Annulene compounds and uses thereof

Abstract

The application provides a fused ring compound described in formula I and application thereof. The fused ring compound of the application has Nav1.8 selective inhibitory activity, and can be used as a Nav inhibitor and for preparing a medicine for treating and / or relieving pain and pain related diseases.

Description

[0001] Priority Information

[0002] The present application claims priority to the Chinese patent application No. 2022104406606 entitled "Fused ring compounds and applications thereof" filed on April 25, 2022 with the State Intellectual Property Office of China, and the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0003] The present application relates to the field of medicine, in particular to a class of fused ring compounds and their application as Nav inhibitors and their application in the preparation of drugs for treating and / or alleviating pain and pain-related diseases. BACKGROUND

[0004] Pain is one of the most common symptoms in clinical practice, nociceptive pain is caused by any destructive or potentially harmful stimulus, neuropathic pain is caused by damage or disease of the somatosensory nervous system. When the normal structure of neurons is destroyed, hyperalgesia or absence symptoms can occur. The body perceives pain as a process of generating and transmitting between neurons by nociceptive stimuli, and the activity of sodium ion channels is an important factor for neurons to conduct excitatory stimuli. Damage to sodium ion channels can easily lead to neuronal damage, resulting in pain perception disorders.

[0005] Sodium ion channels are ion channels formed by intrinsic membrane proteins that allow sodium ions to pass through the cell membrane, composed of alpha subunits (pore-forming proteins) and beta subunits (regulatory proteins). Voltage-gated sodium channels (VGSCs) can be divided into 9 subtypes according to the different alpha subunits, respectively Na v 1.1-1.9 [Genome Biol, 2003, 4(3): 2071-2077.]. According to the sensitivity to tetrodotoxin (TTX), the VGSCs family can be divided into two major categories: tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R), among which VGSCs subtypes Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6, Nav1.7 belong to TTX-S, and Nav1.5, Nav1.8, Nav1.9 belong to TTX-R [Neuron, 2000, 26(1): 13-25.].

[0006] Nav1.8 belongs to TTX-R type, and the encoding gene is SCN10A located in human chromosome 3p21-22 region. Nav1.8 protein is composed of α and β subunits, and the α subunit is the main functional unit. Each α subunit is surrounded by 4 homologous domains to form a central pore of Nav1.8, and each domain contains 6 α-helical transmembrane structures (S1-S6), in which the conserved S4 is the voltage sensor of sodium ion channel. The β subunit mainly has 4 subtypes β1-β4, and in humans, it is mainly β1 and β3, which plays an auxiliary role in the localization and stability of α in the cell membrane, and also participates in the inactivation and voltage sensitivity of α subunit [J Biol Chem, 2004, 279: 24826-24833]. Nav1.8 is mainly expressed in peripheral sensory neurons, such as dorsal root ganglion (DRG) neurons, and the activation threshold of this sodium channel is high, mainly mediating the rising phase of action potential, i.e. the influx of sodium ions [J Neurophysiol, 2001, 86: 629-640]. Nav1.8 plays a very important role in chronic pain. In the carrageenan-induced inflammatory pain model, the mRNA of Nav1.8 and its corresponding TTX-R current are significantly increased [Neuroreport, 1998, 9, 967-972]. Injection of complete Freund's adjuvant (CFA) can increase the mRNA of Nav1.8 in the trigeminal nerve by 2.5 times [J Pain, 2008, 9: 522-531]. Injection of Nav1.8 antisense nucleotide can block the spontaneous pain and hyperalgesia caused by CFA and reduce mechanical pain sensitivity [Pain, 2006, 123: 75-82.]. In some chronic neuropathic pain models, the expression of Nav1.8 in DRG is significantly up-regulated, and high-selectivity Nav1.8 blockers can block mechanical hyperalgesia [Proc Natl Acad Sci USA, 2007, 104: 8520-8525; Neuropharmacology, 2010, 59: 201-207.]. According to a series of studies, Nav1.8 is a high-selectivity pain treatment target, and Nav1.8 selective inhibitors are expected to become a new therapy for treating various types of pain such as inflammatory pain, neuropathic pain, postoperative pain and cancer pain.

[0007] Due to the relative conservation between most voltage-gated sodium ion channel subtypes, lack of selective therapy can cause serious side effects. Navl.8 is mainly distributed in the peripheral nervous system, so selective inhibition of Navl.8 is expected to effectively reduce side effects. Therefore, it is necessary to develop high-activity and high-selectivity Navl.8 inhibitors in clinical applications.

[0008] In view of the above, the present application is proposed. SUMMARY

[0009] One of the objects of the present application is to provide a fused ring compound.

[0010] Another object of the present application is to provide a pharmaceutical composition comprising the fused ring compound.

[0011] Still another object of the present application is to provide use of the fused ring compound or the pharmaceutical composition in the manufacture of a Nav1.8 inhibitor or in the manufacture of a medicament for treating, preventing or controlling a disease or a symptom associated with Nav1.8 channel.

[0012] In order to achieve the above object of the present application, the following technical solutions are adopted:

[0013] In one aspect, the present application provides a compound of Formula I, or a prodrug, tautomer, meso, racemic, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof,

[0014]

[0015] wherein:

[0016] A ring is selected from C6-C12 aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, C3-C8 cycloalkyl, and 3-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S;

[0017] Preferably, A ring is phenyl, pyridyl, thienyl, furanyl, pyrrolidinyl, in particular, A ring is phenyl or pyridyl;

[0018] (R 1 ) m represents m R 1 substituents, m is 0, 1, 2, 3, 4 or 5, preferably 0, 1 or 2;

[0019] R 1 each independently selected from hydrogen atom, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, halo C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, hydroxy, C1-C6 hydroxyalkyl, cyano, amino (-NH2), C1-C6 alkylamino, nitro, amidino, -C(=NOH)NH2, carboxyl, oxo (=O), thioxo (=S), -NHSO2NH2, -SO2Me, -CH2OR e , -SO2N(R f )2, -CON(R f2. C3-C8 cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, and C1-C6 alkyl groups substituted with heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, particularly, R 1 Each is independently selected from hydrogen atom, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxyl, C1-C6 hydroxyalkyl, cyano, amino (-NH2), nitro, amidine, carboxyl, oxo (=O), thio (=S), -NHSO2NH2, -SO2Me, -CH2OR e -SO2N(R) f )2、-CON(R f )2. C3-C8 cycloalkyl, 3-10 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, and C1-C6 alkyl groups substituted with heterocyclic groups containing 1-4 heteroatoms selected from N, O and S;

[0020] R e Selected from hydrogen atoms, C1-C6 alkyl groups, and -C(O)R 7 -S(O)2OH, -S(O)2O-Q + -PO(OH)2, -PO(OH)OQ + and-PO(O - 2W 2+ ;

[0021] R f Each is independently selected from hydrogen atoms, C1-C6 alkyl groups, C3-C8 cycloalkyl groups, and amidine groups; in particular, R f Each is independently selected from hydrogen atoms, C1-C6 alkyl groups, and C3-C8 cycloalkyl groups;

[0022] Q + It is a pharmaceutically acceptable monovalent cation; W 2+ It is a pharmaceutically acceptable divalent cation;

[0023] R 7 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, carboxyl, and -C(O)O - M + The substituents are selected from hydroxyl, amino, carboxyl and -C(O)O - M + One or more of them; M + It is a pharmaceutically acceptable monovalent cation;

[0024] Preferably, R 1each independently selected from the group consisting of a hydrogen atom, halogen, C1-C6alkyl, amidino, oxo (=0), -SO2NH2, -SO2NHCH3-, -NHSO2NH2, morpholinyl, -CONH2, -CH2OPO(OH)2, nitro, hydroxyl, carboxyl, C1-C3alkylamino, dihydroxypropoxy, -C(=NOH)NH2, In particular, R 1 each independently selected from the group consisting of a hydrogen atom, halogen, C1-C6alkyl, amidino, oxo (=0), -SO2NH2, -SO2NHCH3-, -NHSO2NH2, morpholinyl, -CONH2, -CH2OPO(OH)2, and nitro;

[0025] or, two adjacent R 1 and the A ring to which it is attached together form an unsubstituted or substituted by 1-4 substituents selected from the group consisting of halogen, amino (-NH2), hydroxyl, thiol, oxo (=0), thioxo (=S), C1-C6alkyl; said 5-6 membered heterocycle containing 1 to 3 heteroatoms selected from N, O, S;

[0026] Preferably, the benzo[5-6 membered heterocycle] is selected from: In particular, from:

[0027] n is 0 or 1, preferably 0;

[0028] X is a N atom or C-R 2c ;

[0029] Preferably, X is C-R 2c ; more preferably -CH-;

[0030] R 2a , R 2b and R 2c each independently selected from the group consisting of a hydrogen atom, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, hydroxyl, cyano, amino, nitro, C3-C8cycloalkyloxy, C3-C8cycloalkyl and 3-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S;

[0031] Preferably, R 2a , R 2b and R 2c each independently selected from the group consisting of a hydrogen atom, halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6hydroxyalkyl;

[0032] R is preferably a hydrogen atom, halogen, C1-C6alkyl or halogenated C1-C6alkyl, R 2a is a hydrogen atom, halogen or halogenated C1-C6alkyl, R 2b is a hydrogen atom, halogen or halogenated C1-C6alkyl, R 2c is a hydrogen atom or halogen;

[0033] R 3a , R 3b , R 3c and R 3d are each independently selected from a hydrogen atom, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, hydroxy, cyano, amino, nitro, C3-C8cycloalkyloxy, C3-C8cycloalkyl and 3-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S; the substituents of the substituted substituents are selected from halogen, deuterium, C1-C6alkyl, hydroxy, C3-C8cycloalkyl and 3-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S;

[0034] R is preferably a hydrogen atom, halogen, C1-C6alkyl or halogenated C1-C6alkyl, R 3a , R 3b , R 3c and R 3d are each independently selected from halogen, C1-C6alkyl, halogenated C1-C6alkyl, deuterated C1-C6alkyl, deuterated C1-C6alkoxy, C1-C6hydroxyalkyl; preferably halogen;

[0035] Y is O, S, CR c R d or NR c ;

[0036] Y is preferably O, CR c R d or NR c ;

[0037] R c and R d are each independently selected from a hydrogen atom, C1-C6alkyl, hydroxy, C3-C8cycloalkyl and 3-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S; preferably R c and R d are each independently selected from a hydrogen atom, C1-C6alkyl, C3-C8cycloalkyl;

[0038] or R c and R d and the carbon atom to which they are attached form a C3-C8cycloalkyl or a 3-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S; preferably a C3-C8cycloalkyl;

[0039] R 4a , R 4b , R 4c and R 4d are each independently selected from the group consisting of a hydrogen atom, a C1-C6alkyl group, a hydroxyl group, a C3-C8cycloalkyl group and a 3-10 membered heterocyclyl group containing 1-4 heteroatoms selected from N, O and S;

[0040] or R 4a and R 4b form, together with the carbon atom to which they are attached, a C3-C8cycloalkyl group or a 3-10 membered heterocyclyl group containing 1-4 heteroatoms selected from N, O and S;

[0041] or R 4c and R 4d form, together with the carbon atom to which they are attached, a C3-C8cycloalkyl group or a 3-10 membered heterocyclyl group containing 1-4 heteroatoms selected from N, O and S;

[0042] Preferably, R 4a and R 4b are each independently selected from the group consisting of a hydrogen atom, a C1-C6alkyl group, a C3-C8cycloalkyl group;

[0043] Preferably, R 4c and R 4d are each independently selected from the group consisting of a hydrogen atom, a C1-C6alkyl group, a C3-C8cycloalkyl group; or R 4c and R 4d form, together with the carbon atom to which they are attached, a C3-C8cycloalkyl group;

[0044] o is 0, 1 or 2, preferably 0 or 1, more preferably 1.

[0045] In some embodiments, the compound of formula I is selected from the following compounds of formula II:

[0046]

[0047] wherein R 2a , R 2b , R 2c , X, R 3a , R 3b , R 3c , R 3d , Y, R 4a , R 4b , R 4c , R 4d , o are as defined above;

[0048] R 5a , R 5b and R 5cEach is independently selected from hydrogen atoms, halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, halogenated C1-C6 alkyl groups, halogenated C1-C6 alkoxy groups, and C3-C6 cycloalkyl groups;

[0049] R 6 Selected from hydrogen atom, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, hydroxyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, -CH2OR e C3-C8 cycloalkyl groups and 3-10 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O and S; preferably hydrogen atoms or -CH2OR e ;

[0050] R e Selected from hydrogen atoms, C1-C6 alkyl groups, and -C(O)R 7 -S(O)2OH, -S(O)2O - Q + -PO(OH)2, -PO(OH)O - Q + and-PO(O - 2W 2+ ;

[0051] Q + It is a pharmaceutically acceptable monovalent cation; W 2+ It is a pharmaceutically acceptable divalent cation;

[0052] R 7 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, carboxyl, and -C(O)O - M + The substituents are selected from hydroxyl, amino, carboxyl and -C(O)O - M + One or more of them; M + It is a pharmaceutically acceptable monovalent cation;

[0053] Preferably, Q + and M + They may be the same or different, and each is independently selected from quaternary ammonium salt ions and alkali metal ions, preferably Na. + or K + W 2+ Alkaline earth metal ions, preferably Mg 2+ or Ca 2+ .

[0054] In some embodiments, the compound of formula I is selected from the compounds of formula III:

[0055]

[0056] wherein R 2a , R 2b , R 2c , X, R 3a , R 3b , R 3c , R 3d , Y, R 4a , R 4b , R 4c , R 4d , o are defined as before, and R 5a , R 5b and R 5c are defined as in formula II.

[0057] R 5d is selected from the group consisting of a hydrogen atom, halogen, Ci-C6alkyl, Ci-C6alkoxy, haloCi-C6alkyl, haloCi-C6alkoxy, C3-C6cycloalkyl.

[0058] In some embodiments, the compound of formula I is selected from the following compounds of formula IV:

[0059]

[0060] wherein R 2a , R 2b , R 2c , X, R 3a , R 3b , R 3c , R 3d , Y, R 4a , R 4b , R 4c , R 4d , o, R 5a , R 5b , R 5c , R 5d are defined as in formula III.

[0061] In some embodiments, the compound of formula I is selected from the following compounds of formula V:

[0062]

[0063] wherein R 2a , R 2b , R 2c , X, R 3b , Y, R 4a , R 4b , R 4c , R 4d , o, n, A ring, R 1 , m are defined as in formula I.

[0064] In some preferred embodiments, the compound of Formula I is selected from the following compounds:

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073] The terms in the present application are defined as follows:

[0074] The "halogen" can be fluorine, chlorine, bromine or iodine.

[0075] The "C1-C6 alkyl" means a chain alkyl group having 1 to 6 carbon atoms; specific examples thereof can include methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, t-butyl, 1-methyl-butyl, 1-ethyl-butyl, pentyl, n-pentyl, isopentyl, neopentyl, t-pentyl, hexyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, and the like, but not limited thereto.

[0076] The "deutero-C1-C6 alkyl" means that one or more hydrogens of the C1-C6 alkyl defined above are substituted with deuterium.

[0077] The "halo-C1-C6 alkyl" means that one or more hydrogens of the C1-C6 alkyl defined above are substituted with halogen.

[0078] The "C1-C6 hydroxyalkyl" means that one or more hydrogens of the C1-C6 alkyl defined above are substituted with hydroxy.

[0079] The "C2-C6 alkenyl" means a straight chain or branched chain group having 2 to 6 carbon atoms, at least one of which is a carbon-carbon double bond; specific examples of which can include ethenyl, propenyl, 2-propenyl, (E)-2-butenyl, (Z)-2-butenyl, (E)-2-methyl-2-butenyl, (Z)-2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, (Z)-2-pentenyl, (E)-1-pentenyl, (E)-2-pentenyl, (Z)-2-hexenyl, (E)-1-hexenyl, (Z)-1-hexenyl, (E)-2-hexenyl, (Z)-3-hexenyl, (E)-3-hexenyl, (E)-1,3-hexadienyl, 4-methyl-3-pentenyl, or norbornene.

[0080] The "C1-C6 alkoxy" means a RO- group, wherein R is a C1-C6 alkyl group as described above. Specific examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, sec-butoxy, n-pentoxy, isopentoxy, neopentoxy, n-hexoxy, isohexoxy, 3-methylpentoxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, and the like.

[0081] The "halo C1-C6 alkoxy" means a group in which at least one hydrogen of the alkoxy group as described above is replaced with a halogen; specific examples of which include trifluoromethoxy, and the like.

[0082] The "deutero C1-C6 alkoxy" means a RO- group, wherein R is a deutero C1-C6 alkyl group as described above.

[0083] The "C3-C8 cycloalkyl" means a fully saturated cyclic hydrocarbon group containing 3 to 12 carbon atoms; specific examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0084] The "C3-C8 cycloalkyloxy" means a RO- group, wherein R is a C3-C8 cycloalkyl group as described above.

[0085] The "3-10 membered heterocyclyl" means a 3-10 membered ring alkyl group containing 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur in the ring; specific examples of which include piperazine, piperidine, morpholine, and the like.

[0086] The "C6-C12 aryl" means a monocyclic or polycyclic aryl group having 6 to 12 carbon atoms; specific examples of which include phenyl, naphthyl.

[0087] The "5-10 membered heteroaryl" means a 5-10 membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur in the ring; specific examples of which include pyridine, pyridazine, pyrimidine, and the like.

[0088] "Pharmaceutically acceptable salt" includes a salt of the compound of Formula I with an acid or a base; the acid includes inorganic acid, organic acid; preferably, the inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid; preferably, the organic acid includes formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, citric acid, tartaric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, glutamic acid, pamoic acid; the base includes sodium, potassium, calcium, aluminum, lithium and ammonium hydroxide, carbonate, bicarbonate and the like.

[0089] "Pharmaceutically acceptable monovalent cation" includes alkali metal cation, ammonium cation and quaternary ammonium salt cation, for example Li + , Na + , K + , NH4 + .

[0090] "Pharmaceutically acceptable divalent cation" includes alkaline earth metal cation and amino acid cation, for example Ca + , Mg + , divalent ion of arginine. The pharmaceutically acceptable divalent cation (W 2+ ) can be replaced by two pharmaceutically acceptable monovalent cations (Q + ).

[0091] The compounds involved in the present application and their prodrugs, pharmaceutically acceptable salts can have isomers or racemates, such as optical isomers (including diastereoisomers and enantiomers), atropisomers, geometric isomers (cis-trans isomers), conformational isomers, tautomers and mixtures thereof, but not limited to. These isomers are also included in the scope defined by the claims of the present application.

[0092] Another aspect of the present application provides a pharmaceutical composition comprising one or more selected from the compound of Formula I, its prodrug, tautomer, meso, racemate, enantiomer, diastereoisomer and pharmaceutically acceptable salt thereof, and pharmaceutically acceptable adjuvant.

[0093] Still another aspect of the present application provides the use of the compound of Formula I or its prodrug, tautomer, meso, racemate, enantiomer, diastereoisomer or pharmaceutically acceptable salt thereof in the preparation of Nav1.8 inhibitor or for the treatment and / or alleviation of pain and pain-related diseases.

[0094] The pain and pain-related diseases include, but are not limited to, nociceptive pain, inflammatory pain (including but not limited to rheumatoid arthritis pain or vulvodynia), neuropathic pain (including but not limited to post-herpetic neuralgia, idiopathic small fiber neuropathy), musculoskeletal pain (including but not limited to osteoarthritis pain, back pain, cold pain, burn pain or dental pain), postoperative pain (including but not limited to post-bunionectomy pain, abdominoplasty pain, etc.), and interstitial pain, functional pain, muscle or bone injury-related pain, pelvic pain, abdominal pain, chest pain, lumbosacral neuralgia, preoperative pain, intraoperative pain, postoperative pain, intestinal pain (including but not limited to inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis), acute or chronic pain, migraine, trigeminal neuralgia, pancreatitis, renal colic, cancer pain, pain caused by chemotherapy or drug therapy, diabetic neuropathic pain, post-herpes zoster neuralgia, back pain, phantom limb pain, sciatica, small fiber neuropathic pain, erythromelalgia, etc.

[0095] The present application has the following beneficial effects:

[0096] The fused ring compound of the present application has better Nav1.8 selective inhibitory activity and pharmacokinetic properties than the existing structure, and can be used as a Nav1.8 inhibitor to treat or alleviate pain or pain-related diseases, and has important clinical application value.

[0097] The present application has been described in detail above, but the above embodiments are only illustrative in nature and are not intended to limit the present application. In addition, the present application is not limited by any theory described in the foregoing prior art or summary of the invention or the following examples. DETAILED DESCRIPTION

[0098] The present application will be further described below in conjunction with examples, and it should be noted that the following examples are provided only for illustrative purposes and do not constitute a limitation on the scope of the present application.

[0099] Unless otherwise specified, the raw materials, reagents, methods, etc. used in the examples are conventional raw materials, reagents, methods in the art.

[0100] In the present application, room temperature refers to ambient temperature, which is 10-35°C. Overnight refers to 8-15 hours. Reflux refers to the reflux temperature of the solvent under normal pressure.

[0101] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shift (δ) is expressed in 10 -6The NMR measurements were performed on a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCI3), deuterated methanol (CD3OD) as the solvent and tetramethylsilane (TMS) as the internal standard. The MS measurements were performed on a Finnigan LCQ / Deca (ESI) mass spectrometer. The high performance liquid chromatography (HPLC) analysis was performed on a Gilson-215 high pressure liquid chromatograph.

[0102] The thin layer chromatography (TLC) silica gel plates used were Yantai Huanghai HSGF 254 or Qingdao GF 254 silica gel plates. The silica gel plates used in the thin layer chromatography (TLC) had a thickness of 0.15 mm to 0.2 mm. The silica gel plates used in the thin layer chromatography (TLC) for the separation and purification of the products had a thickness of 0.4 mm to 0.5 mm. The silica gel column chromatography generally used Yantai Huanghai silica gel with a mesh size of 200 to 300 as the carrier.

[0103] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing agents used in the reactions, the eluent systems used in the column chromatography for the purification of the compounds and the developing agent systems used in the thin layer chromatography included dichloromethane / methanol systems and petroleum ether / ethyl acetate systems. The volume ratio of the solvents was adjusted according to the polarity of the compounds. A small amount of a basic or acidic reagent such as triethylamine and acetic acid could also be added for adjustment.

[0104] The known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from Shanghai Haohong Biomedical Technology Co., Ltd., Bide Pharmaceutical Co., Ltd., etc. Unless otherwise specified in the examples, the reactions were carried out under an argon or nitrogen atmosphere.

[0105] Example 1 Preparation of 2-(5-fluoro-2,3-dihydro-lH-inden-l-yl)-N-(3- sulfamoylphenyl)-4-(trifluoromethyl)benzamide 1

[0106]

[0107] First step: Preparation of N'-(5-fluoro-2,3-dihydro-lH-inden-l-ylidene)-4- toluenesulfonylhydrazide lb

[0108] Toluene sulfonyl hydrazide (6.73 g, 39.96 mmol) was suspended in methanol solution and heated to 60 °C until toluene sulfonyl hydrazide was completely dissolved. 5-Fluoro-l-indanone la (5.00 g, 33.30 mmol, Shanghai Haohong Biomedical Technology Co., Ltd.) was slowly added to the mixture. After 3 hours, a precipitate was produced, which was filtered and washed with methanol. The precipitate was dried in vacuum to obtain compound lb (8.00 g) (white solid) with a yield of 75.46%. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.49 (dd, J = 8.5, 5.5 Hz, 1H), 7.39 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 9.1 Hz, 1H), 7.08 (t, J = 8.8 Hz, 1H), 3.03 - 2.95 (m, 2H), 2.76 (dd, J = 7.6, 5.2 Hz, 2H), 2.36 (s, 3H).

[0109] Preparation of the second step methyl 2-(6-fluoro-1H-inden-3-yl)-4- (trifluoromethyl)benzoate 1c

[0110] To a mixture of N'-(5-fluoro-2,3-dihydro-1H-inden-1-ylidene)-4- methylbenzenesulfonohydrazide 1b (2.00 g, 6.28 mmol), [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium dichloromethane complex (205.38 mg, 0.25 mol), sodium carbonate (1.07 g, 10.06 mmol) and 1,4-dioxane / water (4:1) (60 mL) was added methyl 2-bromo-4- trifluoromethylbenzoate (1.42 g, 5.03 mmol, Shanghai Hauhao Biomedical Technology Co., Ltd.). Argon protection, the reaction mixture was stirred at 90 °C for 10 h. Cool, the reaction was concentrated under reduced pressure, add 70 mL water and 70 mL ethyl acetate, uniform mixing, standing stratification. The aqueous phase was extracted with ethyl acetate (70 mL x 3). The combined organic phase, saturated sodium chloride solution washing, anhydrous sodium sulfate drying, filtration, concentrated filtrate. Purified by silica gel column chromatography (EA: PE; 1:25 to 1:15) to give compound 1c (1.58 g) (colorless oil), yield: 74.79%. 1 H NMR (400 MHz, Chloroform-d) δ 8.04 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 8.9 Hz, 2H), 7.26 - 7.22 (m, 1H), 6.97 (d, J = 1.8 Hz, 1H), 6.95 (d, J = 1.3 Hz, 1H), 6.51 (t, J = 2.1 Hz, 1H), 3.60 (s, 3H), 3.56 (d, J = 1.5 Hz, 2H).

[0111] Preparation of the third step methyl 2-(5-fluoro-2,3-dihydro-1H-inden-1- yl)-4-(trifluoromethyl)benzoate 1d

[0112] A mixture of methyl 2-(6-fluoro-lH-inden-3-yl)-4-(trifluoromethyl)benzoate lc (1 g, 5.68 mmol), 10% Pd-C catalyst (200 mg) and ethanol (30 mL) was stirred at 60 °C under hydrogen for 30 h. After filtration of the catalyst, the filtrate was evaporated. Purification by silica gel column chromatography (EA: PE; 1:25 to 1:15) gave compound Id (840 mg) (colorless oil), yield: 83.50%. 1 H NMR (400 MHz, Chloroform-d) δ 7.93 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.33 (s, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.91 - 6.78 (m, 2H), 5.13 (t, J = 8.1 Hz, 1H), 3.94 (s, 3H), 3.10 - 2.91 (m, 2H), 2.86 - 2.71 (m, 1H), 2.12 - 1.97 (m, 1H).

