[0135] The term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0136]

[0137] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0138] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m(wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably, it contains 4 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably, it contains 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, azetidinyl, oxadiazolyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups.

[0139] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiral atoms between the rings, the spiro heterocyclic group is divided into a monospiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group and a dispiro heterocyclic group. It is more preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

[0140]

[0141] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0142]

[0143] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0144]

[0145] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0146] wait.

[0147] The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0148] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably, phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0149]

[0150] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0151] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5-10-membered and contains 1 to 3 heteroatoms; more preferably 5-7-membered and contains 1 to 3 heteroatoms; most preferably 5-membered or 6-membered and contains 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, pyridazine, isothiazolyl, isoxazolyl, oxadiazolyl, triazolyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl, pyrimidinyl, thiazolyl, pyridazine or oxazolyl; more preferably thiazolyl, pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0152]

[0153] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0154] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0155] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0156] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0157] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0158] The term "hydroxy" refers to an -OH group.

[0159] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0160] The term "amino" refers to -NH2.

[0161] The term "cyano" refers to -CN.

[0162] The term "nitro" refers to -NO2.

[0163] The term "oxo" refers to =0.

[0164] The term "carboxy" refers to -C(O)OH.

[0165] The term "mercapto" refers to -SH.

[0166] The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0167] The term "acyl" refers to a compound containing a -C(O)R group, where R is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0168] The term "sulfonic acid" refers to -S(O)2OH.

[0169] The term "sulfonate" refers to -S(O)2O(alkyl) or -S(O)2O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0170] The term "sulfonyl" refers to a compound having a -S(O)2R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0171] The term "aminoacyl" refers to -C(O)-NRR', wherein R, R' are each independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0172] The term "aminosulfonyl" or "sulfonylamino" refers to -S(O)2-NRR', wherein R, R' are each independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0173] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0174] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0175] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0176] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0177] Synthesis method of the compound of the present invention

[0178] In order to achieve the purpose of the present invention, the present invention adopts the following technical solutions.

[0179] The compound represented by the general formula (I) of the present invention or its salt can be prepared by the following scheme, and the specific preparation method is as follows.

[0180] (1) Option 1: When for When, according to the method of Scheme 1, compound Ia is used as the starting material to obtain the compound of general formula (I).

[0181]

[0182] Solution 1

[0183] Synthesis of Scheme 1:

[0184] Step 1: Compound Ia is reacted with Ib under high temperature and alkaline conditions to obtain compound Ic, wherein the high temperature is preferably 100°C and the alkaline reagent is preferably cesium carbonate;

[0185] Step 2: Compound Ic is reacted with bis(pinacol)boronate in the presence of high temperature, alkalinity, and a catalyst to obtain compound Id, wherein the high temperature is preferably 100° C., the alkaline agent is preferably potassium acetate, and the catalyst is preferably Pd(dppf)Cl2 catalyst;

[0186] Step 3: Compound Id is reacted with Compound Ie in the presence of high temperature, alkalinity, and a catalyst to obtain Compound If, wherein the high temperature is preferably 90° C., the alkaline agent is preferably potassium carbonate, and the catalyst is preferably Pd(dppf)Cl2 catalyst;

[0187] Step 4: Under alkaline conditions, hydrolyzing compound If to obtain compound Ig, wherein the alkaline agent is preferably lithium hydroxide;

[0188] Step 5: In the presence of a condensing agent, compound Ig is subjected to a condensation reaction with Ih under alkaline conditions to obtain a compound of formula (I), wherein the reagent providing alkaline conditions is preferably DIPEA, and the condensing agent is preferably HATU.

[0189] (2) Option 2: When for When, according to the method of Scheme 2, compound Ii is used as the starting material to obtain compound Ic. Referring again to the synthetic method of Scheme 1, compound Ic is used as the starting material to obtain the compound of formula (I).

[0190]

[0191] Option 2

[0192] Synthesis of Scheme 2:

[0193] Step 1: Compound Ii is reacted with a halogenating agent at room temperature to obtain compound Ij, wherein the halogenating agent is preferably NBS;

[0194] Step 2: Compound Ij is reduced to obtain compound Ik in the presence of high temperature, acidity, and a reducing agent, wherein the high temperature is preferably 65° C., the acidic agent is preferably ammonium chloride, and the reducing agent is preferably zinc powder;

[0195] Step 3: Compound Ik is reacted with a dihalide to produce Compound Ia at elevated temperature in the presence of an alkaline reagent, wherein the elevated temperature is preferably 110° C., the alkaline reagent is preferably potassium carbonate, and the dihalide is preferably 1,2-dibromoethane;

[0196] Step 4: Compound Ia is reacted with Compound Il at room temperature in the presence of a reducing agent and a catalyst to obtain Compound Ic, wherein the reducing agent is preferably sodium cyanoborohydride and the catalyst is preferably anhydrous zinc chloride;

[0197] (3) Option 3: When for When, according to the method of Scheme 3, compound Ik is used as the starting material to obtain compound Ic. Referring again to the synthetic method of Scheme 1, compound Ic is used as the starting material to obtain the compound of formula (I).

[0198]

[0199] Option 3

[0200] Synthesis of Scheme 3:

[0201] Step 1: Compound Ik is condensed with chloroacetyl chloride under low temperature and alkaline conditions to obtain compound Im, wherein the low temperature condition is preferably 0°C and the alkaline reagent is preferably potassium carbonate;

[0202] Step 2: Compound Im undergoes a ring-closure reaction under high temperature and alkaline conditions to produce compound Ia, wherein the high temperature condition is preferably 80°C and the alkaline reagent is preferably potassium acetate;

[0203] Step 3: Compound Ia is reacted with Ib at room temperature under alkaline conditions to obtain Ic, wherein the alkaline reagent is preferably cesium carbonate;

[0204] (4) Option 4: When for When the reaction is carried out according to the method of Scheme 4, compound In is used as the starting material to obtain compound Ic. Referring to the synthesis method of Scheme 1, compound Ic is used as the starting material to obtain the compound of formula (I).

[0205]

[0206] Option 4

[0207] Synthesis of Scheme 4:

[0208] Step 1: reacting compound In with cycloisopropyl malonate at high temperature to obtain compound Io, wherein the high temperature is preferably 100° C.;

[0209] Step 2: Dissolve compound Io in diphenyl ether under high temperature conditions to undergo a self-cyclization reaction to obtain compound Ip, wherein the high temperature condition is preferably 210°C;

[0210] Step 3: reacting compound Ip with phosphorus oxychloride at high temperature to obtain compound Ia, wherein the high temperature is preferably 80°C;

[0211] Step 4: Under high temperature and alkaline sealed tube conditions, react compound Ia with Iq to obtain compound Ic, wherein the high temperature condition is preferably 100°C and the alkaline reagent is preferably DIPEA;

[0212] (5) Option 5: When for When the reaction is complete, the method of Scheme 5 is used, starting from compound Ir to obtain compound Ic. Referring to the synthesis method of Scheme 1, compound Ic is used as the starting material to obtain the compound of formula (I).

[0213]

[0214] Option 5

[0215] Synthesis of Scheme 5:

[0216] Step 1: reacting compound Ir with glyoxylic acid at high temperature to obtain compound Is, wherein the high temperature is preferably 80°C;

[0217] Step 2: reacting compound Is with phosphorus oxychloride at high temperature to obtain compound Ia, wherein the high temperature is preferably 80°C;

[0218] Step 3: Under high temperature and alkaline sealed tube conditions, react compound Ia with Iq to obtain compound Ic, wherein the high temperature condition is preferably 100°C and the alkaline reagent is preferably DIPEA;

[0219] (6) Option 6: When for When the reaction is complete, the method of Scheme 6 is used as the starting material to obtain compound Ic. Referring to the synthesis method of Scheme 1, compound Ic is used as the starting material to obtain the compound of formula (I).

[0220]

[0221] Option 6

[0222] Synthesis of Scheme 6:

[0223] Step 1: Compound It is reacted with NBS at room temperature to obtain compound Iu;

[0224] Step 2: Under high temperature and alkaline sealed tube conditions, compound Iu is reacted with CS2 to obtain compound Ia, wherein the high temperature condition is preferably 80°C and the alkaline reagent is preferably KOH;

[0225] Step 3: Under high temperature and alkaline sealed tube conditions, react compound Ia with Iq to obtain compound Ic, wherein the high temperature condition is preferably 150°C and the alkaline reagent is preferably DIPEA;

[0226] (7) Option 7: When for When the reaction is complete, the method of Scheme 7 is used, starting from compound Iv to obtain compound Ic. Referring to the synthesis method of Scheme 1, compound Ic is used as the starting material to obtain the compound of formula (I).

[0227]

[0228] Option 7

[0229] Synthesis of Scheme 7:

[0230] Step 1: Compound Iv and Iw are reacted at high temperature and catalyzed by p-toluenesulfonic acid to obtain compound Ix;

[0231] Step 2: Compound Ix is reacted with NBS at high temperature to obtain compound Ic;

[0232] Among them, W 1 、W 2 , A ring, B ring, R 1 、R 2 、R 3 , L 1 , L 2 , n are as defined in the general formula (I). DETAILED DESCRIPTION

[0233] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0234] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker dps300 nuclear magnetic spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0235] MS was measured using an 1100 Series LC / MSD Trap (ESI) mass spectrometer (manufacturer: Agilent).

[0236] Preparative liquid chromatography was performed using an LC3000 high performance liquid chromatograph and an LC6000 high performance liquid chromatograph (manufacturer: Chuangxin Tongheng). The chromatographic column was a Daisogel C18 10 μm 60A (20 mm × 250 mm).

[0237] HPLC analysis was performed using a Shimadzu LC-20AD high pressure liquid chromatograph (Agilent TC-C18 250×4.6 mm, 5 μm column) and a Shimadzu LC-2010AHT high pressure liquid chromatograph (Phenomenex C18 250×4.6 mm, 5 μm column).

[0238] The thin layer chromatography silica gel plate used was Qingdao Ocean Chemical GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15 mm to 0.2 mm, and the specification used for thin layer chromatography separation and purification products was 0.4 mm to 0.5 mm.

[0239] Column chromatography generally uses Qingdao Marine Silica Gel 100-200 mesh and 200-300 mesh silica gel as the carrier.

[0240] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Yinuokai, Nanjing Yaoshi, Anaiji Chemical and other companies.

[0241] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0242] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0243] A CEM Discover SP microwave reactor was used for the microwave reaction.

[0244] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0245] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0246] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, and D: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0247] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound include: A: dichloromethane and methanol system, B: petroleum ether, ethyl acetate and dichloromethane system, C: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0248] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention.

[0249] Abbreviations

[0250] μL = microliter;

[0251] μM = micromolar;

[0252] NMR = nuclear magnetic resonance;

[0253] AIBN = azobisisobutyronitrile

[0254] Boc = tert-butoxycarbonyl

[0255] br = broad peak

[0256] d = bimodal

[0257] δ = chemical shift

[0258] ℃ = degrees Celsius

[0259] dd=double peak

[0260] DIPEA = diisopropylethylamine

[0261] DMAP = 4-dimethylaminopyridine

[0262] DMF=N,N-dimethylformamide

[0263] DMSO = dimethyl sulfoxide

[0264] DCM = dichloromethane

[0265] EA = ethyl acetate

[0266] HPLC = High Performance Liquid Chromatography

[0267] Hz = Hertz

[0268] IC 50 = concentration that inhibits 50% of activity

[0269] J = coupling constant (Hz)

[0270] LC-MS = Liquid chromatography-mass spectrometry

[0271] m = multiplet

[0272] M+H + = mass of parent compound + one proton

[0273] mg = milligrams

[0274] mL = milliliters

[0275] mmol = millimole

[0276] mol = mole

[0277] Ms = methylsulfonyl

[0278] MS = Mass Spectrometry

[0279] MsCl = Methanesulfonyl chloride

[0280] m / z = mass-to-charge ratio

[0281] nM = nanomolar

[0282] NBS = N-bromosuccinimide

[0283] NIS = N-iodosuccinimide

[0284] PE = Petroleum Ether

[0285] ppm = parts per million

[0286] Pro = Protecting Group

[0287] s = single peak

[0288] t = triplet

[0289] TEA = triethylamine

[0290] TFA = trifluoroacetic acid

[0291] THF = tetrahydrofuran.

[0292] BPD = Bis-boronic acid pinacol ester

[0293] HATU = 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0294] DCDMH=1,3-dichloro-5,5-dimethylhydantoin

[0295] Pd2(dba)3=tris(dibenzylideneacetone)dipalladium

[0296] Pd(dppf)Cl2=1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride

[0297] Xantphos = 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene

[0298] Example 1: Preparation of (R)-4-(5-methylthiazol-2-yl)-1-(oxetane-3-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (1)

[0299]

[0300] Step 1: Synthesis of methyl 4-bromo-1-(oxetan-3-yl)-1H-indazole-6-carboxylate (1b)

[0301] Methyl 4-bromo-1H-indazole-6-carboxylate (2.0 g, 7.8 mmol), 3-iodooxetane (2.0 g, 11.7 mmol), Cs2CO3 (7.6 g, 23.4 mmol), and DMF (20 mL) were added to a reaction flask at room temperature and reacted at 100°C for 16 hours. After the reaction, 100 mL of water was added and extracted with 100 mL of ethyl acetate. The organic phase was washed three times with water, dried over anhydrous sodium sulfate, and concentrated. Preparative purification (eluent: petroleum ether:ethyl acetate = 2:1) afforded 0.5 g of the title compound as an off-white solid in a yield of 20.6%.

[0302] Step 2: Synthesis of methyl 1-(oxetane-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-6-carboxylate (1c)

[0303] Methyl 4-bromo-1-(oxetane-3-yl)-1H-indazole-6-carboxylate (0.5 g, 1.6 mmol), pinacol diboron (0.6 g, 2.4 mmol), potassium acetate (0.3 g, 3.2 mmol), Pd(dppf)Cl2 (59 mg, 0.08 mmol), and DMF (10 mL) were added to a reaction flask at room temperature. The mixture was evacuated, nitrogen atmosphere was applied, and the reaction was stirred at 110°C for 3 hours. After completion of the reaction, the filtrate was filtered and concentrated to dryness. Preparative purification (eluent: petroleum ether:ethyl acetate = 2:1) afforded 0.5 g of the title compound as a white solid in a yield of 86.6%.

[0304] Step 3: Synthesis of methyl 4-(5-methylthiazol-2-yl)-1-(oxetan-3-yl)-1H-indazole-6-carboxylate (1d)

[0305] At room temperature, methyl 1-(oxetane-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-6-carboxylate (0.43 g, 1.2 mmol), 2-bromo-5-methylthiazole (0.26 g, 1.44 mmol), potassium carbonate (0.40 g, 2.88 mmol), Pd(dppf)Cl2 (132 mg, 0.18 mmol), THF (20 mL), and water (3 mL) were added to a reaction flask. The mixture was evacuated and nitrogen atmosphere was maintained. The reaction was stirred at 90°C for 16 hours. After completion of the reaction, the mixture was filtered and the filtrate was extracted with 100 mL of ethyl acetate and 100 mL of water. The organic phase was washed once with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The mixture was then purified using dichloromethane as the eluent to afford 0.5 g of the title compound as a yellow oil in a yield of 126.5%.

[0306] Step 4: Synthesis of 4-(5-methylthiazol-2-yl)-1-(oxetan-3-yl)-1H-indazole-6-carboxylic acid (1e)

[0307] Methyl 4-(5-methylthiazol-2-yl)-1-(oxetan-3-yl)-1H-indazole-6-carboxylate (0.5 g, 2 mmol), THF (5 mL), methanol (5 mL), and 1N lithium hydroxide (4 mL) were added to a reaction flask at room temperature and stirred for 16 hours. After completion of the reaction, the pH was adjusted to 3-4 with 1N hydrochloric acid, and the mixture was extracted with 20 mL of water and 20 mL of ethyl acetate. The organic phase was washed once with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford 0.4 g of the title compound as a gray solid in a yield of 83.6%.

[0308] Step 5: Synthesis of (R)-4-(5-methylthiazol-2-yl)-1-(oxetan-3-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (Compound 1)

[0309] At room temperature, 4-(5-methylthiazol-2-yl)-1-(oxetan-3-yl)-1H-indazole-6-carboxylic acid (117 mg, 0.37 mmol), DMF (10 mL), HATU (197 mg, 0.52 mmol), DIPEA (191 mg, 1.48 mmol), and (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine (prepared according to WO2010111059) (93 mg, 0.41 mmol) were added to a reaction flask and allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction mixture was poured into 100 mL of ice water, stirred for 10 minutes, and filtered. The filter cake was purified by preparative chromatography (eluent: 0%-100% acetonitrile:water) to afford 15 mg of the title compound as a white solid in an 8.3% yield.

[0310] MS: m / z = 489.18 [M+H] + .

[0311] 1 H NMR (400MHz, DMSO-d6): δppm 9.23(d,J=7.1Hz,1H),9.16(s,2H),9.01(s,1H),8.48(s,1H),7.99(s,1H),7.73(s,1H),6. 11-6.04(m,1H),5.38-5.31(m,1H),5.07-5.03(m,4H),2.50(s,3H),1.64(d,J=7.1Hz,3H).

[0312] Example 2: Preparation of (R)-4-(5-methylthiazol-2-yl)-2-(oxetane-3-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (2)

[0313]

[0314]

[0315] Step 1: Synthesis of methyl 4-bromo-2-(oxetan-3-yl)-2H-indazole-6-carboxylate (2a)

[0316] Methyl 4-bromo-1H-indazole-6-carboxylate (2.0 g, 7.8 mmol), 3-iodooxetane (2.0 g, 11.7 mmol), Cs2CO3 (7.6 g, 23.4 mmol), and DMF (20 mL) were added to a reaction flask at room temperature and reacted at 100°C for 16 hours. After the reaction, 100 mL of water was added and extracted with 100 mL of ethyl acetate. The organic phase was washed three times with water, dried over anhydrous sodium sulfate, and concentrated. Preparative purification (eluent: petroleum ether:ethyl acetate = 2:1) afforded 0.5 g of the title compound as an off-white solid in a yield of 20.6%.

[0317] The subsequent steps were the same as those in Example 1, except that 2a was used instead of 1b, to obtain the title compound 2.

[0318] MS: m / z = 489.18 [M+H] + .

[0319] 1 H NMR (400MHz, DMSO-d6): δppm 9.27(d,J=7.1Hz,1H),9.16(s,2H),8.81(s,1H),8.34(s,1H),8.07(s,1H),7.79(s,1H),6. 22-6.15(m,1H),5.37-5.32(m,1H),5.10-5.04(m,4H),2.56(s,3H),1.65(d,J=7.1Hz,3H).

[0320] Example 3: Preparation of (R)-2-(azetidin-3-yl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (3)

[0321]

[0322] Step 1: Preparation of methyl 4-bromo-2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2H-indazole-6-carboxylate (3a)

[0323] Methyl 4-bromo-1H-indazole-6-carboxylate (2.00 g, 7.87 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (6.68 g, 23.6 mmol), and CsCO (7.74 g, 23.6 mmol) were dissolved in DMF (30 mL) at room temperature, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (40 mL), and washed with water (30 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.4 g of the title compound as a semi-oily white solid in a 49% yield.

[0324] Step 2: Preparation of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-6-methyl ester carboxylic acid (3b).

[0325] Methyl 4-bromo-2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2H-indazole-6-carboxylate (1.20 g, 2.93 mmol), bispinacol boronate (1.12 g, 4.40 mmol), and KOAc (0.862 g, 8.80 mmol) were dissolved in 1,4-dioxane (20 mL) at room temperature. Pd(dppf)Cl2 (0.297 g, 0.406 mmol) was added. The reaction mixture was purged with N2 three times and heated to 90°C with stirring overnight. The reaction mixture was cooled to room temperature and used directly in the next step without further treatment.

[0326] Step 3: Preparation of methyl 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-4-(5-methylthiazol-2-yl)-2H-indazole-6-carboxylate (3c).

[0327] To the above reaction solution at room temperature were added 4 mL of water, 2-bromo-5-methylthiazole (0.942 g, 5.29 mmol), and K2CO3 (1.10 g, 7.94 mmol), followed by Pd(dppf)Cl2 (0.194 g, 0.265 mmol). The reaction solution was purged with N2 three times and stirred at 80°C overnight. 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 2 / 1 to 1 / 1) to afford 1.30 g of the title compound as a white solid in an 87% yield.

[0328] Step 4: Preparation of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-4-(5-methylthiazol-2-yl)-2H-indazole-6-carboxylic acid (3d).

[0329] Methyl 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-4-(5-methylthiazol-2-yl)-2H-indazole-6-carboxylate (1.30 g, 3.04 mmol) and LiOH·H₂O (511 mg, 12.1 mmol) were dissolved in a mixture of EtOH (10 mL), H₂O (4 mL), and MeOH (2 mL) at room temperature. The reaction mixture was heated to 60°C and stirred for 5 h. The reaction mixture was concentrated under reduced pressure and the pH was adjusted to 4-6 with 1N aqueous hydrochloric acid. A large amount of yellow solid precipitated, which was filtered, collected, and dried to afford 930 mg of the title compound as a yellow solid, in a 74% yield.

[0330] Step 5: Preparation of (R)-tert-butyl 3-(4-(5-methylthiazol-2-yl)-6-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)-2H-indazole-2-(tert-butyl)yl)azetidine-1-carboxylate (3e).

[0331] 2-(1-(tert-Butoxycarbonyl)azetidin-3-yl)-4-(5-methylthiazol-2-yl)-2H-indazole-6-carboxylic acid (300 mg, 0.725 mmol), (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine (198 mg, 0.870 mmol), and DIPEA (281 mg, 2.17 mmol) were dissolved in DMF (6 mL) at room temperature. HATU (551 mg, 1.45 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (25 mL x 3). The combined organic phases were washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 2 / 1 to 1 / 1) to give 300 mg of the title compound as a yellow oil in a yield of 71%.