[0113] Preparation of 2-(5-fluoro-2,3-dihydro-lH-inden-l-yl)-4-(trifluoromethyl)benzoic acid le in the fourth step

[0114] Methyl 2-(5-fluoro-2,3-dihydro-lH-inden-l-yl)-4-(trifluoromethyl)benzoate Id (800 mg, 2.36 mmol) was dissolved in tetrahydrofuran (20 ml), and an aqueous solution of sodium hydroxide (189 mg, 4.72 mmol) (5 mL) was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to leave a small amount of aqueous solution, 20 mL of water was added, and the pH was adjusted to 2 with a 2M aqueous hydrochloric acid solution, and a solid was precipitated. The solid was filtered and dried in vacuo. Compound le (670 mg) (pale yellow solid) was obtained, yield: 87.37%. 1 H NMR (400 MHz, Chloroform-d) δ 8.10 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.85 (d, J = 6.9 Hz, 2H), 5.31 (t, J = 7.9 Hz, 1H), 3.00 (qd, J = 16.1, 10.0 Hz, 2H), 2.86 - 2.73 (m, 1H), 2.02 (dq, J = 17.0, 8.5 Hz, 1H).

[0115] Preparation of 2-(5-fluoro-2,3-dihydro-lH-inden-l-yl)-4-(trifluoromethyl)benzoyl chloride If in the fifth step

[0116] Dissolve 2-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-4-(trifluoromethyl)benzoic acid 1e (100 mg, 0.31 mmol) in anhydrous dichloromethane (4 mL) and place in an ice bath. Add oxalyl chloride (0.32 mL, 3.70 mmol) dropwise and continue stirring for 3 hours. Concentrate the reaction to give compound 1f (106 mg) which was used in the next step without purification.

[0117] Preparation of 2-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide 1

[0118] Dissolve m-aminobenzenesulfonamide (64 mg, 0.37 mmol, Bide Pharm) in anhydrous tetrahydrofuran and add N,N-diisopropylethylamine (DIEA, 0.102 mL, 0.62 mmol). Place in an ice bath and add a solution of 2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(trifluoromethyl)benzoyl chloride 1f (106 mg, 0.31 mmol) in anhydrous dichloromethane dropwise. Transfer to room temperature and allow to react overnight. Concentrate the reaction and add 20 mL of water and 20 mL of ethyl acetate. Mix well and allow to separate into layers. Extract the aqueous phase with ethyl acetate (15 mL x 3). Combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter and concentrate the filtrate. Purify using silica gel column chromatography (MeOH:DCM; 1:80 to 1:50) to give compound 1 (91 mg) as a white solid in 61.49% yield. 1 H NMR (400 MHz, Methanol-d4) δ 8.20 (s, 1H), 7.88 - 7.77 (m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.03 (d, J = 9.0 Hz, 1H), 6.96 (dd, J = 8.2, 5.3 Hz, 1H), 6.87 (td, J = 8.9, 2.3 Hz, 1H), 4.75 (t, J = 8.1 Hz, 1H), 3.14 - 2.90 (m, 2H), 2.80 - 2.66 (m, 1H), 2.23 - 2.07 (m, 1H).

[0119] Example 2 Preparation of 2-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-N-((2-morpholinopyridin-3- yl)methyl)-4-(trifluoromethyl)benzamide 2

[0120]

[0121] Compound 2 (57 mg) was prepared using the synthetic route of Example 1, replacing the sixth step starting material m-tolyl sulfonamide with [2-(4-morpholinyl)-3-pyridyl]methanamine. MS m / z (ESI): 500.18 [M+l] + .

[0122] Example 3 Preparation of 2-(5-fluoro-2,3-dihydro-lH-inden-l-yl)-N-(2-oxo-l,2- dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 3

[0123]

[0124] First step: Preparation of 2-(5-fluoro-2,3-dihydro-lH-inden-l-yl)-N-(2- methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide 3a

[0125] Compound 3a (101 mg) was obtained (white solid) in 75.87% yield. MS m / z (ESI): 431.13 [M+l] from the first step using the synthetic route of Example 1, replacing the sixth step starting material m-tolyl sulfonamide with [2-(4-morpholinyl)-3-pyridyl]methanamine. MS m / z (ESI): 500.18 [M+l] + .

[0126] Second step: Preparation of compound 3

[0127] Compound 3 (59 mg) was obtained (white solid) in 60.38% yield. MS m / z (ESI): 431.13 [M+l] from the second step using the synthetic route of Example 1, replacing the sixth step starting material m-tolyl sulfonamide with [2-(4-morpholinyl)-3-pyridyl]methanamine. MS m / z (ESI): 500.18 [M+l]1 H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 10.74 (s, 1H), 7.75 (s, 2H), 7.33 (d, J = 6.5 Hz, 2H), 7.14 (d, J = 8.8 Hz, 1H), 6.94 (dt, J = 14.2, 8.5 Hz, 2H), 6.83 (s, 1H), 6.44 (d, J = 6.1 Hz, 1H), 4.59 (t, J = 8.1 Hz, 1H), 3.08 - 2.87 (m, 2H), 2.65 - 2.55 (m, 1H), 2.17 - 2.04 (m, 1H).

[0128] Preparation of 2-(6-fluoro-2,3-dihydro-lH-inden-l-yl)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (trifluoromethyl)benzamide 4

[0129]

[0130] Using the first to fifth steps of the synthetic route of Example 1, replacing the starting material 5-fluoro-l-indanone with 6-fluoro-l-indanone, the acyl chloride intermediate was obtained, and then using the synthetic route of Example 3, compound 4 (38 mg) was prepared. MS m / z (ESI): 417.18 [M+l] + .

[0131] Preparation of 2-(6-fluoro-l,2,3,4-tetrahydronaphthalen-l-yl)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide 5

[0132]

[0133] Preparation of N'-(6-fluoro-l,2,3,4-tetrahydronaphthalen-l-ylidene)-4- toluenesulfonylhydrazide 5b

[0134] P-toluenesulfonylhydrazide (6.73 g, 36.11 mmol) was suspended in methanol solution and heated to 60 °C until the p-toluenesulfonylhydrazide was completely dissolved. 6-Fluoro-3,4-dihydro-2H-l-naphthalenone 5a (5.00 g, 30.09 mmol, Shanghai Hauhao Biomedical Technology Co., Ltd.) was slowly added to the mixture. After 3 hours, a precipitate was produced, which was filtered and washed with methanol. The precipitate was dried in vacuum. Compound 5b (9.60 g) was obtained (white solid), yield: 95.41%. 1HNMR (400 MHz, Chloroform-d) δ 7.96 (dd, J = 8.7, 6.1 Hz, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.72 (s, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.89 (td, J = 8.6, 2.1 Hz, 1H), 6.78 (d, J = 9.1 Hz, 1H), 2.74 - 2.65 (m, 2H), 2.46 (t, J = 6.5 Hz, 2H), 2.42 (s, 3H), 1.95 - 1.81 (m, 2H).

[0135] Preparation of the second step methyl 2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)- 4(trifluoromethyl)benzoate 5c

[0136] To a mixture of N'-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-ylidene)-4- toluenesulfonylhydrazide 5b (3.00 g, 8.97 mmol), [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium dichloromethane complex (306 mg, 0.375 mol), sodium carbonate (1.59 g, 14.98 mmol) and 1,4-dioxane / water (4:1, 40 mL) was added methyl 2-bromo-4- trifluoromethylbenzoate (2.12 g, 7.49 mmol, Shanghai Hauhao Biomedical Technology Co., Ltd.). Argon protection, the reaction mixture was stirred at 90 °C for 10 h. Cool, the reaction was concentrated under reduced pressure, add 50 mL water and 50 mL ethyl acetate, mix evenly, stand stratification. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. Purified by silica gel column chromatography (EA: PE; 1:20 to 1:10) to give compound 5c (2.02 g) (yellow solid), yield: 76.69%. 1 H NMR (400 MHz, Chloroform-d) δ 7.96 (dd, J = 8.7, 6.1 Hz, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.72 (s, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.89 (td, J = 8.6, 2.1 Hz, 1H), 6.78 (d, J = 9.1 Hz, 1H), 2.74 - 2.65 (m, 2H), 2.46 (t, J = 6.5 Hz, 2H), 2.42 (s, 3H), 1.95 - 1.81 (m, 2H).

[0137] Preparation of the third step methyl 2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)- 4(trifluoromethyl)benzoate 5d

[0138] A mixture of methyl 2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-4(trifluoromethyl)benzoate 5c (2 g, 5.68 mmol), 10% Pd-C catalyst (400 mg) and ethanol (60 mL) was stirred under hydrogen at 60 °C for 30 h. After filtration of the catalyst, the filtrate was evaporated. Purification by silica gel column chromatography (EA: PE; 1:20 to 1:15) gave compound 5d (1.70 g) (white solid) with a yield of 84.52%. 1 H NMR (400 MHz, Chloroform-d) δ 8.08 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.23 (s, 1H), 6.86 (dd, J = 9.5, 2.1 Hz, 1H), 6.75 (td, J = 8.4, 2.4 Hz, 1H), 6.71 - 6.64 (m, 1H), 5.13 (t, J = 6.1 Hz, 1H), 3.73 (s, 3H), 2.95 (dt, J = 13.0, 6.6 Hz, 1H), 2.89 - 2.80 (m, 1H), 2.28 (dt, J = 9.6, 6.3 Hz, 1H), 1.95 - 1.73 (m, 3H).

[0139] Preparation of 2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-4(trifluoromethyl)benzoic acid 5e in the fourth step

[0140] Methyl 2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-4(trifluoromethyl)benzoate 5d (1.7 g, 4.83 mmol) was dissolved in tetrahydrofuran (28 ml), and an aqueous solution of sodium hydroxide (386 mg, 9.65 mmol) (7 mL) was added. The reaction mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure to leave a small amount of aqueous solution, 20 mL of water was added, and the pH was adjusted to 2 with a 2M aqueous hydrochloric acid solution, and a solid was precipitated. The solid was filtered and dried in vacuo. Compound 5e (1.4 g) (yellow solid) was obtained with a yield of 85.75%. MS m / z (ESI): 337.08 [M-1] - .

[0141] Preparation of 2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-4(trifluoromethyl)benzoyl chloride 5f in the fifth step

[0142] Dissolve 2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(trifluoromethyl)benzoic acid 5e (100 mg, 0.29 mmol) in anhydrous dichloromethane (4 mL) and place in an ice bath. Add oxalyl chloride (0.30 mL, 3.55 mmol) dropwise and continue stirring for 3 hours. Concentrate the reaction to give compound 5f (105 mg) which was used in the next step without purification.

[0143] Preparation of 2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide 5

[0144] Dissolve m-aminobenzenesulfonamide (61 mg, 0.35 mmol, Bide Pharm) in anhydrous tetrahydrofuran and add DIEA (98 μL, 0.59 mmol). Place in an ice bath and add a solution of 2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(trifluoromethyl)benzoyl chloride 5f (105 mg, 0.29 mmol) in anhydrous dichloromethane dropwise. Transfer to room temperature and allow to react for 2 hours. Concentrate the reaction and add 20 mL of water and 20 mL of ethyl acetate. Mix well and allow to separate into layers. Extract the aqueous phase with ethyl acetate (10 mL x 3). Combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter and concentrate the filtrate. Purify using silica gel column chromatography (MeOH:DCM; 1:100 to 1:50) to give compound 5 (105 mg) as a white solid in 72.55% yield. 1 H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.73 - 7.60 (m, 3H), 7.53 (t, J = 7.9 Hz, 1H), 7.22 (s, 1H), 6.84 (t, J = 8.6 Hz, 2H), 6.77 (t, J = 8.2 Hz, 1H), 4.56 (t, J = 6.2 Hz, 1H), 3.01 - 2.89 (m, 1H), 2.87 - 2.75 (m, 1H), 2.31 - 2.16 (m, 1H), 2.02 - 1.82 (m, 2H), 1.81 - 1.64 (m, 1H).

[0145] Preparation of 2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-N-(2-oxo-1,2-dihydropyridin-4- yl)-4-(trifluoromethyl)benzamide 6

[0146]

[0147] Step 1: Preparation of 2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-N-(2- methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide 6a

[0148] To a solution of 4-amino-2-methoxypyridine (44 mg, 0.35 mmol, Biodine) in anhydrous tetrahydrofuran, DIEA (98 μL, 0.59 mmol) was added and placed in an ice bath, 2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(trifluoromethyl)benzoyl chloride 5f (105 mg, 0.29 mmol) in anhydrous dichloromethane was added dropwise, after addition, transferred to room temperature and stirred overnight. The reaction solution was concentrated, 20 mL of water and 20 mL of ethyl acetate were added, mixed uniformly, and separated into layers by standing. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification was performed by silica gel column chromatography (MeOH:DCM; 1:100 to 1:50) to obtain compound 6a (109 mg) (white solid), yield: 83.32%. MS m / z (ESI): 445.15 [M+1] + .

[0149] Step 2: Preparation of 2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-N-(2-oxo-1,2- dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 6

[0150] To a solution of 2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide 6a (109 mg, 0.25 mmol) in glacial acetic acid (2 mL), 2 mL of 33% hydrobromic acid in acetic acid was added, heated to 90°C and refluxed overnight. The reaction solution was concentrated and poured into 20 mL of saturated sodium bicarbonate solution, stirred thoroughly until the gas bubbles disappeared. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification was performed by silica gel column chromatography (MeOH:DCM; 1:50 to 1:30) to obtain compound 6 (89 mg) (white solid), yield: 84.31%. 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 10.71 (s, 1H), 7.73 (s, 2H), 7.32 (d, J = 7.2 Hz, 1H), 7.23 (s, 1H), 6.96 (d, J = 9.8 Hz, 1H), 6.89 (t, J = 8.6 Hz, 1H), 6.81 (s, 1H), 6.80 - 6.74 (m, 1H), 6.41 (d, J = 7.1 Hz, 1H), 4.37 (t, J = 7.1 Hz, 1H), 2.99 - 2.87 (m, 1H), 2.82 - 2.71 (m, 1H), 2.18 - 2.07 (m, 1H), 1.93 - 1.76 (m, 2H), 1.73 - 1.58 (m, 1H).

[0151] Example 7 Preparation of 2-(6-fluoro-l,2,3,4-tetrahydronaphthalen-l-yl)-N-(3- (sulfamoylamino)phenyl)-4-(trifluoromethyl)benzamide 7

[0152]

[0153] Using the synthetic route of Example 5, the sixth step starting material m- aminobenzenesulfonamide was replaced with N-(3-aminophenyl)sulfonamide to give compound 7 (46 mg). 1 H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.52 (s, 1H), 7.71 (s, 2H), 7.58 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.23 (t, J = 8.1 Hz, 1H), 7.18 (s, 1H), 7.05 (s, 2H), 7.02 - 6.94 (m, 2H), 6.90 (td, J = 8.6, 2.5 Hz, 1H), 6.85 - 6.79 (m, 1H), 4.42 (t, J = 7.1 Hz, 1H), 3.01 - 2.88 (m, 1H), 2.77 (dd, J = 16.4, 8.5 Hz, 1H), 1.93 - 1.75 (m, 2H), 1.71 - 1.55 (m, 1H).

[0154] Example 8 Preparation of 2-(6-fluoro-l,2,3,4-tetrahydronaphthalen-l-yl)-N-(3-(N- methylsulfamoyl)phenyl)-4-(trifluoromethyl)benzamide 8

[0155]

[0156] Using the synthetic route of Example 5, the sixth step starting material m- aminobenzenesulfonamide was replaced with N-methyl-3-aminobenzenesulfonamide to give compound 8 (53 mg). 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.32 (s, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.76 (q, J = 8.1 Hz, 2H), 7.58 (t, J = 7.9 Hz, 1H), 7.52 (q, J = 4.8 Hz, 2H), 7.25 (s, 1H), 6.96 (dd, J = 9.9, 2.3 Hz, 1H), 6.89 (td, J = 8.6, 2.5 Hz, 1H), 6.84 - 6.75 (m, 1H), 4.44 (t, J = 7.2 Hz, 1H), 2.94 (ddd, J = 15.3, 8.8, 6.0 Hz, 1H), 2.77 (dt, J = 16.7, 4.4 Hz, 1H), 2.44 (d, J = 4.9 Hz, 3H), 2.20 - 2.09 (m, 1H), 1.96 - 1.74 (m, 2H), 1.73 - 1.59 (m, 1H).

[0157] Example 9 Preparation of 2-(7-fluorochroman-4-yl)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide 9

[0158]

[0159] First step Preparation of N'-(7-fluorochroman-4-ylidene)-4-toluenesulfonylhydrazide 9b

[0160] N'- (7-fluorochroman-4-ylidene)-4-toluenesulfonylhydrazide (9.60 g, 30.09 mmol) was dissolved in methanol (100 mL) and heated to 60 °C. 7-fluoro-4-dihydrochromenone 9a (5.00 g, 30.09 mmol) was added slowly to the mixture. After 3 hours, a precipitate was formed and was filtered and washed with methanol. The precipitate was dried in vacuum to give compound 9b (9.60 g) (white solid) in 95.41% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.90 (d, J = 7.7 Hz, 2H), 7.87 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.34 (d, J = 8.0 Hz, 2H), 6.67 (t, J = 7.7 Hz, 1H), 6.56 (d, J = 9.4 Hz, 1H), 4.24 (t, J = 5.9 Hz, 2H), 2.65 (t, J = 5.9 Hz, 2H), 2.43 (s, 3H).

[0161] Second step Preparation of methyl 2-(7-fluoro-2H-chromen-4-yl)-4-(trifluoromethyl)benzoate 9c

[0162] To a mixture of N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide 9b (3.00 g, 8.97 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (306 mg, 0.375 mol), sodium carbonate (1.59 g, 14.98 mmol) and 1,4-dioxane / water (4:1) (40 mL) was added methyl 2-bromo-4-trifluoromethylbenzoate (2.12 g, 7.49 mmol, Shanghai Hauheng Biomedical Technology Co., Ltd.). The reaction mixture was stirred at 90 °C for 10 h under argon protection. The reaction mixture was cooled, concentrated under reduced pressure, 50 mL of water and 50 mL of ethyl acetate were added, mixed uniformly, and separated by standing. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification was performed by silica gel column chromatography (EA:PE; 1:20 to 1:10) to obtain compound 9c (2.02 g) (yellow solid), yield: 76.69%. 1 H NMR (400 MHz, Chloroform-d) δ 8.02 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.60 (s, 1H), 6.68 - 6.58 (m, 1H), 6.50 (d, J = 7.5 Hz, 2H), 5.69 (t, J = 3.8 Hz, 1H), 4.90 (dd, J = 14.2, 3.4 Hz, 2H), 3.63 (s, 3H).

[0163] Preparation of 2-(7-fluoro-2H-chromen-4-yl)-4-(trifluoromethyl)benzoic acid 9d

[0164] Methyl 2-(7-fluoro-2H-chromen-4-yl)-4-(trifluoromethyl)benzoate 9c (1.7 g, 4.80 mmol) was dissolved in tetrahydrofuran (28 ml), and an aqueous solution of sodium hydroxide (386 mg, 9.65 mmol) (7 mL) was added. The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to leave a small amount of aqueous solution, 20 mL of water was added, and the pH was adjusted to 2 with 2M aqueous hydrochloric acid solution, and a solid was precipitated. The solid was filtered and dried in vacuum. Compound 9d (1.4 g) (yellow solid) was obtained, yield: 85.75%. 1 H NMR (400 MHz, Chloroform-d) δ 8.02 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.60 (s, 1H), 6.68 - 6.58 (m, 1H), 6.50 (d, J = 7.5 Hz, 2H), 5.69 (t, J = 3.8 Hz, 1H), 4.90 (dd, J = 14.2, 3.4 Hz, 2H), 3.63 (s, 3H).

[0165] Preparation of 2-(7-fluoro-2H-chromen-4-yl)-4-(trifluoromethyl)benzoyl chloride 9e

[0166] Dissolve 2-(7-fluoro-2H-chromen-4-yl)-4-(trifluoromethyl)benzoic acid 9d (100 mg, 0.29 mmol) in anhydrous dichloromethane (4 mL) and place in an ice bath. Add oxalyl chloride (0.30 mL, 3.55 mmol) dropwise and continue stirring for 3 hours. Concentrate the reaction to give compound 9e (105 mg). The product is used directly in the next step without purification.

[0167] Preparation of 2-(7-fluoro-2H-chromen-4-yl)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide 9f

[0168] Dissolve m-aminobenzenesulfonamide (60 mg, 0.35 mmol, BIDMED) in anhydrous tetrahydrofuran and add DIEA (97 μL, 0.58 mmol). Place in an ice bath and add a solution of 2-(7-fluoro-2H-chromen-4-yl-4-yl)-4-(trifluoromethyl)benzoyl chloride 9e (105 mg, 0.29 mmol) in anhydrous dichloromethane dropwise. After the addition, transfer to room temperature and allow to react for 2 hours. Concentrate the reaction and add 20 mL of water and 20 mL of ethyl acetate. Mix well and allow to separate into layers. Extract the aqueous phase with ethyl acetate (10 mL x 3). Combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Purify using silica gel column chromatography (MeOH:DCM; 1:100 to 1:50) to give compound 9f (105 mg) as a white solid. Yield: 72.55%. 1 H NMR (400 MHz, Methanol-d4) δ 8.05 (t, J = 1.8 Hz, 1H), 7.87 (s, 1H), 7.71 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 8.9 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 6.73 (dd, J = 9.3, 6.3 Hz, 1H), 6.53 (ddd, J = 9.1, 5.4, 2.5 Hz, 2H), 5.94 (t, J = 3.9 Hz, 1H), 4.87 - 4.80 (m, 2H).

[0169] Preparation of 2-(7-fluoro-2H-chromen-4-yl)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide 9f

[0170] A mixture of 2-(7-fluoro-2H-chromen-4-yl)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide 9f (100 mg, 5.68 mmol), 10% Pd-C catalyst (20 mg) and ethanol (8 mL) was stirred at 60 °C under hydrogen for 30 h. After filtration of the catalyst, the filtrate was evaporated to dryness. Purification by silica gel column chromatography (EA: PE; 1:20 to 1:15) afforded compound 9 (82 mg) (white solid) in 81.67% yield. 1 H NMR (400 MHz, Methanol-d4) δ 8.36 (t, J = 1.7 Hz, 1H), 7.85 - 7.80 (m, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.68 (s, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.29 (s, 1H), 6.88 - 6.70 (m, 1H), 6.65 - 6.48 (m, 2H), 4.65 (t, J = 6.9 Hz, 1H), 4.27 - 4.04 (m, 2H), 2.45 - 2.31 (m, 1H), 2.26 - 2.14 (m, 1H).

[0171] Example 10 Preparation of 2-(7-fluorochromen-4-yl)-N-((2-morpholinopyridin-3- yl)methyl)-4-(trifluoromethyl)benzamide 10

[0172]

[0173] Compound 10 (26 mg) was prepared using the synthetic route of Example 9, replacing the fifth step starting material m-aminobenzenesulfonamide with [2-(4- morpholinyl)-3-pyridinyl]methanamine. 1 H NMR (400 MHz, Methanol-d4) δ 8.20 (d, J = 3.7 Hz, 1H), 7.78 (d, J = 7.0 Hz, 1H), 7.66 (d, J = 9.6 Hz, 2H), 7.28 (d, J = 18.9 Hz, 1H), 7.11 - 7.02 (m, 1H), 6.79 - 6.72 (m, 1H), 6.62 - 6.51 (m, 2H), 4.62 (t, J = 4.7 Hz, 1H), 4.29 - 4.18 (m, 1H), 4.17 - 4.07 (m, 1H), 3.89 - 3.81 (m, 4H), 3.15 - 3.07 (m, 4H), 2.35 - 2.21 (m, 1H), 2.23 - 2.08 (m, 1H).

[0174] Example 11 Preparation of 2-(7-fluorochromen-4-yl)-N-(2-oxo-1,2-dihydropyridin-4- yl)-4-(trifluoromethyl)benzamide 11

[0175]

[0176] First step preparation of methyl 2-(7-fluorochroman-4-yl)-4- (trifluoromethyl)benzoate 11a

[0177] A mixture of methyl 2-(7-fluoro-2H-chromen-4-yl)-4(trifluoromethyl)benzoate 9c (500 mg, 1.42 mmol), 10% Pd-C catalyst (100 mg) and ethanol (50 mL) was stirred at 60 °C under hydrogen for 30 h. After filtration of the catalyst, the filtrate was evaporated. Purification by silica gel column chromatography (EA: PE; 1:40 to 1:20) gave compound 11a (458 mg) (white oil), yield: 91.08%. 1 H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.29 (s, 1H), 6.72 - 6.66 (m, 1H), 6.63 (dd, J = 10.2, 2.5 Hz, 1H), 6.55 (td, J = 8.4, 2.6 Hz, 1H), 5.06 (t, J = 6.7 Hz, 1H), 4.20 (t, J = 5.3 Hz, 2H), 2.49 - 2.35 (m, 1H), 2.16 - 2.03 (m, 1H).

[0178] Second step preparation of 2-(7-fluorochroman-4-yl)-4-(trifluoromethyl)benzoic acid 11b

[0179] Methyl 2-(7-fluorochroman-4-yl)-4(trifluoromethyl)benzoate 11a (400 mg, 1.13 mmol) was dissolved in tetrahydrofuran (12 ml), and an aqueous solution of sodium hydroxide (90 mg, 2.26 mmol) (3 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to a small amount of aqueous solution, 20 mL of water was added, and the pH was adjusted to 2 with 2M aqueous hydrochloric acid solution, and a solid was precipitated. The solid was filtered and dried in vacuum. Compound 11b (308 mg) (pale yellow solid) was obtained, yield: 80.17%. 1H NMR (400 MHz, Chloroform-d) δ 8.15 (d, J = 8.1 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 6.71 - 6.66 (m, 1H), 6.63 (dd, J = 10.2, 2.5 Hz, 1H), 6.55 (td, J = 8.3, 2.5 Hz, 1H), 5.20 (t, J = 6.6 Hz, 1H), 4.19 (dt, J = 6.0, 3.2 Hz, 2H), 2.49 - 2.37 (m, 1H), 2.15 - 2.01 (m, 1H).

[0180] Preparation of 2-(7-fluorochroman-4-yl)-4-(trifluoromethyl)benzoyl chloride 11c in the third step

[0181] 2-(7-Fluorochroman-4-yl)-4-(trifluoromethyl)benzoic acid 11b (100 mg, 0.29 mmol) was dissolved in anhydrous dichloromethane (4 ml), placed in an ice bath, and oxalyl chloride (0.30 mL, 3.53 mmol) was added dropwise. After the addition was completed, stirring was continued for 3 hours. The reaction solution was concentrated to obtain compound 11c (105 mg), which was used directly in the next step without purification.

[0182] Preparation of 2-(7-fluorochroman-4-yl)-N-(2-methoxypyridin-4-yl)-4- (trifluoromethyl)benzamide 11d in the fourth step

[0183] 4-Amino-2-methoxypyridine (44 mg, 0.35 mmol, Bide Pharm) was dissolved in anhydrous tetrahydrofuran, DIEA (97 μL, 0.59 mmol) was added, and the mixture was placed in an ice bath. A solution of 2-(7-fluorochroman-4-yl)-4- (trifluoromethyl)benzoyl chloride 11c (105 mg, 0.29 mmol) in anhydrous dichloromethane was added dropwise, and the mixture was transferred to room temperature and stirred overnight. The reaction solution was concentrated, 20 mL of water and 20 mL of ethyl acetate were added, mixed well, and allowed to stand to separate into layers. The aqueous layer was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification was performed by silica gel column chromatography (MeOH:DCM; 1:100 to 1:50) to obtain compound 11d (91 mg) as a white solid (yield: 73.12%).

[0184] Preparation of 2-(7-fluorochroman-4-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4- (trifluoromethyl)benzamide 11 in the fifth step

[0185] To a solution of 2-(7-fluorochroman-4-yl)-N-(2-methoxypyridin-4-yl)-4- (trifluoromethyl)benzamide 11d (91 mg, 0.25 mmol) in glacial acetic acid (2 mL) was added 33% hydrobromic acid in acetic acid (2 mL) and heated to 90 °C for 16 h. The reaction was concentrated and poured into 20 mL of saturated sodium bicarbonate solution and stirred until the effervescence ceased. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Purification by silica gel column chromatography (MeOH:DCM; 1:50 to 1:30) gave compound 11 (59 mg) as a white solid in 66.94% yield. 1 H NMR (400 MHz, Methanol-d4) δ 7.74 - 7.66 (m, 2H), 7.40 (d, J = 7.2 Hz, 1H), 7.31 (s, 1H), 7.04 (d, J = 1.9 Hz, 1H), 6.81 - 6.71 (m, 2H), 6.59 - 6.49 (m, 2H), 4.59 (t, J = 7.1 Hz, 1H), 4.28 - 4.05 (m, 2H), 2.41 - 2.26 (m, 1H), 2.27 - 2.12 (m, 1H).

[0186] Example 12 Preparation of 2-(7-fluorochroman-4-yl)-N-(3-(sulfamoylamino)phenyl)-4- (trifluoromethyl)benzamide 12

[0187]

[0188] Compound 12 (31 mg) was prepared using the synthetic route of Example 9, replacing the fifth step starting material m-aminobenzenesulfonamide with N-(3- aminophenyl)sulfonamide. 1 H NMR (400 MHz, Methanol-d4) δ 7.74 - 7.66 (m, 2H), 7.40 (d, J = 7.2 Hz, 1H), 7.31 (s, 1H), 7.04 (d, J = 1.9 Hz, 1H), 6.81 - 6.71 (m, 2H), 6.59 - 6.49 (m, 2H), 4.59 (t, J = 7.1 Hz, 1H), 4.28 - 4.05 (m, 2H), 2.41 - 2.26 (m, 1H), 2.27 - 2.12 (m, 1H).

[0189] Example 13 Preparation of 2-(7-fluorochroman-4-yl)-N-(3-(N-methylsulfamoyl)phenyl)-4- (trifluoromethyl)benzamide 13

[0190]

[0191] Compound 13 (53 mg) was prepared using the first four steps of the synthetic route of Example 9, replacing the fourth step starting material 4-amino-2-methoxypyridine with 5-amino-1,3- dihydroindol-2-one. 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.33 (s, 1H), 7.94 - 7.75 (m, 3H), 7.59 (t, J = 7.9 Hz, 1H), 7.53 (d, J = 9.2 Hz, 2H), 7.32 (s, 1H), 6.80 (t, J = 7.6 Hz, 1H), 6.71 - 6.64 (m, 2H), 4.57 (t, J = 7.1 Hz, 1H), 4.24 - 4.13 (m, 2H), 2.45 (d, J = 4.9 Hz, 3H), 2.33 - 2.14 (m, 2H).

[0192] Example 14 Preparation of 2-(7-fluorochroman-4-yl)-N-(2-oxoindolin-5-yl)-4- (trifluoromethyl)benzamide 14

[0193]

[0194] Compound 14 (31 mg) was prepared using the first four steps of the synthetic route of Example 11, replacing the fourth step starting material 4-amino-2-methoxypyridine with 5-amino-1,3- dihydroindol-2-one. 1 H NMR (400 MHz, Methanol-d4) δ 7.69 (q, J = 8.2 Hz, 2H), 7.53 (s, 1H), 7.27 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.12 (dd, J = 8.1, 1.5 Hz, 1H), 6.86 - 6.77 (m, 1H), 6.57 (ddd, J = 13.1, 7.4, 4.1 Hz, 2H), 4.63 (t, J = 6.8 Hz, 1H), 4.25 - 4.10 (m, 2H), 3.50 (s, 2H), 2.41 - 2.31 (m, 1H), 2.24 - 2.13 (m, 1H).

[0195] Example 15 Preparation of 2-(7-fluorochroman-4-yl)-N-(2-oxo-2,3-dihydrobenzo[d]oxazol-6- yl)-4-(trifluoromethyl)benzamide 15

[0196]

[0197] Compound 15 (45 mg) was prepared by replacing the 4-amino-2-methoxypyridine starting material in the fourth step with 6-amino-2-benzoxazolone using the first to fourth steps of the synthetic route in Example 11. 1 H NMR (400MHz, DMSO-d6) δ11.61(bs,1H),10.72(s,1H),7.80–7.74(m,3H),7.37(dd,J=8.4,1.7Hz,1H),7.28(s,1H),7.07(d,J=8 .4Hz,1H),6.82–6.76(m,1H),6.66(qd,J=9.3,8.4,2.5Hz,2H),4.54(t,J=7.0Hz,1H),4.18(t,J=4.9Hz,2H),2.33–2.10(m,2H).

[0198] Example 16: Preparation of N-(3-carbamoylphenyl)-2-(7-fluorobenzodihydropyran-4-yl)-4-(trifluoromethyl)benzamide 16

[0199]

[0200] Preparation of N-(3-cyanophenyl)-2-(7-fluorobenzodihydropyran-4-yl)-4-(trifluoromethyl)benzamide 16a (Step 1)

[0201] 11b of 2-(7-fluorobenzodihydropyran-4-yl)-4-(trifluoromethyl)benzoic acid (100 mg, 0.29 mmol) was dissolved in pyridine (0.5 mL) with m-aminobenzonitrile (42 mg, 0.35 mmol). Phosphorus oxychloride (55 μL, 0.58 mmol) was added dropwise under ice bath conditions. After addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and 15 mL of water and 15 mL of ethyl acetate were added. The mixture was thoroughly mixed and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The filtrate was purified by silica gel column chromatography (MeOH:DCM; 1:100 to 1:50) to give compound 16a (98 mg) (white solid), yield: 75.72%. 1H NMR (400 MHz, Chloroform-d) δ 8.05 (s, 1H), 8.04 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.36 (s, 1H), 6.71 - 6.66 (m, 1H), 6.57 (dd, J = 10.1, 2.0 Hz, 1H), 6.49 (td, J = 8.3, 2.2 Hz, 1H), 4.64 (t, J = 7.2 Hz, 1H), 4.25 (dt, J = 9.0, 4.2 Hz, 1H), 4.16 (t, J = 9.1 Hz, 1H), 2.44 - 2.32 (m, 1H), 2.24 - 2.14 (m, 1H).

[0202] Preparation of N-(3-carbamoylphenyl)-2-(7-fluorochroman-4-yl)-4- (trifluoromethyl)benzamide 16

[0203] N-(3-cyanophenyl)-2-(7-fluorochroman-4-yl)-4-(trifluoromethyl)benzamide 16a (98 mg, 0.22 mmol) was dissolved in 5 mL of 4 N hydrogen chloride-1,4-dioxane solution, ethanol (0.26 mL) was added, sealed, stirred at 0-5 °C for 24 hours. The reaction mixture was concentrated under reduced pressure, 7 M ammonia-methanol solution (10 mL) and ammonium chloride (24 mg, 0.44 mmol) were added to the concentrate, and the reaction was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH:DCM; 1:30 to 1:10) to obtain compound 16 (61 mg) (white solid), yield: 59.93%.

[0204] MS m / z (ESI): 458.30 [M+l] + .

[0205] Preparation of N-(3-carbamoylphenyl)-2-(7-fluorochroman-4-yl)-4- (trifluoromethyl)benzamide 16

[0206]

[0207] Compound 17 (50 mg) was prepared by replacing 4-amino-2-methoxypyridine with 3-aminobenzamide as the fourth step starting material in the first to fourth step reactions of the synthetic route of Example 11. 1H NMR (400 MHz, Methanol-d4) δ 8.17 (s, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.28 (s, 1H), 6.82 (t, J = 7.4 Hz, 1H), 6.57 (d, J = 10.5 Hz, 2H), 4.66 (t, J = 6.9 Hz, 1H), 4.25 - 4.08 (m, 2H), 2.42 - 2.32 (m, 1H), 2.24 - 2.14 (m, 1H).

[0208] Example 18 Preparation of 2-(7-fluorochroman-4-yl)-N-(6-oxo-l,6-dihydropyridazin-4-yl)-4- (trifluoromethyl)benzamide 18

[0209]

[0210] First Step Preparation of N-(6-chloropyridazin-4-yl)-2-(7-fluorochroman-4-yl)-4- (trifluoromethyl)benzamide 18a

[0211] 4-amino-6-chloropyridazine (46 mg, 0.35 mmol, Shanghai ChemPartner Co., Ltd.) was dissolved in anhydrous tetrahydrofuran (3 mL), cooled in an ice bath, and sodium hydride (23 mg, 0.58 mmol, 60% purity) was added. The reaction was allowed to proceed for 30 minutes. A solution of 2-(7-fluorochroman-4-yl)-4-(trifluoromethyl)benzoyl chloride lie (105 mg, 0.29 mmol) in anhydrous tetrahydrofuran was added dropwise, and the reaction was allowed to proceed overnight at room temperature under argon protection. 20 mL of water and 20 mL of ethyl acetate were added, and the mixture was allowed to separate into layers. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 18a (67 mg). The product was used directly in the next step without purification. MS m / z (ESI): 452.20 [M+l] + .

[0212] Second Step Preparation of 2-(7-fluorochroman-4-yl)-N-(6-oxo-l,6-dihydropyridazin-4-yl)-4- (trifluoromethyl)benzamide 18

[0213] The crude compound 18a (67 mg, 0.15 mmol) obtained in the previous step was dissolved in acetic acid (5 mL), potassium acetate (87 mg, 0.89 mmol) was added, and the reaction was carried out at 130 °C for 2 hours. The reaction solution was concentrated under reduced pressure, poured into 20 mL of saturated sodium bicarbonate solution, and stirred well until the gas bubbles disappeared. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification was performed by silica gel column chromatography (MeOH:DCM; 1:40 to 1:20) to obtain compound 18 (29 mg) (white solid) with a yield of 45.13%. 1 H NMR (600 MHz, Chloroform-d) δ 12.25 (s, 1H), 9.82 (s, 1H), 8.14 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.32 - 7.18 (m, 2H), 6.62 (t, J = 7.5 Hz, 1H), 6.50 (dd, J = 10.0, 2.2 Hz, 2H), 6.44 - 6.39 (m, 1H), 4.56 (t, J = 6.8 Hz, 1H), 4.19 - 4.13 (m, 1H), 4.07 (t, J = 7.3 Hz, 1H), 2.34 - 2.20 (m, 2H), 2.14 - 2.02 (m, 2H).

[0214] Example 19 Preparation of 5-chloro-2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-N-(3- sulfamoylphenyl)-4-(trifluoromethyl)benzamide amide 19

[0215]

[0216] First step: Preparation of methyl 5-amino-2-bromo-4-(trifluoromethyl)benzoate 19b

[0217] Methyl 3-amino-4-trifluoromethylbenzoate 19a (5 g, 22.81 mmol) was dissolved in DMF (100 mL). N-bromosuccinimide (4.87 g, 27.38 mmol) was added portionwise at 0 °C, and the mixture was stirred at room temperature for 70 minutes. 200 mL of water and 200 mL of ethyl acetate were added, mixed well, and allowed to separate into layers. The aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution 3 times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification was performed by silica gel column chromatography (EA:PE; 1:50 to 1:30) to obtain compound 19b (5.20 g) (white solid) with a yield of 76.47%. 1H NMR (400 MHz, Chloroform-d) δ 7.67 (s, 1H), 7.14 (s, 1H), 4.30 (s, 2H), 3.93 (s, 3H).

[0218] Preparation of 5-amino-2-(6-fluoro-3,4-dihydronaphthalen-1-yl)-4- (trifluoromethyl)benzoic acid methyl ester 19c in the second step

[0219] To a mixture of N'-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-ylidene)-4- methylbenzenesulfonohydrazide 5b (5.35 g, 16.10 mmol), [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium dichloromethane complex (548 mg, 0.67 mmol), sodium carbonate (1.85 g, 26.84 mmol) and 1,4-dioxane / water (4:1) (60 mL) was added 5-amino-2-bromo-4- (trifluoromethyl)benzoic acid methyl ester 19b (4.00 g, 13.42 mmol). Argon protection, the reaction mixture was stirred at 90 °C for 10 h. Cooled, the reaction was concentrated under reduced pressure, added 70 mL of water and 70 mL of ethyl acetate, mixed evenly, separated into layers. The aqueous phase was extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purified by silica gel column chromatography (EA:PE; 1:20 to 1:10) to give compound 19c (3.55 g) (colorless oil), yield: 72.41%. 1 H NMR (400 MHz, Chloroform-d) δ 7.39 (s, 1H), 7.23 (s, 1H), 6.89 (dd, J = 9.1, 2.6 Hz, 1H), 6.72 (td, J = 8.6, 2.7 Hz, 1H), 6.60 (dd, J = 8.5, 5.8 Hz, 1H), 5.92 (t, J = 4.6 Hz, 1H), 3.48 (s, 3H), 2.80-2.86 (s, 2H), 2.42-2.30 (m, 2H).

[0220] Preparation of 5-amino-2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-4- (trifluoromethyl)benzoic acid methyl ester 19d in the third step

[0221] A mixture of methyl 5-amino-2-(6-fluoro-3,4-dihydronaphthalen-1-yl)-4- (trifluoromethyl)benzoate 19c (3.00 g, 8.21 mmol), 10% Pd-C catalyst (600 mg) and ethanol (80 mL) was stirred at 60 °C under hydrogen for 30 h. After filtration of the catalyst, the filtrate was evaporated. Purification by silica gel column chromatography (EA: PE; 1:20 to 1:15) gave compound 19d (2.75 g) (white solid) with a yield of 91.16%. 1 H NMR (400 MHz, Chloroform-d) δ 7.17 (s, 1H), 6.99 (s, 1H), 6.82 (d, J = 9.4 Hz, 1H), 6.74 (d, J = 1.6 Hz, 1H), 6.72 (d, J = 1.7 Hz, 1H), 4.72 (t, J = 6.4 Hz, 1H), 3.85 (s, 3H), 2.91 (ddd, J = 16.9, 8.5, 5.6 Hz, 1H), 2.80 (dt, J = 16.9, 5.4 Hz, 1H), 2.21 - 2.12 (m, 1H), 1.91 - 1.82 (m, 1H), 1.82 - 1.70 (m, 2H).

[0222] Preparation of methyl 5-chloro-2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-4- (trifluoromethyl)benzoate 19e

[0223] CuCl2(1.46 g, 10.89 mmol) was dissolved in anhydrous acetonitrile (60 mL) and under nitrogen protection, tert-nitroso butyl ester (0.97 mL, 8.97 mmol) was added at room temperature, followed by stirring at 65 °C until a black green suspension was formed. A solution of methyl 5-amino-2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-4- (trifluoromethyl)benzoate 19d (2 g, 5.44 mmol) in anhydrous acetonitrile was added dropwise. After addition, stirring was continued for 30 min and then the mixture was allowed to cool to room temperature and stirred overnight. 100 mL of water and 100 mL of ethyl acetate were added, mixed well and allowed to separate into layers. The aqueous phase was extracted with ethyl acetate (70 mL x 3). The combined organic phases were washed with saturated sodium chloride solution 3 times, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Purification by silica gel column chromatography (EA: PE; 1:60 to 1:30) gave compound 19e (1.40 g) (colorless oil) with a yield of 66.48%. 1H NMR (400 MHz, Chloroform-d) δ 7.94 (s, 1H), 7.28 (s, 1H), 6.85 (dd, J = 9.6, 2.4 Hz, 1H), 6.75 (td, J = 8.4, 2.6 Hz, 1H), 6.67 (dd, J = 8.4, 5.9 Hz, 1H), 4.94 (t, J = 6.4 Hz, 1H), 3.92 (s, 3H), 2.95 (dd, J = 16.3, 7.8 Hz, 1H), 2.83 (dt, J = 16.3, 4.5 Hz, 1H), 2.31 - 2.18 (m, 1H), 1.88 (dq, J = 14.3, 7.2 Hz, 1H), 1.82 - 1.73 (m, 2H).

[0224] Step 5: Preparation of 5-chloro-2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-4- (trifluoromethyl)benzoic acid 19f

[0225] Methyl 5-amino-2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-4- (trifluoromethyl)benzoate 19e (1.4 g, 3.62 mmol) was dissolved in tetrahydrofuran (32 ml), and an aqueous solution of sodium hydroxide (290 mg, 7.24 mmol) (5 mL) was added. The reaction mixture was stirred at 60 °C for 6 hours. The reaction solution was concentrated under reduced pressure to a small amount of aqueous solution, 20 mL of water was added, and the pH was adjusted to 2 with 2M aqueous hydrochloric acid solution, and a solid was precipitated. The solid was filtered and dried in vacuo. Compound 19f (690 mg) was obtained (white solid), yield: 51.14%. MS m / z (ESI): 371.00 [M-1] - .

[0226] Step 6: Preparation of 5-chloro-2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-4- (trifluoromethyl)benzoyl chloride 19g

[0227] 5-chloro-2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-4-(trifluoromethyl)benzoic acid 19f (100 mg, 0.27 mmol) was dissolved in anhydrous dichloromethane (4 ml), and placed in an ice bath, and oxalyl chloride (0.27 mL, 3.22 mmol) was added dropwise, and stirring was continued for 3 hours. The reaction solution was concentrated to obtain compound 19g (105 mg), and the product was used directly in the next step without purification.

[0228] Step 7: Preparation of 5-chloro-2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-N-(3- sulfamoylphenyl)-4-(trifluoromethyl)benzamide 19

[0229] To 4-aminobenzenesulfonamide (55 mg, 0.32 mmol, BID) in dry tetrahydrofuran, DIEA (89 μL, 0.54 mmol) was added and the reaction mixture was placed in an ice bath. A solution of 5-chloro-2-(6-fluoro-l,2,3,4-tetrahydronaphthalen-l-yl)-4- (trifluoromethyl)benzoyl chloride 19g (105 mg, 0.27 mmol) in dry dichloromethane was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was concentrated and 20 mL of water and 20 mL of ethyl acetate were added. The mixture was mixed well and allowed to separate into layers. The aqueous layer was extracted with ethyl acetate (10 mL x 3). The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Purification was carried out by silica gel column chromatography (MeOH:DCM; 1:100 to 1:50) to give compound 19 (82 mg) (white solid) in 58.53% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.47 (s, 1H), 8.04 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.59 (s, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.32 (s, 1H), 6.79 - 6.73 (m, 1H), 6.71 - 6.62 (m, 2H), 5.39 (s, 2H), 4.50 - 4.43 (m, 2H), 2.93 - 2.81 (m, 2H), 2.74 (dt, J = 16.8, 4.5 Hz, 2H), 2.16 (tt, J = 13.9, 6.0 Hz, 2H), 1.85 - 1.76 (m, 2H), 1.73 - 1.63 (m, 1H).

[0230] Example 20 Preparation of 5-chloro-2-(6-fluoro-l,2,3,4-tetrahydronaphthalen-l-yl)-N-(2- oxo-l,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 20

[0231]

[0232] Using the synthetic route of Example 19, the starting material 4-aminobenzenesulfonamide was replaced with 4-amino-2-methoxypyridine to obtain the methoxypyridine intermediate and the compound 20 (39 mg) was prepared by following the second step of the synthetic route of Example 3. 1H NMR (400 MHz, Chloroform-d) δ 9.05 (s, 1H), 7.58 (s, 1H), 7.28 (s, 1H), 7.24 (d, J = 7.2 Hz, 1H), 6.81 - 6.74 (m, 2H), 6.70 (d, J = 1.6 Hz, 1H), 6.68 (d, J = 1.7 Hz, 2H), 4.44 (t, J = 7.5 Hz, 1H), 2.92 - 2.80 (m, 1H), 2.80 - 2.69 (m, 1H), 2.24 - 2.11 (m, 1H), 1.90 - 1.75 (m, 2H), 1.75 - 1.64 (m, 1H).

[0233] Example 21 Preparation of 5-chloro-2-(7-fluorochroman-4-yl)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide 21

[0234]

[0235] Using the synthetic route of Example 19, the second step starting material N'-(6-fluoro- 1,2,3,4-tetrahydronaphthalen-1-ylidene)-4-methylbenzenesulfonylhydrazide was replaced with N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide to give compound 21 (39 mg). 1 H NMR (400 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.06 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.64 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.37 (s, 1H), 6.65 (t, J = 7.4 Hz, 1H), 6.50 (dd, J = 10.1, 2.2 Hz, 1H), 6.47 - 6.40 (m, 1H), 5.40 (s, 2H), 4.55 (t, J = 7.1 Hz, 1H), 4.22 - 4.14 (m, 1H), 4.08 (t, J = 9.4 Hz, 1H), 2.33 - 2.25 (m, 1H), 2.19 - 2.08 (m, 1H).

[0236] Example 22 Preparation of 5-chloro-2-(7-fluorochroman-4-yl)-N-(2-oxo-1,2-dihydropyridin-4- yl)-4-(trifluoromethyl)benzamide 22

[0237]

[0238] Using the synthetic route of Example 19, replacing the second step starting material N'-(6-fluoro- 1,2,3,4-tetrahydronaphthalen-1-ylidene)-4-methylbenzenesulfonohydrazide with N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonohydrazide and the seventh step starting material m- aminobenzenesulfonamide with 4-amino-2-methoxypyridine to give the methoxypyridine intermediate and continuing with the second step of the synthetic route of Example 3 gave compound 22 (39 mg). 1 H NMR (400 MHz, Chloroform-d) δ 9.53 (s, 1H), 7.61 (s, 1H), 7.32 (s, 1H), 7.23 (d, J = 7.1 Hz, 1H), 6.80 (d, J = 6.7 Hz, 1H), 6.75 (s, 1H), 6.68 - 6.60 (m, 1H), 6.52 (dd, J = 10.1, 2.5 Hz, 1H), 6.45 (td, J = 8.3, 2.5 Hz, 1H), 4.52 (t, J = 7.2 Hz, 1H), 4.21 - 4.14 (m, 1H), 4.09 (q, J = 7.1 Hz, 2H), 2.35 - 2.23 (m, 1H), 2.15 - 2.03 (m, 1H), 2.02 (s, 1H).

[0239] Example 23 Preparation of 5-chloro-2-(7-fluorochroman-4-yl)-N-(3-oxoisoquinolin-5-yl)-4- (trifluoromethyl)benzamide 23

[0240]

[0241] Using the synthetic route of Example 19, replacing the second step starting material N'-(6-fluoro- 1,2,3,4-tetrahydronaphthalen-1-ylidene)-4-methylbenzenesulfonohydrazide with N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonohydrazide and the seventh step starting material m- aminobenzenesulfonamide with 4-amino-2-methoxypyridine to give the methoxypyridine intermediate and continuing with the second step of the synthetic route of Example 3 gave compound 22 (39 mg). 1H NMR (400 MHz, Chloroform-d) δ 9.14 (s, 1H), 8.67 (s, 1H), 8.17 (s, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.70 (s, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.40 (s, 1H), 6.71 - 6.60 (m, 1H), 6.55 (dd, J = 10.1, 2.4 Hz, 1H), 6.48 (td, J = 8.3, 2.4 Hz, 1H), 4.71 (s, 2H), 4.63 (t, J = 7.1 Hz, 1H), 4.27 - 4.20 (m, 1H), 4.14 (t, J = 9.0 Hz, 1H), 2.38 (dd, J = 11.5, 5.7 Hz, 1H), 2.24 - 2.10 (m, 1H).

[0242] Example 24 Preparation of N-(3-carbamoylphenyl)-5-chloro-2-(7-fluorochroman-4-yl)-4- (trifluoromethyl)benzamide 24

[0243]

[0244] Using the synthetic route of Example 19, replacing the second step starting material N'-(6-fluoro- 1,2,3,4-tetrahydronaphthalen-1-ylidene)-4-methylbenzenesulfonylhydrazide with N'-(7-fluoro- chroman-4-ylidene)-4-methylbenzenesulfonylhydrazide, and the seventh step starting material m- aminobenzenesulfonamide with m-aminobenzonitrile, the benzonitrile intermediate was prepared and the compound 24 (45 mg) was prepared by continuing with the second step reaction of the synthetic route of Example 16. MS m / z (ESI): 492.34 [M+l] + .