[0332] Step 6: Preparation of (R)-2-(azetidin-3-yl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (Compound 3).

[0333] (R)-tert-Butyl 3-(4-(5-methylthiazol-2-yl)-6-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)-2H-indazole-2-(tert-butyl)-azetidine-1-carboxylate (300 mg, 0.511 mmol) was dissolved in DCM (5 mL) at room temperature. TFA (291 mg, 2.56 mmol) was added dropwise at room temperature, and the reaction solution was stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure, and aqueous sodium bicarbonate was added to adjust the pH to 6-7. The solution was extracted with EtOAc (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The residue was separated by preparative liquid chromatography (column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile / water, gradient: 30%-80%) to obtain 84 mg of the title compound as a white solid, yield: 34%.

[0334] MS: m / z = 488.50 [M+H] + .

[0335] 1H NMR(300MHz,DMSO-d6)δ9.35(d,J=7.4Hz,1H),9.16(s,2H),8.88(s,1H),8.33(s,1H),8.11(s,1H),7.81 (s,1H),5.97-5.95(m,1H),5.36(t,J=6.9Hz,1H),4.52-4.49(m,4H),2.57(s,3H),1.66(d,J=7.1Hz,3H).

[0336] Example 4: Preparation of (R)-1-(azetidin-3-yl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (4)

[0337]

[0338] The title compound 4 was prepared in the same manner as in Example 2, except that tert-butyl 3-iodoazetidine-1-carboxylate was used instead of 3-iodooxetane.

[0339] MS: m / z = 488.43 [M+H] + .

[0340] 1 H NMR(300MHz,DMSO-d6)δ9.29(d,J=7.1Hz,1H),9.16(s,2H),9.09(s,1H),8.44(s,1H),8.02(s,1H),7.7 5(s,1H),5.93-5.90(m,1H),5.36-5.33(m,1H),4.53-4.50(m,4H),2.55(s,3H),1.65(d,J=7.1Hz,3H).

[0341] Example 5: Preparation of (R)-2-(1-methylazepine-3-yl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (5)

[0342]

[0343]

[0344] (R)-2-(azetidin-3-yl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (84.0 mg, 0.173 mmol), MeOH (5 mL), and 37% HCHO aqueous solution (65.2 mg, 0.863 mmol) were added to a reaction flask and stirred at room temperature for 1 hour. NaBH3CN (21.7 mg, 0.345 mmol) was then added, and the reaction mixture was stirred overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (15 mL) and washed with water (15 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (chromatographic column: Hedea ODS-2C18, 300 mm*250 mm, 10 μm; eluent: 0%-100% acetonitrile: aqueous solution) to give 55 mg of the title product as a white solid, in a yield of 63.9%.

[0345] MS: m / z = 502.74 [M+H] + .

[0346] 1 H NMR(300MHz,DMSO-d6)δ9.38(d,J=7.4Hz,1H),9.17(s,2H),8.90(s,1H),8.35(s,1H),8.10(s,1H),7.84(s,1H) ,5.99-5.96(m,1H),5.38(t,J=6.9Hz,1H),4.55-4.50(m,4H),2.59(s,3H),2.20(s,3H),1.68(d,J=7.1Hz,3H).

[0347] Example 6: Preparation of (R)-1-(1-methylazepine-3-yl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (6)

[0348]

[0349] The title compound 6 was prepared in the same manner as in Example 5, except that compound 4 was used instead of compound 3.

[0350] MS: m / z = 502.05 [M+H] + .

[0351] 1H NMR(300MHz,DMSO-d6)δ9.30(d,J=7.1Hz,1H),9.17(s,2H),9.11(s,1H),8.46(s,1H),8.03(s,1H),7.75(s,1 H),5.95-5.91(m,1H),5.36-5.33(m,1H),4.54-4.51(m,4H),2.55(s,3H),2.18(s,3H),1.65(d,J=7.1Hz,3H).

[0352] Example 7: Preparation of (R)-8-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (7)

[0353]

[0354]

[0355] Step 1: Preparation of methyl 3-bromo-4-hydroxy-5-nitrobenzoate (7b).

[0356] Methyl 4-hydroxy-3-nitrobenzoate (10.0 g, 50.7 mmol) was dissolved in DMF (100 mL) at room temperature. NBS (9.88 g, 55.8 mmol) was slowly added portionwise at 0°C. After addition, the reaction mixture was warmed to room temperature and stirred for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure. 70 mL of water was added to the residue, resulting in the precipitation of a large amount of yellow solid. The mixture was allowed to stand for 5 min, filtered, and washed with water (10 mL x 3). The filter cake was collected to afford 14 g of the title compound as a yellow solid in a 99% yield.

[0357] Step 2: Preparation of methyl 3-amino-5-bromo-4-hydroxybenzoate (7c).

[0358] At room temperature, methyl 3-bromo-4-hydroxy-5-nitrobenzoate (13.5 g, 49.1 mmol) and NH4Cl (13.5 g, 245 mmol) were dissolved in a mixed solvent of EtOH (100 mL) and water (20 mL). Zn powder (15.9 g, 245 mmol) was slowly added in portions at 0°C. After the addition, stirring was continued at 0°C for 20 minutes, then the temperature was raised to 80°C and stirred for 5 hours. The mixture was cooled to room temperature, filtered, and the filter cake was washed with methanol and collected. The resulting filtrate was concentrated to obtain a small amount of crude product. The above filter cake was dissolved in 100 mL of 6N sodium hydroxide aqueous solution, stirred for 10 minutes, filtered, and the filter cake was washed with methanol. The filtrate was collected and the pH of the filtrate was adjusted to 5-6 with 6N hydrochloric acid aqueous solution. The filtrate was concentrated under reduced pressure to obtain the majority of the crude product. The two crude products were combined and separated and purified by silica gel column chromatography (mobile phase: DCM / MeOH = 20 / 1-10:1) to obtain 7.0 g of the title compound as a light yellow solid. Yield: 58%.

[0359] Step 3: Preparation of methyl 8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (7d).

[0360] Methyl 3-amino-5-bromo-4-hydroxybenzoate (2.00 g, 8.20 mmol) and K2CO3 (2.26 g, 16.4 mmol) were dissolved in DMF (15 mL) at room temperature. 1,2-Dibromoethane (0.845 mL, 9.86 mmol) was added, and the reaction mixture was stirred in an oil bath at 100°C for 2 h. The reaction mixture was concentrated under reduced pressure, and 30 mL of water was added to the residue, followed by extraction with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: PE / EA = 2 / 1 to 1:1) to afford 1.5 g of the title compound as a light yellow solid in a 68% yield.

[0361] Step 4: Preparation of methyl 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (7e).

[0362] Methyl 8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (1.10 g, 4.06 mmol), bis-pinacol boronate (1.55 g, 6.09 mmol), and KOAc (1.20 g, 12.2 mmol) were dissolved in 1,4-dioxane (15 mL) at room temperature. Pd(dppf)Cl2 (0.297 g, 0.406 mmol) was added. The reaction mixture was purged with N2 three times and stirred in an oil bath at 90°C overnight. The reaction mixture was cooled to room temperature and used directly in the next step without further treatment.

[0363] Step 5: Preparation of methyl 8-(5-methylthiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (7f).

[0364] To the reaction mixture from the previous step was added 3 mL of water, 2-bromo-5-methylthiazole (836 mg, 4.70 mmol), and KCO (1.49 g, 10.8 mmol) at room temperature, followed by Pd(dppf)Cl (0.263 g, 0.360 mmol). The reaction mixture was purged three times under N and stirred at 80°C overnight. 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: PE / EA = 2 / 1 to 1:1) to afford 820 mg of the title compound as a yellow solid in a 77% yield.

[0365] Step 6: Preparation of 8-(5-methylthiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (7 g).

[0366] Methyl 8-(5-methylthiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (80.0 mg, 0.275 mmol) and LiOH·H2O (50.0 mg, 1.10 mmol) were dissolved in a mixture of EtOH (5 mL) and THF (2 mL) at room temperature. The reaction mixture was stirred at 80°C for 3 h. The reaction mixture was concentrated under reduced pressure, 4 mL of water was added, and the pH was adjusted to 4-5 with 6N aqueous hydrochloric acid. A large amount of yellow solid precipitated, which was filtered, collected, and dried to afford 60 mg of the title compound as a yellow solid, in a yield of 79%.

[0367] LC-MS: m / z 277.22 [M+H] + .

[0368] Step 7: Preparation of (R)-8-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (Compound 7).

[0369] 8-(5-Methylthiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (35.0 mg, 0.127 mmol), (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine (34.7 mg, 0.152 mmol), and DIPEA (49.1 mg, 0.381 mmol) were dissolved in DMF (3 mL) at room temperature. HATU (96.5 mg, 0.245 mmol) was added, and the reaction mixture was stirred at room temperature overnight. 10 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm, 100 Å, mobile phase: acetonitrile / water, gradient: 30%-80%) to obtain 32 mg of the title compound as a yellow solid, in a yield of 56%.

[0370] MS: m / z = 450.49 [M+H] + .

[0371] 1 H NMR(300MHz,DMSO-d6)δ9.08(s,2H),8.95(d,J=6.3Hz,1H),7.98(s,1H),7.52(s,1H),7.13(s,1H),6.2 2(s,1H),5.29-5.25(m,1H),4.39-4.36(m,2H),3.41-3.37(m,2H),2.48(s,3H),1.58(d,J=7.2Hz,3H).

[0372] Example 8: Preparation of 8-(5-methylthiazol-2-yl)-4-((tetrahydrofuran-3-yl)methyl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (8)

[0373]

[0374]

[0375] Step 1: Preparation of methyl 8-(5-methylthiazol-2-yl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (8a).

[0376] Methyl 8-(5-methylthiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (100 mg, 0.344 mmol), tetrahydrofuran-3-carbaldehyde (101 mg, 1.03 mmol), and ZnCl2 (83.6 mg, 0.688 mmol) were dissolved in anhydrous DCM (20 mL) at room temperature. The reaction was stirred at room temperature for 10 minutes. NaBH3CN (66.0 mg, 1.03 mmol) was added, and the reaction was stirred at room temperature overnight under N2 protection. 20 mL of water was added to the reaction mixture, and the mixture was stirred for 5 minutes. The organic phase was separated and the aqueous phase was extracted with DCM (15 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 1 / 1) to obtain 150 mg of the title compound as a yellow oil. Yield: 47%.

[0377] Step 2: Preparation of 8-(5-methylthiazol-2-yl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (8b).

[0378] Methyl 8-(5-methylthiazol-2-yl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (150 mg, 0.401 mmol) and LiOH·H₂O (67.4 mg, 1.60 mmol) were dissolved in a mixture of EtOH (5 mL) and THF (2 mL) at room temperature. The reaction mixture was stirred at 60°C for 4 h. The reaction mixture was concentrated under reduced pressure, 2 mL of water was added, and the pH was adjusted to 3-5 with 1N dilute aqueous HCl. A large amount of yellow solid precipitated, which was filtered, collected, and dried to afford 140 mg of the title compound as a yellow solid, in a 96% yield.

[0379] Step 3: Preparation of 8-(5-methylthiazol-2-yl)-4-((tetrahydrofuran-3-yl)methyl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (Compound 8).

[0380] 8-(5-Methylthiazol-2-yl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (140 mg, 0.389 mmol), (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine (106 mg, 0.467 mmol), and DIPEA (150 mg, 1.17 mmol) were dissolved in DMF (5 mL) at room temperature. HATU (296 mg, 0.778 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm, 100 Å, mobile phase: acetonitrile / water, gradient: 30%-80%) to give 128 mg of the title compound as a white solid, yield: 61%.

[0381] MS: m / z = 534.57 [M+H] + .

[0382] 1 H NMR(400MHz,DMSO-d6)δ9.11-8.99(m,3H),8.30-8.07(m,1H),7.67-7.64(m,1H),7.55-7.21(m,1H),5.27-5.10(m,1H),4.44-4.10(m ,2H),3.82-3.63(m,4H),3.48-3.44(m,3H),3.30-3.11(m,1H),2.65-2.58(m,1H),2.50(s,3H),2.01-1.98(m,1H),1.64-1.59(m,4H).

[0383] Example 9: Preparation of (R)-4-(azetidin-3-ylmethyl)-8-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (9)

[0384]

[0385] Step 1: Preparation of (R)-tert-butyl 3-((8-(5-methylthiazol-2-yl)-6-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)azetidine-1-carboxylate (9a)

[0386] Compound 9a was prepared by the same method as in Example 8, except that tert-butyl 3-formylazetidine-1-carboxylate was used instead of tetrahydrofuran-3-carbaldehyde in step 1.

[0387] Step 2: Preparation of (R)-4-(azetidin-3-ylmethyl)-8-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (9)

[0388] At room temperature, tert-butyl (R)-3-((8-(5-methylthiazol-2-yl)-6-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)azetidine-1-carboxylate (130 mg, 0.210 mmol) was dissolved in DCM (10 mL). TFA (192 mg, 1.68 mmol) was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, and aqueous ammonia was added to adjust the pH to 6-7. The mixture was extracted with EtOAc (15 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile / water, gradient: 30%-80%) to obtain 56 mg of the title compound as a white solid, yield: 51.4%.

[0389] MS: m / z = 519.13 [M+H] + .

[0390] 1 H NMR (300MHz, CDCl3) δ9.10(s,1H),9.04(s,1H),8.57(s,1H),8.29(s,1H),7.68(s,1H),7.54(s,1H),5.41-5.38(m,1H),4.86-4.84(m,2 H),4.43-4.42(m,2H),4.39-4.36(m,2H),4.20-4.18(m,2H),4.04-4.03(m,2H),3.48-3.47(m,1H),2.58(s,3H),1.75(d,J=7.2Hz,3H).

[0391] Example 10: Preparation of (R)-4-((1-methylazepine-3-yl)methyl)-8-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (10)

[0392]

[0393] The title compound 10 was prepared by the same preparation method as in Example 5, except that (R)-4-(azetidin-3-ylmethyl)-8-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (Compound 9) was used instead of (R)-2-(azetidin-3-yl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (Compound 3).

[0394] MS: m / z = 532.20 [M+H] + .

[0395] 1 H NMR (300MHz, CDCl3) δ9.10(s,1H),9.04(s,1H),8.57(s,1H),8.29(s,1H),7.68(s,1H),7.54(s,1H),5.41-5.38(m,1H),4.86-4.84(m,2H),4. 43-4.42(m,2H),4.39-4.36(m,2H),4.20-4.18(m,2H),4.04-4.03(m,2 H), 3.48-3.47 (m, 1H), 2.58 (s, 3H), 2.20 (s, 3H), 1.75 (d, J = 7.2Hz, 3H).

[0396] Example 11: Preparation of (R)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (11)

[0397]

[0398] Step 1: Preparation of methyl 3-bromo-5-(2-chloroacetylamino)-4-hydroxybenzoate (11a).

[0399] Methyl 3-amino-5-bromo-4-hydroxybenzoate (245 mg, 1.00 mmol) and KCO (414 mg, 3.00 mmol) were dissolved in MeCN (5 mL) at 0°C. Chloroacetyl chloride (0.09 ml, 1.20 mmol) in acetonitrile was slowly added dropwise with stirring. After addition, the reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure, and 10 mL of water was added to the residue. The mixture was extracted with EtOAc (15 mL x 3). The combined organic phases were dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to afford 160 mg of the title compound as a yellow solid, which was used directly in the next step. Yield: 49%.

[0400] Step 2: Preparation of methyl 8-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (11b).

[0401] Methyl 3-bromo-5-(2-chloroacetylamino)-4-hydroxybenzoate (120 mg, 0.374 mmol) was dissolved in anhydrous EtOH (5 mL) at room temperature, and KOAc (110 mg, 1.12 mmol) was added. The reaction mixture was heated to 80°C and stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc (20 mL) and washed with water (15 mL x 2). The separated organic phase was dried over anhydrous NaSO, filtered, and concentrated to afford 100 mg of the title compound as a white solid in a 94% yield.

[0402] Step 3: Preparation of ethyl 3-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (11c).

[0403] Methyl 8-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (2.50 g, 8.77 mmol), bis-pinacol boronate (3.35 g, 13.2 mmol), and KOAc (2.58 g, 26.3 mmol) were dissolved in 1,4-dioxane (30 mL) at room temperature. Pd(dppf)Cl2 (641 mg, 0.877 mmol) was added. The reaction mixture was purged with nitrogen three times, heated to 90°C, and stirred overnight. The reaction mixture was cooled to room temperature and used directly in the next step without further treatment.

[0404] Step 4: Preparation of methyl 8-(5-methylthiazol-2-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (11d).

[0405] To the above reaction solution at room temperature were added 5 mL of water, 2-bromo-5-methylthiazole (3.10 g, 17.4 mmol), and K2CO3 (3.61 g, 26.1 mmol), followed by Pd(dppf)Cl2 (630 mg, 0.871 mmol). The reaction solution was purged three times under N2 protection and stirred overnight at 80°C. 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: PE / EA = 2 / 1 to 1 / 1) to afford 980 mg of the title compound as a yellow solid in a 37% yield.

[0406] Step 5: Preparation of 8-(5-methylthiazol-2-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (11e).

[0407] Methyl 8-(5-methylthiazol-2-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (50.0 mg, 0.164 mmol) and LiOH·H2O (27.5 mg, 0.656 mmol) were dissolved in a mixture of EtOH (5 mL) and THF (2 mL) at room temperature. The reaction mixture was stirred at 60°C for 3 h. The reaction mixture was concentrated under reduced pressure, 2 mL of water was added, and the pH was adjusted to 4-5 with 1N dilute aqueous HCl. A large amount of yellow solid precipitated, which was filtered, collected, and dried to afford 32 mg of the title compound as a yellow solid, in a yield of 66%.

[0408] Step 6: Preparation of (R)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (Compound 11).

[0409] 8-(5-Methylthiazol-2-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (63.0 mg, 0.217 mmol), (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine (59.3 mg, 0.260 mmol), and DIPEA (83.8 mg, 0.650 mmol) were dissolved in DMF (5 mL) at room temperature. HATU (164 mg, 0.433 mmol) was added, and the reaction mixture was stirred at room temperature overnight. 10 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm, 100 Å, mobile phase: acetonitrile / water, gradient: 30%-80%) to give 30 mg of the title compound as a yellow solid, in a 30% yield.

[0410] MS: m / z = 464.36 [M+H] + .

[0411] 1 H NMR (300MHz, DMSO-d6) δ11.015 (s, 1H), 9.20 (d, J = 4.2Hz, 1H), 9.10 (s,2H),8.38(s,1H),7.70(s,1H),7.43(s,1H),5.29(t,J=6.9Hz,1H),4.87(s,2H),2.50(s,3H),1.60(d,J=6.9Hz,3H).

[0412] Example 12: Preparation of 8-(5-methylthiazol-2-yl)-3-oxo-4-((tetrahydrofuran-2-yl)methyl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (12)

[0413]

[0414] Step 1: Preparation of methyl 8-(5-methylthiazol-2-yl)-3-oxo-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (12a)

[0415] Methyl 8-(5-methylthiazol-2-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (50.0 mg, 0.164 mmol), 2-(bromomethyl)tetrahydrofuran (54.3 mg, 0.329 mmol), and Cs2CO3 (162 mg, 0.492 mmol) were dissolved in DMF (3 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and 10 mL of water was added to the residue, followed by extraction with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to afford 120 mg of the title compound as a yellow oil in a 93% yield.

[0416] Step 2: Preparation of 8-(5-methylthiazol-2-yl)-3-oxo-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (12b).

[0417] Methyl 8-(5-methylthiazol-2-yl)-3-oxo-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (110 mg, 0.284 mmol) and LiOH·H2O (47.6 mg, 1.13 mmol) were dissolved in a mixture of EtOH (5 mL) and THF (2 mL) at room temperature. The reaction mixture was stirred at 60°C for 6 h. The reaction mixture was concentrated under reduced pressure, 2 mL of water was added, and the pH was adjusted to 3-5 with 1N dilute aqueous HCl. The resulting solution was concentrated under reduced pressure to afford 130 mg of the crude title compound (containing the LiCl salt, ~90 mg of product) as a yellow solid in an 85% yield.

[0418] Step 3: Preparation of 8-(5-methylthiazol-2-yl)-3-oxo-4-((tetrahydrofuran-2-yl)methyl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (Compound 12).

[0419] 8-(5-Methylthiazol-2-yl)-3-oxo-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (90.0 mg, 0.241 mmol), (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine (83.1 mg, 0.289 mmol), and DIPEA (93.3 mg, 0.723 mmol) were dissolved in DMF (5 mL) at room temperature. HATU (183 mg, 0.482 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, 10 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm, 100 Å, mobile phase: acetonitrile / water, gradient: 30%-80%) to give 93 mg of the title compound as a white solid, in a yield of 71%.

[0420] MS: m / z = 548.43 [M+H] + .

[0421] 1 H NMR(300MHz,DMSO-d6)δ9.19(d,J=7.2Hz,1H),9.11(s,2H),8.47(s,1H),7.82(s,1H),7.71(s,1H),5.33-5.29(m,1H),4 .94(s,2H),4.12-4.02(m,3H),3.75-3.71(m,1H),3.63-3.59(m,1H),2.50(s,3H),1.94-1.79(m,3H),1.79-1.61(m,4H).

[0422] Example 13: Preparation of (R)-8-(5-methylthiazol-2-yl)-3-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (13)

[0423]

[0424] The title compound 13 was prepared by the same method as in Example 12, except that 4-(bromomethyl)tetrahydro-2H-pyran was used instead of 2-(bromomethyl)tetrahydrofuran in step 1.

[0425] MS: m / z = 562.36 [M+H] + .

[0426] 1 H NMR (300MHz, DMSO-d6) δ9.23(d,J=7.2Hz,1H),9.12(s,2H),8.49(s,1H),7.72(s,1H),7.68(s,1H),5.31(t,J=6.9Hz,1H),3.97-3.94(m, 2H),3.83-3.79(m,2H),3.25-3.17(m,2H),2.50(s,3H),1.94-1.93(m,1H),1.62(d,J=7.2Hz,3H),1.55-1.51(m,1H),1.29-1.26(m,1H).

[0427] Example 14: Preparation of (R)-4-(azetidin-3-ylmethyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (14)

[0428]

[0429]

[0430] Step 1: Preparation of (R)-tert-butyl 3-((8-(5-methylthiazol-2-yl)-3-oxo-6-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)azetidine-1-carboxylate (14a)

[0431] The title compound 14a was prepared in the same manner as in Example 12, except that tert-butyl 3-(bromomethyl)azetidine-1-carboxylate was used instead of 2-(bromomethyl)tetrahydrofuran.

[0432] Step 2: Preparation of (R)-4-(azetidin-3-ylmethyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (14)

[0433] At room temperature, tert-butyl (R)-3-((8-(5-methylthiazol-2-yl)-3-oxo-6-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)azetidine-1-carboxylate (150 mg, 0.237 mmol) was dissolved in 1,4-dioxane (5 mL). HCl·1,4-dioxane (1.00 mL, 4.00 mmol) was added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile / water, gradient: 30%-80%) to obtain 56 mg of the title compound as a white solid, yield: 44%.

[0434] MS: m / z = 533.56 [M+H] + .

[0435] 1 H NMR(300MHz, CDCl3)δ9.54(s,1H),9.03(s,1H),8.55(s,1H),8.27(s,1H),7.66(s,1H),7.55(s,1H),5.39-5.37(m,1H),4.86- 4.84(m,2H),4.43-4.42(m,2H),4.20-4.18(m,2H),4.04-4.03(m,2H),3.48-3.47(m,1H),2.58(s,3H),1.75(d,J=7.2Hz,3H).

[0436] Example 15: Preparation of (R)-4-((1-methylazepine-3-yl)methyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (15)

[0437]

[0438] The preparation method is the same as that of Example 5, except that (R)-4-(azetidin-3-ylmethyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (Compound 14) is used instead of (R)-2-(azetidin-3-yl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (Compound 3) to prepare the title compound 15.

[0439] MS: m / z = 547.23 [M+H] + .

[0440] 1 H NMR (300MHz, CDCl3) δ9.54(s,1H),9.03(s,1H),8.55(s,1H),8.27(s,1H),7.66(s,1H),7.55(s,1H),5.39-5.37(m,1H),4.86-4.84( m,2H),4.43-4.42(m,2H),4.20-4.18(m,2H),4.04-4.03(m,2H),3.48-3.47(m,1H),2.58(s,3H),2.17(s,3H),1.75(d,J=7.2Hz,3H).

[0441] Example 16: Preparation of (R)-8-(5-methylthiazol-2-yl)-4-(pyrrolidin-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinoline-6-carboxamide (16)

[0442]

[0443] Step 1: Preparation of methyl 3-bromo-4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)benzoate (16b).

[0444] Methyl 4-amino-3-bromobenzoate (3.00 g, 13.0 mmol), cycloisopropyl malonate (2.38 g, 17.0 mmol), triethyl orthoformate (7.72 g, 52.2 mmol), and isopropyl alcohol (30 mL) were added to a reaction flask at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the filter cake was washed with n-hexane and dried to obtain 4.7 g of the title product as a white solid, in a yield of 94.0%.

[0445] Step 2: Preparation of methyl 8-bromo-4-oxo-1,4-dihydroquinoline-6-carboxylate (16c).

[0446] Methyl 3-bromo-4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-ylidene)methyl)amino)benzoate (4.7 g, 12.2 mmol) and diphenyl ether (30 mL) were added to a reaction flask at room temperature. The flask was then placed in an oil bath preheated to 180°C and heated to 210°C for 1 hour. After the reaction, the flask was cooled to room temperature and n-hexane (50 mL) was added. A solid precipitated, which was filtered and dried to yield 3.8 g of the title product as a black solid in a 93.2% yield.

[0447] Step 3: Preparation of methyl 8-bromo-4-chloro-1,4-dihydroquinoline-6-carboxylate (16d).

[0448] Methyl 8-bromo-4-oxo-1,4-dihydroquinoline-6-carboxylate (3.00 g, 10.7 mmol) and phosphorus oxychloride (30 mL) were added to a reaction flask at room temperature and heated to 80°C for 1 hour. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. 60 mL of ethyl acetate and 60 mL of water were added to the residue, and the pH was adjusted to neutral by adding saturated sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (mobile phase: PE / EA = 2:1) to obtain 2.12 g of the title product as a gray solid, in a 66.0% yield.

[0449] Step 4: Preparation of methyl 8-bromo-4-(pyrrolidin-1-yl)quinoline-6-carboxylate (16e).

[0450] At room temperature, methyl 8-bromo-4-chloro-1,4-dihydroquinoline-6-carboxylate (260 mg, 0.870 mmol), pyrrolidine (390 mg, 4.35 mmol), DIPEA (339 mg, 42.0 mmol), and DMF (10 mL) were added to a sealed reaction tube and heated to 100°C for 1 hour. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain 330 mg of the title product as a yellow solid, which was used directly in the next step.

[0451] Step 5: Preparation of methyl 8-(5-methylthiazol-2-yl)-4-(pyrrolidin-1-yl)quinoline-6-carboxylate (16f).

[0452] Methyl 8-bromo-4-(pyrrolidin-1-yl)quinoline-6-carboxylate (200 mg, 0.599 mmol), 5-methylthiazole (119 mg, 1.20 mmol), CuI (114 mg, 0.599 mmol), Pd(OAc)2 (0.328 g, 0.449 mmol), and DMF (7.00 mL) were added to a reaction flask at room temperature. Under a nitrogen atmosphere, the mixture was heated to 140°C and reacted for 8 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and extracted with 50 mL of ethyl acetate and 50 mL of water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (mobile phase: DCM:MeOH = 20:1) to obtain 0.19 g of the title product as a yellow solid in a 90.1% yield.

[0453] Step 6: Preparation of 8-(5-methylthiazol-2-yl)-4-(pyrrolidin-1-yl)quinoline-6-carboxylic acid (16 g).

[0454] Methyl 8-(5-methylthiazol-2-yl)-4-(pyrrolidin-1-yl)quinoline-6-carboxylate (0.19 g, 0.538 mmol), lithium hydroxide (225 mg, 5.38 mmol), tetrahydrofuran (15.0 mL), methanol (15.0 mL), and H₂O (5.00 mL) were added to a reaction flask at room temperature and stirred at room temperature for 14 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and the pH was adjusted to 3-4 with 1N hydrochloric acid. A solid precipitated, which was filtered and dried to obtain 0.12 g of the title product as a brown solid in a 62.4% yield.

[0455] Step 7: Preparation of (R)-8-(5-methylthiazol-2-yl)-4-(pyrrolidin-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinoline-6-carboxamide (Compound 16).

[0456] At room temperature, 8-(5-methylthiazol-2-yl)-4-(pyrrolidin-1-yl)quinoline-6-carboxylic acid (120 mg, 0.353 mmol), (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine (96.8 mg, 0.424 mmol), DIPEA (183 mg, 1.41 mmol), HATU (187 mg, 0.494 mmol) and DMF (5.0 mL) were added to a reaction flask and stirred at room temperature for 2 hours. After the reaction, 30 mL of ethyl acetate and 30 mL of water were added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm, 100 Å, mobile phase: acetonitrile / water = 0%-100%) to obtain 30 mg of the title product as a yellow solid, in a yield of 16.6%.

[0457] MS: m / z = 513.45 [M+H] + .

[0458] 1 HNMR (300MHz, DMSO-d6): δppm: 14.38(s,1H),9.45(d,1H),9.16(s,2H),8.98(s,1H),8.74(s,1H),8.5 6(d,1H),7.91(s,1H),6.97(d,1H),5.35(m,1H),4.01(m,4H),2.62(s,3H),2.07(m,4H),1.67(d,3H).

[0459] Example 17: Preparation of (R)-8-(5-methylthiazol-2-yl)-2-(pyrrolidin-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinoxaline-6-carboxamide (17)

[0460]

[0461] Step 1: Preparation of methyl 8-bromo-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (17b).

[0462] At room temperature, methyl 3,4-diamino-5-bromobenzoate (5.00 g, 20.4 mmol), glyoxylic acid (2.26 g, 30.6 mmol), and anhydrous ethanol (80 mL) were added to a reaction flask. The temperature was raised to 80°C and the reaction was allowed to proceed for 2 hours. The reaction solution was directly concentrated to obtain 7.2 g of the title product as a yellow solid, which was used directly in the next step.

[0463] Step 2: Preparation of methyl 8-bromo-2-chloroquinoxaline-6-carboxylate (17c).

[0464] Methyl 8-bromo-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (7.2 g) and phosphorus oxychloride (35 mL) were added to a reaction flask at room temperature and heated to 80°C for 1 hour. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. 60 mL of ethyl acetate and 60 mL of water were added to the residue, and the pH was adjusted to neutral by adding saturated sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (mobile phase: PE / EA = 2:1) to obtain 5.12 g of the title product as a yellow solid, with a total yield of 83.2% over two steps.

[0465] Step 3: Preparation of methyl 8-bromo-2-(pyrrolidin-1-yl)quinoxaline-6-carboxylate (17d).

[0466] Methyl 8-bromo-2-chloroquinoxaline-6-carboxylate (4.20 g, 14.0 mmol), pyrrolidine (4.97 g, 70.0 mmol), DIPEA (5.46 g, 42.0 mmol), and DMF (30 mL) were added to a sealed reaction tube at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: PE / EA = 2:1) to obtain 1.66 g of the title product as a yellow solid, in a yield of 35.3%.

[0467] Step 4: Preparation of (7-(methoxycarbonyl)-3-(pyrrolidin-1-yl)quinoxalin-5-yl)boronic acid (17e).

[0468] Methyl 8-bromo-2-(pyrrolidin-1-yl)quinoxaline-6-carboxylate (1.45 g, 4.30 mmol), bis(pinacol boronate) (2.18 g, 8.60 mmol), potassium acetate (1.26 g, 12.9 mmol), 1,4-dioxane (25 mL), and Pd(dppf)Cl2 (0.157 g, 0.215 mmol) were added to a reaction flask at room temperature. Under a nitrogen atmosphere, the temperature was raised to 90°C and the reaction was allowed to proceed for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, concentrated under reduced pressure, and extracted with 50 mL of ethyl acetate and 50 mL of water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (mobile phase: DCM:MeOH = 20:1) to afford 0.90 g of the title product as a yellow solid in a 69.8% yield.

[0469] Step 5: Preparation of methyl 8-(5-methylthiazol-2-yl)-2-(pyrrolidin-1-yl)quinoxaline-6-carboxylate (17f).

[0470] At room temperature, (7-(methoxycarbonyl)-3-(pyrrolidin-1-yl)quinoxalin-5-yl)boronic acid (0.90 g, 2.99 mmol), 2-bromo-5-methylthiazole (0.532 g, 2.99 mmol), potassium carbonate (0.825 g, 5.98 mmol), water (5 mL), tetrahydrofuran (25 mL), and Pd(dppf)Cl2 (0.328 g, 0.449 mmol) were added to a reaction flask. Under a nitrogen atmosphere, the temperature was raised to 90°C and the reaction was allowed to proceed for 16 hours. After completion of the reaction, the product was concentrated under reduced pressure and extracted with 50 mL of ethyl acetate and 50 mL of water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 2:1) to obtain 0.40 g of the title product as a yellow solid in a 37.7% yield.

[0471] Step 6: Preparation of 8-(5-methylthiazol-2-yl)-2-(pyrrolidin-1-yl)quinoxaline-6-carboxylic acid (17 g).

[0472] Methyl 8-(5-methylthiazol-2-yl)-2-(pyrrolidin-1-yl)quinoxaline-6-carboxylate (0.35 g, 0.989 mmol), 1N lithium hydroxide solution (10 mL), tetrahydrofuran (20 mL), and methanol (20 mL) were added to a reaction flask at room temperature and stirred for 14 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and the pH was adjusted to 3-4 with 1N hydrochloric acid. A solid precipitated, which was filtered to afford 0.25 g of the title product as an orange-yellow solid in a 74.4% yield.

[0473] Step 7: Preparation of (R)-8-(5-methylthiazol-2-yl)-2-(pyrrolidin-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinoxaline-6-carboxamide (Compound 17).

[0474] At room temperature, 8-(5-methylthiazol-2-yl)-2-(pyrrolidin-1-yl)quinoxaline-6-carboxylic acid (50.0 mg, 0.147 mmol), (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine (36.9 mg, 0.160 mmol), DIPEA (76.5 mg, 4.00 mmol), HATU (78.2 mg, 0.210 mmol) and DMF (5 mL) were added to a reaction flask and stirred at room temperature for 2 hours. After the reaction, 30 mL of ethyl acetate and 30 mL of water were added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 μm, 100 Å, mobile phase: acetonitrile / water = 0%-100%) to obtain 22 mg of the title product as a yellow solid, in a yield of 29.0%.

[0475] MS: m / z = 514.52 [M+H] + .

[0476] 1 HNMR(300MHz,DMSO-d6): δppm:9.28(d,1H),9.16(s,2H),9.09(s,1H),8.66(s,1H),8.4 7(s,1H),7.70(s,1H),5.37(m,1H),3.74(m,4H),2.50(m,3H),2.07(m,4H),1.65(d,3H).

[0477] Example 18: Preparation of (R)-4-((3-methyloxetan-3-yl)methyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (18)

[0478]

[0479] The title compound 18 was prepared by the same method as in Example 12, except that 3-(bromomethyl)-3-methyloxetane was used instead of 2-(bromomethyl)tetrahydrofuran in step 1.

[0480] MS: m / z = 548.18 [M+H] + .

[0481] 1H NMR (300MHz, CDCl3) δ8.92(s,2H),8.35(s,1H),7.60(d,J=7.2Hz,2H),6.94(d,J=6.9Hz,1H),5.36-5.32(m,1H),4.8 4(s,2H),4.67-4.64(m,2H),4.25-4.22(m,2H),4.21-4.08(m,2H),2.55(s,3H),1.71(d,J=7.2Hz,2H),1.40(s,3H).

[0482] Example 19: Preparation of (R)-4-(5-methylthiazol-2-yl)-2-morpholinyl-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzo[d]oxazole-6-carboxamide (19)

[0483]

[0484] Step 1: Preparation of methyl 4-amino-3-bromo-5-hydroxybenzoate (19b).

[0485] Methyl 4-amino-3-hydroxybenzoate (1.90 g, 11.40 mmol), NBS (1.90 g, 13.7 mmol), and dichloromethane (20 mL) were added to a reaction flask at room temperature and allowed to react for 1 hour. After completion of the reaction, 50 mL of dichloromethane and 50 mL of water were added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: DCM:MeOH = 20:1) to obtain 2.0 g of the title product as a brown oil in a 71.7% yield.

[0486] LC-MS: m / z 246.01[M+H] + .

[0487] Step 2: Preparation of (2-amino-3-hydroxy-5-(methoxycarbonyl)phenyl)boronic acid (19c).

[0488] Methyl 4-amino-3-bromo-5-hydroxybenzoate (2.00 g, 8.13 mmol), bis(pinacol boronate) (BPD) (4.13 g, 16.26 mmol), potassium acetate (2.39 g, 24.39 mmol), 1,4-dioxane (25 mL), and Pd(dppf)Cl2 (298 mg, 0.407 mmol) were added to a reaction flask at room temperature. The mixture was heated to 90°C under a nitrogen atmosphere and reacted for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, concentrated under reduced pressure, and extracted with 50 mL of ethyl acetate and 50 mL of water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: DCM:MeOH = 20:1) to obtain 2.27 g of the crude title product as a brown solid, which was used directly in the next step.

[0489] Step 3: Preparation of methyl 4-amino-3-hydroxy-5-(5-methylthiazol-2-yl)benzoate (19d).

[0490] At room temperature, (2-amino-3-hydroxy-5-(methoxycarbonyl)phenyl)boronic acid (2.27 g, 7.70 mmol), 2-bromo-5-methylthiazole (1.37 g, 7.70 mmol), potassium carbonate (2.12 g, 15.4 mmol), water (5 mL), tetrahydrofuran (25 mL), and Pd(dppf)Cl2 (845 mg, 1.16 mmol) were added to a reaction flask. Under a nitrogen atmosphere, the temperature was raised to 90°C and the reaction was allowed to proceed for 16 hours. After completion of the reaction, the product was concentrated under reduced pressure and extracted with 50 mL of ethyl acetate and 50 mL of water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 2:1) to obtain 1.05 g of the title product as a yellow solid in a 51.7% yield.

[0491] Step 4: Preparation of methyl 4-(5-methylthiazol-2-yl)-2-thioxo-2,3-dihydrobenzo[d]oxazole-6-carboxylate (19e).

[0492] Methyl 4-amino-3-hydroxy-5-(5-methylthiazol-2-yl)benzoate (730 mg, 2.80 mmol), carbon disulfide (5.0 mL), KOH (0.19 g, 3.4 mmol), and ethanol (10 mL) were added to a sealed reaction tube at room temperature. The temperature was raised to 80°C and the reaction was allowed to proceed for 2 hours. After completion of the reaction, the mixture was filtered and the filter cake was dried to obtain 0.42 g of the title product as a yellow solid in a yield of 49.0%.

[0493] Step 5: Preparation of 4-(5-methylthiazol-2-yl)-2-morpholinyl-benzo[d]oxazole-6-carboxylic acid methyl ester (19f).

[0494] Methyl 4-(5-methylthiazol-2-yl)-2-thioxo-2,3-dihydrobenzo[d]oxazole-6-carboxylate (200 mg, 0.654 mmol), morpholine (227 mg, 2.61 mmol), DIPEA (339 mg, 2.61 mmol), and DMF (10.0 mL) were added to a sealed reaction tube at room temperature. The temperature was raised to 150°C and the reaction was allowed to proceed for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (Daisogei column model: 30 mm x 250 mm, C18, 10 μm, 100A, mobile phase: acetonitrile / water = 0%-100%) to afford 100 mg of the title product as a gray solid.

[0495] Step 6: Preparation of 4-(5-methylthiazol-2-yl)-2-morpholinyl-benzo[d]oxazole-6-carboxylic acid (19 g).

[0496] Methyl 4-(5-methylthiazol-2-yl)-2-morpholinobenzo[d]oxazole-6-carboxylate (100 mg, 0.279 mmol), 1N lithium hydroxide solution (5 mL), tetrahydrofuran (10 mL), and methanol (10 mL) were added to a reaction flask at room temperature and stirred for 14 hours. After the reaction, the pH was adjusted to 3-4 with 1N hydrochloric acid solution. A solid precipitated and was filtered to afford 50 mg of the title product as a brown solid in a 40.4% yield.

[0497] Step 7: Preparation of (R)-4-(5-methylthiazol-2-yl)-2-morpholinyl-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzo[d]oxazole-6-carboxamide (19h).

[0498] At room temperature, 4-(5-methylthiazol-2-yl)-2-morpholinyl-benzo[d]oxazole-6-carboxylic acid (50.0 mg, 0.145 mmol), (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine (36.3 mg, 0.159 mmol), DIPEA (82.7 mg, 0.636 mmol), HATU (77.1 mg, 0.203 mmol) and DMF (5.0 mL) were added to a reaction flask and stirred at room temperature for 2 hours. After the reaction, 30 mL of ethyl acetate and 30 mL of water were added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 μm, 100 Å, mobile phase: acetonitrile / water = 0%-100%) to obtain 17 mg of the title product as a white solid, in a yield of 22.7%.

[0499] MS: m / z = 519.44 [M+H] + .

[0500] 1 H NMR (300MHz, DMSO-d6) δ9.05(s,2H),8.53(s,1H),7.83(s,1H),7.60(s,1H),5.35-5.38(m,1H),3.84(s,8H),2.57(m,3H),1.72(m,J=7.14Hz,2H).

[0501] Example 20: Preparation of 4-(5-methylthiazol-2-yl)-2-(tetrahydrofuran-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (20)

[0502]

[0503] The title compound 20 was prepared in the same manner as in Example 2, except that 3-iodotetrahydrofuran was used instead of 3-iodooxetane.

[0504] MS: m / z = 503.00 [M+H] + .

[0505] 1 H NMR (400MHz, DMSO-d6): δppm 9.21(s,1H),9.17(s,2H),8.67(s,1H),8.40(s,1H),8.08(s,1H),7.78(s,1H),5.60(s,1H),5 .34-5.30(m,1H),4.10(m,2H),3.93(m,2H),2.55(s,3H),2.50(s,1H),1.65(d,J=7.1Hz,3H).

[0506] Example 21: Preparation of 4-(5-methylthiazol-2-yl)-1-(tetrahydrofuran-3-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (21)

[0507]

[0508] The title compound 20 was prepared in the same manner as in Example 1, except that 3-iodotetrahydrofuran was used instead of 3-iodooxetane.

[0509] MS: m / z = 503.00 [M+H] + .

[0510] 1 H NMR (400MHz, DMSO-d6): δppm 9.21(s,1H),9.16(s,2H),8.93(s,1H),8.44(s,1H),7.97(s,1H),7.74(s,1H),5.54-5.35(m,1H),5.3 3-5.30(m,1H),4.16-4.10(m,3H),3.93-3.90(m,1H),2.54(s,3H),2.40(s,1H),1.62(d,J=7.1Hz,3H).

[0511] Example 22: Preparation of (R)-4-(5-methylthiazol-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (22)

[0512]

[0513] The title compound 22 was prepared in the same manner as in Example 1, except that 4-iodotetrahydro-2H-pyran was used instead of 3-iodooxetane.

[0514] MS: m / z = 517.00 [M+H] + .