[0245] Example 25 Preparation of N-(3-carbamoylphenyl)-5-chloro-2-(7-fluorochroman-4-yl)-4- (trifluoromethyl)benzamide 25

[0246]

[0247] Using the synthetic route of Example 19, replacing the second step starting material N'-(6-fluoro- 1,2,3,4-tetrahydronaphthalen-1-ylidene)-4-methylbenzenesulfonylhydrazide with N'-(7-fluoro- chroman-4-ylidene)-4-methylbenzenesulfonylhydrazide, and the seventh step starting material m- aminobenzenesulfonamide with m-aminobenzonitrile, the benzonitrile intermediate was prepared and the compound 24 (45 mg) was prepared by continuing with the second step reaction of the synthetic route of Example 16. MS m / z (ESI): 492.34 [M+l] 1H NMR (400 MHz, Methanol-d4) δ 8.17 (s, 1H), 7.86 - 7.82 (m, 1H), 7.81 (s, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.36 (s, 1H), 6.80 (dd, J = 8.9, 6.7 Hz, 1H), 6.58 - 6.51 (m, 2H), 4.62 (t, J = 7.0 Hz, 1H), 4.21 - 4.12 (m, 2H), 2.39 - 2.28 (m, 1H), 2.24 - 2.11 (m, 1H).

[0248] Example 26 Preparation of 5-chloro-2-(7-fluorochroman-4-yl)-4-methyl-N-(2-oxo-1,2- dihydropyridin-4-yl)benzamide 26

[0249]

[0250] First Step Preparation of methyl 2-bromo-4-methyl-5-nitrobenzoate 26b

[0251] Compound methyl 2-bromo-4-methylbenzoate 26a (5 g, 21.83 mmol, Bidmed) was dissolved in concentrated sulfuric acid (25 mL). Potassium nitrate (2.21 g, 21.83 mmol) in sulfuric acid (10 mL) was added at 0 °C. After stirring at 0 °C for 1.5 h, the reaction mixture was poured into 400 mL of ice water. The precipitate was collected by filtration and rinsed with a large amount of water. Compound 26b (4.20 g) was obtained as a white solid in 70.21% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.49 (s, 1H), 7.70 (s, 1H), 3.96 (s, 3H), 2.63 (s, 3H).

[0252] Second Step Preparation of methyl 2-(7-fluorochroman-4-yl)-4-methyl-5-nitrobenzoate 26c

[0253] To a mixture of N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonohydrazide 9b (2.93 g, 8.76 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (298 mg, 0.37 mmol), sodium carbonate (1.55 g, 14.60 mmol) and 1,4-dioxane / water (4:1) (50 mL) was added 2-bromo-4-methyl-5-nitrobenzoic acid methyl ester 26b (2.00 g, 7.30 mmol). Argon protection, the reaction mixture was stirred at 90 °C for 10 h. Cooling, the reaction was concentrated under reduced pressure, added 50 mL of water and 50 mL of ethyl acetate, evenly mixed, stratified. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purified by silica gel column chromatography (EA:PE; 1:30 to 1:15) to give compound 26c (1.95 g) (colorless oil), yield: 77.84%. 1 H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 7.32 (s, 1H), 6.61 (dd, J = 9.8, 2.2 Hz, 1H), 6.52 - 6.38 (m, 2H), 5.65 (t, J = 3.8 Hz, 1H), 5.03 - 4.78 (m, 2H), 3.66 (s, 3H), 2.67 (s, 3H).

[0254] Preparation of 5-amino-2-(7-fluorochroman-4-yl)-4-methylbenzoic acid methyl ester 26d

[0255] A mixture of 2-(7-fluorochroman-4-yl)-4-methyl-5-nitrobenzoic acid methyl ester 26c (1.90 g, 5.53 mmol), 10% Pd-C catalyst (380 mg) and ethanol (40 mL) was stirred at 60 °C under hydrogen for 30 h. After filtering out the catalyst, the filtrate was evaporated. Purified by silica gel column chromatography (EA:PE; 1:20 to 1:15) to give compound 26d (1.54 g) (colorless oil), yield: 88.24%. 1H NMR (400 MHz, Chloroform-d) δ 7.23 (s, 1H), 6.74 (ddd, J = 8.6, 6.7, 1.0 Hz, 1H), 6.63 (s, 1H), 6.57 (dd, J = 10.3, 2.6 Hz, 1H), 6.50 (td, J = 8.4, 2.6 Hz, 1H), 4.94 (t, J = 6.4 Hz, 1H), 4.16 (ddd, J = 5.9, 4.0, 1.2 Hz, 2H), 3.87 (s, 3H), 2.39 - 2.27 (m, 1H), 2.07 (s, 3H), 2.06 - 1.97 (m, 1H).

[0256] Preparation of 5-chloro-2-(7-fluorochroman-4-yl)-4-methylbenzoic acid methyl ester 26e in the fourth step

[0257] CuCl2(1.02 g, 7.61 mmol) was dissolved in anhydrous acetonitrile (50 mL), and under nitrogen protection, nitroso tert-butyl ester (0.85 mL, 7.14 mmol) was added at room temperature, followed by stirring at 65 °C until a black green suspension was formed. A solution of 5-amino-2-(7-fluorochroman-4-yl)-4-methylbenzoic acid methyl ester 26d (1.5 g, 4.76 mmol) in anhydrous acetonitrile was added dropwise. After the addition was completed, stirring was continued for 30 min, and then the temperature was raised to room temperature and stirring was continued overnight. 70 mL of water and 70 mL of ethyl acetate were added, mixed uniformly, and the layers were separated by standing. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated sodium chloride solution 3 times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification was performed by silica gel column chromatography (EA: PE; 1:70 to 1:40) to obtain compound 26e (969 mg) (colorless oil), yield: 60.85%. 1 H NMR (400 MHz, Chloroform-d) δ 7.23 (s, 1H), 6.74 (ddd, J = 8.6, 6.7, 1.0 Hz, 1H), 6.63 (s, 1H), 6.57 (dd, J = 10.3, 2.6 Hz, 1H), 6.50 (td, J = 8.4, 2.6 Hz, 1H), 4.94 (t, J = 6.4 Hz, 1H), 4.16 (ddd, J = 5.9, 4.0, 1.2 Hz, 2H), 3.87 (s, 3H), 2.39 - 2.27 (m, 1H), 2.07 (s, 3H), 2.06 - 1.97 (m, 1H).

[0258] Preparation of 5-chloro-2-(7-fluorochroman-4-yl)-4-methylbenzoic acid 26f in the fifth step

[0259] Methyl 5-chloro-2-(7-fluorochroman-4-yl)-4-methylbenzoate 26e (960 mg, 2.87 mmol) was dissolved in tetrahydrofuran (24 ml), sodium hydroxide (229 mg, 5.74 mmol) in water (6 mL) was added. The reaction mixture was stirred at 70 °C overnight. The reaction was concentrated under reduced pressure to a small amount of water solution, 15 mL water was added, the pH was adjusted to 2 with 2M aqueous hydrochloric acid solution, a solid was precipitated, the solid was filtered and dried in vacuum. Compound 26f (525 mg) was obtained (white solid), yield: 57.08%. MS m / z (ESI): 319.20 [M-1] - .

[0260] Step 6 Preparation of 5-chloro-2-(7-fluorochroman-4-yl)-4-methylbenzoyl chloride 26g

[0261] Methyl 5-chloro-2-(7-fluorochroman-4-yl)-4-methylbenzoate 26f (100 mg, 0.31 mmol) was dissolved in anhydrous dichloromethane (4 ml), placed in an ice bath, oxalyl chloride (0.39 mL, 4.68 mmol) was added dropwise, after addition, continue to stir for 6 hours. The reaction was concentrated to obtain compound 26g (106 mg), the product was used directly in the next step without purification.

[0262] Step 7 Preparation of 5-chloro-2-(7-fluorochroman-4-yl)-4-methyl-N-(2-oxo-1,2- dihydropyridin-4-yl)benzamide 26

[0263] To a solution of 4-amino-2-methoxypyridine (47 mg, 0.38 mmol, Bide Pharma) in dry tetrahydrofuran, N,N-diisopropylethylamine (102 μL mL, 0.62 mmol) was added and placed in an ice bath. A solution of 5-chloro-2-(7-fluorobenzodioxan-4-yl)-4-methylbenzoyl chloride 26g (106 mg, 0.31 mmol) in dry dichloromethane was added dropwise and upon completion, the reaction was transferred to room temperature and stirred overnight. The reaction was concentrated, 20 mL of water and 20 mL of ethyl acetate was added, mixed well and allowed to separate. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was taken up in glacial acetic acid (2 mL) and 33% hydrobromic acid in acetic acid (2 mL) was added. The reaction was heated to 90 °C and refluxed overnight. The reaction was concentrated and poured into 20 mL of saturated sodium bicarbonate solution and stirred well until the effervescence ceased. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Purification was carried out on a silica gel column (MeOH:DCM; 1:40 to 1:30) to obtain compound 26 (69 mg) (white solid) with a yield of 53.48%. 1 H NMR (400 MHz, Chloroform-d) δ 9.12 (s, 1H), 7.46 (s, 1H), 7.23 (d, J = 7.0 Hz, 1H), 6.90 (d, J = 7.0 Hz, 1H), 6.85 (s, 1H), 6.70 (s, 1H), 6.68 - 6.60 (m, 1H), 6.51 (dd, J = 10.1, 2.4 Hz, 1H), 6.42 (td, J = 8.3, 2.3 Hz, 1H), 4.54 (t, J = 6.7 Hz, 1H), 4.11 (dt, J = 18.9, 7.4 Hz, 2H), 2.28 (dd, J = 13.6, 7.7 Hz, 1H), 2.23 (s, 3H), 2.05 (d, J = 10.2 Hz, 1H).

[0264] Example 27 Preparation of 2-fluoro-6-(7-fluorobenzodioxan-4-yl)-N-(2-oxo-1,2- dihydropyridin-4-yl)-3-(trifluoromethyl)benzamide 27

[0265]

[0266] First step Preparation of methyl 2-fluoro-6-(7-fluoro-2H-chromen-4-yl)-3- (trifluoromethyl)benzoate 27b

[0267] To a mixture of N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide 9b (3.00 g, 8.97 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (293 mg, 0.359 mol), sodium carbonate (1.59 g, 14.98 mmol) and 1,4-dioxane / water (4:1) (40 mL) was added methyl 6-bromo-2-fluoro-3-(trifluoromethyl)benzoate 27a (2.16 g, 7.18 mmol). Argon protection, the reaction mixture was stirred at 90 °C for 10 h. Cooling, the reaction was concentrated under reduced pressure, 50 mL of water and 50 mL of ethyl acetate were added, mixed evenly, and separated into layers. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification was performed by silica gel column chromatography (EA:PE; 1:20 to 1:10) to obtain compound 27b (2.45 g) (colorless oil), yield: 73.75%. 1 H NMR (400 MHz, Chloroform-d) δ 7.72 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.70 - 6.58 (m, 2H), 6.54 (td, J = 8.4, 2.5 Hz, 1H), 5.73 (t, J = 3.9 Hz, 1H), 4.86 (d, J = 3.8 Hz, 2H), 3.67 (s, 3H).

[0268] Preparation of compound 27 in the second step

[0269] Compound 27 (31 mg) was prepared by replacing the first step raw material compound 9c with compound 27b using the synthetic route of Example 11. MS m / z (ESI): 451.34 [M+l] + .

[0270] Preparation of compound 28, 2-fluoro-6-(7-fluorochroman-4-yl)-N-(3-sulfamoylphenyl)-3- (trifluoromethyl)benzamide 28 in Example 28

[0271]

[0272] Compound 28 (38 mg) was prepared by replacing the raw material 4-amino-2-methoxypyridine with m-aminobenzenesulfonamide using the synthetic route of Example 27. 1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.34 (t, J = 1.9 Hz, 1H), 7.93 - 7.75 (m, 2H), 7.71 - 7.53 (m, 2H), 7.45 (s, 2H), 7.08 (d, J = 8.3 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.77 - 6.62 (m, 2H), 4.38 (t, J = 7.1 Hz, 1H), 4.21 (t, J = 4.4 Hz, 2H), 2.30 (dq, J = 15.1, 5.6, 5.1 Hz, 1H), 2.19 - 2.07 (m, 1H).

[0273] Example 29 Preparation of N-(3-carbamoylphenyl)-2-fluoro-6-(7-fluorochroman-4-yl)-3- (trifluoromethyl)benzamide 29

[0274]

[0275] Compound 29 (31 mg) was prepared using the synthetic route of Example 27, replacing the starting material 4-amino-2-methoxypyridine with m-aminobenzamide. 1 H NMR (400 MHz, Chloroform-d) δ 9.64 (s, 1H), 8.21 (dt, J = 6.7, 2.5 Hz, 1H), 8.07 (d, J = 1.9 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.45 - 7.34 (m, 2H), 6.93 (d, J = 8.2 Hz, 1H), 6.72 (dd, J = 8.6, 6.4 Hz, 1H), 6.53 (dd, J = 10.1, 2.6 Hz, 1H), 6.41 (td, J = 8.3, 2.6 Hz, 1H), 6.34 (s, 1H), 5.32 (s, 1H), 4.47 (t, J = 7.0 Hz, 1H), 4.16 (ddd, J = 10.1, 6.4, 3.3 Hz, 1H), 4.08 (ddd, J = 11.2, 8.3, 2.9 Hz, 1H), 2.39 - 2.28 (m, 1H), 2.17 - 2.08 (m, 1H).

[0276] Example 30 2-(7-Fluoro-2,2-dimethylchroman-4-yl)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4-

[0277] Preparation of 2-(7-Fluoro-2,2-dimethylchroman-4-yl)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4-

[0278]

[0279]

[0280] First step: Preparation of 7-fluoro-2,2-dimethylchroman-4-one 30b 1 H NMR (400 MHz, Chloroform-d) δ 7.79 (dd, J = 8.8, 6.7 Hz, 1H), 6.61 (td, J = 8.5, 2.4 Hz, 1H), 6.53 (dd, J = 10.1, 2.4 Hz, 1H), 2.64 (s, 2H), 1.39 (s, 6H).

[0281] Second step: Preparation of N'-(7-fluoro-2,2-dimethylchroman-4- ylidene)-4-methylbenzenesulfonohydrazide 30c

[0282] P-toluenesulfonohydrazide (1.58 g, 8.50 mmol) was suspended in methanol solution, glacial acetic acid (0.5 mL) was added dropwise, and then 30b (1.50 g, 7.72 mmol) was added to the mixture, heated to 70 °C and reacted overnight. After the reaction mixture was cooled to room temperature, a large amount of precipitate was produced. The precipitate was filtered and washed with methanol. The precipitate was dried in vacuum. Compound 30c (2.34 g) (white solid) was obtained, yield: 83.59%. 1 H NMR (400 MHz, Chloroform-d) δ 7.90 (d, J = 8.4 Hz, 2H), 7.85 - 7.77 (m, 2H), 7.34 (d, J = 8.1 Hz, 2H), 6.61 (td, J = 8.5, 2.5 Hz, 1H), 6.50 (dd, J = 9.9, 2.5 Hz, 1H), 2.56 (s, 2H), 2.43 (s, 3H), 1.33 (s, 6H).

[0283] Third step: Preparation of methyl 2-(7-fluoro-2,2-dimethyl-2H-chromen-4- yl)-4-(trifluoromethyl)benzoate 30d

[0284] To a mixture of compound 30c (768 mg, 2.12 mmol), [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium dichloromethane complex (72 mg, 0.11 mol), sodium carbonate (373 mg, 4.24 mmol) and 1,4-dioxane / water (4:1) (16 mL) was added methyl 2-bromo-4-(trifluoromethyl)benzoate (500 mg, 1.77 mmol). Argon protection, the reaction mixture was stirred at 85 °C for 16 h. Cooling, the reaction was concentrated under reduced pressure, 30 mL of water and 30 mL of ethyl acetate were added, mixed evenly, and separated by standing. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification was performed by silica gel column chromatography (EA:PE; 1:40 to 1:20) to obtain compound 30d (623 mg) (colorless oil), yield: 92.72%. 1 H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J = 8.1 Hz, 1H), 7.77 - 7.63 (m, 1H), 7.55 (d, J = 1.9 Hz, 1H), 6.61 (dd, J = 10.0, 2.4 Hz, 1H), 6.55 - 6.42 (m, 2H), 5.46 (s, 1H), 3.65 (s, 3H), 1.51 (s, 6H).

[0285] Preparation of compound 30 in the fourth step

[0286] Compound 30 (31 mg) was prepared by replacing the first step raw material compound 9c with compound 30d using the synthetic route of Example 11. 1 H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J = 8.0 Hz, 1H), 7.52 - 7.45 (m, 1H), 7.36 (s, 1H), 7.24 (d, J = 7.2 Hz, 1H), 6.82 (d, J = 7.1 Hz, 1H), 6.71 (s, 1H), 6.57 (dd, J = 8.6, 6.5 Hz, 1H), 6.51 (dd, J = 10.3, 2.6 Hz, 1H), 6.41 (td, J = 8.3, 2.6 Hz, 1H), 4.49 (dd, J = 12.2, 6.1 Hz, 1H), 2.23 (dd, J = 13.5, 6.0 Hz, 1H), 1.91 (t, J = 12.9 Hz, 1H), 1.41 (s, 3H), 1.25 (s, 3H).

[0287] Preparation of 4-(5-chloro-2-(7-fluorochroman-4-yl)-4- (trifluoromethyl)benzamido)picolinamide 31

[0288]

[0289] Using the synthetic route of Example 19, the second step starting material N'-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-ylidene)-4-methylbenzenesulfonylhydrazide was replaced with N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide and the seventh step starting material m- aminobenzenesulfonamide was replaced with 4-aminopyridine-2-carboxamide to give compound 31 (34 mg). 1 H NMR (400 MHz, Methanol-d4) δ 8.53 (d, J = 5.5 Hz, 1H), 8.29 (d, J = 2.2 Hz, 1H), 7.93 (dd, J = 5.5, 2.2 Hz, 1H), 7.85 (s, 1H), 7.41 (s, 1H), 6.78 (dd, J = 9.5, 6.3 Hz, 1H), 6.59 - 6.46 (m, 2H), 4.60 (t, J = 7.3 Hz, 1H), 4.21 (ddd, J = 11.3, 5.9, 3.5 Hz, 1H), 4.13 (ddd, J = 11.4, 8.7, 2.8 Hz, 1H), 2.39 - 2.27 (m, 1H), 2.29 - 2.16 (m, 1H).

[0290] Example 32 Preparation of N-(3-carbamoyl-4-fluorophenyl)-2-fluoro-6-(7-fluorochroman-4-yl)-3- (trifluoromethyl)benzamide 32

[0291]

[0292] Example 32 Preparation of N-(3-carbamoyl-4-fluorophenyl)-2-fluoro-6-(7-fluorochroman-4-yl)-3- (trifluoromethyl)benzamide 32

[0293] A mixture of methyl 2-fluoro-6-(7-fluoro-2H-chromen-4-yl)-3-(trifluoromethyl)benzoate 27b (500 mg, 1.35 mmol), 10% Pd-C catalyst (100 mg) and ethanol (50 mL) was stirred at 60 °C under hydrogen for 30 h. After filtration of the catalyst, the filtrate was evaporated to dryness. Purification by silica gel column chromatography (EA: PE; 1:40 to 1:20) gave compound 32a (420 mg) (colorless oil) in 83.55% yield. 1H NMR (600 MHz, Chloroform-d) δ 7.56 (t, J = 7.7 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.72 (ddd, J = 8.7, 6.4, 1.0 Hz, 1H), 6.60 (dd, J = 10.2, 2.6 Hz, 1H), 6.55 (td, J = 8.3, 2.6 Hz, 1H), 4.35 (t, J = 6.9 Hz, 1H), 4.22 - 4.11 (m, 2H), 3.95 (s, 3H), 2.39 - 2.28 (m, 1H), 2.16 - 2.04 (m, 1H).

[0294] Preparation of the second step 2-fluoro-6-(7-fluorochroman-4-yl)-3- (trifluoromethyl)benzoic acid 32b

[0295] Compound 32a (400 mg, 1.07 mmol) was dissolved in tetrahydrofuran (20 ml), and an aqueous solution of sodium hydroxide (86 mg, 2.15 mmol) (5 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to a small amount of aqueous solution, 20 mL of water was added, and the pH was adjusted to 2 with 2M aqueous hydrochloric acid solution, and a solid was precipitated, filtered, and dried in vacuo. Compound 32b (353 mg) was obtained as a yellowish solid (yield: 91.71%).

[0296] MS m / z (ESI): 356.86 [M-1] - .

[0297] Preparation of the third step N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(7- fluorochroman-4-yl)-3-(trifluoromethyl)benzamide 32c

[0298] Compound 32b (100 mg, 279.12 μmol) was dissolved in anhydrous dichloromethane (4 ml), and placed in an ice bath, and oxalyl chloride (0.29 mL, 3.35 mmol) was added dropwise, and stirring was continued for 3 hours. The reaction solution was concentrated to obtain an acyl chloride, which was used as prepared. 3-Cyano-4-fluoroaniline (57 mg, 418.69 μmol, Bide Pharmaceutical) was dissolved in anhydrous tetrahydrofuran, and DIEA (92 μL, 0.56 mmol) was added, and placed in an ice bath, and the prepared acyl chloride solution in anhydrous dichloromethane was added dropwise, and transferred to room temperature and stirred overnight. The reaction solution was concentrated, 20 mL of water and 20 mL of ethyl acetate were added, mixed uniformly, and allowed to stand to separate into layers. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification was performed by silica gel column chromatography (MeOH:DCM; 1:100 to 1:50) to obtain compound 32c (106 mg) as a white solid (yield: 79.72%).1 H NMR (400 MHz, Chloroform-d) δ 8.05 (dd, J = 5.4, 2.7 Hz, 1H), 7.91 (s, 1H), 7.77 (ddd, J = 9.1, 4.5, 2.8 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 5.8 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.71 (dd, J = 8.5, 6.4 Hz, 1H), 6.58 (dd, J = 10.1, 2.6 Hz, 1H), 6.53 (td, J = 8.3, 2.6 Hz, 1H), 4.50 (t, J = 7.1 Hz, 1H), 4.27 - 4.11 (m, 2H), 2.45 - 2.33 (m, 1H), 2.25 - 2.13 (m, 1H).

[0299] Fourth Step Preparation of 2-fluoro-N-(4-fluoro-3-(N'-hydroxy carbamoyl)phenyl)-6-(7- fluorochroman-4-yl)-3-(trifluoromethyl)benzamide 32

[0300] Preparation of (trifluoromethyl)benzamide 32d

[0301] Compound 32c (100 mg, 209.92 umol) was dissolved in 95% ethanol (3 mL), hydroxylamine hydrochloride (28 mg, 419.84 umol) and Et3N (56 uL, 419.84 umol) were added, the reaction mixture was stirred at 80 °C for 4 hours. The mixture was cooled to ambient temperature. The reaction was concentrated, 20 mL water and 20 mL ethyl acetate were added, mixed well, and allowed to separate into layers. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude 32d, which was used directly in the next step without further purification.

[0302] Fifth Step Preparation of 2-fluoro-N-(3-carbamoyl-4-fluorophenyl)-6-(7-fluorochroman-4-yl)-3- (trifluoromethyl)benzamide 32

[0303] The crude compound 32d of previous step was dissolved in acetic acid (1 ml). To the mixture was added acetyl chloride (16.4 μL, 230.91 μmol). The reaction mixture was stirred at room temperature for 30 min. To the mixture was added PdCl2(3.72 mg, 20.99 μmol) and triethylsilane (43.6 μL, 272.89 μmol). The reaction mixture was continued to stir at 70-75 °C for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was concentrated under reduced pressure, poured into 20 mL of saturated sodium bicarbonate solution, stirred well until the gas bubble disappeared. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Purification by silica gel column chromatography (MeOH:DCM; 1:15 to 1:10) gave compound 32 (59 mg) (white solid) with a yield of 60.38%.

[0304] MS m / z (ESI): 494.27 [M+l] + .

[0305] Example 33 Preparation of N-(3-carbamoyl-4-fluorophenyl)-5-chloro-2-(7- fluorochromen-4-yl)-4-(trifluoromethyl)benzamide 33

[0306]

[0307] Using the first to fifth steps of the synthetic route of Example 19, the second step starting material N'-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-ylidene)-4- toluenesulfonylhydrazide was replaced by N'-(7-fluorochromen-4-ylidene)-4- toluenesulfonylhydrazide, and the third to fifth steps of the synthetic route of Example 32 were used to prepare compound 33 (38 mg).

[0308] MS m / z (ESI): 510.28 [M+l] + .

[0309] Example 34 Preparation of (4-(5-chloro-2-(7-fluorochromen-4-yl)-4- (trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate 34

[0310]

[0311] First step preparation of 5-chloro-N-(1-(chloromethyl)-2-oxo-1,2- dihydropyridin-4-yl)-2-(7-fluorochromen-4-yl)-4-(trifluoromethyl)benzamide 34a

[0312] Compound 22 (200 mg, 0.43 mmol) was dissolved in N,N-dimethylformamide (0.2 mL) and anhydrous dichloromethane (2.4 mL), chloromethyl chloroformate (114 μL, 1.29 mmol) was added, the reaction was stirred at room temperature for 4 hours, the reaction was diluted with ethyl acetate (20 mL), the organic phase was washed with saturated sodium bicarbonate solution (10 mL x 3) and saturated sodium chloride solution (10 mL x 3) respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 34a (190 mg), which was used directly in the next step without further purification.

[0313] Preparation of the second step (4-(5-chloro-2-(7-fluorochroman-4-yl)-4- (trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl di-tert-butyl phosphate 34b

[0314] Compound 34a (190 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (4 mL), potassium di-tert-butyl phosphate (185 mg, 0.74 mmol, Shanghai Biotech Co., Ltd.) and tetrabutylammonium iodide (13.7 mg, 0.037 mmol, Shanghai Biotech Co., Ltd.) were added, the reaction was stirred at 70 °C for 4 hours, the reaction was diluted with ethyl acetate (20 mL), the organic phase was washed with saturated sodium bicarbonate solution (10 mL x 3) and saturated sodium chloride solution (10 mL x 3) respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 34b (260 mg), which was used directly in the next step without further purification. MS m / z (ESI): 689.34 [M+1] + .