[0515] 1 H NMR (300MHz, CDCl3): δppm 8.99(s,2H),8.60(s,1H),8.15(s,2H),7.67(s,1H),7.16(s,1H),5.45-5.41(m,1H),4.79-4.73(m,1H),4.2 0-4.17(m,2H),3.66-3.60(m,2H),2.61(s,3H),2.47-2.39(m,2H),2.01-1.98(m,2H),1.78(d,J=5.4Hz,3H).

[0516] Example 23: Preparation of 4-(5-methylthiazol-2-yl)-1-((tetrahydrofuran-2-yl)methyl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (23)

[0517]

[0518] The title compound 23 was prepared in the same manner as in Example 1, except that 2-(bromomethyl)tetrahydrofuran was used instead of 3-iodooxetane.

[0519] MS: m / z = 517.10 [M+H] + .

[0520] 1 H NMR (400MHz, DMSO-d6): δppm 9.27(d,J=6.9Hz,1H),9.16(s,2H),8.64(s,1H),8.34(s,1H),8.08(s,1H),7.77(s,1H),5.38-5.33(m,1H),4.58-4.56(m,2H), 4.33-4.30(m,1H),3.69-3.65(m,1H),3.62-3.57(m,1H),2.56(s,3H),1.97-1.95(m,1H),1.80-1.74(m,3H),1.73-1.65(m,3H).

[0521] Example 24: Preparation of 4-(5-methylthiazol-2-yl)-2-((tetrahydrofuran-2-yl)methyl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (24)

[0522]

[0523] The title compound 24 was prepared in the same manner as in Example 2, except that 2-(bromomethyl)tetrahydrofuran was used instead of 3-iodooxetane.

[0524] MS: m / z = 517.10 [M+H] + .

[0525] 1 H NMR (400MHz, DMSO-d6): δppm 9.24(d,J=9.0Hz,1H),9.15(s,2H),8.89(s,1H),8.40(s,1H),7.97(s,1H),7.74(s,1H),5.38-5.33(m,1H),4.62-4.58(m,2H),4. 37-4.35(m,1H),3.77-3.75(m,1H),3.65-3.63(m,1H),2.59(s,3H),1.81-1.79(m,1H),1.77-1.74(m,3H),1.64(d,J=7.2Hz,3H).

[0526] Example 25: Preparation of (R)-4-(5-methylthiazol-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (25)

[0527]

[0528] The title compound 25 was prepared in the same manner as in Example 1, except that 4-(bromomethyl)tetrahydro-2H-pyran was used instead of 3-iodooxetane.

[0529] MS: m / z = 531.00 [M+H] + .

[0530] 1 H NMR (300MHz, CDCl3): δppm 8.98(s,2H),8.53(s,1H),8.04-8.01(m,2H),7.55(s,1H),6.90-6.88(m,1H),5.45-5.41(m,1H),4.34(d,J=4.8Hz,2 H),3.96-3.93(m,2H),3.37-3.31(m,2H),2.60(s,3H),2.36-2.31(m,1H),1.77(d,J=5.2Hz,3H),1.49-1.41(m,4H).

[0531] Example 26: Preparation of (R)-4-(5-methylthiazol-2-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (26)

[0532]

[0533] The title compound 26 was prepared in the same manner as in Example 2, except that 4-(bromomethyl)tetrahydro-2H-pyran was used instead of 3-iodooxetane.

[0534] MS: m / z = 531.00 [M+H] + .

[0535] 1 H NMR (300MHz, CDCl3): δppm 8.96(s,2H),8.74(s,1H),8.14(s,1H),7.93(s,1H),7.55(s,1H),6.66-6.64(m,1H),5.43-5.38(m,1H), 4.35(d,J=4.5Hz,2H),3.99-3.95(m,2H),3.41-3.31(m,2H),2.56(s,3H),2.37-2.32(m,1H),1.75(d,J= 5.2Hz,3H),1.50-1.43(m,4H).

[0536] Example 27: Preparation of (R)-1-(((3,3-difluorocyclobutyl)methyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (27)

[0537]

[0538] The title compound 27 was prepared in the same manner as in Example 1, except that 3-(bromomethyl)-1,1-difluorocyclobutane was used instead of 3-iodooxetane.

[0539] MS: m / z = 537.00 [M+H] + .

[0540] 1 H NMR (300MHz, CDCl3): δppm 8.99(s,2H),8.62(s,1H),8.06(s,2H),7.65(s,1H),6.98(s,1H),5.47-5.40(m,1H),4.56(d,J=5.4Hz 1H), 2.68 (s, 1H), 2.65-2.61 (m, 2H), 2.60 (s, 3H), 2.52-2.40 (m, 2H), 1.77 (d, J = 5.4Hz, 3H).

[0541] Example 28: Preparation of (R)-2-(((3,3-difluorocyclobutyl)methyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (28)

[0542]

[0543] The title compound 28 was prepared in the same manner as in Example 2, except that 3-(bromomethyl)-1,1-difluorocyclobutane was used instead of 3-iodooxetane.

[0544] MS: m / z = 537.00 [M+H] + .

[0545] 1H NMR (300MHz, CDCl3): δppm 8.99(s,2H),8.70(s,1H),8.20(s,1H),8.11(s,1H),7.61(s,1H),6.91(s,1H),5.44-5.37(m,1H),4.59(d,J=5.4Hz 1H), 2.75 (s, 1H), 2.61-2.50 (m, 2H), 2.49 (s, 3H), 2.47-2.42 (m, 2H), 1.76 (d, J = 5.4Hz, 3H).

[0546] Example 29: Preparation of 1-((4-methylmorpholin-2-yl)methyl)-4-(5-methylthiazol-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (29)

[0547]

[0548] The title compound 29 was prepared by the same method as in Example 4, except that tert-butyl 2-((tosyloxy)methyl)morpholine-4-carboxylate was used instead of tert-butyl 3-iodoazetidine-1-carboxylate.

[0549] MS: m / z = 546.10 [M+H] + .

[0550] 1 HNMR (300MHz, CDCl3): δppm 9.05(s,2H),8.73(s,1H),8.12-8.09(m,2H),7.69-7.57(m,2H),5.51-5 .45(m,1H),4.61-4.53(m,1H),4.35(s,1H),3.93(d,J=8.3Hz,1H),3.73( t,J=9.0Hz,1H),2.98-2.90(m,1H),2.83-2.78(m,1H),2.62(s,3H),2.42 (d, J = 6.0 Hz, 3H), 2.33 (s, 1H), 2.18-2.06 (m, 1H), 1.80 (d, J = 6.0 Hz, 3H).

[0551] Example 30: Preparation of 1-((4-methylmorpholin-2-yl)methyl)-4-(5-methylthiazol-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (30)

[0552]

[0553] The title compound 30 was prepared in the same manner as in Example 3, except that tert-butyl 2-((tosyloxy)methyl)morpholine-4-carboxylate was used instead of tert-butyl 3-iodoazetidine-1-carboxylate.

[0554] MS: m / z = 546.10 [M+H] + .

[0555] 1 HNMR (300MHz,CDCl3):δppm 9.04(s,2H),8.80(s,1H),8.19(d,J=6.0Hz,1H),7.95(s,1H),7.61(s,2H),7. 04-7.00(m,1H),5.49-5.44(m,1H),4.64-4.56(m,2H),4.25(s,1H),3.95(d,J= 9.0Hz,1H),3.81-3.79(m,1H),2.99-2.96(m,1H),2.79-2.77(m,1H),2.52(s, 3H), 2.41 (s, 3H), 2.26-2.24 (m, 1H), 2.08-2.06 (m, 1H), 1.80 (d, J = 9.0Hz, 3H).

[0556] Example 31: Preparation of 1-((1-methylpyrrolidin-3-yl)methyl)-4-(5-methylthiazol-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (31)

[0557]

[0558] Step 1: Preparation of (1-methylpyrrolidin-3-yl)methanol (31b)

[0559] Methyl 1-methyl-5-oxopyrrolidine-3-carboxylate (1.00 g, 6.37 mmol) was dissolved in THF (15 mL) at 0°C. LiAlH₄ (535 mg, 12.7 mmol) was slowly added portionwise. After the addition, the reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. Water (~15 mL) was slowly added dropwise to the reaction mixture in an ice bath and diluted with ethyl acetate (40 mL). The reaction mixture was filtered through celite and washed with EtOAc (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 450 mg of the title compound as a yellow oil in a 61.4% yield.

[0560] Step 2: Preparation of methyl (1-methylpyrrolidin-3-yl) 4-methylbenzenesulfonate (31c)

[0561] At room temperature, (1-methylpyrrolidin-3-yl)methanol (450 mg, 3.91 mmol) and TEA (790 mg, 7.82 mmol) were dissolved in DCM (10 mL). DMAP (477 mg, 3.91 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE:EtOAc = 4:1) to obtain 720 mg of the title compound as a yellow oil, in a yield of 68.6%.

[0562] MS: m / z = 270.00 [M+H] + .

[0563] The subsequent steps were the same as those in Example 1, except that 31c was used instead of 3-iodooxetane, to obtain the title compound 31.

[0564] MS: m / z = 530.00 [M+H] + .

[0565] 1 H NMR (400MHz, CDCl3): δppm 9.07(s,2H),8.77(s,1H),8.14(s,1H),7.59(s,1H),7.26-7.25(m,1H),5.44-5.37(m,1H),4.57-4.28(m,3H),3 .53-3.52(m,2H),2.94-2.88(m,3H),2.54(s,3H),2.33-2.26(m,2H),2.13-2.09(m,2H),1.78(d,J=5.2Hz,3H).

[0566] Example 32: Preparation of 2-((1-methylpyrrolidin-3-yl)methyl)-4-(5-methylthiazol-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (32)

[0567]

[0568] The title compound 32 was prepared in the same manner as in Example 2, except that methyl (1-methylpyrrolidin-3-yl)-4-methylbenzenesulfonate (31c) was used instead of 3-iodooxetane.

[0569] MS: m / z = 530.00 [M+H] + .

[0570] 1H NMR (400MHz, CDCl3): δppm 9.06(s,1H),9.03(s,1H),8.77(s,1H),8.22-8.18(m,1H),7.94(s,1H) ,7.74-7.72(m,1H),7.49(s,1H),5.39-5.34(m,1H),4.66-4.58(m,3H) ,3.99-3.95(m,2H),3.16-3.13(m,1H),3.05(m,3H),2.95-2.88(m,1H) ,2.52(s,3H),2.40-2.37(m,1H),1.85-1.82(m,1H),1.75-1.74(m,3H).

[0571] Example 33: Preparation of (R)-8-(5-methylthiazol-2-yl)-4-(tetrahydro-2H-pyran-4-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (33)

[0572]

[0573] The title compound 33 was prepared in the same manner as in Example 8, except that tetrahydro-4H-pyran-4-one was used instead of tetrahydrofuran-3-carbaldehyde.

[0574] MS: m / z = 534.44 [M+H] + .

[0575] 1 H NMR (300MHz, CD3Cl): δppm 8.92(s,2H),7.97(s,1H),7.54(s,1H),7.26(s,1H),6.92(d,J=5.7Hz,1H),5.34-5.30(m,1H),4 .46(s,2H),4.09-3.99(m,3H),3.57-3.50(m,2H),3.41(s,2H),2.53(s,3H),1.83-1.67(m,7H).

[0576] Example 34: Preparation of (R)-4-(2-ethoxyethyl)-8-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (34)

[0577]

[0578] Step 1: Preparation of 2-ethoxyethyl 4-(2-ethoxyethyl)-8-(5-methylthiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (34a)

[0579] Methyl 8-(5-methylthiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (7f) (150 mg, 0.516 mmol) and 1-bromo-2-ethoxyethane (711 mg, 4.65 mmol) were dissolved in DMF (3 mL) at room temperature. NaH (60% dissolved in mineral oil) (31.2 mg, 0.773 mmol) was slowly added, and the reaction mixture was stirred at 60°C overnight. After completion of the reaction, 5 mL of MeOH was added to quench the reaction, and the mixture was concentrated under reduced pressure to obtain a crude yellow product, which was used directly in the next step.

[0580] MS: m / z = 421.23 [M+H] + .

[0581] Step 2: Preparation of 4-(2-ethoxyethyl)-8-(5-methylthiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (34b)

[0582] 2-Ethoxyethyl 4-(2-ethoxyethyl)-8-(5-methylthiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (160 mg, 0.381 mmol) and LiOH·H₂O (64.0 mg, 1.52 mmol) were dissolved in a mixture of EtOH (5 mL), THF (2 mL), and water (1 mL) at room temperature. The reaction mixture was stirred at 60°C overnight. The reaction mixture was concentrated under reduced pressure, 2 mL of water was added, and the pH was adjusted to 5-6 with 1N dilute aqueous hydrochloric acid. A large amount of yellow solid precipitated, which was filtered, collected, and dried to afford 100 mg of the title compound as a yellow solid (yield: 75%).

[0583] MS: m / z = 349.33 [M+H] + .

[0584] Step 3: Preparation of (R)-4-(2-ethoxyethyl)-8-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (34)

[0585] 4-(2-Ethoxyethyl)-8-(5-methylthiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (100 mg, 0.286 mmol), (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine (78.4 mg, 0.344 mmol), and DIPEA (111 mg, 0.860 mmol) were dissolved in DMF (5 mL) at room temperature. HATU (218 mg, 0.573 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, 10 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm, 100 Å, mobile phase: acetonitrile / water, gradient: 10%-100%) to give 51 mg of the title compound as a white solid, in a yield of 34%.

[0586] MS: m / z = 522.34 [M+H] + .

[0587] 1 H NMR (300MHz, CDCl3): δppm 8.91(s,2H),7.95(s,1H),7.53(s,1H),6.91(d,J=6.6Hz,1H),5.35-5.30(m,1H),4.61-4.32(m,2H), 3.66-3.55(m,6H),3.47(q,J=6.9Hz,2H),2.51(s,3H),1.67(d,J=7.2Hz,3H),1.17(t,J=6.9Hz,3H).

[0588] Example 35: Preparation of (R)-8-(5-methylthiazol-2-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (35)

[0589]

[0590]

[0591] Step 1: Preparation of (R)-8-(5-methylthiazol-2-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (35)

[0592] (R)-8-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (7) (100 mg, 0.223 mmol) and DIPEA (57.4 mg, 0.445 mmol) were dissolved in DCM (5 mL) in an ice bath. Tetrahydro-2H-pyran-4-carbonyl chloride (49.7 mg, 0.334 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, 10 mL of water and 10 mL of DCM were added, and the separated aqueous phase was extracted with DCM (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm, 100 Å, mobile phase: acetonitrile / water, gradient: 10%-100%) to give 105 mg of the title compound as a white solid, yield: 84%.

[0593] MS: m / z = 562.49 [M+H] + .

[0594] 1 H NMR (300MHz, CDCl3): δppm 8.95(s,2H),8.51(s,1H),7.91(s,1H),7.56(s,1H),7.38(s,1H),5.40-5.36(m,1H),4.56-4.49(m,2H),4 .09-3.97(m,4H),3.45-3.38(m,2H),3.15(s,1H),2.54(s,3H),2.01-1.91(m,4H),1.65(d,J=7.2Hz,3H).

[0595] Example 36: Preparation of (R)-4-(cyclopropanecarbonyl)-8-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (36).

[0596]

[0597] The title compound 36 was prepared in the same manner as in Example 35, except that cyclopropanecarbonyl chloride was used instead of tetrahydro-2H-pyran-4-carbonyl chloride.

[0598] MS: m / z = 518.50 [M+H] + .

[0599] 1H NMR (300MHz, CDCl3): δppm 8.93(s,2H),8.44(s,1H),8.14(s,1H),7.58(s,1H),6.92(d,J=6.3Hz,1H),5.38-5.33(m,1H),4.60-4.57(m,2H) ,4.11-4.06(m,2H),2.55(s,3H),2.12-1.95(m,1H),1.70(d,J=7.2Hz,3H),1.23-1.18(m,2H),0.99-0.95(m,2H).

[0600] Example 37: Preparation of (R)-4-(2-ethoxyethyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (37)

[0601]

[0602] The title compound 37 was prepared by the same method as in Example 12, except that 1-bromo-2-ethoxyethane was used instead of 2-(bromomethyl)tetrahydrofuran in step 1.

[0603] MS: m / z = 536.52 [M+H] + .

[0604] 1 H NMR (300MHz, DMSO-d6): δppm 9.20(d,J=4.2Hz,1H),9.11(s,2H),8.46(s,1H),7.80(s,1H),7.71(s,1H),5.33-5.29(m,1H),4.93(s,2H),4.18- 4.14(m,2H),3.62-3.59(m,2H),3.44(q,J=6.9Hz,2H),2.51(s,3H),1.62(d,J=7.2Hz,3H),1.01(t,J=6.9Hz,3H).

[0605] Example 38: Preparation of 4-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (38)

[0606]

[0607] Step 1: Preparation of tert-butyl (2S,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (38b)

[0608] 2-((2R,4R)-1-(tert-Butoxycarbonyl)-4-fluoropyrrolidin-2-yl)acetic acid (5.00 g, 0.0215 mol) was dissolved in THF (60 mL) at 0°C. LiAlH4 (2.45 g, 0.0645 mmol) was slowly added portionwise. After addition, the reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. Water (~15 mL) was slowly added dropwise to the reaction mixture in an ice bath and diluted with ethyl acetate (40 mL). The reaction mixture was filtered through Celite and washed with EtOAc (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 3.60 g of the title compound as a yellow oil in a 76% yield.

[0609] MS: m / z = 220.04 [M+H] + .

[0610] Step 2: Preparation of ((2S,4R)-4-fluoropyrrolidin-2-yl)methanol (38c)

[0611] At room temperature, tert-butyl (2S,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (3.60 g, 0.0164 mol) was dissolved in DCM (40 mL). TFA (21.5 mL, 0.164 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the pH adjusted to 8-9 with saturated NaHCO₃ solution, and then concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 1.81 g of the title compound as a yellow oil in a 92% yield.

[0612] MS: m / z = 120.01 [M+H] + .

[0613] Step 3: Preparation of ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (38d)

[0614] ((2S,4R)-4-Fluoropyrrolidin-2-yl)methanol (1.25 g, 0.0105 mmol) and 37% aqueous formaldehyde (3.94 g, 0.0525 mmol) were dissolved in MeOH (20 mL) at room temperature and stirred for 30 min. NaBH3CN (1.32 g, 0.0210 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 710 mg of the title compound as a yellow oil, with a yield of 50%.

[0615] MS: m / z = 133.95 [M+H] + .

[0616] Step 4: Preparation of (2S,4R)-2-(chloromethyl)-4-fluoro-1-methylpyrrolidine (38e)

[0617] At room temperature, ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (700 mg, 5.22 mmol) was dissolved in DCM (10 mL). SOCl2 (1.14 mL, 15.7 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 550 mg of the title compound as a yellow oil, in a 69% yield.

[0618] MS: m / z = 151.92 [M+H] + .

[0619] The subsequent steps were the same as those of Example 12, except that 38e was used instead of 2-(bromomethyl)tetrahydrofuran to give the title compound 38.

[0620] MS: m / z = 579.50 [M+H] + .

[0621] 1 H NMR (300MHz, DMSO-d6): δppm 9.38-9.34(m,1H),9.24(s,2H),8.52(d,J=9.0Hz1H),5.43-5.28(m,2H),4.98-4.78(m,2H),4.55-4.43(m,1H),3.95-3 .76(m,2H),3.59-3.57(m,1H),3.04-3.02(m,1H),2.90(s,3H),2.51(s,3H),2.39-2.27(m,1H),1.62(t,J=6.9Hz,3H).

[0622] Example 39: Preparation of 4-(((S)-4-methyl-5-oxomorpholin-2-yl)methyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (39)

[0623]

[0624] Step 1: Preparation of (S)-2-chloro-N-(2,3-dihydroxypropyl)-N-methylacetamide (39b)

[0625] (S)-3-(Methylamino)propane-1,2-diol (1.00 g, 9.52 mmol) and triethylamine (2.08 mL, 11.4 mmol) were dissolved in a mixture of MeCN (20 mL) and MeOH (3 mL) at room temperature. Chloroacetyl chloride (0.728 mL, 10.5 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was used directly in the next step, yielding 1.70 g of the title compound as a colorless oil in a 98% yield.

[0626] MS: m / z = 181.88 [M+H] + .

[0627] Step 2: Preparation of (S)-6-(hydroxymethyl)-4-methylmorpholin-3-one (39c)

[0628] (S)-2-Chloro-N-(2,3-dihydroxypropyl)-N-methylacetamide (1.70 g, 9.34 mmol) was dissolved in 2-methyl-2-tert-butanol (15 mL) at room temperature, and t-BuOK (2.09 g, 18.7 mmol) was added. The reaction mixture was stirred at room temperature for 15 h. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (DCM:MeOH = 20:1) to obtain 370 mg of the title compound as a colorless oil, in a yield of 27%.

[0629] MS: m / z = 146.00 [M+H] + .

[0630] Step 3: Preparation of (S)-4-(methyl-5-oxomorpholin-2-yl)methyl 4-methylbenzenesulfonate (39d)

[0631] (S)-6-(Hydroxymethyl)-4-methylmorpholin-3-one (370 mg, 2.04 mmol), triethylamine (1.60 mL, 11.4 mmol), and DMAP (25 mg) were dissolved in DCM (15 mL) at room temperature. TsCl (1.12 g, 5.73 mmol) was then added, and the reaction mixture was stirred at room temperature for 15 h. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE / EtOAc = 3 / 1) to afford 550 mg of the title compound as a colorless oil, in a 72% yield.

[0632] The subsequent steps were the same as those of Example 12, except that 39d was used instead of 2-(bromomethyl)tetrahydrofuran to give the title compound 39.

[0633] MS: m / z = 591.00 [M+H] + .

[0634] 1 H NMR (300MHz, CDCl3): δppm 8.96(s,2H),8.56(s,1H),7.91(s,1H),7.65(s,1H),7.18(s,1H),5.37-5.34(m,1H),4.95-4.82(m,2H),4.28-4.05(m,5H), 3.48-3.43(m,1H),3.31-3.29(m,1H),2.98(s,3H),2.58(s,3H),1.75(d,J=5.4Hz,3H).

[0635] Example 40: Preparation of 4-((((R)-3-methyl-2-oxooxazolin-5-yl)methyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (40)

[0636]

[0637] Step 1: Preparation of (R)-3-(benzyl(methyl)amino)propane-1,2-diol (40b).

[0638] At room temperature, dissolve N-methyl-1-phenylmethanamine (10.0 g, 0.0826 mol) in methanol (100 mL). Add (R)-oxirane-2-ylmethanol (6.42 g, 0.0867 mmol) portionwise. After addition, stir the reaction mixture at 65°C overnight. The reaction mixture is concentrated under reduced pressure to afford 15.0 g of the title compound as a colorless oil (yield: 98%).

[0639] MS: m / z = 196.01 [M+H] + .

[0640] Step 2: Preparation of (R)-3-(methylamino)propane-1,2-diol (40c).

[0641] (R)-3-(Benzyl(methyl)amino)propane-1,2-diol (12.0 g, 0.0615 mol) was dissolved in MeOH (150 mL) at room temperature. 10% wet Pd / C (1.71 g) was added. The reaction mixture was stirred at room temperature overnight under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filter cake was washed with MeOH (20 mL x 3). The filtrate was collected, and the organic phase was concentrated under reduced pressure and dried to afford 6.10 g of the title compound as a colorless oil, in a 92% yield.

[0642] MS: m / z = 106.06 [M+H] + .

[0643] Step 3: Preparation of (S)-5-(hydroxymethyl)-3-methyloxazolidin-2-one (40d).

[0644] (R)-3-(Methylamino)propane-1,2-diol (3.00 g, 0.0286 mmol) and t-BuOK (157 mg, 0.00143 mmol) were dissolved in diethyl carbonate (21 mL) at room temperature. The reaction mixture was stirred at 100°C overnight. The mixture was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (DCM:MeOH = 20:1) to obtain 1.70 g of the title compound as a colorless oil, in a 46% yield.

[0645] MS: m / z = 131.86 [M+H] + .

[0646] Step 4: Preparation of (S)-5-(chloromethyl)-3-methyloxazolidin-2-one (40e).

[0647] (S)-5-(Hydroxymethyl)-3-methyloxazolidin-2-one (500 mg, 3.82 mmol) was dissolved in THF (15 mL) at room temperature, and SOCl (0.831 mL, 11.4 mmol) was added. The reaction mixture was stirred at 50°C overnight. The reaction mixture was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 330 mg of the title compound as a yellow oil, in a 53% yield.

[0648] MS: m / z = 149.84 [M+H] + .

[0649] The subsequent steps were the same as those of Example 12, except that 40e was used instead of 2-(bromomethyl)tetrahydrofuran to give the title compound 40.

[0650] MS: m / z = 577.10 [M+H] + .

[0651] 1 H NMR (300MHz, DMSO-d6): δppm 9.14-9.10(m,3H),8.47(s,1H),7.77(s,1H),7.72(s,1H),5.32-5.27(m,1H),5.03-4.92(m,2H),4.65-4.53(m,1H), 4.46-4.38(m,1H),4.26-4.19(m,1H),3.67(t,J=8.1Hz,1H),3.37-3.35(m,1H),2.74(s,3H),1.62(t,J=6.9Hz,3H).

[0652] Example 41: Preparation of 4-((1,4-dioxan-2-yl)methyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (41)

[0653]

[0654] Step 1: Preparation of 2-((benzyloxy)methyl)-1,4-dioxane (41b)

[0655] 3-(Benzyloxy)propane-1,2-diol (1.00 g, 5.49 mmol) was dissolved in a solution of NaOH (5.48 g, 137 mmol) in water (15 mL) at room temperature. Tetrabutylammonium iodide (402 mg, 1.09 mmol) and 1,2-dichloroethane (13.8 g, 137 mmol) were added, and the reaction mixture was stirred at 50°C for 72 h. Water (40 mL) and DCM (20 mL) were added to the reaction mixture, and the layers were separated. The aqueous phase was extracted with DCM (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to afford 360 mg of the title compound as a colorless oil, yield: 31%.

[0656] Step 2: Preparation of (1,4-dioxan-2-yl)methanol (41c)

[0657] 2-((Benzyloxy)methyl)-1,4-dioxane (360 mg, 1.73 mmol) was dissolved in MeOH (10 mL) at 0°C. Pd(OH)2 / C (50 mg) and 3 drops of concentrated hydrochloric acid were added. The reaction mixture was purged three times under a hydrogen atmosphere and stirred at 50°C for 15 h. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to afford 200 mg of the title compound as a colorless oil (98% yield).

[0658] MS: m / z = 119.10 [M+H] + .

[0659] Step 3: Preparation of methyl (1,4-dioxan-2-yl) 4-methylbenzenesulfonate (41d)

[0660] At room temperature, (1,4-dioxan-2-yl)methanol (200 mg, 1.69 mmol), triethylamine (1.60 mL, 11.4 mmol), and pyridine (0.5 mL) were dissolved in DCM (15 mL). TsCl (1.12 g, 5.73 mmol) was added, and the reaction mixture was stirred at room temperature for 15 h. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE / EtOAc = 3 / 1) to obtain 100 mg of the title compound as a colorless oil, in a yield of 21%.

[0661] The subsequent steps were the same as those of Example 12, except that 41d was used instead of 2-(bromomethyl)tetrahydrofuran to give the title compound 41.

[0662] MS: m / z = 564.10 [M+H] + .

[0663] 1 H NMR (300MHz, CDCl3): δppm 8.93(s,2H),8.34(s,1H),7.90(s,1H),7.56(s,1H),6.90(s,1H),5.38-5.34(m,1H),4.9 0-4.76(m,2H),3.94-3.64(m,8H),3.45-3.38(m,1H),2.54(s,3H),1.71(d,J=6.9Hz,3H).

[0664] Example 42: Preparation of (R)-4-((3,3-difluorocyclobutyl)methyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (42)

[0665]

[0666] Step 1: Preparation of (3,3-difluorocyclobutyl)methyl 4-methylbenzenesulfonate (42b)

[0667] At room temperature, (3,3-difluorocyclobutyl)methanol (500 mg, 3.82 mmol), triethylamine (1.60 mL, 11.4 mmol), and pyridine (0.5 mL) were dissolved in DCM (15 mL). TsCl (1.12 g, 5.73 mmol) was added, and the reaction mixture was stirred at room temperature for 15 h. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE / EtOAc = 3 / 1) to obtain 700 mg of the title compound as a colorless oil, in a 66% yield.

[0668] The subsequent steps were the same as those of Example 12, except that 42b was used instead of 2-(bromomethyl)tetrahydrofuran to give the title compound 42.

[0669] MS: m / z = 568.00 [M+H] + .

[0670] 1 H NMR (300MHz, CDCl3): δppm 8.98(s,2H),8.52(s,1H),7.69-7.67(m,2H),7.04(s,1H),5.39-5.35(m,1H ), 4.87 (s, 2H), 4.29-4.18 (m, 2H), 2.69-2.47 (m, 8H), 1.77 (d, J = 5.4Hz, 3H).

[0671] Example 43: Preparation of (R)-4-(cyclopropylmethyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (43)

[0672]

[0673] The title compound 43 was prepared in the same manner as in Example 12, except that (bromomethyl)cyclopropane was used instead of 2-(bromomethyl)tetrahydrofuran.

[0674] MS: m / z = 518.00 [M+H] + .

[0675] 1 H NMR (300MHz, DMSO-d6): δppm 9.20(d,J=4.2Hz,1H),9.11(s,2H),8.46(s,1H),7.80(s,1H),7.71(s,1H),5.33-5.29(m,1H),4.93(s,2H),4.18- 4.14(m,2H),3.62-3.59(m,2H),3.44(q,J=6.9Hz,2H),2.51(s,3H),1.62(d,J=7.2Hz,3H),1.01(t,J=6.9Hz,3H).

[0676] Example 44: Preparation of 4-(2,2-difluorocyclopropane-1-carbonyl)-8-(5-methylthiazol-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (44)

[0677]

[0678] The title compound 44 was prepared in the same manner as in Example 35, except that 2,2-difluorocyclopropane-1-carbonyl chloride was used instead of tetrahydro-2H-pyran-4-carbonyl chloride.

[0679] MS: m / z = 554.00 [M+H] + .

[0680] 1 H NMR (300MHz, CDCl3): δppm 8.95(d,J=4.2Hz,2H),8.69(s,1H),7.90(s,1H),7.63(s,1H),6.95(s,1H),5.43-5.35(m,1H),4.75-4.72(m,2 H), 4.53-4.50 (m, 2H), 3.59 (s, 1H), 2.83-2.79 (m, 1H), 2.56 (s, 3H), 2.37-2.35 (m, 1H), 1.71 (d, J = 5.4Hz, 3H).

[0681] Example 45: Preparation of (R)-4-(3,3-difluorocyclobutane-1-carbonyl)-8-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (45)

[0682]

[0683] The title compound 45 was prepared in the same manner as in Example 35, except that 3,3-difluorocyclobutane-1-carbonyl chloride was used instead of tetrahydro-2H-pyran-4-carbonyl chloride.

[0684] MS: m / z = 568.10 [M+H] + .

[0685] 1 H NMR (300MHz, CDCl3): δppm 8.97(s,2H),8.55(s,1H),7.72(s,1H),7.54(s,1H),7.12-7.01(m,1H),5.43-5.36(m,1H),4.63-4.57(m,2H),4.24-4.19 (m,1H),4.02-3.97(m,1H),4.45-3.40(m,1H),3.03-2.90(m,2H),2.87-2.82(m,2H),2.57(s,3H),1.75(d,J=5.4Hz,3H).

[0686] Example 46: Preparation of (R)-4-benzoyl-8-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (46)

[0687]

[0688] The title compound 46 was prepared in the same manner as in Example 35, except that benzoyl chloride was used instead of tetrahydro-2H-pyran-4-carbonyl chloride.

[0689] MS: m / z = 554.00 [M+H] + .

[0690] 1 H NMR (300MHz, CDCl3): δppm 8.90(s,2H),8.43(s,1H),7.91(s,1H),7.58-7.44(m,6H),7.01(s,1H),5.36-5.29(m,1H),4.57-4.54 (m,1H),4.36-4.33(m,1H),4.12-4.11(m,1H),4.10-3.99(m,1H),2.56(s,3H),1.67(d,J=5.4Hz,3H).

[0691] Example 47: Preparation of (R)-4-(cyclopropylmethyl)-8-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (47)

[0692]

[0693] The title compound 47 was prepared in the same manner as in Example 8, except that cyclopropanecarboxaldehyde was used instead of tetrahydrofuran-3-carboxaldehyde.

[0694] MS: m / z = 504.00 [M+H] + .

[0695] 1H NMR (300MHz, CDCl3): δppm 8.91(s,2H),7.96(s,1H),7.53(s,1H),7.38(s,1H),6.88(s,1H),5.35-5.31(s,1H),4.51(s,2H),3.56-3.54(m, 2H),3.23-3.21(m,2H),2.52(s,3H),1.68-1.66(m,3H),1.05-1.04(m,1H),0.57-0.55(m,2H),0.23-0.21(m,2H).

[0696] Example 48: Preparation of 4-((2,2-difluorocyclopropyl)methyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (48)

[0697]

[0698] Step 1: Preparation of (2,2-difluorocyclopropyl)methanol (48b)

[0699] 2,2-Difluorocyclopropane-1-carboxylic acid (1.00 g, 8.19 mmol) was dissolved in THF (15 mL) at 0°C. LiAlH4 (623 mg, 16.4 mmol) was slowly added portionwise. The reaction solution was stirred at 0°C for 1 h, then warmed to room temperature and stirred overnight. After completion of the reaction, ice water (15 mL) was added dropwise to quench the reaction. The colloid precipitated and was filtered through celite. EtOAc (20 mL) was added to the filtrate to dilute it. The layers were separated, and the aqueous phase was extracted with EtOAc (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 412 mg of the title compound as a colorless oil in a 46.5% yield.

[0700] Step 2: Preparation of methyl (2,2-difluorocyclopropyl)-4-methylbenzenesulfonate (48c)

[0701] At room temperature, (2,2-difluorocyclopropyl)methanol (412 mg, 3.82 mmol), triethylamine (1.60 mL, 11.4 mmol), and pyridine (0.5 mL) were dissolved in DCM (15 mL). TsCl (1.12 g, 5.73 mmol) was added, and the reaction mixture was stirred at room temperature for 15 h. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE / EtOAc = 3 / 1) to obtain 200 mg of the title compound as a colorless oil, in a 20% yield.

[0702] The subsequent steps were the same as those of Example 12, except that 48c was used instead of 2-(bromomethyl)tetrahydrofuran to give the title compound 48.

[0703] MS: m / z = 554.00 [M+H] + .

[0704] 1 H NMR (300MHz, CDCl3): δppm 8.94(s,2H),8.37(s,1H),7.71-7.70(m,1H),7.59(s,1H),6.93-6.91(m,1H),5.38-5.35(m,1H),4.85(s,2H) ,4.35-4.31(m,1H),4.05-3.96(m,1H),2.55(s,3H),1.81-1.72(m,4H),1.51-1.47(m,1H),1.38-1.36(m,1H).

[0705] Example 49: Preparation of (R)-4-(cyclobutylmethyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (49)

[0706]

[0707] The title compound 49 was prepared in the same manner as in Example 12, except that (bromomethyl)cyclobutane was used instead of 2-(bromomethyl)tetrahydrofuran.

[0708] MS: m / z = 532.00 [M+H] + .

[0709] 1 H NMR (300MHz, CDCl3): δppm 8.92(s,2H),8.29(s,1H),7.64(s,1H),7.57(s,1H),6.84(d,J=6.3Hz,1H),5.36-5.32(m,1H),4.81(s,2H),4.0 8(d,J=7.2Hz,2H),2.73-2.68(m,1H),2.55(s,3H),2.03-2.01(m,2H),1.87-1.85(m,4H),1.72(d,J=7.2Hz,3H).

[0710] Example 50: Preparation of (R)-4-((1-methylcyclobutyl)methyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (50)

[0711]

[0712] The title compound 50 was prepared in the same manner as in Example 48, except that 1-methylcyclobutane-1-carboxylic acid was used instead of 2,2-difluorocyclopropane-1-carboxylic acid.

[0713] MS: m / z = 546.00 [M+H] + .

[0714] 1 H NMR (300MHz, CDCl3): δppm 8.93(s,2H),8.32(s,1H),7.74(s,1H),7.59(s,1H),6.88(d,J=6.0Hz,1H),5.39-5.30(m,1H),4.83(s,2H),4.08-3.95( dd, J1=24.3Hz, J2=14.7Hz, 2H), 2.55 (s, 3H), 1.99-1.77 (m, 4H), 1.68 (d, J=5.4Hz, 3H), 1.62-1.59 (m, 2H), 1.10 (s, 3H).

[0715] Example 51: Preparation of (R)-4-(cyclohexylmethyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (51)

[0716]

[0717] The title compound 51 was prepared in the same manner as in Example 12, except that (bromomethyl)cyclohexane was used instead of 2-(bromomethyl)tetrahydrofuran.

[0718] MS: m / z = 560.00 [M+H] + .

[0719] 1H NMR (300MHz, CDCl3): δppm 8.94(s,2H),8.31(s,1H),7.68(s,1H),7.58(s,1H),6.91-6.89(m,1H),5.39-5.32(m,1 H),4.87(s,2H),3.94-3.83(m,1H),2.55(s,3H),1.77-1.62(m,9H),1.16-1.04(m,5H).

[0720] Example 52: Preparation of 4-((1-methyl-5-oxopyrrolidin-3-yl)methyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (52)

[0721]

[0722] The title compound 52 was prepared in the same manner as in Example 48, except that 1-methyl-5-oxopyrrolidine-3-carboxylic acid methyl ester was used instead of 2,2-difluorocyclopropane-1-carboxylic acid, and NaBH4 was used instead of LiAlH4.

[0723] MS: m / z = 575.00 [M+H] + .

[0724] 1 H NMR (300MHz, CDCl3): δppm 8.98(s,2H),8.42-8.39(m,1H),7.60-7.50(m,2H),7.24(s,1H),5.41-5.32(m,1H),4.84(s,2H),4.27-4.23(m,1H),3.96-3.88(m,1 H),3.48-3.45(m,1H),3.25-3.15(m,1H),2.83-2.74(m,4H),2.57(s,3H),2.56-2.55(m,1H),2.22-2.17(m,1H),1.76-1.73(m,3H).

[0725] Example 53: Preparation of methyl 2-((8-(5-methylthiazol-2-yl)-3-oxo-6-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)morpholine-4-carboxylate (53)

[0726]

[0727] Step 1: Preparation of tert-butyl 2-((8-(5-methylthiazol-2-yl)-3-oxo-6-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)morpholine-4-carboxylate (53a)

[0728] The title compound 53a was prepared in the same manner as in Example 12, except that tert-butyl 2-((tosyloxy)methyl)morpholine-4-carboxylate was used in place of 2-(bromomethyl)tetrahydrofuran.

[0729] Step 2: Preparation of 8-(5-methylthiazol-2-yl)-4-(morpholin-2-ylmethyl)-3-oxo-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide hydrochloride (53b)

[0730] Tert-butyl 2-((8-(5-methylthiazol-2-yl)-3-oxo-6-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)morpholine-4-carboxylate (100 mg, 0.151 mmol) was added to dichloromethane (3 mL) at room temperature, followed by a 4 M hydrochloric acid solution in dioxane (1 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to afford 90 mg of the title compound as a white solid, which was used directly in the next step.

[0731] MS: m / z = 563.0 [M+H] + .

[0732] Step 3: Preparation of methyl 2-((8-(5-methylthiazol-2-yl)-3-oxo-6-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)morpholine-4-carboxylate (53)

[0733] 8-(5-Methylthiazol-2-yl)-4-(morpholin-2-ylmethyl)-3-oxo-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (30.0 mg, 0.0500 mmol) and triethylamine (15.2 mg, 0.150 mmol) were added to dichloromethane (3 mL) at room temperature, followed by the addition of methyl chloroformate (9.40 mg, 0.100 mmol), and the reaction was stirred at room temperature for 2 hours. Water (5 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined and concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (chromatographic column model: Gemini-C18 150 x 21.2 mm, 5 μm, mobile phase: acetonitrile / water, 0.1% FA, gradient: 40%-70%) to obtain 14.8 mg of the title compound as a white solid, yield: 43.5%.

[0734] MS: m / z = 620.5 [M+H] + .

[0735] 1 H NMR (400MHz, CDCl3): δppm 8.95(s,2H),8.35(d,J=1.6Hz,1H),7.90(s,1H),7.60(d,J=0.8Hz,1H),6.94-6.88( m,1H),5.40-5.33(m,1H),4.90(d,J=15.2Hz,1H),4.81(dd,J=14.8,1.2Hz,1H),4.20 -4.03(m,2H),4.02-3.84(m,3H),3.81-3.74(m,1H),3.70(s,3H),3.49-3.41(m,1H) ,3.07-2.95(m,1H),2.86-2.76(m,1H),2.56(d,J=0.8Hz,3H),1.73(d,J=7.2Hz,3H).

[0736] Example 54: Preparation of methyl 2-((8-(5-methylthiazol-2-yl)-3-oxo-6-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)piperidine-4-carboxylate (54)

[0737]

[0738] The title compound 54 was prepared in the same manner as in Example 53, except that tert-butyl 3-((tosyloxy)methyl)piperidine-1-carboxylate was used instead of tert-butyl 2-((tosyloxy)methyl)morpholine-4-carboxylate.

[0739] MS: m / z = 619.0 [M+H] + .

[0740] 1 H NMR (400MHz, CDCl3): δppm 8.96(s,2H),8.42(s,1H),7.61(s,2H),5.40-5.33(m,1H),4.85(d,J=1.8Hz,2H),4.02-3.84(m,4H),3.62(s,3H) ,2.91(t,J=12.0Hz,1H),2.83-2.75(m,1H),2.56(s,3H),1.99(s,2H),1.74(d,J=7.2Hz,3H),1.70-1.52(s,2H).

[0741] Example 55: Preparation of methyl 3-((8-(5-methylthiazol-2-yl)-3-oxo-6-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)carbamoyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)pyrrolidine-1-carboxylate (55)

[0742]

[0743] The title compound 55 was prepared in the same manner as in Example 53, except that tert-butyl 3-((toluenesulfonyloxy)methyl)pyrrolidine-1-carboxylate was used instead of tert-butyl 2-((toluenesulfonyloxy)methyl)morpholine-4-carboxylate.

[0744] MS: m / z = 605.1 [M+H] + .

[0745] 1H NMR (400MHz, DMSO-d6): δppm 9.23-9.21(d,J=7.2Hz,1H),9.11(s,2H),8.50(s,1H),7.72(s,1H),7.69(s,1H),5.32-5.28(m,1H ),4.96(s,2H),4.09-4.07(d,J=8.0Hz,2H),3.55-3.53(m,3H),3.40-3.36(m,2H),3.26-3.20(m,1 H), 3.12-3.06 (m, 1H), 2.62-2.55 (m, 1H), 2.52 (s, 3H), 1.99-1.88 (m, 1H), 1.71-1.66 (m, 1H), 1.63-1.62 (d, J = 4.0Hz, 3H).

[0746] Example 56: Preparation of 4-((4-methylmorpholin-2-yl)methyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (56)

[0747]

[0748] Step 1: Preparation of 4-((4-methylmorpholin-2-yl)methyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (56).

[0749] 8-(5-Methylthiazol-2-yl)-4-(morpholin-2-ylmethyl)-3-oxo-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide hydrochloride (53b) (50.0 mg, 0.0830 mmol) and potassium carbonate (28.7 mg, 0.207 mmol) were added to acetonitrile (5 mL) at room temperature. Methyl iodide (14.0 mg, 0.0100 mmol) was then added, and the reaction mixture was heated to 60°C and stirred for 2 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated on a preparative TLC plate (dichloromethane:methanol = 40:1) to afford 18.7 mg of the title compound as a white solid in a yield of 38.9%.