[0315] Preparation of the third step 4-(5-chloro-2-(7-fluorochroman-4-yl)-4- (trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate 34

[0316] Compound 34b (260 mg, 0.38 mmol) was dissolved in a mixture solvent of acetonitrile (3 mL), acetic acid (3 mL) and water (3 mL), heated to 70 °C and stirred for 3 hours. After the reaction was completed, it was concentrated under reduced pressure, slurried with acetonitrile, filtered, washed with acetonitrile, and dried to give compound 34 (110 mg). MS m / z (ESI): 577.13 [M+1] + .

[0317] Preparation of Example 35 N-(3-carbamoyl-4-chlorophenyl)-5-chloro-2-(7- fluorochroman-4-yl)-4-(trifluoromethyl)benzamide 35

[0318]

[0319] Compound 35 (18 mg) was prepared using the first to fifth steps of the synthetic route of Example 19, replacing the second step starting material N'-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-ylidene)-4- methylbenzenesulfonohydrazide with N'-(7-fluorochroman-4-ylidene)-4- methylbenzenesulfonohydrazide, and the third to fifth steps of the synthetic route of Example 32, replacing the third step starting material 3-cyano-4-fluoroaniline with 3-cyano-4-chloroaniline. 1 H NMR (500 MHz, Methanol-d4) δ 7.84 (d, J = 2.6 Hz, 1H), 7.81 (s, 1H), 7.70 (dd, J = 8.8, 2.6 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.38 (s, 1H), 6.84 - 6.74 (m, 1H), 6.59 - 6.52 (m, 2H), 4.60 (t, J = 7.1 Hz, 2H), 4.25 - 4.17 (m, 1H), 4.18 - 4.10 (m, 2H), 2.39 - 2.28 (m, 2H), 2.25 - 2.15 (m, 1H).

[0320] Example 36 Preparation of 5-chloro-2-(7-fluorochroman-4-yl)-N-(2-oxo-1,2- dihydropyridin-4-yl)benzamide 36

[0321]

[0322] Compound 36 (58 mg) was prepared using the synthetic route of Example 19, starting with the second step, replacing the starting material 5-amino-2-bromo-4- (trifluoromethyl)benzoic acid methyl ester with 5-amino-2-bromobenzoic acid methyl ester, and replacing the starting material N'-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1- ylidene)-4-methylbenzenesulfonohydrazide with N'-(7-fluorochroman-4-ylidene)-4- methylbenzenesulfonohydrazide, replacing the seventh step starting material m- aminobenzenesulfonamide with 4-amino-2-methoxypyridine to give the methoxypyridine intermediate, and continuing with the second step of the synthetic route of Example 3. 1H NMR (600 MHz, Methanol-d4) δ 7.55 (d, J = 2.3 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.03 (dd, J = 5.3, 3.2 Hz, 2H), 6.80 - 6.76 (m, 1H), 6.75 (dd, J = 7.2, 2.1 Hz, 1H), 6.55 - 6.49 (m, 2H), 4.51 (dd, J = 7.9, 6.2 Hz, 1H), 4.21 (ddd, J = 11.2, 6.5, 3.3 Hz, 1H), 4.13 (ddd, J = 11.2, 8.5, 2.8 Hz, 1H), 2.35 - 2.26 (m, 1H), 2.20 - 2.10 (m, 1H).

[0323] Example 37 Preparation of N-(3-carbamoylphenyl)-5-chloro-6-(7-fluorochroman-4- yl)benzamide 37

[0324]

[0325] Compound 37 was prepared using the synthetic route of Example 19, starting with the second step, replacing the starting material 5-amino-2-bromo-4- (trifluoromethyl)benzoic acid methyl ester with 5-amino-2-bromobenzoic acid methyl ester and the starting material N'-(6-fluoro-l,2,3,4-tetrahydronaphthalen-l- ylidene)-4-methylbenzenesulfonohydrazide with N'-(7-fluorochroman-4- ylidene)-4-methylbenzenesulfonohydrazide, and replacing the seventh step starting material m- aminobenzenesulfonamide with m-aminobenzamide. 1 H NMR (500 MHz, Methanol-d4) δ 8.16 (t, J = 1.9 Hz, 1H), 7.85 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 7.64 (dt, J = 7.8, 1.4 Hz, 1H), 7.57 (d, J = 2.2 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.40 (dd, J = 8.4, 2.3 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.85 - 6.79 (m, 1H), 6.56 - 6.49 (m, 2H), 4.57 (t, J = 6.9 Hz, 1H), 4.21 (ddd, J = 11.2, 6.6, 3.3 Hz, 1H), 4.13 (ddd, J = 11.1, 8.3, 2.8 Hz, 1H), 2.37 - 2.28 (m, 1H), 2.21 - 2.10 (m, 1H).

[0326] Example 38 Preparation of N-(3-carbamoylphenyl)-2-fluoro-6-(7-fluorochroman-4- yl)benzamide 38

[0327]

[0328] Compound 38 was prepared using the synthetic procedure of Example 29, replacing the starting material 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid methyl ester with methyl 2-bromo-6-fluorobenzoate. 1 H NMR (500 MHz, Methanol-d4) δ 8.16 (t, J = 2.0 Hz, 1H), 7.85 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 7.64 (dt, J = 7.9, 1.3 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.32 (dd, J = 8.7, 2.8 Hz, 1H), 7.15 (td, J = 8.5, 2.8 Hz, 1H), 7.04 (dd, J = 8.8, 5.4 Hz, 1H), 6.86 - 6.79 (m, 1H), 6.55 - 6.49 (m, 2H), 4.57 (t, J = 6.9 Hz, 1H), 4.21 (ddd, J = 11.2, 6.6, 3.3 Hz, 1H), 4.13 (ddd, J = 11.2, 8.3, 2.8 Hz, 1H), 2.36 - 2.27 (m, 1H), 2.19 - 2.11 (m, 1H).

[0329] Example 39 Preparation of N-(3-carbamoylphenyl)-5-fluoro-2-(7-fluorochroman-4-yl)benzamide 39

[0330]

[0331] Compound 39 was prepared using the synthetic procedure of Example 29, replacing the starting material 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid methyl ester with methyl 2-bromo-5-fluorobenzoate. 1 H NMR (500 MHz, Methanol-d4) δ 8.16 (t, J = 2.0 Hz, 1H), 7.85 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 7.64 (dt, J = 7.9, 1.3 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.32 (dd, J = 8.7, 2.8 Hz, 1H), 7.15 (td, J = 8.5, 2.8 Hz, 1H), 7.04 (dd, J = 8.8, 5.4 Hz, 1H), 6.86 - 6.79 (m, 1H), 6.55 - 6.49 (m, 2H), 4.57 (t, J = 6.9 Hz, 1H), 4.21 (ddd, J = 11.2, 6.6, 3.3 Hz, 1H), 4.13 (ddd, J = 11.2, 8.3, 2.8 Hz, 1H), 2.36 - 2.27 (m, 1H), 2.19 - 2.11 (m, 1H).

[0332] Preparation of Example 40, N-(3-carbamoylphenyl)-4,5-fluoro-2-(7-fluorochroman-4- yl)benzamide 40

[0333]

[0334] Compound 40 was prepared using the synthetic procedure of Example 29, replacing the starting material, methyl 6-bromo-2-fluoro-3-(trifluoromethyl)benzoate, with methyl 2-bromo-4,5-difluorobenzoate. 1 H NMR (500 MHz, Methanol-d4) δ 8.15 (t, J = 1.9 Hz, 1H), 7.84 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 7.64 (dt, J = 7.8, 1.4 Hz, 1H), 7.54 (dd, J = 10.5, 7.9 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 6.89 (dd, J = 11.9, 7.7 Hz, 1H), 6.83 (dd, J = 9.5, 6.4 Hz, 1H), 6.59 - 6.51 (m, 2H), 4.61 (t, J = 7.0 Hz, 1H), 4.21 (ddd, J = 11.2, 6.4, 3.3 Hz, 1H), 4.14 (ddd, J = 11.2, 8.5, 2.8 Hz, 1H), 2.40 - 2.28 (m, 2H), 2.22 - 2.09 (m, 1H).

[0335] Preparation of Example 41, N-(3-(aminomethyl)phenyl)-5-chloro-2-(7-fluorochroman-4- yl)-4-trifluoromethylbenzamide 41

[0336]

[0337] First Step, Preparation of tert-butyl (3-(5-chloro-2-(7-fluorochroman-4-yl)-4- (trifluoromethyl)benzamido)carbamate) 41b

[0338] Compound 5-chloro-2-(7-fluorochroman-4-yl)-4-(trifluoromethyl)benzoic acid 41a was prepared using the method of Example 19, first through fifth steps, replacing the starting material of the second step, N'-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-ylidene)-4- toluenesulfonylhydrazide, with N'-(7-fluorochroman-4-ylidene)-4- toluenesulfonylhydrazide.

[0339] Compound 41a (100 mg, 226.87 pmol) was dissolved in anhydrous dichloromethane (4 ml) and placed in an ice bath. Oxalyl chloride (0.23 mL, 2.67 mmol) was added dropwise, and stirring was continued for 3 hours. The reaction solution was concentrated to obtain an acyl chloride, which was used as prepared. tert-Butyl (3-aminobenzyl)carbamate (71 mg, 320.24 pmol) was dissolved in anhydrous tetrahydrofuran, and DIEA (93 pL, 0.53 mmol) was added. The mixture was placed in an ice bath, and an anhydrous dichloromethane solution of the prepared acyl chloride was added dropwise. After the addition was completed, the mixture was transferred to room temperature and stirred overnight. The reaction solution was concentrated, 20 mL of water and 20 mL of ethyl acetate were added, mixed uniformly, and allowed to stand to separate into layers. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification by silica gel column chromatography (MeOH:DCM; 1:100 to 1:50) yielded compound 41b (98 mg) (white solid) at a yield of 63.42%. 1 H NMR (400 MHz, Chloroform-d) d 8.02 (s, 1H), 7.64 (s, 1H), 7.55 - 7.45 (m, 2H), 7.37 (s, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H), 6.72 - 6.63 (m, 1H), 6.58 (dd, J = 10.1, 2.6 Hz, 1H), 6.51 (td, J = 8.4, 2.7 Hz, 1H), 4.98 (t, J = 6.0 Hz, 1H), 4.64 (t, J = 7.3 Hz, 1H), 4.28 (d, J = 6.1 Hz, 2H), 4.25 - 4.17 (m, 1H), 4.14 (ddd, J = 11.3, 8.6, 2.6 Hz, 1H), 2.42 - 2.29 (m, 1H), 2.21 - 2.08 (m, 1H), 1.60 - 1.14 (m, 9H).

[0340] Preparation of second step N-(3-(aminomethyl)phenyl)-5-chloro-2-(7- fluorochroman-4-yl)-4-trifluoromethylbenzamide 41

[0341] Compound 41b (98 mg) was dissolved in 2 mL of dichloromethane, and 2 mL of a 4N hydrogen chloride-1,4-dioxane solution was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, dissolved in dichloromethane, neutralized with an ammonia methanol solution, and concentrated under reduced pressure. Purification by silica gel column chromatography (MeOH:DCM; 1:40 to 1:20) yielded compound 41 (39 mg) (white solid) at a yield of 48.12%.

[0342] Example 42 Preparation of N-(3-(aminomethyl)-4-fluorophenyl)-5-chloro-2-(7- fluorochromen-4-yl)-4-trifluoromethylbenzamide 42

[0343]

[0344] The compound 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(7-fluorochromen-4-yl)-4- trifluoromethylbenzamide 42a was prepared using the procedure of Example 32, Step 3, replacing the compound 2-fluoro-6-(7-fluorochromen-4-yl)-3-(trifluoromethyl)benzoic acid 32b with the compound 5-chloro-2-(7-fluorochromen-4-yl)-4- (trifluoromethyl)benzoic acid 41a.

[0345] The compound 42a (100 mg, 202.91 μmol) was dissolved in ethanol (4 mL) and placed in an ice bath under nitrogen protection. NiCl2-6H2O (53 mg, 223.20 μmol) and NaBH4(23 mg, 608.73 μmol) were added sequentially. After the addition was complete, the reaction was stirred at room temperature overnight. After the reaction was complete as monitored by TLC, the reaction was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with 2N HCl solution, then the pH was adjusted to ~9 with saturated NaHCO3solution. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated. Purification by silica gel column chromatography (MeOH:DCM; 1:40 to 1:20) gave the compound 42 (32 mg) (white solid) in 31.74% yield. MS m / z (ESI): 497.18 [M+l] + .

[0346] Example 43 Preparation of 5-chloro-N-(2-((R)-2,3-dihydroxypropoxy)pyridin-4-yl)-2-(7- fluorochromen-4-yl)-4-trifluoromethylbenzamide 43

[0347]

[0348] First step preparation of 5-chloro-N-(2-(((S)-2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)pyridin- 4-yl)-2-(7-fluorochromen-4-yl)-4-trifluoromethylbenzamide 43c

[0349] The preparation of compound 5-chloro-2-(7-fluorochroman-4-yl)-4- (trifluoromethyl)benzoyl chloride 43a was carried out using the method of the first to sixth steps of Example 19, replacing the second step raw material N'-(6-fluoro-1,2,3,4- tetrahydronaphthalen-1-ylidene)-4-methylbenzenesulfonylhydrazide with N'-(7-fluoro- chroman-4-ylidene)-4-methylbenzenesulfonylhydrazide to obtain compound 43a.

[0350] Compound 43b (62 mg, 274.70 μmol) was dissolved in anhydrous tetrahydrofuran, DIEA (80 μL, 0.48 mmol) was added, and it was placed in an ice bath, and a freshly prepared 43a (90 mg, 228.92 μmol) anhydrous dichloromethane solution was added dropwise, and after addition, it was transferred to room temperature and stirred overnight. The reaction solution was concentrated, 20 mL of water and 20 mL of ethyl acetate were added, mixed uniformly, and allowed to stand to separate into layers. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification was carried out using silica gel column chromatography (MeOH:DCM; 1:200 to 1:150) to obtain compound 43c (114 mg) (white solid) at a yield of 85.72%. 1 H NMR (400 MHz, Chloroform-d) δ 8.03 (dd, J = 5.9, 2.3 Hz, 1H), 7.64 (s, 1H), 7.38 (s, 1H), 7.17 (s, 1H), 7.04 - 6.95 (m, 1H), 6.63 (t, J = 7.5 Hz, 1H), 6.56 (dd, J = 10.1, 2.5 Hz, 1H), 6.49 (td, J = 8.4, 2.6 Hz, 1H), 4.58 (t, J = 7.3 Hz, 1H), 4.46 (td, J = 6.4, 4.9 Hz, 1H), 4.41 - 4.28 (m, 2H), 4.21 (ddd, J = 11.1, 5.6, 3.5 Hz, 1H), 4.18 - 4.08 (m, 2H), 3.83 (dd, J = 8.4, 6.2 Hz, 1H), 2.41 - 2.28 (m, 1H), 2.18 - 2.05 (m, 1H), 1.42 (s, 3H), 1.35 (s, 3H).

[0351] Preparation of compound 5-chloro-N-(2-((R)-2,3-dihydroxypropoxy)pyridin-4-yl)- 2-(7-fluorochroman-4-yl)-4-trifluoromethylbenzamide 43

[0352] Compound 43c (100 mg, 202.91 μmol) was dissolved in 2 mL of dichloromethane, and 2 mL of 4 N hydrogen chloride-1,4-dioxane solution was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction solution was evaporated under reduced pressure, water was added, and the pH was adjusted to basic with sodium carbonate. The reaction mixture was extracted with ethyl acetate (10 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification was performed by silica gel column chromatography (MeOH:DCM; 1:40 to 1:20) to obtain compound 43 (69 mg) (white solid) at a yield of 74.11%. 1 H NMR (500 MHz, Methanol-d4) δ 8.02 (d, J = 5.8 Hz, 1H), 7.82 (s, 1H), 7.40 (s, 1H), 7.29 (d, J = 1.8 Hz, 1H), 7.17 (dd, J = 5.8, 1.8 Hz, 1H), 6.83 - 6.74 (m, 1H), 6.58 - 6.52 (m, 2H), 4.58 (t, J = 7.2 Hz, 1H), 4.35 (dd, J = 11.0, 4.4 Hz, 1H), 4.28 (dd, J = 10.9, 6.0 Hz, 1H), 4.21 (ddd, J = 11.3, 6.0, 3.4 Hz, 1H), 4.14 (ddd, J = 11.3, 8.7, 2.7 Hz, 1H), 4.02 - 3.93 (m, 1H), 3.71 - 3.59 (m, 2H), 2.39 - 2.30 (m, 1H), 2.25 - 2.15 (m, 1H). Preparation of Example 44 N-(3-(carbamoylamino)-4-fluorophenyl)-5-chloro-2-(7-fluorobenzopyran-4-yl)-4- trifluoromethylbenzamide 44

[0353]

[0354] Preparation of first step 5-(5-chloro-2-(7-fluorobenzodihydropyranyl-4-yl)-4- (trifluoromethyl)benzamide)-2-fluorobenzoic acid methyl ester 44b

[0355] Methyl 2-fluoro-5-nitrobenzoate (1 g, 4.95 mmol) was dissolved in 10 mL of methanol, and 1 mL of concentrated hydrochloric acid was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and 20 mL of water was added. The reaction mixture was adjusted to pH 2 with 2 M aqueous hydrochloric acid solution, and the precipitate was filtered and dried in vacuo. Compound 43a (1 g) was obtained as a yellow solid at a yield of 100%. 1 H NMR (400 MHz, Chloroform-d) δ 7.99 (dd, J = 6.1, 2.8 Hz, 1H), 7.97 - 7.90 (m, 2H), 7.66 (s, 1H), 7.40 (s, 1H), 7.16 (dd, J = 10.0, 9.0 Hz, 1H), 6.66 (dd, J = 8.6, 6.4 Hz, 1H), 6.58 (dd, J = 10.1, 2.6 Hz, 1H), 6.51 (td, J = 8.3, 2.6 Hz, 1H), 4.65 - 4.56 (m, 1H), 4.23 (ddd, J = 11.2, 5.7, 3.5 Hz, 1H), 4.15 (ddd, J = 11.5, 9.1, 2.7 Hz, 1H), 3.88 (s, 3H), 2.42 - 2.31 (m, 1H), 2.22 - 2.11 (m, 1H).

[0356] Preparation of 5-(5-chloro-2-(7-fluorobenzopyran-4-yl)-4- trifluoromethylbenzamide)-2-fluorobenzoic acid 44c

[0357] Compound 44b (100 mg, 190.17 µmol) was dissolved in methanol (8 ml), and an aqueous solution of sodium hydroxide (30 mg, 760.66 µmol) (2 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to a small amount of aqueous solution, 20 mL of water was added, and the pH was adjusted to 2 with 2 M aqueous hydrochloric acid solution, and a solid was precipitated. The solid was filtered and dried in vacuo. Compound 44c (90 mg) was obtained as a yellowish solid at a yield of 92.47%. MS m / z (ESI): 510.09 [M-1] - .

[0358] Preparation of N-(3-(carbamoylamino)-4-fluorophenyl)-5-chloro-2-(7- fluorobenzopyran-4-yl)-4-trifluoromethylbenzamide 44

[0359] Compound 44c (50 mg, 97.69 μmol) was dissolved in tetrahydrofuran solution, CDI (16 mg, 97.69 μmol) was added, the reaction mixture was stirred at room temperature for 1 hour, DIEA (68 μL, 0.39 mmol) and guanidine hydrochloride (19 mg, 195.38 μmol) were added successively. The reaction mixture was warmed to 50 °C and stirred overnight. The reaction solution was concentrated, 20 mL of water and 20 mL of ethyl acetate were added, mixed uniformly, and allowed to stand to separate into layers. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification was performed by silica gel column chromatography (MeOH:DCM; 1:150 to 1:100) to obtain compound 44 (26 mg) (white solid), yield: 48.14%. 1 H NMR (400 MHz, Chloroform-d) δ 8.22 (br s, 1H), 8.08 (dd, J = 6.4, 2.8 Hz, 1H), 7.87 (dt, J = 7.7, 3.5 Hz, 1H), 7.65 (s, 1H), 7.38 (s, 1H), 7.10 (dd, J = 10.6, 8.9 Hz, 1H), 6.68 - 6.62 (m, 1H), 6.56 (dd, J = 10.1, 2.6 Hz, 1H), 6.49 (td, J = 8.3, 2.6 Hz, 1H), 4.61 (t, J = 7.3 Hz, 1H), 4.26 - 4.17 (m, 1H), 4.17 - 4.11 (m, 1H), 2.40 - 2.29 (m, 1H), 2.21 - 2.08 (m, 1H).

[0360] Example 45 Preparation of 2-(5-chloro-2-(7-fluorobenzodioxan-4-yl)-4- trifluoromethylbenzamide)thiophene-3-carboxamide 45

[0361]

[0362] Using the synthetic route of Example 19, the second step starting material N'-(6-fluoro- 1,2,3,4-tetrahydronaphthalen-1-ylidene)-4-methylbenzenesulfonylhydrazide was replaced with N'-(7-fluorobenzodioxan-4-ylidene)-4-methylbenzenesulfonylhydrazide, and the seventh step starting material m-aminobenzenesulfonamide was replaced with 2- aminothiophene-3-carboxamide to prepare compound 45 (39 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.89 (s, 1H), 7.43 (s, 1H), 7.36 (d, J = 5.8 Hz, 1H), 6.99 (d, J = 5.9 Hz, 1H), 6.77 (dd, J = 8.1, 6.7 Hz, 1H), 6.56 - 6.49 (m, 2H), 4.74 (t, J = 7.1 Hz, 1H), 4.20 (ddd, J = 11.3, 6.1, 3.4 Hz, 1H), 4.13 (ddd, J = 11.3, 8.7, 2.7 Hz, 1H), 2.42 - 2.33 (m, 1H), 2.23 - 2.13 (m, 1H).

[0363] Example 46 Preparation of 5-(5-chloro-2-(7-fluorochroman-4-yl)-4- trifluoromethylbenzamido)thiophene-3-carboxamide 46

[0364]

[0365] Using the synthetic route of Example 19, the second step starting material N'-(6-fluoro- 1,2,3,4-tetrahydronaphthalen-1-ylidene)-4-methylbenzenesulfonylhydrazide was replaced with N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide and the seventh step starting material m- aminobenzenesulfonamide was replaced with 2-aminothiophene-4-carboxamide to give compound 46 (31 mg) 1 H NMR (500 MHz, Methanol-d4) δ 7.89 (s, 1H), 7.43 (s, 1H), 7.36 (d, J = 5.8 Hz, 1H), 6.99 (d, J = 5.9 Hz, 1H), 6.77 (dd, J = 8.1, 6.7 Hz, 1H), 6.56 - 6.49 (m, 2H), 4.74 (t, J = 7.1 Hz, 1H), 4.20 (ddd, J = 11.3, 6.1, 3.4 Hz, 1H), 4.13 (ddd, J = 11.3, 8.7, 2.7 Hz, 1H), 2.42 - 2.33 (m, 1H), 2.23 - 2.13 (m, 1H).

[0366] Example 47 Preparation of 5-(5-chloro-2-(7-fluorochroman-4-yl)-4- (trifluoromethyl)benzamido)furan-3-carboxylic acid 47

[0367]

[0368] Using the synthetic sequence of Example 19, replacing the second step starting material N'-(6-fluoro- 1,2,3,4-tetrahydronaphthalen-1-ylidene)-4-methylbenzenesulfonohydrazide with N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonohydrazide, and the seventh step starting material m- aminobenzenesulfonamide with 5-amino-2-methylbenzoic acid, and adding an additional step of ester hydrolysis, compound 47 (29 mg) was prepared. 1 HNMR (600 MHz, Methanol-d4) δ 7.83 (s, 1H), 7.38 (s, 1H), 7.26 (d, J = 3.6 Hz, 1H), 6.78 (dd, J = 9.0, 6.4 Hz, 1H), 6.60 (d, J = 3.6 Hz, 1H), 6.59 - 6.52 (m, 2H), 4.61 (t, J = 7.2 Hz, 1H), 4.20 (ddd, J = 11.1, 6.1, 3.4 Hz, 1H), 4.14 (ddd, J = 11.3, 8.6, 2.7 Hz, 1H), 2.39 - 2.31 (m, 1H), 2.21 - 2.14 (m, 1H).

[0369] Example 48 Preparation of 5-chloro-N-(1,3-dioxoisoindolin-5-yl)-2-(7-fluorochroman-4-yl)-4- (trifluoromethyl)benzamide 48

[0370]

[0371] Using the synthetic sequence of Example 19, replacing the second step starting material N'-(6-fluoro- 1,2,3,4-tetrahydronaphthalen-1-ylidene)-4-methylbenzenesulfonohydrazide with N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonohydrazide, and the seventh step starting material m- aminobenzenesulfonamide with 5-amino-2-methylbenzoic acid, and adding an additional step of ester hydrolysis, compound 47 (29 mg) was prepared. 1 H NMR (600 MHz, Chloroform-d) δ 8.61 (s, 1H), 8.42 (s, 1H), 8.13 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.73 (s, 1H), 7.42 (s, 1H), 6.71 - 6.64 (m, 1H), 6.55 (dd, J = 10.2, 2.6 Hz, 1H), 6.49 (td, J = 8.4, 2.6 Hz, 1H), 4.63 (t, J = 7.4 Hz, 1H), 4.25 (dt, J = 9.5, 4.2 Hz, 1H), 4.19 - 4.12 (m, 1H), 2.42 - 2.36 (m, 1H), 2.23 - 2.14 (m, 1H).