[0750] MS: m / z = 577.1 [M+H] + .

[0751] 1H NMR (400MHz, CDCl3): δppm 8.95(d,J=2.8Hz,2H),8.34(dd,J=3.8,2.0Hz,1H),7.85(d,J=2.0Hz,1H),7.59(s,1H),7.02- 6.92(m,1H),5.41-5.33(m,1H),4.88(dd,J=14.8,2.4Hz,1H),4.79(d,J=14.8Hz,1H),4.13-4. 03(m,2H),3.96-3.85(m,2H),3.66-3.56(m,1H),2.86(d,J=10.6Hz,1H),2.69-2.61(m,1H),2. 55(d,J=0.8Hz,3H),2.32(s,3H),2.25-2.17(m,1H),2.06-1.99(m,1H),1.73(d,J=7.2Hz,3H).

[0752] Example 57: Preparation of 8-(5-methylthiazol-2-yl)-3-oxo-4-(((R)-tetrahydrofuran-2-yl)methyl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (57)

[0753]

[0754] The title compound 57 was prepared by the same method as in Example 12, except that 2-(bromomethyl)tetrahydrofuran was replaced with (R)-(tetrahydrofuran-2-yl)-4-methylbenzenesulfonic acid methyl ester.

[0755] MS: m / z = 548.00 [M+H] + .

[0756] 1 H NMR (300MHz, CDCl3): δppm 8.94(s,2H),8.32(s,1H),7.93(s,1H),7.59(s,1H),6.91-6.88(m,1H),5.39-5.35(m,1H),4.92-4.75(m,2H),4 .16-4.14(m,2H),4.00-3.92(m,2H),3.77-3.75(m,1H),2.55(s,3H),2.20-1.95(m,4H),1.72(d,J=5.2Hz,3H).

[0757] Example 58: Preparation of 8-(5-methylthiazol-2-yl)-3-oxo-4-(((S)-tetrahydrofuran-2-yl)methyl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (58)

[0758]

[0759] The title compound 58 was prepared in the same manner as in Example 12, except that methyl (S)-(tetrahydrofuran-2-yl)-4-methylbenzenesulfonate was used instead of 2-(bromomethyl)tetrahydrofuran.

[0760] MS: m / z = 548.00 [M+H] + .

[0761] 1 H NMR (300MHz, CDCl3): δppm 8.94(s,2H),8.33(s,1H),7.90(s,1H),7.58(s,1H),6.91-6.89(m,1H),5.39-5.35(m,1H),4.91-4.76(m,2H),4.12-4.11 (m,1H),4.07-4.05(m,1H),3.93-3.90(m,2H),3.75-3.73(m,1H),2.55(s,3H),2.18-1.94(m,4H),1.72(d,J=5.2Hz,3H).

[0762] Example 59: Preparation of (R)-4-(cyanomethyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (59)

[0763]

[0764] The title compound 59 was prepared in the same manner as in Example 12, except that bromoacetonitrile was used instead of 2-(bromomethyl)tetrahydrofuran.

[0765] MS: m / z = 503.00 [M+H] + .

[0766] 1H NMR (300MHz, CDCl3): δppm 8.96(s,2H),8.49(s,1H),7.72(s,1H),7.62(s,1H),7.15-7.14(m,1H),5.41-5.34(m,1H ),5.07-5.03(m,1H),4.91(s,2H),4.83-4.79(m,1H),2.57(s,3H),1.73(d,J=5.4Hz,3H).

[0767] Example 60: Preparation of (R)-4-(2-hydroxy-2-methylpropyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (60)

[0768]

[0769] Step 1: Preparation of methyl 4-(2-hydroxy-2-methylpropyl)-8-(5-methylthiazol-2-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (60a).

[0770] Methyl 8-(5-methylthiazol-2-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (100 mg, 0.329 mmol), 2,2-dimethyloxirane (47.4 mg, 0.658 mmol), and cesium carbonate (215 mg, 0.658 mmol) were dissolved in DMF (3 mL) at room temperature. The reaction mixture was stirred at 50°C for 15 h. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE / EtOAc = 3 / 1) to afford 55 mg of the title compound as a yellow solid in a 44% yield.

[0771] MS: m / z = 377.00 [M+H] + .

[0772] The subsequent steps were the same as those of Example 12, except that compound 60a was used instead of compound 12a to prepare the title compound 60.

[0773] MS: m / z = 536.00 [M+H] + .

[0774] 1H NMR (300MHz, CDCl3): δppm 8.94(s,2H),8.16(s,1H),7.92(s,1H),7.57(s,1H),7.17-7.16(m,1H),5.38-5.31(m,1H),4.75(s,2H ),4.24-4.20(m,1H),4.05-4.01(m,1H),2.56(s,3H),1.75(d,J=5.4Hz,3H),1.38(s,3H),1.34(s,3H).

[0775] Example 61: Preparation of (R)-8-(5-methylthiazol-2-yl)-3-oxo-4-(prop-2-yn-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (61)

[0776]

[0777] The title compound 61 was prepared in the same manner as in Example 12, except that 3-bromoprop-1-yne was used instead of 2-(bromomethyl)tetrahydrofuran.

[0778] MS: m / z = 502.00 [M+H] + .

[0779] 1 H NMR (300MHz, CDCl3): δppm 8.95(s,2H),8.37(s,1H),7.86(s,1H),7.59(s,1H),6.98-6.96(m,1H),5.39-5.35(m, 1H), 4.87 (s, 2H), 4.85-4.73 (m, 2H), 2.55 (s, 3H), 2.29 (s, 1H), 1.72 (d, J = 5.2Hz, 3H).

[0780] Example 62: Preparation of (R)-8-(5-methylthiazol-2-yl)-3-oxo-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (62)

[0781]

[0782] The title compound 62 was prepared by the same method as in Example 48, except that 2-(tetrahydro-2H-pyran-4-yl)acetic acid was used instead of 2,2-difluorocyclopropane-1-carboxylic acid.

[0783] MS: m / z = 576.10 [M+H] + .

[0784] 1 H NMR (300MHz, CDCl3): δppm 8.96(s,2H),8.49(s,1H),7.68(s,1H),7.63(s,1H),7.20-7.18(m,1H),5.40-5.33(m,1H) ,4.10-3.94(m,4H),3.41-3.34(m,2H),2.57(s,3H),1.67-1.33(m,8H),1.41-1.33(m,1H).

[0785] Example 63: Preparation of (R)-4-(((1,1-dioxotetrahydro-2H-thiopyran-4-yl)methyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (63)

[0786]

[0787] The title compound 63 was prepared in the same manner as in Example 48, except that tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide was used instead of 2,2-difluorocyclopropane-1-carboxylic acid.

[0788] MS: m / z = 610.00 [M+H] + .

[0789] 1 H NMR (300MHz, CDCl3): δppm 8.97(s,2H),8.59(s,1H),7.66(s,2H),7.34-7.33(m,1H),5.38-5.31(m,1H),4.86(s,2H),4.09-4.00 (m,2H),3.09-3.05(m,2H),2.94-2.88(m,2H),2.58(s,3H),2.06-2.01(m,5H),1.75(d,J=5.4Hz,3H).

[0790] Example 64: Preparation of 2-methyl-7-(5-methylthiazol-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzo[d][1,3]dioxazole-5-carboxamide (64)

[0791]

[0792] Step 1: Preparation of methyl 2-methyl-2-(tetrahydro-2H-pyran-4-yl)benzo[d][1,3]dioxazole-5-carboxylate (64b)

[0793] Methyl 3,4-dihydroxybenzoate (1.00 g, 5.95 mmol), 1-(tetrahydro-2H-pyran-4-yl)ethan-1-one (1.14 g, 8.93 mmol), and TsOH (204 mg, 1.19 mmol) were dissolved in toluene (10 mL) at room temperature. The reaction mixture was stirred at 110°C overnight. After completion of the reaction, the mixture was concentrated under reduced pressure. 10 mL of water and 10 mL of EtOAc were added to the residue, and the separated aqueous phase was extracted with EtOAc (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE:EtOAc = 3:1) to afford 1.50 g of the title compound as a colorless oil (yield: 89%).

[0794] MS: m / z = 279.00 [M+H] + .

[0795] Step 2: Preparation of methyl 7-bromo-2-methyl-2-(tetrahydro-2H-pyran-4-yl)benzo[d][1,3]dioxazole-5-carboxylate (64c).

[0796] Methyl 2-methyl-2-(tetrahydro-2H-pyran-4-yl)benzo[d][1,3]dioxazole-5-carboxylate (1.40 g, 5.04 mmol) was dissolved in DMF (15 mL) at room temperature, and NBS (1.78 g, 10.1 mmol) was added. The reaction mixture was stirred at 50°C overnight. After completion of the reaction, the mixture was concentrated under reduced pressure. 10 mL of water and 20 mL of EtOAc were added to the residue, and the separated aqueous phase was extracted with EtOAc (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE:EtOAc = 2:1) to afford 1.60 g of the title compound as a colorless oil in an 89% yield.

[0797] MS: m / z = 258.00 [M+H] + .

[0798] The subsequent steps were the same as those in Example 1, except that 64c was used instead of 1b, to give the title compound 64.

[0799] MS: m / z = 535.00 [M+H] + .

[0800] 1H NMR (400MHz, CDCl3): δppm 8.77(s,2H),7.87-7.83(m,1H),7.40(s,1H),7.13(s,1H),6.85(s,1H),5.20-5.17(m,1H),4.05-4.02(m,2H),3 .40-3.35(m,2H),2.49(s,3H),2.13-2.08(m,1H),1.70-1.62(m,2H),1.61-1.56(m,5H),1.53(d,J=6.8Hz,3H).

[0801] Example 65: Preparation of (R)-1-(4-methoxyphenyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (65).

[0802]

[0803] The title compound 65 was prepared in the same manner as in Example 1, except that 1-iodo-4-methoxybenzene was used instead of 3-iodooxetane.

[0804] MS: m / z 539.00[M+H] + .

[0805] 1 H NMR (400MHz, CDCl3) δppm: 9.00 (s, 2H), 8.74 (s, 1H), 8.43 (s, 1H), 8.21 (s, 1H), 7.71 (s, 1H), 7.60 (s, 1H), 7.5 5(s,1H),7.41(s,1H),7.09-7.05(m,1H),5.43-5.36(m,1H),3.89(s,3H),2.64(s,3H),1.78(d,J=7.2Hz,3H).

[0806] Example 66: Preparation of (R)-1-(4-fluorophenyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (66).

[0807]

[0808] The title compound 66 was prepared in the same manner as in Example 1, except that 1-fluoro-4-iodobenzene was used instead of 3-iodooxetane.

[0809] MS: m / z 526.90 [M+H] + .

[0810] 1 H NMR (400MHz, CDCl3) δppm: 9.00 (s, 2H), 8.77 (s, 1H), 8.51 (s, 1H), 8.28 (s, 1H), 7.67 (s, 1H), 7.6 6-7.65(m,2H),7.48(s,1H),7.29(s,1H),5.42-5.39(m,1H),2.66(s,3H),1.78(d,J=7.2Hz,3H).

[0811] Example 67: Preparation of (R)-1-((3-fluorooxetane-3-yl)methyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (67)

[0812]

[0813] The title compound 67 was prepared in the same manner as in Example 1, except that (3-fluorooxetane-3-yl)methyl-4-methylbenzenesulfonate was used instead of 3-iodooxetane.

[0814] MS: m / z = 521.00 [M+H] + .

[0815] 1 H NMR(300MHz, CDCl3)δ9.03(s,2H),8.59(s,1H),8.47(s,1H),8.15(s,1H),7.71(s,1H),7.59-7.51(m,1H), 5.44-5.40(m,1H),4.98(s,1H),4.93(s,1H),4.89-4.78(m,4H),2.63(s,3H),1.80-1.79(d,J=5.1Hz,3H).

[0816] Example 68: Preparation of (R)-2-((3-fluorooxetan-3-yl)methyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (68).

[0817]

[0818] The title compound 68 was prepared in the same manner as in Example 2, except that (3-fluorooxetane-3-yl)methyl-4-methylbenzenesulfonate was used instead of 3-iodooxetane.

[0819] MS: m / z = 521.13 [M+H] + .

[0820] 1 H NMR(300MHz, CDCl3)δ9.15(s,1H),9.08(s,2H),8.46-8.41(m,2H),8.33(s,1H),7.85(s,1H),5.44- 5.40(m,1H),5.01(s,1H),4.96(s,1H),4.86-4.78(m,4H),2.71(s,3H),1.85-1.83(d,J=5.4Hz,3H).

[0821] Example 69: Preparation of (R)-4-((3-fluorooxetane-3-yl)methyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl))pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (69)

[0822]

[0823] The title compound 69 was prepared by the same method as in Example 12, except that (3-fluorooxetan-3-yl)methyl-4-methylbenzenesulfonate was used instead of 2-(bromomethyl)tetrahydrofuran.

[0824] MS: m / z 552.13 [M+H] + .

[0825] 1 H NMR(400MHz, CDCl3)δ8.95(s,2H),8.52(s,1H),7.82(s,1H),7.63(s,1H),7.11(s,1H),5.35-5.3 2(m,1H),4.87(m,2H),4.82-4.75(m,4H),4.68-4.47(m,2H),2.58(s,3H),1.74(d,J=7.1Hz,3H).

[0826] Example 70: Preparation of (R)-4-(5-methylthiazol-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (70)

[0827]

[0828] The title compound 70 was prepared in the same manner as in Example 1, except that 4-iodotetrahydro-2H-pyran was used instead of 3-iodooxetane.

[0829] MS: m / z = 517.00 [M+H] + .

[0830] 1 H NMR (300MHz, CDCl3) δppm 8.99(s,2H),8.60(s,1H),8.15(s,2H),7.67(s,1H),7.16(s,1H),5.45-5.41(m,1H),4.79-4.73(m,1H),4.2 0-4.17(m,2H),3.66-3.60(m,2H),2.61(s,3H),2.47-2.39(m,2H),2.01-1.98(m,2H),1.78(d,J=5.4Hz,3H).

[0831] Example 71: Preparation of (R)-4-(5-methylthiazol-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (71)

[0832]

[0833] The title compound 71 was prepared in the same manner as in Example 2, except that 4-iodotetrahydro-2H-pyran was used instead of 3-iodooxetane.

[0834] MS: m / z = 517.00 [M+H] + .

[0835] 1 H NMR (300MHz, CDCl3): δppm 8.99(s,2H),8.74(s,1H),8.24(s,1H),8.17(s,1H),7.63(s,1H),6.99(s,1H),5.43-5.37(m,1H),4.76-4 .70(m,1H),4.18-4.17(m,2H),3.66-3.59(m,2H),2.58(s,3H),2.35-2.25(m,4H),1.76(d,J=5.1Hz,3H).

[0836] Example 72: Preparation of (R)-4-(5-methylthiazol-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (72)

[0837]

[0838] The title compound 72 was prepared by the same method as in Example 1, except that 4-(bromomethyl)tetrahydro-2H-pyran was used instead of 3-iodooxetane.

[0839] MS: m / z = 531.00 [M+H] + .

[0840] 1 H NMR (300MHz, CDCl3) δppm 8.98(s,2H),8.53(s,1H),8.04-8.01(m,2H),7.55(s,1H),6.90-6.88(m,1H),5.45-5.41(m,1H),4.34(d,J=4.8Hz,2 H),3.96-3.93(m,2H),3.37-3.31(m,2H),2.60(s,3H),2.36-2.31(m,1H),1.77(d,J=5.2Hz,3H),1.49-1.41(m,4H).

[0841] Example 73: Preparation of (R)-4-(5-methylthiazol-2-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (73)

[0842]

[0843] The title compound 73 was prepared by the same method as in Example 2, except that 4-(bromomethyl)tetrahydro-2H-pyran was used instead of 3-iodooxetane.

[0844] MS: m / z = 531.00 [M+H] + .

[0845] 1 H NMR (300MHz, CDCl3): δppm 8.96(s,2H),8.74(s,1H),8.14(s,1H),7.93(s,1H),7.55(s,1H),6.66-6.64(m,1H),5.43-5.38(m,1H),4.35(d,J=4.5H z,2H),3.99-3.95(m,2H),3.41-3.31(m,2H),2.56(s,3H),2.37-2.32(m,1H),1.75(d,J=5.2Hz,3H),1.50-1.43(m,4H).

[0846] Example 74: Preparation of (R)-1-((3,3-difluorocyclobutyl)methyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (74)

[0847]

[0848] The title compound 74 was prepared in the same manner as in Example 1, except that (3,3-difluorocyclobutyl)methyl 4-methylbenzenesulfonate was used instead of 3-iodooxetane.

[0849] MS: m / z = 537.00 [M+H] + .

[0850] 1 H NMR (300MHz, CDCl3) δppm 8.99 (s, 2H), 8.62 (s, 1H), 8.06 (s, 2H), 7.65 (s, 1H), 6.98 (s, 1H), 5.47-5.40 (m, 1H), 4.56 (d, J = 5.4Hz 1H), 2.68 (s, 1H), 2.65-2.61 (m, 2H), 2.60 (s, 3H), 2.52-2.40 (m, 2H), 1.77 (d, J = 5.4Hz, 3H).

[0851] Example 75: Preparation of (R)-2-((3,3-difluorocyclobutyl)methyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (75)

[0852]

[0853] The title compound 75 was prepared in the same manner as in Example 2, except that (3,3-difluorocyclobutyl)methyl 4-methylbenzenesulfonate was used instead of 3-iodooxetane.

[0854] MS: m / z = 537.00 [M+H] + .

[0855] 1H NMR (300MHz, CDCl3): δppm 8.99(s,2H),8.70(s,1H),8.20(s,1H),8.11(s,1H),7.61(s,1H),6.91(s,1H),5.44-5.37(m,1H),4.59(d,J=5.4Hz 1H), 2.75 (s, 1H), 2.61-2.50 (m, 2H), 2.49 (s, 3H), 2.47-2.42 (m, 2H), 1.76 (d, J = 5.4Hz, 3H).

[0856] Example 76: Preparation of 1-((1-methylpyrrolidin-3-yl)methyl)-4-(5-methylthiazol-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (76)

[0857]

[0858] The title compound 76 was prepared in the same manner as in Example 1, except that (1-methylpyrrolidin-3-yl)methyl 4-methylbenzenesulfonate was used instead of 3-iodooxetane.

[0859] MS: m / z = 530.00 [M+H] + .

[0860] 1 H NMR (300MHz, CDCl3) δppm 9.07(s,2H),8.77(s,1H),8.14(s,1H),7.59(s,1H),7.26-7.25(m,1H),5.44-5.37(m,1H),4.57-4.28(m,3H),3 .53-3.52(m,2H),2.94-2.88(m,3H),2.54(s,3H),2.33-2.26(m,2H),2.13-2.09(m,2H),1.78(d,J=5.2Hz,3H).

[0861] Example 77: Preparation of 2-((1-methylpyrrolidin-3-yl)methyl)-4-(5-methylthiazol-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (77)

[0862]

[0863] The title compound 77 was prepared in the same manner as in Example 2, except that (1-methylpyrrolidin-3-yl)methyl 4-methylbenzenesulfonate was used instead of 3-iodooxetane.

[0864] MS: m / z = 530.00 [M+H] + .

[0865] 1 H NMR (300MHz, CDCl3): δppm 9.06(s,1H),9.03(s,1H),8.77(s,1H),8.22-8.18(m,1H),7.94(s,1H) ,7.74-7.72(m,1H),7.49(s,1H),5.39-5.34(m,1H),4.66-4.58(m,3H) ,3.99-3.95(m,2H),3.16-3.13(m,1H),3.05(m,3H),2.95-2.88(m,1H) ,2.52(s,3H),2.40-2.37(m,1H),1.85-1.82(m,1H),1.75-1.74(m,3H).

[0866] Example 78: Preparation of (R)-4-(2-fluoroethyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (78)

[0867]

[0868] The title compound 78 was prepared in the same manner as in Example 12, except that 1-fluoro-2-iodoethane was used instead of 2-(bromomethyl)tetrahydrofuran.

[0869] MS: m / z = 510.00 [M+H] + .

[0870] 1 H NMR (400MHz, CDCl3) δppm 8.97(s,2H),8.67(s,1H),7.84(s,1H),7.68(s,1H),7.31(m,1H),5.36-5.34(m,1H),4.88(s,2H ),4.88-4.87(m,1H),4.68-4.66(m,1H),4.36-4.30(m,2H),2.60(s,3H),1.75(d,J=5.1Hz,3H).

[0871] Example 79: Preparation of (R)-4-(3-fluoropropyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (79)

[0872]

[0873] The title compound 79 was prepared by the same method as in Example 12, except that 1-fluoro-3-iodopropane was used instead of 2-(bromomethyl)tetrahydrofuran.

[0874] MS: m / z = 524.00 [M+H] + .

[0875] 1 H NMR (400MHz, CDCl3) δppm 8.96(s,2H),8.55(s,1H),7.72(s,1H),7.64(s,1H),7.12(s,1H),5.39-5.32(m,1H),4.85(s,2H),4.61-4 .59(m,1H),4.48-4.47(m,1H),4.20-4.17(m,2H),2.57(s,3H),2.15-2.05(m,2H),1.74(d,J=5.4Hz,3H).

[0876] Example 80: Preparation of (R)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-4-(3,3,3-trifluoropropyl))-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (80)

[0877]

[0878] The title compound 80 was prepared in the same manner as in Example 12, except that 1,1,1-trifluoro-3-iodopropane was used instead of 2-(bromomethyl)tetrahydrofuran.

[0879] MS: m / z = 560.00 [M+H] + .