[0372] Example 49 Preparation of 5-chloro-2-(7-fluorochroman-4-yl)-N-(5-oxopyrrolidin-3-yl)-4- (trifluoromethyl)benzamide 49

[0373]

[0374] Compound 41a (50 mg, 133.43 pmol) was dissolved in tetrahydrofuran solution, and DIEA (46 pL, 0.27 mmol) and HATU (76 mg, 200.15 pmol) were added successively. The reaction mixture was stirred at room temperature for 15 min, and 4-aminopyrrolidin-2-one hydrochloride (20 mg, 146.78 pmol) was added, and the reaction was continued for 5 h. 20 mL of water was added to the reaction system, and extraction was performed with ethyl acetate (10 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification was performed by silica gel column chromatography (MeOH:DCM; 1:150 to 1:100) to obtain compound 49 (51 mg) (white solid) at a yield of 83.67%. 1 H NMR (400 MHz, Chloroform-d) d 7.58 (s, 1H), 7.45 (t, J = 5.9 Hz, 1H), 7.36 (s, 1H), 6.66 (td, J = 7.5, 6.4, 1.9 Hz, 1H), 6.61 (dd, J = 10.1, 2.6 Hz, 1H), 6.52 (td, J = 8.3, 2.6 Hz, 1H), 6.23 (d, J = 5.7 Hz, 1H), 4.82 - 4.70 (m, 1H), 4.65 - 4.55 (m, 1H), 4.25 (ddd, J = 10.2, 4.8, 3.0 Hz, 1H), 4.17 (ddd, J = 11.4, 9.0, 2.7 Hz, 1H), 3.87 - 3.78 (m, 1H), 3.36 (ddd, J = 25.6, 10.6, 2.6 Hz, 1H), 2.74 (dd, J = 17.4, 8.0 Hz, 1H), 2.41 - 2.24 (m, 2H), 2.25 - 2.09 (m, 1H).

[0375] Example 50 Preparation of N-(3-carbamoylphenyl)-5-chloro-2-(8-fluorochroman-4-yl)-4- (trifluoromethyl)benzamide 50

[0376]

[0377] Using the synthetic route of Example 25, the starting material N'-(7-fluorochroman-4- ylidene)-4-methylbenzenesulfonylhydrazide was replaced with N'-(8-fluorochroman-4- ylidene)-4-methylbenzenesulfonylhydrazide to obtain compound 50 (61 mg).1 H NMR (600 MHz, Methanol-d4) δ 8.16 (t, J = 2.0 Hz, 1H), 7.85 - 7.83 (m, 1H), 7.82 (s, 1H), 7.64 (dt, J = 7.7, 1.3 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.37 (s, 1H), 6.95 - 6.87 (m, 1H), 6.77 - 6.70 (m, 1H), 6.60 (d, J = 7.8 Hz, 1H), 4.69 (dd, J = 8.2, 6.3 Hz, 1H), 4.27 (ddd, J = 11.1, 6.1, 3.3 Hz, 1H), 4.18 (ddd, J = 11.3, 8.9, 2.7 Hz, 1H), 2.46 - 2.33 (m, 1H), 2.28 - 2.17 (m, 1H).

[0378] Example 51 Preparation of 5-chloro-2-(8-fluorochroman-4-yl)-N-(2-oxo-1,2- dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 51

[0379]

[0380] Using the synthetic route of Example 22, substituting N'-(7-fluorochroman-4- ylidene)-4-methylbenzenesulfonylhydrazide for N'-(8-fluorochroman-4-ylidene)-4- methylbenzenesulfonylhydrazide, compound 51 (57 mg) was prepared. 1 H NMR (600 MHz, Methanol-d4) δ 8.16 (t, J = 2.0 Hz, 1H), 7.85 - 7.83 (m, 1H), 7.82 (s, 1H), 7.64 (dt, J = 7.7, 1.3 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.37 (s, 1H), 6.95 - 6.87 (m, 1H), 6.77 - 6.70 (m, 1H), 6.60 (d, J = 7.8 Hz, 1H), 4.69 (dd, J = 8.2, 6.3 Hz, 1H), 4.27 (ddd, J = 11.1, 6.1, 3.3 Hz, 1H), 4.18 (ddd, J = 11.3, 8.9, 2.7 Hz, 1H), 2.46 - 2.33 (m, 1H), 2.28 - 2.17 (m, 1H).

[0381] Example 52 Preparation of N-(3-carbamoylphenyl)-5-chloro-2-(7,8-difluorochroman-4- yl)-4-(trifluoromethyl)benzamide 52

[0382]

[0383] Compound 52 (47 mg) was obtained by using the synthetic route of Example 25, replacing the starting material, N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide, with N'-(7,8-difluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide. 1 HNMR (600 MHz, Methanol-d4) δ 8.14 (t, J = 2.0 Hz, 1H), 7.84 (d, J = 9.0 Hz, 2H), 7.65 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.41 (s, 1H), 6.67 (td, J = 9.4, 7.0 Hz, 1H), 6.59 (t, J = 7.1 Hz, 1H), 4.65 (t, J = 7.3 Hz, 1H), 4.33 (ddd, J = 11.3, 5.8, 3.4 Hz, 1H), 4.26 - 4.20 (m, 1H), 2.43 - 2.35 (m, 1H), 2.32 - 2.22 (m, 1H).

[0384] Example 53 Preparation of 5-chloro-2-(7,8-difluorochroman-4-yl)-N-(2-oxo-1,2- dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 53

[0385]

[0386] Compound 53 (39 mg) was obtained by using the synthetic route of Example 22, replacing the starting material, N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide, with N'-(7,8-difluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide. 1 HNMR (600 MHz, Methanol-d4) δ 8.14 (t, J = 2.0 Hz, 1H), 7.84 (d, J = 9.0 Hz, 2H), 7.65 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.41 (s, 1H), 6.67 (td, J = 9.4, 7.0 Hz, 1H), 6.59 (t, J = 7.1 Hz, 1H), 4.65 (t, J = 7.3 Hz, 1H), 4.33 (ddd, J = 11.3, 5.8, 3.4 Hz, 1H), 4.26 - 4.20 (m, 1H), 2.43 - 2.35 (m, 1H), 2.32 - 2.22 (m, 1H).

[0387] Example 54 Preparation of N-(3-carbamoylphenyl)-5-chloro-2-(6-fluorochroman-4-yl)-4- (trifluoromethyl)benzamide 54

[0388]

[0389] Compound 54 (64 mg) was prepared using the synthetic route of Example 25, replacing the starting material N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide with N'-(6-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide. 1 H NMR (600 MHz, Chloroform-d) δ 9.33 (br s, 1H), 8.23 - 8.06 (m, 2H), 7.72 (s, 1H), 7.50 - 7.34 (m, 2H), 6.85 - 6.69 (m, 2H), 6.43 (d, J = 9.3 Hz, 1H), 6.21 (br s, 1H), 5.50 (br s, 1H), 4.64 (t, J = 7.5 Hz, 1H), 4.29 - 4.16 (m, 1H), 4.16 - 4.04 (m, 1H), 2.42 - 2.32 (m, 1H), 2.20 - 2.10 (m, 1H).

[0390] Example 55 Preparation of 5-chloro-2-(6-fluorochroman-4-yl)-N-(2-oxo-l,2- dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 55

[0391]

[0392] Compound 55 (49 mg) was prepared using the synthetic route of Example 22, replacing the starting material N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide with N'-(6-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide. 1 H NMR (600 MHz, Chloroform-d) δ 11.94 (br s, 1H), 9.58 (br s, 1H), 7.63 (s, 1H), 7.33 (s, 1H), 7.22 (d, J = 7.2 Hz, 1H), 6.88 - 6.80 (m, 1H), 6.76 (d, J = 5.9 Hz, 2H), 6.71 (s, 1H), 6.44 - 6.36 (m, 1H), 4.55 (t, J = 7.5 Hz, 1H), 4.19 (dt, J = 9.7, 4.0 Hz, 1H), 4.06 (t, J = 9.8 Hz, 1H), 2.37 - 2.26 (m, 1H), 2.13 - 2.05 (m, 1H).

[0393] Example 56 Preparation of N-(3-carbamoyl-4-fluorophenyl)-5-chloro-2-(7- fluorochroman-4-yl)-4-(trifluoromethyl)benzamide 56

[0394]

[0395] Compound 56 (48 mg) was prepared using the synthetic route of Example 25, replacing the starting material m-aminobenzamide with 5-amino-2-fluorobenzamide. 1 H NMR (400 MHz, Chloroform-d) δ 9.84 (s, 1H), 8.56 (ddd, J = 9.2, 4.5, 2.9 Hz, 1H), 8.19 (dd, J = 6.7, 2.9 Hz, 1H), 7.77 (s, 1H), 7.40 (s, 1H), 7.21 (dd, J = 11.4, 9.0 Hz, 1H), 6.98 - 6.87 (m, 1H), 6.80 - 6.71 (m, 1H), 6.66 (td, J = 7.9, 4.9 Hz, 1H), 6.49 (d, J = 7.9 Hz, 1H), 5.12 (s, 1H), 4.71 (dd, J = 8.4, 6.2 Hz, 1H), 4.32 (ddd, J = 11.3, 5.9, 3.4 Hz, 1H), 4.21 (ddd, J = 11.4, 9.0, 2.6 Hz, 1H), 2.49 - 2.34 (m, 1H), 2.27 - 2.12 (m, 1H).

[0396] Example 57 Preparation of N-(3-carbamoyl-4-fluorophenyl)-5-chloro-2-(8- fluorochroman-4-yl)-4-(trifluoromethyl)benzamide 57

[0397]

[0398] Compound 57 (58 mg) was prepared using the synthetic route of Example 25, replacing the starting material N'-(7-fluorochroman-4-ylidene)-4- toluenesulfonylhydrazide with N'-(8-fluorochroman-4-ylidene)-4- toluenesulfonylhydrazide, and replacing the starting material m- aminobenzamide with 5-amino-2-fluorobenzamide. 1 H NMR (400 MHz, Chloroform-d) δ 9.84 (s, 1H), 8.56 (ddd, J = 9.2, 4.5, 2.9 Hz, 1H), 8.19 (dd, J = 6.7, 2.9 Hz, 1H), 7.77 (s, 1H), 7.40 (s, 1H), 7.21 (dd, J = 11.4, 9.0 Hz, 1H), 6.98 - 6.87 (m, 1H), 6.80 - 6.71 (m, 1H), 6.66 (td, J = 7.9, 4.9 Hz, 1H), 6.49 (d, J = 7.9 Hz, 1H), 5.12 (s, 1H), 4.71 (dd, J = 8.4, 6.2 Hz, 1H), 4.32 (ddd, J = 11.3, 5.9, 3.4 Hz, 1H), 4.21 (ddd, J = 11.4, 9.0, 2.6 Hz, 1H), 2.49 - 2.34 (m, 1H), 2.27 - 2.12 (m, 1H).

[0399] Example 58 Preparation of N-(3-carbamoyl-4-fluorophenyl)-5-chloro-2-(6- fluorochromen-4-yl)-4-(trifluoromethyl)benzamide 58

[0400]

[0401] Compound 58 (53 mg) was prepared using the synthetic route of Example 25, replacing the starting material N'-(7-fluorochromen-4-ylidene)-4- toluenesulfonylhydrazide with N'-(6-fluorochromen-4-ylidene)-4- toluenesulfonylhydrazide, and replacing the starting material m- aminobenzamide with 5-amino-2-fluorobenzamide. 1 H NMR (600 MHz, Chloroform-d) δ 10.00 (br s, 1H), 8.54 (dt, J = 8.4, 3.4 Hz, 1H), 8.13 (s, 1H), 7.76 (s, 1H), 7.38 (s, 1H), 7.17 (dd, J = 11.4, 9.0 Hz, 1H), 6.81 - 6.68 (m, 3H), 6.42 (d, J = 9.0 Hz, 1H), 5.23 (br s, 1H), 4.63 (t, J = 7.5 Hz, 1H), 4.22 (ddd, J = 11.2, 5.6, 3.5 Hz, 1H), 4.10 (td, J = 10.1, 9.4, 2.8 Hz, 1H), 2.48 - 2.35 (m, 1H), 2.22 - 2.10 (m, 1H).

[0402] Example 59 Preparation of N-(4-carbonylphenyl)-5-chloro-2-(7-fluorochroman-4-yl)- 4-(trifluoromethyl)benzamide 59

[0403]

[0404] Compound 59 (43 mg) was prepared using the synthetic route of Example 25, replacing the starting material m-aminobenzamide with p- aminobenzamide. 1 H NMR (600 MHz, Methanol-d4) δ 7.93 - 7.86 (m, 2H), 7.82 (s, 1H), 7.79 - 7.76 (m, 2H), 7.38 (s, 1H), 6.80 (dd, J = 9.5, 6.5 Hz, 1H), 6.58 - 6.53 (m, 2H), 4.61 (t, J = 7.1 Hz, 1H), 4.20 (ddd, J = 11.4, 6.2, 3.4 Hz, 1H), 4.14 (ddd, J = 11.3, 8.6, 2.8 Hz, 1H), 2.39 - 2.31 (m, 1H), 2.24 - 2.15 (m, 1H).

[0405] Preparation of Example 60, N-(4-amino-3-fluorophenyl)-5-chloro-2-(7- fluorochromen-4-yl)-4-(trifluoromethyl)benzamide 60

[0406]

[0407] Compound 60 (63 mg) was prepared using the synthetic route of Example 25, replacing the starting material m-aminobenzamide with 4-amino-2-fluorobenzamide. 1 H NMR (600 MHz, Methanol-d4) δ 7.84 (t, J = 8.5 Hz, 1H), 7.82 (s, 1H), 7.80 (dd, J = 13.7, 2.1 Hz, 1H), 7.43 - 7.38 (m, 2H), 6.81 - 6.76 (m, 1H), 6.57 - 6.52 (m, 2H), 4.60 (t, J = 7.2 Hz, 1H), 4.21 (ddd, J = 11.3, 6.1, 3.4 Hz, 1H), 4.14 (ddd, J = 11.4, 8.8, 2.7 Hz, 1H), 2.39 - 2.31 (m, 1H), 2.25 - 2.16 (m, 1H).

[0408] Example 61 Preparation of Example 61, N-(4-amino-3-fluorophenyl)-5-chloro-2-(8- fluorochromen-4-yl)-4-(trifluoromethyl)benzamide 61

[0409]

[0410] Compound 61 (68 mg) was prepared using the synthetic route of Example 25, replacing the starting material N'-(7-fluorochromen-4-ylidene)-4- toluenesulfonylhydrazide with N'-(8-fluorochromen-4-ylidene)-4- toluenesulfonylhydrazide, and replacing the starting material m- aminobenzamide with 4-amino-2-fluorobenzamide. 1 H NMR (600 MHz, Methanol-d4) δ 7.86 - 7.83 (m, 2H), 7.80 (dd, J = 13.7, 2.0 Hz, 1H), 7.43 - 7.40 (m, 2H), 6.94 - 6.89 (m, 1H), 6.74 (td, J = 8.0, 4.8 Hz, 1H), 6.59 (dd, J = 7.9, 1.4 Hz, 1H), 4.71 - 4.60 (m, 1H), 4.30 (ddd, J = 11.5, 5.9, 3.4 Hz, 1H), 4.20 (ddd, J = 11.4, 9.0, 2.6 Hz, 1H), 2.47 - 2.34 (m, 1H), 2.31 - 2.22 (m, 1H).

[0411] Example 62 Preparation of N-(4-amino-3-fluorophenyl)-5-chloro-2-(6-fluorochroman-4-yl)-4- (trifluoromethyl)benzamide 62

[0412]

[0413] Compound 62 (58 mg) was prepared using the synthetic route of Example 25, replacing the starting material N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide with N'-(6-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide, and replacing the starting material m-aminobenzamide with 4-amino-2-fluorobenzamide. 1 H NMR (600 MHz, Methanol-d4) δ 7.87 - 7.83 (m, 2H), 7.80 (dd, J = 13.6, 2.0 Hz, 1H), 7.43 - 7.40 (m, 2H), 6.86 - 6.79 (m, 2H), 6.54 (dd, J = 9.2, 2.9 Hz, 1H), 4.62 (dd, J = 8.5, 6.4 Hz, 1H), 4.22 (ddd, J = 11.3, 5.8, 3.4 Hz, 1H), 4.11 (ddd, J = 11.4, 9.2, 2.7 Hz, 1H), 2.39 - 2.31 (m, 1H), 2.26 - 2.16 (m, 1H).

[0414] Example 63 Preparation of N-(4-amino-3-chlorophenyl)-5-chloro-2-(7-fluorochroman-4-yl)-4- (trifluoromethyl)benzamide 63

[0415]

[0416] Compound 63 (64 mg) was prepared using the synthetic route of Example 25, replacing the starting material m-aminobenzamide with 4-amino-2-chlorobenzamide. 1H NMR (600 MHz, Chloroform-d) δ 7.98 (d, J = 2.0 Hz, 1H), 7.91 (br s, 1H), 7.70 - 7.64 (m, 2H), 7.54 (dd, J = 8.5, 2.0 Hz, 1H), 7.46 (s, 1H), 6.68 (dd, J = 8.5, 6.4 Hz, 1H), 6.60 (dd, J = 10.1, 2.6 Hz, 1H), 6.55 (td, J = 8.3, 2.6 Hz, 1H), 4.60 (dd, J = 8.7, 6.4 Hz, 1H), 4.28 (ddd, J = 11.2, 5.6, 3.5 Hz, 1H), 4.18 (ddd, J = 11.5, 9.3, 2.5 Hz, 1H), 2.43 - 2.35 (m, 1H), 2.25 - 2.15 (m, 1H).

[0417] Example 64 Preparation of N-(3-carbamoyl-4-chlorophenyl)-5-chloro-2-(7- fluorochromen-4-yl)-4-(trifluoromethyl)benzamide 64

[0418]

[0419] Compound 64 (55 mg) was prepared using the synthetic route of Example 25, replacing the starting meta-aminobenzamide with 5-amino-2-chlorobenzamide. 1 H NMR (600 MHz, Chloroform-d) δ 7.98 (d, J = 2.0 Hz, 1H), 7.91 (br s, 1H), 7.70 - 7.64 (m, 2H), 7.54 (dd, J = 8.5, 2.0 Hz, 1H), 7.46 (s, 1H), 6.68 (dd, J = 8.5, 6.4 Hz, 1H), 6.60 (dd, J = 10.1, 2.6 Hz, 1H), 6.55 (td, J = 8.3, 2.6 Hz, 1H), 4.60 (dd, J = 8.7, 6.4 Hz, 1H), 4.28 (ddd, J = 11.2, 5.6, 3.5 Hz, 1H), 4.18 (ddd, J = 11.5, 9.3, 2.5 Hz, 1H), 2.43 - 2.35 (m, 1H), 2.25 - 2.15 (m, 1H).

[0420] Example 65 Preparation of N-(3-carbamoyl-4-bromophenyl)-5-chloro-2-(7- fluorochromen-4-yl)-4-(trifluoromethyl)benzamide 65

[0421]

[0422] Compound 65 (59 mg) was prepared using the synthetic route of Example 25, replacing the starting meta-aminobenzamide with 5-amino-2-bromobenzamide. 1H NMR (500 MHz, Methanol-d4) δ 7.85 (d, J = 2.4 Hz, 1H), 7.81 (s, 1H), 7.66 - 7.58 (m, 2H), 7.37 (s, 1H), 6.82 - 6.76 (m, 1H), 6.59 - 6.52 (m, 2H), 4.60 (t, J = 7.1 Hz, 1H), 4.20 (ddd, J = 11.3, 6.1, 3.4 Hz, 1H), 4.14 (ddd, J = 11.3, 8.6, 2.8 Hz, 1H), 2.39 - 2.30 (m, 1H), 2.23 - 2.13 (m, 1H).

[0423] Example 66 Preparation of 5-chloro-2-(8-fluorochroman-4-yl)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide 66

[0424]

[0425] Using the synthetic route of Example 19, the second step starting material N'-(6-fluoro- 1,2,3,4-tetrahydronaphthalen-1-ylidene)-4-methylbenzenesulfonylhydrazide was replaced with N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide to give compound 66 (51 mg). 1 H NMR (600 MHz, Methanol-d4) δ 8.35 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.75 - 7.68 (m, 2H), 7.55 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.92 (dd, J = 10.9, 8.2 Hz, 1H), 6.75 (td, J = 8.0, 4.7 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 4.52 (t, J = 7.1 Hz, 1H), 4.31 (ddd, J = 10.4, 6.6, 3.2 Hz, 1H), 4.20 (ddd, J = 11.2, 8.2, 2.6 Hz, 1H), 2.40 (ddt, J = 13.9, 6.6, 3.2 Hz, 1H), 2.25 (dtd, J = 11.8, 8.3, 3.0 Hz, 1H).

[0426] Example 67 N-(3-carbamoyl-4-fluorophenyl)-2-fluoro-6-(7-fluorochroman-4-yl)-3- (trifluoromethyl)benzamide

[0427]

[0428] Compound 67 (31 mg) was prepared using the synthetic route of Example 27, replacing starting material 4-amino-2-methoxypyridine with 5-amino-2-fluorobenzamide. 1 H NMR (600 MHz, Methanol-d4) δ 8.10 (dd, J = 6.5, 2.8 Hz, 1H), 7.92 (dt, J = 7.7, 3.5 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.27 (t, J = 9.7 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.86 (dd, J = 9.5, 6.3 Hz, 1H), 6.66 - 6.50 (m, 2H), 4.47 (t, J = 7.1 Hz, 1H), 4.26 (ddd, J = 10.4, 6.6, 3.2 Hz, 1H), 4.20 - 4.13 (m, 1H), 2.41 - 2.33 (m, 1H), 2.27 - 2.17 (m, 1H).

[0429] Example 68 Preparation of 2-fluoro-6-(8-fluorobenzopyranyl-4-yl)-4-methoxy-N-(3- sulfamoylphenyl)-3-(trifluoromethyl)benzamide 68

[0430]

[0431] Compound 68 (27 mg) was prepared using the synthetic route of Example 27, replacing starting material 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid methyl ester with 6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoic acid ethyl ester (synthesis referenced in WO 2019 / 014352), replacing starting material N'-(7-fluorobenzopyran-4-ylidene)-4- toluenesulfonylhydrazide with N'-(8-fluorobenzopyran-4-ylidene)-4- toluenesulfonylhydrazide, and replacing starting material 4-amino-2-methoxypyridine with m-aminobenzenesulfonamide. 1 H NMR (600 MHz, Methanol-d4) δ 8.31 (s, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 6.95 - 6.85 (m, 1H), 6.77 (td, J = 8.0, 4.7 Hz, 1H), 6.68 (d, J = 7.9 Hz, 1H), 6.61 (s, 1H), 4.53 (t, J = 7.4 Hz, 1H), 4.39 - 4.32 (m, 1H), 4.23 - 4.14 (m, 1H), 3.77 (s, 3H), 2.43 - 2.35 (m, 1H), 2.37 - 2.28 (m, 1H).

[0432] Example 69 Preparation of N-(3-carbamoyl-4-fluorophenyl)-2-fluoro-6-(8-fluorochroman-4-yl)-4-methoxy-3-(trifluoromethyl)benzamide 69

[0433]

[0434] Compound 69 (30 mg) was prepared using the synthetic route of Example 68, replacing the starting material m-aminobenzenesulfonamide with 5-amino-2-fluorobenzamide. 1 H NMR (600 MHz, Methanol-d4) δ 8.04 (dd, J = 6.5, 2.8 Hz, 1H), 7.88 (dt, J = 7.9, 3.6 Hz, 1H), 7.23 (t, J = 9.7 Hz, 1H), 6.96 - 6.89 (m, 1H), 6.77 (td, J = 8.0, 4.6 Hz, 1H), 6.68 (d, J = 7.9 Hz, 1H), 6.60 (s, 1H), 4.52 (t, J = 7.4 Hz, 1H), 4.38 - 4.31 (m, 1H), 4.22 - 4.16 (m, 1H), 2.42 - 2.35 (m, 1H), 2.36 - 2.27 (m, 1H).

[0435] Example 70 Preparation of 5-chloro-2-(7-(trifluoromethoxy)chroman-4-yl)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide 70

[0436]

[0437] Compound 70 (17 mg) was prepared using the synthetic route of Example 19, replacing the starting material N'-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-ylidene)-4- methylbenzenesulfonohydrazide with N'-(7-(trifluoromethoxy)chroman-4-ylidene)-4- methylbenzenesulfonohydrazide. 1 H NMR (600 MHz, Chloroform-d) δ 8.47 (s, 1H), 8.09 (s, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.67 (s, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.40 (s, 1H), 6.78 - 6.65 (m, 2H), 6.60 (d, J = 8.5 Hz, 1H), 5.21 (s, 1H), 4.61 (dd, J = 8.8, 6.2 Hz, 1H), 4.24 (dt, J = 11.1, 4.2 Hz, 1H), 4.18 - 4.07 (m, 1H), 2.40 - 2.27 (m, 1H), 2.24 - 2.12 (m, 1H).

[0438] Example 71 Preparation of 5-chloro-2-(7-(trifluoromethyl)chroman-4-yl)-N-(3- sulfamoylphenyl)-4-(trifluoromethyl)benzamide 71

[0439]

[0440] Compound 71 (47 mg) was prepared using the synthetic route of Example 19, replacing the second step starting material N'-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1- ylidene)-4-methylbenzenesulfonohydrazide with N'-(7-(trifluoromethyl)chroman-4- ylidene)-4-methylbenzenesulfonohydrazide. 1 H NMR (600 MHz, Methanol-d4) δ 8.33 (t, J = 1.9 Hz, 1H), 7.87 (s, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.11 - 7.03 (m, 2H), 6.99 (d, J = 8.1 Hz, 1H), 4.72 (t, J = 7.6 Hz, 1H), 4.30 (dt, J = 9.7, 4.6 Hz, 1H), 4.25 - 4.17 (m, 1H), 2.44 - 2.35 (m, 1H), 2.33 - 2.26 (m, 1H).

[0441] Example 72 Preparation of N-(3-carbamoyl-4-fluorophenyl)-5-chloro-2-(7- (trifluoromethyl)chroman-4-yl)-4-(trifluoromethyl)benzamide 72

[0442]

[0443] Compound 72 (41 mg) was prepared using the synthetic route of Example 19, replacing the second step starting material N'-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1- ylidene)-4-methylbenzenesulfonohydrazide with N'-(7-(trifluoromethyl)chroman-4- ylidene)-4-methylbenzenesulfonohydrazide, and replacing the seventh step starting material m- aminobenzenesulfonamide with 5-amino-2-fluorobenzamide. 1H NMR (600 MHz, Chloroform-d) δ 9.84 (s, 1H), 8.54 (dt, J = 8.1, 3.6 Hz, 1H), 8.21 (dd, J = 6.8, 2.8 Hz, 1H), 7.81 (s, 1H), 7.44 (s, 1H), 7.22 (dd, J = 11.3, 9.0 Hz, 1H), 7.11 (s, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.81 - 6.75 (m, 1H), 5.13 (s, 1H), 4.72 (t, J = 7.6 Hz, 1H), 4.32 (dt, J = 11.6, 4.2 Hz, 1H), 4.27 - 4.16 (m, 1H), 2.47 - 2.37 (m, 1H), 2.36 - 2.25 (m, 1H).

[0444] Example 73 Preparation of 5-chloro-2-(7-(trifluoromethyl)chroman-4-yl)-N-(2-oxo-1,2- dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 73

[0445]

[0446] Using the synthetic route of Example 19, replacing the second step starting material N'-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-ylidene)-4-methylbenzenesulfonylhydrazide with N'-(7-(trifluoromethyl)chroman-4-ylidene)-4-methylbenzenesulfonylhydrazide and the seventh step starting material m- aminobenzenesulfonamide with 4-amino-2-methoxypyridine, the methoxypyridine intermediate was prepared and the compound 73 (44 mg) was prepared using the second step of the synthetic route of Example 3. 1 H NMR (600 MHz, Chloroform-d) δ 11.95 (br s, 1H), 9.25 (br s, 1H), 7.64 (s, 1H), 7.34 (s, 1H), 7.23 (d, J = 7.2 Hz, 1H), 7.08 (s, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 6.77 (d, J = 7.1 Hz, 1H), 6.73 (s, 1H), 4.61 (t, J = 7.7 Hz, 1H), 4.27 (dt, J = 9.2, 4.1 Hz, 1H), 4.21 - 4.09 (m, 1H), 2.41 - 2.29 (m, 1H), 2.25 - 2.11 (m, 1H).

[0447] Example 74 Preparation of 2-fluoro-N-(3-sulfamoylphenyl)-3-(trifluoromethyl)-6-(7- (trifluoromethyl)chroman-4-yl)benzamide 74

[0448]

[0449] Compound 74 (46 mg) was prepared using the synthetic protocol of Example 27, replacing the starting material N'-(7-fluorochroman-4-ylidene)-4- methylbenzenesulfonylhydrazide with N'-(7-(trifluoromethyl)chroman-4- ylidene)-4-methylbenzenesulfonylhydrazide and the starting material 4-amino-2- methoxypyridine with m-aminobenzenesulfonamide. 1 H NMR (600 MHz, Methanol-d4) δ 8.36 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.12 - 7.00 (m, 4H), 4.56 (t, J = 7.2 Hz, 1H), 4.32 (ddd, J = 10.2, 6.2, 3.5 Hz, 1H), 4.25 - 4.17 (m, 1H), 2.44 - 2.35 (m, 1H), 2.34 - 2.24 (m, 1H).

[0450] Example 75 Preparation of N-(3-amino-4-fluorophenyl)-2-fluoro-3- (trifluoromethyl)-6-(7-(trifluoromethyl)chroman-4-yl)benzamide 75

[0451]

[0452] Compound 75 (37 mg) was prepared using the synthetic protocol of Example 27, replacing the starting material N'-(7-fluorochroman-4-ylidene)-4- methylbenzenesulfonylhydrazide with N'-(7-(trifluoromethyl)chroman-4- ylidene)-4-methylbenzenesulfonylhydrazide and the starting material 4-amino-2- methoxypyridine with 5-amino-2-fluorobenzamide. 1 H NMR (600 MHz, Methanol-d4) δ 8.36 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.12 - 7.00 (m, 4H), 4.56 (t, J = 7.2 Hz, 1H), 4.32 (ddd, J = 10.2, 6.2, 3.5 Hz, 1H), 4.25 - 4.17 (m, 1H), 2.44 - 2.35 (m, 1H), 2.34 - 2.24 (m, 1H).

[0453] Example 76 Preparation of 2-fluoro-N-(2-hydroxypyridin-4-yl)-3-(trifluoromethyl)-6-(7- (trifluoromethyl)chroman-4-yl)benzamide 76

[0454]

[0455] Compound 76 (21 mg) was prepared using the synthetic route of Example 27, replacing the starting material N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide with N'-(7-(trifluoromethyl)chroman-4-ylidene)-4-methylbenzenesulfonylhydrazide and the starting material 4-amino-2-methoxypyridine with m-aminobenzenesulfonamide. 1 H NMR (600 MHz, Methanol-d4) δ 7.75 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.08 - 7.02 (m, 2H), 7.00 (d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 6.66 (d, J = 7.2 Hz, 1H), 4.52 (t, J = 7.5 Hz, 1H), 4.32 (dt, J = 10.0, 4.5 Hz, 1H), 4.23 - 4.16 (m, 1H), 2.42 - 2.24 (m, 2H).

[0456] Example 77 Preparation of 2-fluoro-N-(3-sulfamoylphenyl)-3-(trifluoromethyl)-6-(8- fluorochroman-4-yl)benzamide 77

[0457]

[0458] Compound 77 (59 mg) was prepared using the synthetic route of Example 27, replacing the starting material N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide with N'-(8-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide and the starting material 4-amino-2-methoxypyridine with m-aminobenzenesulfonamide. 1H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.75 - 7.68 (m, 4H), 7.55 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.92 (dd, J = 10.9, 8.2 Hz, 1H), 6.75 (td, J = 8.0, 4.7 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 4.52 (t, J = 7.1 Hz, 1H), 4.31 (ddd, J = 10.4, 6.6, 3.2 Hz, 1H), 4.20 (ddd, J = 11.2, 8.2, 2.6 Hz, 1H), 2.44 - 2.36 (m, 2H), 2.30 - 2.21 (m, 2H).

[0459] Example 78 Preparation of N-(3-amino-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)-6-(8- fluorochroman-4-yl)benzamide 78

[0460]

[0461] Using the synthetic route of Example 27, substituting N'-(7-fluorochroman-4- ylidene)-4-methylbenzenesulfonylhydrazide for N'-(8-fluorochroman-4-ylidene)-4- methylbenzenesulfonylhydrazide and 5-amino-2-fluorobenzamide for 4-amino-2- methoxypyridine, provided compound 78 (47 mg). 1 H NMR (400 MHz, Chloroform-d) δ 10.01 (s, 1H), 8.59 (ddd, J = 9.0, 4.5, 2.8 Hz, 1H), 8.12 (dd, J = 6.7, 2.9 Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.20 (dd, J = 11.4, 9.0 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.91 (ddd, J = 10.4, 8.0, 1.6 Hz, 1H), 6.73 - 6.61 (m, 2H), 6.56 (dd, J = 7.6, 1.4 Hz, 1H), 5.02 (s, 1H), 4.54 (t, J = 7.0 Hz, 1H), 4.29 (ddd, J = 11.3, 6.5, 3.3 Hz, 1H), 4.19 (ddd, J = 11.2, 8.3, 2.8 Hz, 1H), 2.49 - 2.37 (m, 1H), 2.27 - 2.14 (m, 1H).

[0462] Example 79 Preparation of 2-fluoro-N-(2-hydroxypyridin-4-yl)-3-(trifluoromethyl)-6-(8- fluorochroman-4-yl)benzamide 79

[0463]

[0464] Compound 79 (25 mg) was prepared using the synthetic route of Example 27, replacing the starting material N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide with N'-(7-(trifluoromethyl)chroman-4-ylidene)-4-methylbenzenesulfonylhydrazide. 1 H NMR (600 MHz, Methanol-d4) δ 7.73 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.99 (d, J = 2.1 Hz, 1H), 6.94 - 6.90 (m, 1H), 6.77 - 6.68 (m, 2H), 6.61 (d, J = 7.8 Hz, 1H), 4.47 (t, J = 7.2 Hz, 1H), 4.31 (ddd, J = 10.3, 6.3, 3.4 Hz, 1H), 4.22 - 4.15 (m, 1H), 2.41 - 2.34 (m, 1H), 2.30 - 2.20 (m, 1H).

[0465] Example 80 Preparation of N-(3-carbamoyl-4-fluorophenyl)-5-chloro-2-(7,8- difluorochroman-4-yl)-4-(trifluoromethyl)benzamide 80

[0466]

[0467] Compound 80 (37 mg) was prepared using the synthetic route of Example 19, replacing the starting material N'-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-ylidene)-4- methylbenzenesulfonylhydrazide with N'-(7,8-difluorochroman-4-ylidene)-4- methylbenzenesulfonylhydrazide and replacing the starting material m- aminobenzenesulfonamide with 5-amino-2-fluorobenzamide in the seventh step. 1H NMR (500 MHz, Methanol-d4) δ 8.07 (dd, J = 6.4, 2.8 Hz, 1H), 7.91 (ddd, J = 9.0, 4.3, 2.8 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.25 (dd, J = 10.5, 8.9 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.73 - 6.59 (m, 2H), 4.48 (t, J = 7.1 Hz, 1H), 4.34 (ddd, J = 11.3, 6.4, 3.3 Hz, 1H), 4.23 (ddd, J = 11.2, 8.5, 2.8 Hz, 1H), 2.43 - 2.33 (m, 1H), 2.31 - 2.20 (m, 1H).

[0468] Example 81 Preparation of N-(3-amino-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)-6-(8- fluorochroman-4-yl)benzamide 81

[0469]

[0470] Using the synthetic route of Example 27, substituting N'-(7-fluorochroman-4- ylidene)-4-methylbenzenesulfonylhydrazide for N'-(7-fluorochroman-4-ylidene)-4- methylbenzenesulfonylhydrazide and 5-amino-2-fluorobenzamide for 4-amino-2- methoxypyridine, provided compound 81 (36 mg). 1 H NMR (500 MHz, Methanol-d4) δ 8.07 (dd, J = 6.4, 2.8 Hz, 1H), 7.91 (ddd, J = 9.0, 4.3, 2.8 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.25 (dd, J = 10.5, 8.9 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.73 - 6.59 (m, 2H), 4.48 (t, J = 7.1 Hz, 1H), 4.34 (ddd, J = 11.3, 6.4, 3.3 Hz, 1H), 4.23 (ddd, J = 11.2, 8.5, 2.8 Hz, 1H), 2.43 - 2.33 (m, 1H), 2.31 - 2.20 (m, 1H).

[0471] Example 82 Preparation of 2-fluoro-N-(3-sulfamoylphenyl)-3-(trifluoromethyl)-6-(7,8- difluorochroman-4-yl)benzamide 82

[0472]

[0473] Compound 82 (66 mg) was prepared using the synthetic protocol of Example 27, replacing the starting material N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide with N'-(7,8-difluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide and replacing the starting material 4-amino-2-methoxypyridine with m-aminobenzenesulfonamide. 1 H NMR (600 MHz, Methanol-d4) δ 8.35 (d, J = 2.2 Hz, 1H), 7.84 - 7.78 (m, 1H), 7.72 (dd, J = 17.6, 8.2 Hz, 2H), 7.55 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.72 - 6.65 (m, 1H), 6.63 (t, J = 7.4 Hz, 1H), 4.49 (t, J = 7.1 Hz, 1H), 4.34 (ddd, J = 10.4, 6.5, 3.4 Hz, 1H), 4.23 (ddd, J = 11.6, 8.4, 2.6 Hz, 1H), 2.43 - 2.35 (m, 1H), 2.30 - 2.22 (m, 1H).

[0474] Example 83 Preparation of N-(3-amino-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)-6-(6- (trifluoromethoxy)chroman-4-yl)benzamide 83

[0475]

[0476] Compound 83 (38 mg) was prepared using the synthetic protocol of Example 27, replacing the starting material N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide with N'-(6-(trifluoromethoxy)chroman-4-ylidene)-4-methylbenzenesulfonylhydrazide and replacing the starting material 4-amino-2-methoxypyridine with 5-amino-2-fluorobenzamide. 1H NMR (600 MHz, Chloroform-d) δ 9.99 (s, 1H), 8.58 (dt, J = 8.1, 3.5 Hz, 1H), 8.15 (dd, J = 6.7, 2.8 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 1.3 Hz, 1H), 7.20 (dd, J = 11.4, 9.0 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 9.0 Hz, 1H), 6.70 - 6.63 (m, 2H), 4.84 (s, 1H), 4.53 (t, J = 7.1 Hz, 1H), 4.22 (ddd, J = 10.3, 6.5, 3.3 Hz, 1H), 4.17 - 4.10 (m, 1H), 2.45 - 2.38 (m, 1H), 2.21 - 2.14 (m, 1H).

[0477] Example 84 Preparation of 2-fluoro-N-(3-sulfamoylphenyl)-3-(trifluoromethyl)-6-(6- (trifluoromethoxy)chroman-4-yl)benzamide 84

[0478]

[0479] Compound 84 (40 mg) was prepared using the synthetic route of Example 27, replacing the starting material N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide with N'-(6-(trifluoromethoxy)chroman-4-ylidene)-4-methylbenzenesulfonylhydrazide and the starting material 4-amino-2-methoxypyridine with m-aminobenzenesulfonamide. 1 H NMR (600 MHz, Chloroform-d) δ 9.99 (s, 1H), 8.58 (dt, J = 8.1, 3.5 Hz, 1H), 8.15 (dd, J = 6.7, 2.8 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 1.3 Hz, 1H), 7.20 (dd, J = 11.4, 9.0 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 9.0 Hz, 1H), 6.70 - 6.63 (m, 2H), 4.84 (s, 1H), 4.53 (t, J = 7.1 Hz, 1H), 4.22 (ddd, J = 10.3, 6.5, 3.3 Hz, 1H), 4.17 - 4.10 (m, 1H), 2.45 - 2.38 (m, 1H), 2.21 - 2.14 (m, 1H).

[0480] Example 85 Preparation of N-(3-amino-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)-6-(7- (trifluoromethoxy)chroman-4-yl)benzamide 85

[0481]

[0482] Compound 85 (34 mg) was prepared using the synthetic protocol of Example 27, replacing the starting material N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide with N'-(7-(trifluoromethoxy)chroman-4-ylidene)-4-methylbenzenesulfonylhydrazide and the starting material 4-amino-2-methoxypyridine with 5-amino-2-fluorobenzamide. 1 H NMR (600 MHz, Methanol-d4) δ 8.36 (t, J = 2.0 Hz, 1H), 7.81 (dd, J = 8.1, 2.2 Hz, 1H), 7.76 - 7.68 (m, 2H), 7.55 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.74 - 6.70 (m, 2H), 4.50 (t, J = 7.1 Hz, 1H), 4.28 (ddd, J = 11.2, 6.3, 3.3 Hz, 1H), 4.18 (ddd, J = 11.3, 8.6, 2.7 Hz, 1H), 2.42 - 2.34 (m, 1H), 2.29 - 2.20 (m, 1H).

[0483] Example 86 Preparation of 2-fluoro-N-(3-sulfamoylphenyl)-3-(trifluoromethyl)-6-(7- (trifluoromethoxy)chroman-4-yl)benzamide 86

[0484]

[0485] Compound 86 (73 mg) was prepared using the synthetic protocol of Example 27, replacing the starting material N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide with N'-(7-(trifluoromethoxy)chroman-4-ylidene)-4-methylbenzenesulfonylhydrazide and the starting material 4-amino-2-methoxypyridine with 5-amino-2-fluorobenzamide. 1 H NMR (600 MHz, Methanol-d4) δ 8.36 (t, J = 2.0 Hz, 1H), 7.81 (dd, J = 8.1, 2.2 Hz, 1H), 7.76 - 7.68 (m, 2H), 7.55 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.74 - 6.70 (m, 2H), 4.50 (t, J = 7.1 Hz, 1H), 4.28 (ddd, J = 11.2, 6.3, 3.3 Hz, 1H), 4.18 (ddd, J = 11.3, 8.6, 2.7 Hz, 1H), 2.42 - 2.34 (m, 1H), 2.29 - 2.20 (m, 1H).

[0486] Preparation of Example 87, N-(3-amino-4-fluorophenyl)-2-fluoro-3- (trifluoromethyl)-6-(7-chlorochroman-4-yl)benzamide 87

[0487]

[0488] Using the synthetic route of Example 19, the second step starting material N'-(6-fluoro- 1,2,3,4-tetrahydronaphthalen-1-ylidene)-4-methylbenzenesulfonylhydrazide was replaced with N'-(7-chlorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide and the seventh step starting material m- aminobenzenesulfonamide was replaced with 5-amino-2-fluorobenzamide to give compound 87 (22 mg). MS m / z (ESI): 525.20 [M + 1] - .

[0489] Preparation of Example 88, 2-fluoro-N-(3-sulfamoylphenyl)-3-(trifluoromethyl)-6-(7- chlorochroman-4-yl)benzamide 88

[0490]

[0491] Using the synthetic route of Example 19, the second step starting material N'-(6-fluoro- 1,2,3,4-tetrahydronaphthalen-1-ylidene)-4-methylbenzenesulfonylhydrazide was replaced with N'-(7-chlorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide to give compound 88 (19 mg). MS m / z (ESI): 545.40 [M + 1] + .

[0492] Preparation of Example 89, 5-chloro-2-(7-fluorochroman-4-yl)-N-(2-sulfamoylpyridin-4- yl)-4-(trifluoromethyl)benzamide 89

[0493]

[0494] Preparation of first step, 5-chloro-2-(7-fluorochroman-4-yl)-4-(trifluoromethyl)benzamide 89a

[0495] Compound 41a (100 mg, 226.87 pmol) was dissolved in dry dichloromethane (4 ml) and placed in an ice bath. Oxalyl chloride (0.23 mL, 2.67 mmol) was added dropwise and stirring was continued for 3 h. The reaction was concentrated to give acyl chloride which was used as such. A reaction flask containing a mixture of ethyl acetate (2 mL) and aqueous ammonia (2 mL) was placed in an ice bath and the prepared acyl chloride in dry dichloromethane was added dropwise. The reaction was allowed to warm to room temperature and stirred for 1 h. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were combined and allowed to separate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Purification was done by silica gel column chromatography (MeOH:DCM; 1 : 100 to 1 :50) to give compound 89a (89 mg) (white solid) with 89.23% yield. 1 HNMR (500 MHz, Chloroform-d) δ 7.61 (s, 1H), 7.33 (s, 1H), 6.65 (ddd, J = 8.5, 6.5, 1.0 Hz, 1H), 6.60 (dd, J = 10.1, 2.6 Hz, 1H), 6.53 (td, J = 8.3, 2.6 Hz, 1H), 6.27 (br s, 1H), 5.93 (br s, 1H), 4.22 (ddd, J = 11.3, 6.0, 3.5 Hz, 1H), 4.16 (ddd, J = 11.4, 8.8, 2.8 Hz, 1H), 2.40 - 2.31 (m, 1H), 2.15 - 2.05 (m, 1H).

[0496] Second step: Preparation of 2-(benzylthio)-4-iodopyridine 89c

[0497] Benzyl mercaptan (2.78 g, 22.42 mmol) was dissolved in dry tetrahydrofuran and sodium hydride (897 mg, 22.42 mmol, 60%) was added in portions under stirring at 0 °C. The mixture was stirred at 0 °C for 1 h. To the mixture was added a solution of compound 2-fluoro-4-iodopyridine 89b (5 g, 22.42 mmol) in tetrahydrofuran dropwise under stirring at 0 °C. The resulting mixture was stirred at room temperature for 12 h. The reaction was quenched by the addition of water and extracted with ethyl acetate. The organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Purification was done by silica gel column chromatography (EA:PE; 1 : 100 to 1 :70) to give compound 89c (7.05 g) (colorless oil) with 96.10% yield.

[0498] Third step: Preparation of 4-iodopyridine-2-sulfonyl chloride 89d

[0499] Compound 2-(benzylsulfanyl)-4-iodopyridine 89c (5 g, 15.28 mmol) was dissolved in dichloromethane (60 mL), glacial acetic acid (8.6 mL) and water (17 mL) were added. 1,3-Dichloro-5,5-dimethylhydantin (9.03 g, 45.85 mmol) was added under stirring condition at 0 °C. The mixture was stirred at room temperature for 10 h, quenched with water and extracted with DCM. The combined organic layer was washed with sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with three volumes of PE and filtered to get compound 89d (3.10 g) as a yellow solid, yield: 66.84 %.

[0500] Fourth step: Preparation of N,N-bis(2,4-dimethoxybenzyl)-4-iodopyridine-2- sulfonamide 89e

[0501] Compound 4-iodopyridine 2-sulfonyl chloride 89d (3 g, 9.88 mmol) was dissolved in dichloromethane under nitrogen atmosphere, DIEA (4.3 mL, 24.71 mmol) was added followed by bis(2,4 dimethoxybenzyl)amine (2.82 g, 8.90 mmol) in portions. The mixture was stirred at 20 °C for 1.5 h, quenched with water and extracted with dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Purification was done by silica gel column chromatography (MeOH:DCM; 1:200 to 1:150) to get compound 89e (3.09 g) as a white solid, yield: 53.49 %. 1 H NMR (400 MHz, Chloroform-d) δ 8.19 (d, J = 5.0 Hz, 1H), 7.83 (d, J = 1.5 Hz, 1H), 7.66 (dd, J = 5.0, 1.6 Hz, 1H), 7.24 (d, J = 8.3 Hz, 2H), 6.40 (dd, J = 8.3, 2.4 Hz, 2H), 6.22 (d, J = 2.4 Hz, 2H), 4.56 (s, 4H), 3.79 (s, 6H), 3.63 (s, 6H).

[0502] Fifth step: Preparation of N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)- 5-chloro-2-(7-fluorochroman-4-yl)-4-(trifluoromethyl)benzamide 89f

[0503] To a mixture of N,N-bis(2,4-dimethoxybenzyl)-4-iodopyridine-2-sulfonamide 89e (169 mg, 288.98 pmol), tris(dibenzylideneacetone)dipalladium (22.05 mg, 24.08 pmol), Xantphos (20.90 mg, 36.12 pmol), cesium carbonate (66 mg, 481.63 pmol) and 1,4-dioxane (60 mL) was added 5-chloro-2-(7-fluorochroman-4-yl)-4-(trifluoromethyl)benzamide 89a (90 mg, 240.81 pmol). Argon protection, the reaction mixture was stirred at 110 °C for 1.5 hours. Cooling, the reaction was concentrated under reduced pressure, 20 mL of water and 20 mL of ethyl acetate were added, mixed evenly, and separated into layers. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification was performed by silica gel column chromatography (MeOH:DCM; 1:80 to 1:40) to give compound 89f (149 mg) (white solid), yield: 74.52%. MS m / z (ESI): 831.20 [M+l] +

[0504] Preparation of 5-chloro-2-(7-fluorochroman-4-yl)-N-(2-sulfamidopyridin-4-yl)-4- (trifluoromethyl)benzamide 89

[0505] Compound 89f (140 mg, 168.63 pmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added dropwise under ice bath. After the addition was completed, the reaction was carried out at room temperature for 4 hours. TLC monitoring showed that the reaction was completed. The reaction was poured into ice water, extracted with dichloromethane, and the combined organic phase was washed with saturated sodium bicarbonate solution. Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was recrystallized with dichloromethane to give compound 89 (81 mg) (white solid), yield: 90.65%. 1 H NMR (500 MHz, Methanol-d4) d 8.56 (d, J = 5.5 Hz, 1H), 8.35 (d, J = 1.8 Hz, 1H), 7.86 (s, 1H), 7.83 (dd, J = 5.5, 2.1 Hz, 1H), 7.43 (s, 1H), 6.82 - 6.73 (m, 1H), 6.57 - 6.49 (m, 2H), 4.64 - 4.56 (m, 1H), 4.22 (ddd, J = 11.3, 5.9, 3.5 Hz, 1H), 4.13 (ddd, J = 11.4, 8.9, 2.7 Hz, 1H), 2.39 - 2.30 (m, 1H), 2.27 - 2.19 (m, 1H).

[0506] Example 90. Preparation of 2-fluoro-N-(2-sulfamidylpyridin-4-yl)-6-(7- (trifluoromethoxy)chroman-4-yl)-3-(trifluoromethyl)benzamide 90

[0507]

[0508] Using the synthetic route of Example 27, replacing the starting material N'-(7- fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide with N'-(7- (trifluoromethoxy)chroman-4-ylidene)-4-methylbenzenesulfonylhydrazide, to give the intermediate 2-fluoro-6-(7-(trifluoromethoxy)chroman-4-yl)-3- (trifluoromethyl)benzoic acid, then using the synthetic route of Example 89, Compound 90 (77 mg) was prepared. 1 H NMR (500 MHz, Methanol-d4) δ 8.58 (d, J = 5.5 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 5.5, 2.1 Hz, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.91 - 6.88 (m, 1H), 6.73 - 6.67 (m, 2H), 4.48 (dd, J = 8.1, 6.4 Hz, 1H), 4.28 (ddd, J = 11.3, 6.0, 3.4 Hz, 1H), 4.17 (ddd, J = 11.4, 8.7, 2.8 Hz, 1H), 2.40 - 2.31 (m, 1H), 2.32 - 2.21 (m, 1H).

[0509] Example 91. Preparation of 2-fluoro-N-(2-sulfamidylpyridin-4-yl)-6-(7- (trifluoromethyl)chroman-4-yl)-3-(trifluoromethyl)benzamide 91

[0510]

[0511] Using the synthetic route of Example 27, replacing the starting material N'-(7- fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide with N'-(7- (trifluoromethoxy)chroman-4-ylidene)-4-methylbenzenesulfonylhydrazide, to give the intermediate 2-fluoro-6-(7-(trifluoromethoxy)chroman-4-yl)-3- (trifluoromethyl)benzoic acid, then using the synthetic route of Example 89, Compound 90 (77 mg) was prepared. 1H NMR (500 MHz, Methanol-d4) δ 8.57 (d, J = 5.5 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 7.80 (dd, J = 5.5, 2.1 Hz, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.06 - 6.98 (m, 3H), 4.54 (t, J = 7.4 Hz, 1H), 4.32 (ddd, J = 11.3, 5.8, 3.6 Hz, 1H), 4.19 (ddd, J = 11.5, 8.7, 2.9 Hz, 1H), 2.42 - 2.27 (m, 2H).