[0880] 1 H NMR (400MHz, CDCl3) δppm 8.97(s,2H),8.66(s,1H),7.70-7.67(m,2H),7.27(s,1H),5.37-5.35(m,1H) ,4.86(s,2H),4.32-4.278(m,2H),2.59-2.48(m,5H),1.76(d,J=5.1Hz,3H).

[0881] Example 81: Preparation of 4-(1-cyanoethyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (81)

[0882]

[0883] The title compound 81 was prepared in the same manner as in Example 12, except that 2-bromopropionitrile was used instead of 2-(bromomethyl)tetrahydrofuran.

[0884] MS: m / z = 517.00 [M+H] + .

[0885] 1 H NMR (400MHz, CDCl3) δppm 8.96(s,2H),8.56(s,1H),7.96-7.91(m,1H),7.65(s,1H),7.12(s,1H),5.99-5.79(m,1H ), 5.37 (s, 1H), 4.91-4.78 (m, 2H), 2.59 (s, 3H), 1.84-1.81 (m, 3H), 1.74 (d, J = 5.4Hz, 3H).

[0886] Example 82: Preparation of (R)-1-(4,4-difluorocyclohexyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (82)

[0887]

[0888] The title compound 82 was prepared in the same manner as in Example 1, except that 4,4-difluorocyclohexyl 4-methylbenzenesulfonate was used instead of 3-iodooxetane.

[0889] MS: m / z = 551.00 [M+H] + .

[0890] 1 H NMR (300MHz, CDCl3) δppm 8.97(s,2H),8.60(s,1H),8.06(s,2H),7.64(s,1H),7.02-7.00(m,1H),5.44-5.41(m,1H),4 .65-4.64(m,1H),2.59(s,3H),2.34-2.27(m,4H),2.04-1.90(m,4H),1.77(d,J=5.1Hz,3H).

[0891] Example 83: Preparation of 4-(5-methylthiazol-2-yl)-1-((S)-tetrahydrofuran-3-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (83)

[0892]

[0893] The title compound 83 was prepared in the same manner as in Example 1, except that (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate was used instead of 3-iodooxetane.

[0894] MS: m / z = 503.00 [M+H] + .

[0895] 1 H NMR (300MHz, CDCl3) δppm 9.07(s,2H),8.96(s,1H),8.47(s,1H),8.35(s,1H),8.17(s,1H),7.82(s,1H),5.45-5.41(m,2H),4.31-4 .28(m,1H),4.29-4.26(m,2H),4.20-4.19(m,1H),2.88(s,3H),2.55-2.52(m,2H),1.83(d,J=5.4Hz,3H).

[0896] Example 84: Preparation of 4-(5-methylthiazol-2-yl)-1-((R)-tetrahydrofuran-3-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (84)

[0897]

[0898] The title compound 84 was prepared in the same manner as in Example 1, except that (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate was used instead of 3-iodooxetane.

[0899] MS: m / z = 503.00 [M+H] + .

[0900] 1H NMR (300MHz, CDCl3) δppm 8.99(s,2H),8.62(s,1H),8.18-8.15(m,2H),7.67(s,1H),7.04(s,1H),5.43-5.37(m,2H),4 .29-4.21(m,3H),4.04-4.02(m,1H),2.61(s,3H),2.53-2.51(m,2H),1.78(d,J=5.4Hz,3H).

[0901] Example 85: Preparation of (R)-1-(2-cyanoethyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (85)

[0902]

[0903] The title compound 85 was prepared in the same manner as in Example 1, except that 3-bromopropionitrile was used instead of 3-iodooxetane.

[0904] MS: m / z = 486.10 [M+H] + .

[0905] 1 H NMR (300MHz, CDCl3) δppm 9.05(s,2H),8.72(s,1H),8.60(s,1H),8.24(s,1H),7.86(s,1H),7.76(s,1H),5.44-5.41 (m, 1H), 4.78 (t, J = 4.8Hz, 2H), 3.07 (t, J = 4.8Hz, 2H), 2.66 (s, 3H), 1.80 (d, J = 4.8Hz, 3H).

[0906] Example 86: Preparation of (R)-2-(2-cyanoethyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (86)

[0907]

[0908] The title compound 86 was prepared in the same manner as in Example 2, except that 3-bromopropionitrile was used instead of 3-iodooxetane.

[0909] MS: m / z = 486.10 [M+H] + .

[0910] 1H NMR (300MHz, CDCl3): δppm 9.47(s,1H),9.13(s,2H),8.82(s,1H),8.68(s,1H),8.45(s,1H),7.87(s,1H),5.43-5.42 (m, 1H), 4.83 (t, J = 4.5Hz, 2H), 3.21 (t, J = 4.5Hz, 2H), 2.72 (s, 3H), 1.86 (d, J = 5.1Hz, 3H).

[0911] Example 87: Preparation of (R)-1-(cyanomethyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (87)

[0912]

[0913] The title compound 87 was prepared in the same manner as in Example 1, except that 2-bromoacetonitrile was used instead of 3-iodooxetane.

[0914] MS: m / z = 472.10 [M+H] + .

[0915] 1 H NMR (300MHz, CDCl3) δppm 9.04(s,2H),8.67(s,1H),8.53(s,1H),8.18(s,1H),7.75(s,1H),7.52(s,1H),5.43-5.41(m,3H),2.66(s,3H),1.81(d,J=4.8Hz,3H).

[0916] Example 88: Preparation of (R)-2-(cyanomethyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (88)

[0917]

[0918] The title compound 88 was prepared in the same manner as in Example 2, except that 2-bromoacetonitrile was used instead of 3-iodooxetane.

[0919] MS: m / z = 472.00 [M+H] + .

[0920] 1H NMR (300MHz, CDCl3): δppm 9.04(s,2H),8.80(s,1H),8.43(s,1H),8.30(s,1H),7.68(s,1H),7.44(s,1H),5.47-5.42(m,3H),2.62(s,3H),1.80(d,J=4.2 Hz,3H).

[0921] Example 89: Preparation of (R)-1-(2-hydroxy-2-methylpropyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (89)

[0922]

[0923] The title compound 89 was prepared in the same manner as in Example 1, except that 2,2-dimethyloxirane was used instead of 3-iodooxetane.

[0924] MS: m / z = 505.10 [M+H] + .

[0925] 1 H NMR (300MHz, CDCl3) δppm 8.99(s,2H),8.66(s,1H),8.16(s,1H),8.11(s,1H),7.66(s,1H),7.15(s,1H),5 .43-5.41(m,1H),4.41(s,2H),2.61(s,3H),1.77(d,J=5.1Hz,3H),1.24(s,6H).

[0926] Example 90: Preparation of (R)-2-(2-hydroxy-2-methylpropyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (90)

[0927]

[0928] The title compound 90 was prepared in the same manner as in Example 2, except that 2,2-dimethyloxirane was used instead of 3-iodooxetane.

[0929] MS: m / z = 505.10 [M+H] + .

[0930] 1H NMR (300MHz, CDCl3): δppm 9.01(s,2H),8.73(s,1H),8.24(s,1H),8.20(s,1H),7.61(s,1H),7.06(s,1H),5 .43-5.40(m,1H),4.44(s,2H),2.57(s,3H),1.77(d,J=5.4Hz,3H),1.23(s,6H).

[0931] Example 91: Preparation of (R)-1-((1-fluorocyclopropyl)methyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (91)

[0932]

[0933] The title compound 91 was prepared in the same manner as in Example 1, except that (1-fluorocyclopropyl)methyl 4-methylbenzenesulfonate was used instead of 3-iodooxetane.

[0934] MS: m / z = 505.00 [M+H] + .

[0935] 1 H NMR (300MHz, CDCl3) δppm 8.99(s,2H),8.68(s,1H),8.11(s,1H),8.07(s,1H),7.65(s,1H),6.89(s,1H),5.45-5.41(m,1H),4 .84(s,1H),4.79(s,1H),2.60(s,3H),1.76(d,J=5.4Hz,3H),1.16-1.10(m,2H),0.97-0.92(m,2H).

[0936] Example 92: Preparation of (R)-2-((1-fluorocyclopropyl)methyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (92)

[0937]

[0938] The title compound 92 was prepared in the same manner as in Example 2, except that (1-fluorocyclopropyl)methyl 4-methylbenzenesulfonate was used instead of 3-iodooxetane.

[0939] MS: m / z = 505.00 [M+H] + .

[0940] 1H NMR (300MHz, CDCl3): δppm 9.02(s,2H),8.77(s,1H),8.34(s,1H),8.30(s,1H),7.63(s,1H),5.45-5.38(m,1H),4.85(s ,1H),4.79(s,1H),2.58(s,3H),1.76(d,J=5.4Hz,3H),1.27-1.21(m,2H),1.04-0.94(m,2H).

[0941] Example 93: Preparation of (R)-4-((1-fluorocyclopropyl)methyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (93)

[0942]

[0943] The title compound 93 was prepared in the same manner as in Example 12, except that (1-fluorocyclopropyl)methyl 4-methylbenzenesulfonate was used instead of 2-(bromomethyl)tetrahydrofuran.

[0944] MS: m / z = 536.10 [M+H] + .

[0945] 1 H NMR (400MHz, CDCl3) δppm 8.96(s,2H),9.56(s,1H),7.99(s,1H),7.65(s,1H),7.17(s,1H),5.38-5.32(m,1H),4.88(s,2H),4 .47(s,1H),4.38(s,1H),2.58(s,3H),1.73(d,J=5.4Hz,3H),1.14-1.08(m,2H),0.96-0.94(m,2H).

[0946] Example 94: Preparation of 4-(5-methylthiazol-2-yl)-1-(tetrahydrofuran-3-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (94)

[0947]

[0948] The title compound 94 was prepared in the same manner as in Example 1, except that tetrahydrofuran-2-yl 4-methylbenzenesulfonate was used in place of 3-iodooxetane.

[0949] MS: m / z 503.00 [M+H]+ .

[0950] 1 H NMR (300MHz, DMSO-d6) δ9.27(d,J=5.4Hz,1H),9.18(s,2H),8.68(s,1H),8.41(s,1H),8.09(s,1H),7.78(s,1H),5.67-5.61( m,1H),5.41-5.39(m,1H),4.11-3.98(m,2H),3.96-3.91(m,2H),2.43-2.40(m,3H),2.29-2.33(m,2H),1.67(d,J=5.1Hz,3H).

[0951] Example 95: Preparation of 4-(5-methylthiazol-2-yl)-2-(tetrahydrofuran-3-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (95)

[0952]

[0953] The title compound 95 was prepared in the same manner as in Example 2, except that tetrahydrofuran-2-yl 4-methylbenzenesulfonate was used in place of 3-iodooxetane.

[0954] MS: m / z 503.00 [M+H] + .

[0955] 1 H NMR (300MHz, DMSO-d6) δ9.21(d,J=7.14Hz,1H),9.16(s,2H),8.94(s,1H),8.44(s,1H),7.97(s,1H),7.73(s,1H),5.54( s,1H),5.45-5.31(m,1H),4.16-4.08(m,3H),3.93-3.90(m,1H),2.54(m,4H),2.51-2.49(m,1H),1.67(d,J=7.1Hz,3H).

[0956] Example 96: Preparation of 1-((4-methylmorpholin-2-yl)methyl)-4-(5-methylthiazol-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (96)

[0957]

[0958] The title compound 96 was prepared in the same manner as in Example 1, except that (4-methylmorpholin-2-yl)methyl 4-methylbenzenesulfonate was used instead of 3-iodooxetane.

[0959] MS: m / z = 546.10 [M+H] + .

[0960] 1 H NMR (300MHz, CDCl3): δppm: 9.05 (s, 2H), 8.73 (s, 1H), 8.12-8.09 (m, 2H), 7.69- 7.57(m,2H),5.51-5.45(m,1H),4.61-4.53(m,1H),4.35(s,1H),3.93(d,1H,J=8 .3Hz),3.73(t,J=9.0Hz,1H),2.98-2.90(m,1H),2.83-2.78(m,1H),2.62(s,3H ), 2.42 (d, J = 6.0Hz, 3H), 2.33 (s, 1H), 2.18-2.06 (m, 1H), 1.80 (d, J = 6.0Hz, 3H).

[0961] Example 97: Preparation of 2-((4-methylmorpholin-2-yl)methyl)-4-(5-methylthiazol-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (97)

[0962]

[0963] The title compound 97 was prepared by the same method as in Example 2, except that (4-methylmorpholin-2-yl)methyl 4-methylbenzenesulfonate was used instead of 3-iodooxetane.

[0964] MS: m / z = 546.10 [M+H] + .

[0965] 1H NMR (300MHz, CDCl3): δppm: 9.04 (s, 2H), 8.80 (s, 1H), 8.19 (d, J = 6.0Hz, 1H), 7.95 (s, 1H),7.61(s,2H),7.04-7.00(m,1H),5.49-5.44(m,1H),4.64-4.56(m,2H),4.25(s,1H ),3.95(d,J=9.0Hz,1H,),3.81-3.79(m,1H),2.99-2.96(m,1H),2.79-2.77(m,1H),2 .52(s,3H),2.41(s,3H),2.26-2.24(m,1H),2.08-2.06(m,1H),1.80(d,J=9.0Hz,3H).

[0966] Example 98: Preparation of (R)-1-(2-fluoroethyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (98)

[0967]

[0968] The title compound 98 was prepared in the same manner as in Example 1, except that 1-fluoro-2-iodoethane was used instead of 3-iodooxetane.

[0969] MS: m / z 479.00 [M+H] + .

[0970] 1 H NMR (300MHz, CDCl3) δppm: 9.01 (s, 2H), 8.65 (s, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.65 (s, 1H) ), 7.20 (s, 1H), 5.46-5.39 (m, 1H), 4.95-4.71 (m, 4H), 2.60 (s, 3H), 1.78 (d, J = 5.4Hz, 3H).

[0971] Example 99: Preparation of (R)-2-(2-fluoroethyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (99)

[0972]

[0973] The title compound 99 was prepared in the same manner as in Example 2, except that 1-fluoro-2-iodoethane was used instead of 3-iodooxetane.

[0974] MS: m / z 479.00 [M+H] + .

[0975] 1 H NMR (300MHz, CDCl3) δppm: 9.00 (s, 2H), 8.76 (s, 1H), 8.21 (s, 1H), 8.10 (s, 1H), 7.59 (s, 1H) ), 7.00 (s, 1H), 5.43-5.39 (m, 1H), 5.02-4.74 (m, 4H), 2.56 (s, 3H), 1.76 (d, J = 5.4Hz, 3H).

[0976] Example 100: Preparation of (R)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1-(3,3,3-trifluoropropyl)-1H-indazole-6-carboxamide (100)

[0977]

[0978] The title compound 100 was prepared in the same manner as in Example 1, except that 1,1,1-trifluoro-3-iodopropane was used instead of 3-iodooxetane.

[0979] MS: m / z 529.10 [M+H] + .

[0980] 1 H NMR (300MHz, CDCl3) δppm: 9.05 (s, 2H), 8.75 (s, 1H), 8.55 (s, 1H), 8.21 (s, 1H), 7.89 (s, 1H), 7.77 (s, 1H), 5.45-5.41 (m, 1H), 4.72 (t, J = 5.4Hz, 2H), 2.87-2.81 (m, 2H), 2.67 (s, 3H), 1.82 (d, J = 5.4Hz, 3H).

[0981] Example 101: Preparation of (R)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2-(3,3,3-trifluoropropyl)-2H-indazole-6-carboxamide (101)

[0982]

[0983] The title compound 101 was prepared in the same manner as in Example 2, except that 1,1,1-trifluoro-3-iodopropane was used instead of 3-iodooxetane.

[0984] MS: m / z 529.10 [M+H]+ .

[0985] 1 H NMR (300MHz, CDCl3) δppm: 9.02 (s, 2H), 8.67 (s, 1H), 8.34 (s, 1H), 8.27 (s, 1H), 7.65 (s, 1H), 5. 45-5.39(m,1H),4.74(t,J=5.4Hz,2H),3.02-2.91(m,2H),2.60(s,3H),1.78(d,J=5.4Hz,3H).

[0986] Example 102: Preparation of (R)-1-(3-fluoropropyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (102)

[0987]

[0988] The title compound 102 was prepared in the same manner as in Example 1, except that 1-fluoro-3-iodopropane was used instead of 3-iodooxetane.

[0989] MS: m / z 493.00[M+H] + .

[0990] 1 H NMR (300MHz, CDCl3) δppm: 8.99 (s, 2H), 8.65 (s, 1H), 8.12 (s, 1H), 8.04 (s, 1H), 7.66 (s, 1H), 6.96 (s ,1H),5.46-5.39(m,1H),4.63-4.36(m,4H),2.60(s,3H),2.42-2.29(m,2H),1.78(d,J=5.4Hz,3H).

[0991] Example 103: Preparation of (R)-2-(3-fluoropropyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (103)

[0992]

[0993] The title compound 103 was prepared in the same manner as in Example 2, except that 1-fluoro-3-iodopropane was used instead of 3-iodooxetane.

[0994] MS: m / z 493.10 [M+H] + .

[0995] 1 H NMR (300MHz, CDCl3) δppm: 8.98 (s, 2H), 8.73 (s, 1H), 8.19 (s, 1H), 8.06 (s, 1H), 7.60 (s, 1H), 6.88 (s ,1H),5.44-5.37(m,1H),4.67-4.40(m,4H),2.56(s,3H),2.52-2.39(m,2H),1.75(d,J=5.4Hz,3H).

[0996] Example 104: Preparation of (R)-1-(2-fluoro-2-methylpropyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (104)

[0997]

[0998] The title compound 104 was prepared in the same manner as in Example 1, except that 2-fluoro-2-methylpropyl 4-methylbenzenesulfonate was used instead of 3-iodooxetane.

[0999] MS: m / z 507.20 [M+H] + .

[1000] 1 H NMR(300MHz, CDCl3)δppm:9.03(s,2H),8.59(s,1H),8.48(s,1H),8.19(s,1H),7.72(s,1H),7.52(s,1H),5.43 -5.38(m,1H),4.63(d,J=15.9Hz,2H),2.63(s,3H),1.79(d,J=5.4Hz,3H),1.40(dd,J1=15.9Hz,J2=2.1Hz,6H).

[1001] Example 105: Preparation of (R)-2-(2-fluoro-2-methylpropyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (105)

[1002]

[1003] The title compound 105 was prepared in the same manner as in Example 2, except that 2-fluoro-2-methylpropyl 4-methylbenzenesulfonate was used instead of 3-iodooxetane.

[1004] MS: m / z 507.10 [M+H] + .

[1005] 1 H NMR (300MHz, CDCl3) δppm: 8.99 (s, 2H), 8.77 (s, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.61 (s, 1H), 6.89 (s, 1H) ,5.45-5.38(m,1H),4.63(d,J=15.9Hz,2H),2.57(s,3H),1.76(d,J=5.1Hz,3H),1.40(d,J=15.9Hz,6H).

[1006] Example 106: Preparation of (R)-4-(2-fluoro-2-methylpropyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl))-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (106)

[1007]

[1008] The title compound 106 was prepared by the same method as in Example 12, except that 2-fluoro-2-methylpropyl 4-methylbenzenesulfonate was used instead of 2-(bromomethyl)tetrahydrofuran.

[1009] MS: m / z 538.10[M+H] + .

[1010] 1 H NMR(300MHz, CDCl3)δppm:8.95(s,2H),8.51(s,1H),7.96(s,1H),7.63(s,1H),7.06(s,1H),5.38-5.31(m,1 H), 4.86 (s, 2H), 4.33-4.16 (m, 2H), 2.57 (s, 3H), 1.73 (d, J = 5.4Hz, 3H), 1.43 (dd, J1 = 15.9Hz, J2 = 4.8Hz, 6H).

[1011] Example 107: Preparation of (R)-4-(5-methylthiazol-2-yl)-1-(2,2,2-trifluoroethyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (107)

[1012]

[1013] The title compound 107 was prepared in the same manner as in Example 1, except that 1,1,1-trifluoro-2-iodoethane was used instead of 3-iodooxetane.

[1014] MS: m / z 515.00 [M+H] + .

[1015] 1 H NMR(400MHz, CDCl3)δppm:9.00(s,2H),8.72(s,1H),8.23(s,1H),8.07(s,1H),7.67(s,1H ), 7.20 (s, 1H), 5.46-5.41 (m, 1H), 5.07-5.01 (m, 1H), 2.61 (s, 3H), 1.78 (d, J = 6.8Hz, 3H).

[1016] Example 108: Preparation of (R)-4-(5-methylthiazol-2-yl)-2-(2,2,2-trifluoroethyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (108)

[1017]

[1018] The title compound 108 was prepared in the same manner as in Example 2, except that 1,1,1-trifluoro-2-iodoethane was used instead of 3-iodooxetane.

[1019] MS: m / z 515.00[M+H] + .

[1020] 1 H NMR(400MHz, CDCl3)δppm:9.02(s,2),8.70(s,1),8.37(s,1),8.12(s,1),7.72(s,1 ),7.36(s,1),5.45-5.42(m,1),5.06-5.02(m,2),2.63(s,3),1.79(d,J=7.2Hz,3).

[1021] Example 109: Preparation of (R)-1-isobutyl-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (109)

[1022]

[1023] The title compound 109 was prepared in the same manner as in Example 1, except that 1-iodo-2-methylpropane was used instead of 3-iodooxetane.

[1024] MS: m / z 489.00 [M+H] + .

[1025] 1 H NMR(400MHz, CDCl3)δppm:9.04(s,2),8.59(s,1),8.50(s,1),8.40(s,1),7.70(s,1),7.52(s,1),5.51-5 .34(m,1H),4.30(d,J=7.3Hz,2H),2.62(s,3H),2.45(s,1H),1.79(d,J=7.1Hz,3H),0.98(d,J=7.2Hz,6H).

[1026] Example 110: Preparation of (R)-2-isobutyl-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (110)

[1027]

[1028] The title compound 110 was prepared in the same manner as in Example 2, except that 1-iodo-2-methylpropane was used instead of 3-iodooxetane.

[1029] MS: m / z 489.00[M+H] + .

[1030] 1 H NMR(400MHz, CDCl3)δppm:8.97(s,2H),8.59(s,1H),8.10(s,1H),8.05(s,1H),7.64(s,1H),7.09-7.07(m,1H),5.4 6-5.39(m,1H),4.25(d,J=3.6Hz,2H),2.59(s,3H),2.42-2.32(m,1H),1.76(d,J=7.2Hz,3H),0.92(d,J=6.8Hz,6H).

[1031] Example 111: Preparation of (R)-8-(5-methylthiazol-2-yl)-3-oxo-4-(2,2,2-trifluoroethyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl))-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (111)

[1032]

[1033] The title compound 111 was prepared by the same method as in Example 12, except that 1,1,1-trifluoro-2-iodoethane was used instead of 2-(bromomethyl)tetrahydrofuran.

[1034] MS: m / z 545.90 [M+H]+ .

[1035] 1 H NMR(300MHz, CDCl3)δppm:9.14(s,1H),9.02(s,2H),7.94(s,1H),7.89(s,1H),7.78(s,1H),5.39-5 .32(m,1H),4.95(s,2H),4.76-4.69(m,1H),4.67-4.59(m,1H),2.64(s,3H),1.80(d,J=5.4Hz,3H).

[1036] Example 112: Preparation of (R)-4-isobutyl-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (112)

[1037]

[1038] The title compound 112 was prepared in the same manner as in Example 12, except that 1-iodo-2-methylpropane was used instead of 2-(bromomethyl)tetrahydrofuran.

[1039] MS: m / z 520.00[M+H] + .

[1040] 1 H NMR(300MHz, CDCl3)δppm:8.98(s,2H),8.71(s,1H),7.74(s,1H),7.68(s,1H),7.44(s,1H),5.38-5.31(m,1H),4 .86(s,2H),3.89(d,J=6.0Hz,2H),2.60(s,3H),2.13-2.08(m,1H),1.77(d,J=5.4Hz,2H),0.96(d,J=4.8Hz,6H).

[1041] Example 113: Preparation of (R)-4-(5-methylthiazol-2-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (113)

[1042]

[1043] The title compound 113 was prepared in the same manner as in Example 1, except that (1-(trifluoromethyl)cyclopropyl)methyl 4-methylbenzenesulfonate was used instead of 3-iodooxetane.

[1044] MS: m / z 555.00 [M+H] + .

[1045] 1 H NMR (400MHz, CDCl3) δppm: 9.00 (s, 2H), 8.63 (s, 1H), 8.19 (s, 1H), 8.08 (s, 1H), 7.67 (s, 1H), 7.1 (s, 1H), 5.4 4-5.41(m,1H),4.77-4.67(m,2H),2.61(s,3H),1.78(d,J=7.2Hz,3H),1.11-1.00(m,2H),0.86-0.84(m,2H).

[1046] Example 114: Preparation of (R)-4-(5-methylthiazol-2-yl)-2-((1-(trifluoromethyl)cyclopropyl)methyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (114)

[1047]

[1048] The title compound 114 was prepared in the same manner as in Example 2, except that (1-(trifluoromethyl)cyclopropyl)methyl 4-methylbenzenesulfonate was used instead of 3-iodooxetane.

[1049] MS: m / z 555.00[M+H] + .

[1050] 1 H NMR(400MHz, CDCl3)δppm:9.00(s,2H),8.72(s,1H),8.23(s,1H),8.19(s,1H),7.63(s,1H),7.04(s,1H), 5.44-5.37(m,1H),4.71(s,2H),2.58(s,3H),1.76(d,J=7.2Hz,3H),1.19-1.09(m,2H),0.88-0.83(m,2H).

[1051] Example 115: Preparation of (R)-8-(5-methylthiazol-2-yl)-3-oxo-4-((1-(trifluoromethyl)cyclopropyl)methyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl))ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (115)

[1052]

[1053] The title compound 115 was prepared by the same method as in Example 12, except that (1-(trifluoromethyl)cyclopropyl)methyl 4-methylbenzenesulfonate was used instead of 2-(bromomethyl)tetrahydrofuran.

[1054] MS: m / z 585.90 [M+H] + .

[1055] 1 H NMR (300MHz, CDCl3) δppm:9.67(s,1H),9.07(s,2H),8.96(s,1H),8.09(s,1H),7.92(s,1H),5.36-5.35(m,1H ), 4.90 (s, 2H), 4.43-4.33 (m, 2H), 2.69 (s, 3H), 1.82 (d, J = 5.1Hz, 3H), 1.08-1.07 (m, 2H), 0.92-0.90 (m, 2H).

[1056] Example 116: Preparation of (R)-4-(2,2-difluoropropyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (116)

[1057]

[1058] The title compound 116 was prepared by the same method as in Example 12, except that 2,2-difluoropropyl 4-methylbenzenesulfonate was used instead of 2-(bromomethyl)tetrahydrofuran.

[1059] MS: m / z 541.90 [M+H] + .

[1060] 1 H NMR(300MHz, CDCl3)δppm:8.97(s,2H),8.63(s,1H),7.87(s,1H),7.65(s,1H),7.30-7.29( m,1H),5.39-5.32(m,1H),4.89(s,2H),4.54-4.34(m,2H),2.58(s,3H),1.75-1.64(m,6H).

[1061] Example 117: Preparation of 4-(2-fluoroethyl)-2-methyl-8-(5-methylthiazol-2-yl)-3-oxo-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (117)

[1062]

[1063] Step 1: Preparation of 4-(2-fluoroethyl)-2-methyl-8-(5-methylthiazol-2-yl)-3-oxo-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (117)

[1064] 2-Methyl-8-(5-methylthiazol-2-yl)-3-oxo-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (117a) (100 mg, 0.210 mmol) (prepared as in Example 11, except that 2-chloropropionyl chloride was used instead of chloroacetyl chloride to obtain Intermediate 117a), 1-fluoro-2-iodoethane (72.9 mg, 0.420 mmol), and CsCO (138 mg, 0.420 mmol) were dissolved in DMF (3 mL) at room temperature. The reaction mixture was stirred at 50°C overnight. The reaction mixture was concentrated under reduced pressure, and 10 mL of water was added to the residue, followed by extraction with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (column model: Daisogei 30 mm × 250 mm, C18, 10 μm, 100A, mobile phase: acetonitrile / water, gradient: 30%-80%) to give 50.0 mg of the title compound as a white solid, yield: 45%.

[1065] MS: m / z 523.90 [M+H] + .

[1066] 1 H NMR(300MHz, CDCl3)δppm:8.99(s,2H),8.79(s,1H),7.84(s,1H),7.70(s,1H),7.46(s,1H),5.37-5.34(m,1H) ,4.77-4.76(m,1H),4.67-4.66(m,1H),4.65-4.64(m,1H),4.36-4.22(m,2H),2.61(s,3H),1.77-1.72(m,6H).

[1067] Example 118: Preparation of 4-(3-fluoropropyl)-2-methyl-8-(5-methylthiazol-2-yl)-3-oxo-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (118)

[1068]

[1069] The title compound 118 was prepared in the same manner as in Example 117, except that 1-fluoro-3-iodopropane was used instead of 1-fluoro-2-iodoethane.

[1070] MS: m / z 538.00[M+H] + .

[1071] 1 H NMR (300MHz, CDCl3) δppm: 9.37 (s, 1H), 9.05 (s, 2H), 8.33 (s, 1H), 7.85-7.83(m,2H),5.36-5.34(m,1H),4.96-4.95(m,1H),4.60-4.58(m,1H),4.50-4.47(m,1H), 4.20-4.17(m,2H),2.66(s,3H),2.13-2.25(m,2H),1.81(d,J=5.1Hz,3H),1.71(d,J=4.8Hz,3H).

[1072] Biological evaluation

[1073] Test Example 1: Evaluation of the inhibitory activity of the compounds of the present invention on human P2X3 receptors

[1074] Fluorescence Image Plate Reader (FLIPR, Molecular Devices, 0296) was used to monitor changes in intracellular calcium levels to evaluate the inhibitory activity of the compounds of the present invention on human P2X3 receptors.

[1075] Experimental procedure: HEK293-pCMV6-P2X3 cell line (Pharmaron, Clone #34) was revived and inoculated in complete medium (DMEM, high glucose (31053028, Gibco) + 10% fetal bovine serum (FBS) (Gibco, 10099141) + 4mM GlutaMAX (Gibco, 35050-061) + 1× penicillin-streptomycin, liquid (100×, Gibco, 15140-122) + 350 μg / ml geneticin (Invitrogen, 10131-027) were cultured in a 37°C, 5% CO2 incubator. When the cells reached 70% to 90% confluency, they were digested with trypsin (Thermofisher, 12604021) and resuspended in cell seeding medium (DMEM, high glucose (31053028, Gibco) + 2% fetal bovine serum (FBS) (Gibco, 10099141) + 4mM GlutaMAX (Gibco, 35050-061) was added and 11,000 cells / well / 25 μL was seeded into a 384-well cell culture plate (Corning, 3845) and cultured in a 37°C, 5% CO2 incubator for 22 hours. Component A powder (FLIPR Calcium 6 Assay Kit, Molecular Devices, R8191) was diluted to 2× working concentration with assay buffer (1× HBSS (Gibco, 14025076) + 20 mM HEPES (Gibco, 15630080)) and equilibrated to room temperature for use. The 384-well cell culture plate was equilibrated at room temperature for 10 minutes, the culture medium was removed, and 25 μL assay buffer and 25 μL Centrifuge 2× Fraction A at 200g for 3-5 seconds at room temperature and incubate at 37°C for 2 hours. Dilute α,β-MeATP (Sigma, M6517) to 2.1 μM in assay buffer, transfer 50 μL to a 384-well plate, and incubate at room temperature. Remove the plate and incubate at room temperature for 10 minutes. Add the test compound working solution (starting at 10,000 nM, diluted 3-fold in cell seeding medium to a final DMSO concentration of 0.1%) to the corresponding wells of the 384-well plate and incubate at room temperature for 30 minutes. Add 10 μL of the diluted α,β-MeATP to the corresponding wells using a FLIPR Tetra (Molecular Devices, 0296). Fluorescence data were collected using an excitation wavelength of 470-495 nm and an emission wavelength of 515-575 nm.

[1076] Compound IC was calculated using GraphPad's four-parameter nonlinear fitting formula.50 :

[1077]

[1078] X: log value of compound concentration; Y: ratio.

[1079] The inhibitory activity of the compounds of the present invention on P2X3 receptors is shown in Table 1 below. Wherein, A represents IC 50 <200nM; B represents IC 50 =200-500nM; C represents IC 50 =500-1000nM; D represents IC 50 >1000nM.

[1080] Table 1. IC inhibition of P2X3 receptors by the compounds of the present invention 50 value

[1081] Compound <![CDATA[P2X3 IC 50 (nM)]]> Example 1 A Example 2 B Example 3 D Example 4 D Example 5 C Example 6 C Example 7 C Example 8 A Example 11 D Example 12 A Example 13 A Example 14 D Example 15 D Example 16 C Example 17 C Example 18 A Example 19 C Example 20 A Example 21 B Example 22 A Example 23 A Example 24 A Example 25 B Example 26 B Example 27 A Example 28 A Example 29 B Example 30 C Example 31 D Example 32 D Example 33 B Example 34 B Example 35 B

[1082] Example 36 A Example 37 A Example 38 B Example 39 B Example 40 A Example 41 B Example 42 A Example 43 A Example 44 B Example 45 A Example 46 B Example 47 B Example 48 A Example 49 B Example 50 A Example 51 B Example 52 B Example 53 B Example 54 B Example 55 B Example 56 C Example 57 A Example 58 A Example 59 A Example 60 A Example 61 B Example 62 B Example 63 B Example 64 D Example 65 B Example 66 B Example 67 A Example 68 A Example 69 A Example 70 B

[1083] Example 71 B Example 72 B Example 73 B Example 74 A Example 75 A Example 76 D Example 77 D Example 78 A Example 79 A Example 80 A Example 81 A Example 82 B Example 83 A Example 84 A Example 85 A Example 86 A Example 87 A Example 88 B Example 89 A Example 90 A Example 91 A Example 92 A Example 93 A Example 94 A Example 95 B Example 96 B Example 97 C Example 98 A Example 99 A Example 100 A Example 101 A Example 102 A Example 103 A Example 104 A Example 105 B

[1084] Example 106 B Example 107 A Example 108 A Example 109 B Example 110 A Example 111 A Example 112 A Example 113 B Example 114 B Example 115 B Example 116 A Example 117 A Example 118 A

[1085] Conclusion: As shown in Table 1 above, the compounds of the present invention exhibit significant P2X3 receptor antagonist activity.

[1086] Test Example 2: In vitro P2X2 / 3 receptor selectivity evaluation

[1087] The selectivity of the compounds of the present invention for P2X2 / 3 receptors was determined using a fluorescence image plate reader (FLIPR, Molecular Devices, 0296), and the changes in intracellular calcium levels were monitored to evaluate the inhibitory activity of the compounds of the present invention on human P2X2 / 3 receptors.

[1088] Experimental Procedure: HEK293 / hP2X2 / X3 cells (Bioduro clone #164) were revived and seeded into 384-well plates coated with 1X Matrigel (BD Bioscience, 354230) at 5 μL / well. The cells were incubated at 37°C in a 5% CO2 incubator for 30 minutes. The cells were then treated by removing the culture medium (DMEM, high glucose (31053028, Gibco) + 10% FBS + 4 mM GlutaMAX + 1X PS + 350 μg / ml G418), washing once with PBS, and digesting the cells with 0.25% Trypsin-EDTA (Invitrogen, 25200056). The cell density was adjusted to 7.5 × 10 5 / mL. Add the diluted cells to a 384-well assay plate (Corning, 3709) at 20 μL / well. Incubate the plate in a 37°C, 5% CO2 incubator overnight. Discard the cell culture medium from the 384-well assay plate and add 20 μL / well of freshly prepared Fluo-8 buffer (AAT Bioquest, 21080). Incubate in a 37°C, 5% CO2 incubator in the dark for 1 hour.

[1089] Prepare various compound concentrations (10 μM starting concentration, 3-fold serial dilutions for a total of 10 concentrations) and add 5 μL / well to a 384-well assay plate. Incubate at 37°C in a 5% CO2 incubator for 30 minutes. Prepare αββC80 inoculum (TOCRIS, 3209) at a 6X EC80 and add 5 μL / well to the 384-well assay plate using a FLIPR for data collection.

[1090] The inhibitory activity of the compounds of the present invention on P2X3 / 3 receptors is shown in Table 2 below. 50 >10000nM; B represents IC 50 =10000-1000nM; C represents IC 50 =1000-100nM; D represents IC 50 <100nM.

[1091] Table 2. IC inhibition of P2X2 / 3 receptors by the compounds of the present invention 50 value

[1092] Compound <![CDATA[P2X2 / 3 IC 50 (nM)]]> Example 21 A Example 60 A

[1093] Conclusion: As shown in Table 2 above, the compounds of the present invention showed no significant antagonistic activity against P2X2 / 3 receptors, and other examples in the present invention also did not show significant antagonistic effects against P2X2 / 3.

[1094] Test Example 3: Efficacy of the compounds of the present invention on the ATP-citrate guinea pig acute cough model

[1095] Animals: Dunkin Hartley guinea pigs, male, 250–400 g, purchased from Fangyuanyuan Farm in Beijing, ordinary grade, animal production license number: SCXK (Beijing) 2020-0001.

[1096] Experimental procedure: 56 male guinea pigs were selected and divided into a model control group, Example 21 group, Example 80 group, Example 81 group, Example 93 group, Example 98 group, and Example 116 group, with 8 animals in each group. 45 minutes before stimulating the guinea pigs to cough, each group was given 40 mg / kg of the corresponding drug. First, 2 mg / mL ATP (Sigma) solution was ultrasonically atomized and inhaled to sensitize the guinea pigs for 1 minute. After the guinea pigs developed a cough, they were quickly taken out and allowed to move freely for 3 minutes. 5 minutes later, 2 M citric acid solution was atomized and inhaled to induce cough for 5 minutes. From the start of the citric acid atomization, the cough latency and the number of coughs in the guinea pigs were observed within 5 minutes. Based on the cough latency and the number of coughs in the guinea pigs, the antitussive effect of the compound of the present invention on the guinea pig cough model was evaluated.

[1097] The therapeutic effects of the compounds of the present invention on the ATP-citrate guinea pig acute cough model are shown in Table 3 below.

[1098] Table 3. Changes in the incubation period of cough in guinea pigs

[1099]

[1100] Note: * : P<0.05vs model group; ** : P < 0.01 vs. model group, T-test. Cough inhibition rate (%) = (average cough times in model group - average cough times in drug-administered group) / average cough times in model group * 100%.

[1101] Conclusion: As shown in Table 3 above, the compounds of the present invention can significantly reduce the frequency of coughs and prolong the average cough latency.

[1102] Test Example 4: Pharmacokinetics

[1103] Animals: Wistar male rats, 180-220 g, 7-8 weeks old, purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd., SPF grade, animal production license number: SCXK (Beijing) 2016-0011.

[1104] Experimental Procedure: An oral dose of 3 mg / kg was used. Animals were anesthetized using inhalation anesthesia with the following parameters: flow rate: 1.0 L / min, oxygen pressure: 0.1 MPa, solubility: 4.5%, and anesthesia duration: 3 minutes. After anesthesia, 0.5 mL of blood was collected from the animal's orbital cavity. The blood collection tube was pre-anticoagulated with 10 mg / mL lithium heparin to plasma at a volume ratio of 1:10. After mixing the blood and anticoagulant, the tube was centrifuged at 3000 rpm for 10 minutes. The supernatant was collected and frozen at -20°C until further use. A 50 μL plasma sample was placed in a 1.5 mL EP tube, 5 μL of internal standard working solution was added, and the tube was vortexed for 60 seconds to mix thoroughly. After vortexing, 0.2 mL of acetonitrile was added, the tube was vigorously vortexed for 1 minute, and the tube was centrifuged at 16,000 rpm for 10 minutes. 0.2 mL of the supernatant was removed, filtered through a 0.22 μm filter, and transferred to a sample vial for analysis. Separate and measure under mass spectrometry conditions (Waters, TQ-S micro), and record the peak area of ​​each sample and internal standard.

[1105] LC / MS / MS parameters:

[1106] Mobile phase A: 0.1% formic acid in acetonitrile

[1107] Mobile phase B: 0.1% formic acid in water

[1108] Chromatographic column: Waters UPLC C18 1.7μm, 2.1*50mm

[1109] gradient:

[1110]

[1111] The data processing software was used to integrate the analyte and the internal standard to obtain the peak area. The concentration of the analyte (x) was used as the horizontal axis, and the peak area ratio of the analyte to the internal standard (y) was used as the vertical axis. The weighted least square method (weight 1 / x 2 ) was used for regression calculation, and the resulting linear regression equation was used as the plasma calibration curve. Statistical analysis was performed using DAS to obtain various pharmacokinetic parameters and drug-time curves.

[1112] Table 4. Pharmacokinetic parameters of the compounds of the present invention

[1113]

[1114]

[1115] Conclusion: As shown in Table 4 above, the compounds of the present invention have good pharmacokinetic properties.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, in: Ring A is thiazolyl; Selected from: wherein each B ring is independently optionally further substituted with a C1-C6 alkyl group; W 1 and W 2 CR 6 ; L 1 for L 2 Selected from single bonds, -CO-; Every R 1 Each independently selected from C1-C6 alkyl; R 2 is selected from pyrimidinyl, pyrazinyl or pyridazinyl; which is optionally further substituted by one or more groups selected from C1-C6 alkyl, C1-C6 haloalkyl; R 3 selected from hydrogen, halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4 to 7 membered heterocyclyl, C6-C 10 Aryl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl, 4 to 7 membered heterocyclic group, C6-C 10 Aryl is optionally further selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)OR a One or more groups are substituted; R 4 and R 5 Each is independently selected from hydrogen, C1-C6 alkyl; Every R 4’ and R 5’ Each is independently selected from hydrogen, C1-C6 alkyl; R 6 selected from hydrogen; R a Selected from C1-C6 alkyl m is 1 or 2; and n is 0 or 1.

2. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, in, B ring, R 1 、R 2 、R 3 、L 1 、L 2 and n as defined in claim 1.

3. The compound represented by general formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: L 2 Selected from single bond, -(CH2) m -and-CO-; R 3 is selected from 4 to 6 membered heterocyclic groups, wherein the 4 to 6 membered heterocyclic groups are optionally further selected from halogen, oxo, C1-C6 alkyl, -C(O)OR a One or more groups are substituted; R a Selected from C1-C6 alkyl; m is 1 or 2.

4. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein L 2 is selected from a single bond, -CH2- and -CO-; R 3 Selected from C3-C6 cycloalkyl, the C3-C6 cycloalkyl is optionally further substituted by one or more groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl.

5. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: L 2 is selected from a single bond, -CH2- and -CO-; R 3 is selected from phenyl, which is optionally further substituted by one or more groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy.

6. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: L 2 Selected from single bond, -(CH2) m - and -(CH)CH3-; R 3 Selected from cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, wherein the C1-C6 alkyl is optionally further substituted by one or more groups selected from halogen and hydroxy; m is 1 or 2.

7. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: L 1 for 8. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

9. A method for preparing the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, comprising the following steps: In the presence of a condensing agent, compound Ig and compound Ih undergo a condensation reaction under alkaline conditions to obtain a compound represented by general formula (I). Among them, A ring, B ring, W 1 、W 2 、R 1 、R 2 、R 3 , L 1 , L 2 , n as defined in claim 1.

10. The method according to claim 9, wherein: The reagent providing alkaline conditions is DIPEA, and the condensation agent is HATU.

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11, in the preparation of a P2X3 receptor antagonist.

13. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11, in the preparation of a medicament for preventing and / or treating a disease associated with P2X3 receptor activity, wherein the disease is acute cough and chronic cough.

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