[0512] Example 92 Preparation of 2-fluoro-N-(2-sulfamidinylpyridin-4-yl)-6-(7,8- difluorochroman-4-yl)-3-(trifluoromethyl)benzamide 92

[0513]

[0514] Using the synthetic route of Example 27, substituting N'-(7-fluorochroman-4- ylidene)-4-methylbenzenesulfonylhydrazide for N'-(7-fluorochroman-4-ylidene)-4- methylbenzenesulfonylhydrazide, to give the intermediate 2-fluoro-6-(7,8-difluorochroman- 4-yl)-3-(trifluoromethyl)benzoic acid, then using the synthetic route of Example 89, to give compound 92 (69 mg). 1 H NMR (500 MHz, Methanol-d4) δ 8.57 (d, J = 5.5 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 7.80 (dd, J = 5.5, 2.1 Hz, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.06 - 6.98 (m, 3H), 4.54 (t, J = 7.4 Hz, 1H), 4.32 (ddd, J = 11.3, 5.8, 3.6 Hz, 1H), 4.19 (ddd, J = 11.5, 8.7, 2.9 Hz, 1H), 2.42 - 2.27 (m, 2H).

[0515] Example 93 Preparation of 5-chloro-N-(4-fluoro-3-(N'-hydroxyaminocarbonyl)phenyl)- 2-(7-fluorochroman-4-yl)-4-(trifluoromethyl)benzamide 93

[0516]

[0517] Compound 93 (57 mg) was prepared using the third and fourth steps of the synthetic route of Example 32, substituting compound 2-fluoro-6-(7-fluorochroman-4-yl)-3- (trifluoromethyl)benzoic acid 32b with compound 5-chloro-2-(7-fluorochroman-4-yl)-4- (trifluoromethyl)benzoic acid 41a. 1 H NMR (500 MHz, Methanol-d4) δ 7.84 - 7.80 (m, 2H), 7.78 (ddd, J = 8.9, 4.4, 2.8 Hz, 1H), 7.36 (s, 1H), 7.18 (dd, J = 10.1, 8.9 Hz, 1H), 6.83 - 6.77 (m, 1H), 6.60 - 6.52 (m, 2H), 4.63 - 4.58 (m, 1H), 4.20 (ddd, J = 11.3, 6.1, 3.5 Hz, 1H), 4.15 (ddd, J = 11.3, 8.5, 2.8 Hz, 1H), 2.40 - 2.30 (m, 1H), 2.23 - 2.12 (m, 1H).

[0518] Example 94 Preparation of 2-fluoro-N-(4-fluoro-3-(N'-hydroxyaminocarbonyl)phenyl)-6-(7- (trifluoromethyl)chroman-4-yl)-3-(trifluoromethyl)benzamide 94

[0519]

[0520] Compound 94 (27 mg) was prepared using the first step of the synthetic route of Example 27, substituting starting material N'-(7-fluorochroman-4-ylidene)-4-methylbenzenesulfonylhydrazide with N'-(7-(trifluoromethoxy)chroman-4-ylidene)-4-methylbenzenesulfonylhydrazide, and then using the first through fourth steps of the synthetic route of Example 32. 1 H NMR (500 MHz, Methanol-d4) δ 7.84 - 7.80 (m, 2H), 7.78 (ddd, J = 8.9, 4.4, 2.8 Hz, 1H), 7.36 (s, 1H), 7.18 (dd, J = 10.1, 8.9 Hz, 1H), 6.83 - 6.77 (m, 1H), 6.60 - 6.52 (m, 2H), 4.63 - 4.58 (m, 1H), 4.20 (ddd, J = 11.3, 6.1, 3.5 Hz, 1H), 4.15 (ddd, J = 11.3, 8.5, 2.8 Hz, 1H), 2.40 - 2.30 (m, 1H), 2.23 - 2.12 (m, 1H).

[0521] Example 95 Preparation of 2-fluoro-N-(4-fluoro-3-(N'-hydroxyaminocarbonyl)phenyl)-6-(7,8- difluorochromen-4-yl)-3-(trifluoromethyl)benzamide 95

[0522]

[0523] Using the first step of the synthetic route of Example 27, substituting the starting material N'-(7-fluorochromen-4-ylidene)-4-methylbenzenesulfonylhydrazide for N'-(7,8-difluorochromen-4-ylidene)-4-methylbenzenesulfonylhydrazide, and using the procedure of the first through fourth steps of the synthetic route of Example 32, compound 95 (29 mg) was prepared. 1 H NMR (500 MHz, Methanol-d4) δ 7.83 (dd, J = 6.2, 2.7 Hz, 1H), 7.79 (ddd, J = 8.9, 4.4, 2.8 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.20 (dd, J = 10.1, 8.9 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.72 - 6.65 (m, 1H), 6.65 - 6.60 (m, 1H), 4.48 (t, J = 7.0 Hz, 1H), 4.34 (ddd, J = 11.2, 6.4, 3.3 Hz, 1H), 4.23 (ddd, J = 11.3, 8.5, 2.8 Hz, 1H), 2.43 - 2.33 (m, 1H), 2.29 - 2.21 (m, 1H).

[0524] Example 96 Preparation of 5-chloro-N-(4-bromo-3-(N'-hydroxyaminocarbonyl)phenyl)-2-(7- fluorochromen-4-yl)-4-(trifluoromethyl)benzamide 96

[0525]

[0526] Using the third and fourth steps of the synthetic route of Example 32, substituting compound 2-fluoro-6-(7-fluorochromen-4-yl)-3-(trifluoromethyl)benzoic acid 32b for compound 5-chloro-2-(7-fluorochromen-4-yl)-4-(trifluoromethyl)benzoic acid 41a, and substituting 3-cyano-4-bromoaniline for 3-cyano-4-fluoroaniline, compound 96 (16 mg) was prepared. 1H NMR (600 MHz, Methanol-d4) δ 7.82 (s, 1H), 7.76 (d, J = 2.6 Hz, 1H), 7.70 (dd, J = 8.7, 2.6 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.36 (s, 1H), 6.79 (dd, J = 8.1, 6.7 Hz, 1H), 6.61 - 6.53 (m, 2H), 4.59 (t, J = 7.1 Hz, 1H), 4.20 (ddd, J = 11.2, 6.2, 3.4 Hz, 1H), 4.14 (ddd, J = 11.4, 8.7, 2.7 Hz, 1H), 2.38 - 2.30 (m, 1H), 2.22 - 2.13 (m, 1H).

[0527] Example 97 Preparation of 2-fluoro-6-(8-fluoro-7-(trifluoromethoxy)chroman-4-yl)-N-(3- sulfamoylphenyl)-3-(trifluoromethyl)benzamide 97

[0528]

[0529] First step: Preparation of (2-fluoro-3-(trifluoromethoxy)phenyl)boronic acid 97b

[0530] Compound 2-fluoro-3-(trifluoromethoxy)benzene 97a (5.00 g, 27.76 mmol) was dissolved in dry tetrahydrofuran (70 mL), and triisopropyl borate (5.74 g, 30.54 mmol) was added at room temperature. The reaction solution was cooled to -70 °C, and LDA (2 M, 15.28 mL, 30.54 mmol) was added dropwise under nitrogen protection. After the dropwise addition was completed, the reaction solution was slowly warmed to room temperature, and the reaction was quenched by adding dilute hydrochloric acid. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 97b (5.1 g) (brown-yellow liquid) at a yield of 82.04%. The product was used directly in the next step without purification.

[0531] Second step: Preparation of 2-fluoro-3-(trifluoromethoxy)phenol 97c

[0532] Compound (2-fluoro-3-(trifluoromethoxy)phenyl)boronic acid 97b (5.00 g, 22.33 mmol) was dissolved in diethyl ether (60 mL) and cooled in an ice water bath. Hydrogen peroxide (60 mL, 30%) was added dropwise to the reaction solution, and the reaction solution was stirred at room temperature overnight after the dropwise addition was completed. After the reaction was completed, water was added to the reaction system, and the organic phase was extracted with diethyl ether three times, combined, washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 97c (4.05 g) (light yellow liquid) at a yield of 92.49%. 1H NMR (400 MHz, Chloroform-d) δ 7.01 (td, J = 8.2, 1.8 Hz, 1H), 6.95 (ddd, J = 8.5, 7.3, 1.9 Hz, 1H), 6.85 (ddt, J = 8.3, 6.7, 1.6 Hz, 1H), 6.00 (br s, 1H).

[0533] Preparation of 2-fluoro-1-(prop-2-yn-1-yloxy)-3-(trifluoromethoxy)benzene 97d in the third step

[0534] Compound 2-fluoro-3-(trifluoromethoxy)phenol 97c (4.00 g, 20.40 mmol) was dissolved in acetonitrile (60 mL), potassium carbonate (3.66 g, 26.52 mmol) was added, and bromopropargyl (2.43 g, 20.40 mmol) was added dropwise at 0 °C. After the dropwise addition was completed, the reaction mixture was stirred at room temperature overnight. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with diethyl ether three times. The organic layers were combined, washed with water, and then washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 97d (4.45 g) (colorless liquid). The yield was 93.17%. 1 H NMR (400 MHz, Chloroform-d) δ 7.11 - 7.04 (m, 2H), 7.01 - 6.91 (m, 1H), 4.79 (d, J = 2.4 Hz, 2H), 2.56 (t, J = 2.4 Hz, 1H).

[0535] Preparation of 1-((3-chloroprop-2-yn-1-yl)oxy)-2-fluoro-3-(trifluoromethoxy)benzene 97e in the fourth step

[0536] Compound 2-fluoro-1-(prop-2-yn-1-yloxy)-3-(trifluoromethoxy)benzene 97d (4.40 g, 18.79 mmol) was dissolved in acetonitrile (60 mL), N-chlorosuccinimide (5.02 g, 37.58 mmol) and silver nitrate (0.96 g, 5.64 mmol) were added, and tetrabutylammonium fluoride (2.95 g, 11.27 mmol) was added to the reaction mixture under argon. The reaction mixture was stirred at room temperature overnight. The silver salt was removed by filtration, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with diethyl ether twice. The organic layers were combined, washed with weak acid twice, and then washed with saturated sodium bicarbonate solution twice. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 97e (1.08 g) (colorless liquid). The yield was 20.41%. The product was used in the next step without purification.

[0537] Preparation of 8-fluoro-7-(trifluoromethoxy)chroman-4-one 97f in the fifth step

[0538] Compound 1 -((3-chloropropyl-2-yne- 1 -yl)oxy)-2-fluoro-3-(trifluoromethoxy)benzene 97e (1.00 g, 3.72 mmol) was added dropwise to concentrated hydrochloric acid (20 mL) at 0 °C, stirred at 0 °C for 1 h. The reaction was slowly added to a large amount of ice water, extracted with ether twice, the organic phase was combined, washed with saturated sodium bicarbonate solution twice, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, purified by silica gel column chromatography (EA: PE; 1 :20 to 1 :10) to give compound 97f (205 mg) (white solid), yield: 22.01 %. 1 H NMR (400 MHz, Chloroform-d) δ 7.70 (dd, J = 8.9, 2.2 Hz, 1H), 6.95 (ddd, J = 8.9, 6.2, 1.5 Hz, 1H), 4.67 (dd, J = 6.9, 6.0 Hz, 2H), 2.87 (dd, J = 6.9, 6.0 Hz, 2H).

[0539] Preparation of compound N'-(8-fluoro-7-(trifluoromethoxy)chroman-4- ylidene)-4-methylbenzenesulfonohydrazide 97g

[0540] P-methylbenzenesulfonohydrazide (179 mg, 0.96 pmol) was suspended in methanol solution, heated to 60 °C until p-methylbenzenesulfonohydrazide was completely dissolved. Compound 8-fluoro-7-(trifluoromethoxy)chroman-4-one 97f (200 mg, 0.80 pmol) was slowly added to the mixture. Stirring was continued for 6 h, a precipitate was produced after the reaction was cooled, the precipitate was filtered, rinsed with methanol. The precipitate was dried in vacuum to give compound 97g (321 mg) (white solid), yield: 95.97 %. MS m / z (ESI): 419.20 [M+l] + .

[0541] Again, using the synthetic route of Example 27, the starting material N'-(7- fluorochroman-4-ylidene)-4-methylbenzenesulfonohydrazide was replaced by compound N'-(8-fluoro-7-(trifluoromethoxy)chroman-4-ylidene)-4- methylbenzenesulfonohydrazide 97g to prepare compound 97 (29 mg). 1H NMR (600 MHz, Methanol-d4) δ 8.08 (dd, J = 6.6, 2.7 Hz, 1H), 7.91 (dt, J = 7.9, 3.5 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.24 (t, J = 9.7 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.81 (t, J = 7.7 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 4.53 (t, J = 7.1 Hz, 1H), 4.37 (ddd, J = 10.2, 6.2, 3.5 Hz, 1H), 4.29 - 4.22 (m, 1H), 2.44 - 2.36 (m, 1H), 2.34 - 2.25 (m, 1H).

[0542] Example 98 Preparation of N-(3-amino-4-fluorophenyl)-2-fluoro-6-(8-fluoro-7- (trifluoromethoxy)chroman-4-yl)-3-(trifluoromethyl)benzamide 98

[0543]

[0544] Compound 98 (35 mg) was prepared using the synthetic route of Example 97, replacing the starting material m-aminobenzenesulfonamide with 5-amino-2- fluorobenzamide starting material. 1 H NMR (600 MHz, Methanol-d4) δ 8.08 (dd, J = 6.6, 2.7 Hz, 1H), 7.91 (dt, J = 7.9, 3.5 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.24 (t, J = 9.7 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.81 (t, J = 7.7 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 4.53 (t, J = 7.1 Hz, 1H), 4.37 (ddd, J = 10.2, 6.2, 3.5 Hz, 1H), 4.29 - 4.22 (m, 1H), 2.44 - 2.36 (m, 1H), 2.34 - 2.25 (m, 1H).

[0545] Biological Part Testing:

[0546] Test Example 1, Blocking activity of the compounds of the present application on sodium channel 1.8 (Navl.8)

[0547] 1. Detection method: Whole-cell manual patch clamp technique to detect the effect of compounds on voltage-gated Navl.8 channel current

[0548] 2. Preparation and analysis of test compounds

[0549] Negative control: 0.5% DMSO in electrophysiological extracellular solution

[0550] Test compounds: A certain mass of compound was dissolved in DMSO to prepare a 20 mM DMSO stock solution. On the day of the test, the 20 mM compound stock solution was diluted with the extracellular solution to the final concentration to be tested, and the DMSO content in the test drug solution was ensured to be no more than 0.5%, which had no effect on the Nav1.8 channel current. For example, 100 nM and 1 μΜ compound solutions were prepared by gradient dilution as follows: 5 μL of DMSO stock solution was first taken and added to 10 mL of extracellular solution, and then dissolved uniformly to obtain a 10 μΜ compound solution; 1 mL of 10 μΜ compound was then taken and added to 9 mL of extracellular solution, and then dissolved uniformly to obtain a 1 μΜ compound solution; 1 mL of 1 μΜ compound was then taken and added to 9 mL of extracellular solution, and then dissolved uniformly to obtain a 100 nM compound solution. All positive controls in this experiment used VX-150 as the positive control drug, and the half-inhibitory concentration was 33.45 ± 0.86 nM, which was consistent with the results reported in the original literature. The negative control used in this experiment was an extracellular solution containing 0.5% DMSO, and the change in channel current was ≤5% after 10 minutes of administration.

[0551] 3. Cell culture

[0552] Nav1.8 cell strain: HEK293 (Flp-In T-Rex-293) cells stably expressing human Nav1.8 sodium channel, with the following coding gene information: NM_001293306.2.

[0553] Culture and passage conditions and methods: The cell strain was cultured in a constant temperature incubator at 37°C and 5% CO2. The Nav1.8 stable strain was cultured in DMEM (Gibco Company) high-sugar complete medium containing 10% tetracycline-free fetal bovine serum (HyClone Company) and 100 μg / mL Hygromycin B. The cells were passaged at about 90% density the day before the experiment, and first the medium was removed and the cells were washed with 37°C preheated phosphate buffer solution (PBS). After the PBS buffer was discarded, trypsin was added for digestion and then transferred to a centrifuge tube, centrifuged at 800 rpm for 3 minutes, the supernatant was discarded, and complete medium containing 1 μg / mL Doxcycline was added for resuspension. The cells were passaged into a 6-well plate, induced for 20 hours, and then separated and passaged into a coverslip coated with polylysine for 1-2 hours of continuous culture before being used for electrophysiological recording experiments.

[0554] 4. Electrophysiological experiment

[0555] Nav1.8 sodium channel currents were recorded using whole-cell voltage clamp technique at room temperature (23-25 °C).

[0556] Whole-cell voltage clamp recording experiments were performed using an Axon patch 700B patch-clamp amplifier (Molecular Devices), a Digidata 1440A digitizer (Molecular Devices), glass microelectrodes were pulled from glass electrode blanks (World Precision Instrunents) using a puller (P97, Sutter) and had a tip resistance of 1.5-2.5 MΩ after being filled with internal solution. The glass microelectrode was inserted into the amplifier probe and connected to the patch-clamp amplifier. Clamp voltage and data recording were controlled and recorded by a computer using pClamp 10 software (Molecular Devices) with a sampling frequency of 20 kHz and a filter frequency of 2 kHz.

[0557] Extracellular and intracellular solutions for electrophysiological experiments:

[0558] Extracellular solution (mM): 140 NaCl, 3 KCl, 1 CaCl2, 1 MgCl2, 10 HEPES and 20 Glucose, pH 7.3 adjusted with NaOH.

[0559] Intracellular solution (mM): 140 CsF, 10 NaCl, 10 HEPES, 1.1 EGTA and 20 Glucose, pH 7.3 adjusted with CsOH.

[0560] Electrophysiological stimulation protocol: After obtaining the whole-cell recording (GΩ seal condition with high impedance), the cell was clamped at -80 mV for 4-5 minutes to allow the equilibration of the internal solution with the intracellular solution, and then the electrophysiological recording was started. Current stimulation and compound activity detection protocol: The cell was clamped at -80 mV, a depolarizing voltage stimulus of +10 mV was given for 20 ms, and then repolarized to -80 mV, with a stimulation frequency of 0.5 Hz. After the Nav1.8 sodium channel current was determined to be stable (about 1 minute), the drug administration process was started, and the cell current no longer changed until the compound inhibition reached steady state. Each concentration of compound was tested in at least 3 cells (n≥3). After all the tested compounds, a single concentration of 100 nM VX-150 was given as a positive control.

[0561] 5. Data analysis

[0562] Data acquisition and analysis were performed using pClamp 10 (Molecular Devices), GraphPad Prism 5 (GraphPad Software) and Excel (Microsoft) software. The effect of the compound on the current was calculated using the following formula:

[0563] Inhibition rate (%) = [1 - the size of the current after adding the drug (I Drug ) / the size of the current before adding the drug (I Control )] x 100.

[0564] Table 1. Blocking activity of some compounds of the present application on Nav1.8 channel at a concentration of 100 nM

[0565] Compound No. Inhibition rate (%) Example 4 76％ Example 5 71％ Example 9 81％ Example 16 76％ Example 19 94％ Example 20 96％ Example 21 91％ Example 22 95％ Example 25 65％ Example 27 76％

[0566] Table 2. Blocking activity of some compounds of the present application on Nav1.8 channel at a concentration of 30 nM

[0567]

[0568]

[0569] Table 3. Blocking activity of some compounds of the present application on Nav1.8 channel at a concentration of 10 nM

[0570] Compound No. Inhibition rate (%) Example 56 73％ Example 57 72％ Example 58 66％ Example 66 65％ Example 67 77％ Example 68 81％ Example 69 62％ Example 74 84％ Example 75 54％ Example 76 47％ Example 77 84％ Example 78 62％ Example 79 36％ Example 87 84％ Example 88 81％

[0571] Table 4. Blocking activity of some compounds of the present application on Nav1.8 channel at a concentration of 1 nM

[0572]

[0573] Test 2, pharmacokinetic test of the compound of the present application

[0574] 1. Experimental animals

[0575] Healthy ICR mice, male, body weight 18-20 g, 6 for a group.

[0576] 2. Experimental drugs

[0577] The compounds of example 9, example 21, example 22 and the control compound VX-150 (synthesized according to the patent WO2014120808) in the present application.

[0578] 3. Drug preparation

[0579] Weigh a certain amount of drug, and prepare it with different solvents according to different administration routes. The intragastrical administration solvent is 0.5% MC, and the intravenous administration solvent is 5% DMSO+10% Solutol+10% ethanol+75% saline.

[0580] 4. Administration

[0581] ICR mice are fasted for 12 hours before administration and allowed to drink water freely. The intravenous administration dose is 2 mg / kg, and the intragastrical administration dose is 10 mg / kg.

[0582] 5. Sampling and determination

[0583] At 0.083, 0.5, 1.0, 3.0, 5.0 and 8.0 hours after intravenous administration, and at 0.5, 1.0, 3.0, 5.0, 8.0 and 24 hours after intragastrical administration, 10 μL of whole blood is taken from the tail vein of the mouse, added to 30 μL of 0.1M trisodium citrate in a test tube, and frozen in a refrigerator at -20°C; 10 μL of plasma sample (the sample is taken from the refrigerator at -80°C, naturally thawed at room temperature, and vortexed for 30 seconds) is added to a 1.5 mL centrifuge tube, 100 μL of internal standard solution (D5&D8 100 ng / mL acetonitrile solution) is added, vortexed for 60 seconds, and centrifuged for 3 minutes (centrifugal force 12000 rpm); 100 μL of supernatant is transferred to a 96-well injection plate containing an equal volume of water, mixed by oscillation, and then subjected to LC-MS / MS injection analysis.

[0584] 6. Pharmacokinetic parameter results

[0585] The pharmacokinetic parameters of the compound of the present application and the control compound are shown in Table 3 below.

[0586] Table 3 Pharmacokinetic parameters of the compounds of Examples 9, 21, 22 and the control compound of the present application

[0587]

[0588] Conclusion: The above research results show that the compound of the present application has significantly better pharmacokinetic properties than the control compound in mice.

[0589] The above examples are only used to illustrate the technical solutions of the present application, and are not intended to limit the present application. Although the present application has been described in detail with reference to the foregoing examples, it should be understood by those skilled in the art that the technical solutions described in the foregoing examples can be modified, or some or all of the technical features can be replaced by equivalents, without departing from the spirit and essence defined in the claims of the present application; and these modifications or replacements are still within the scope defined by the claims of the present application.

Claims

1. A compound of Formula I, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, ###0001### Formula I wherein: A ring is a phenyl ring or a pyridyl ring; n is 0; X is -CH-; o is 0 or 1. I 2. The compound of Formula I according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein: o is 1. The compound of Formula I is selected from the following compounds of Formula II: ###0002### Formula II (R 1 ) m represents m R 1 substituents, m is 1, 2; R 1 each independently is selected from the group consisting of halogen, -SO2NH2, oxo (=0), -SO2NHCH3, amidino, -CONH2, C1-C3 alkylamino, hydroxyl, -C(=NOH)NH2; The compound of Formula I is selected from the following compounds of Formula III: ###0003### Formula III The compound of Formula I is selected from the following compounds of Formula IV: ###0004### Formula IV R 2a , R 2b , and R 2c are each independently selected from the group consisting of a hydrogen atom, a halogen, a substituted or unsubstituted C1-C6alkyl group, a substituted or unsubstituted C1-C6alkoxy group; the substituents of the said substituted groups being selected from the group consisting of a halogen; R 3a selected from a hydrogen atom or a halogen; R 3b selected from the group consisting of hydrogen atom, halogen, substituted C1-C6alkyl, substituted C1-C6alkoxy; the substituents of the said substituted substituents are selected from the group consisting of halogen; R 3c selected from a hydrogen atom or a substituted Ci-C6alkyl group, said substituted substituent being selected from a halogen; R 3d is a hydrogen atom; Y is O or CR c R d ; R c and R d is a hydrogen atom; R 4a , R 4b , R 4c and R 4d are hydrogen atoms; The compound of Formula I is selected from the following compounds of Formula V: ###0005### Formula V The compound of Formula I is selected from the following compounds: ###0006### R 2a is a halogen, Ci-C6alkyl or haloCi-C6alkyl, R 2b is a hydrogen atom, halogen or haloCi-C6alkyl, R 2c is a hydrogen atom or halogen; and / or 8. A pharmaceutical composition comprising one or more of a compound selected from any one of claims 1-7, a tautomer thereof, and a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

3. A compound of formula I according to claim 1 or 2, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein 9. Use of a compound of any one of claims 1-7, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 8, for the manufacture of a Navl.8 inhibitor.

10. Use of a compound of any one of claims 1-7, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 8, for the manufacture of a medicament for the treatment and / or alleviation of pain and pain-related disorders; said pain and pain-related disorders include nociceptive pain, inflammatory pain, neuropathic pain, musculoskeletal pain, postoperative pain and intractable pain, functional pain, pain associated with muscle or bone injury, pelvic pain, abdominal pain, chest pain, lumbosacral radicular pain, preoperative pain, intraoperative pain, postoperative pain, intestinal pain, acute or chronic pain, migraine, trigeminal neuralgia, pancreatitis, renal colic, cancer pain, pain caused by chemotherapy or drug therapy, diabetic neuropathic pain, post-herpetic neuralgia, back pain, phantom limb pain, sciatica, small fiber neuropathic pain, and erythromelalgia. wherein R 2a , R 2b , R 2c , X, R 3a , R 3b , R 3c , R 3d , Y, R 4a , R 4b , R 4c , R 4d , o are as defined in the respective claims; R 5a , R 5b , and R 5c are each independently selected from a hydrogen atom, a halogen; R 6 selected from a hydrogen atom, a C1-C6alkyl group.

4. A compound of formula I according to claim 1 or 2, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein ​ ​ wherein R 2a , R 2b , R 2c , X, R 3a , R 3b , R 3c , R 3d , Y, R 4a , R 4b , R 4c , R 4d , o are as defined in the respective claims, R 5a , R 5b , R 5c and R 5d are each independently selected from the group consisting of a hydrogen atom, a halogen.

5. A compound of formula I according to claim 1 or 2, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein ​ ​ wherein R 2a , R 2b , R 2c , X, R 3a , R 3b , R 3c , R 3d , Y, R 4a , R 4b , R 4c , R 4d , o are as defined in the respective claims, R 5a , R 5b , R 5c and R 5d are each independently selected from the group consisting of a hydrogen atom, a halogen.

6. A compound of formula I according to claim 1 or 2, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein ​ V wherein R 2a , R 2b , R 2c , X, R 3b , Y, R 4a , R 4b , R 4c , R 4d , o, n, A ring, R 1 , m are as defined in the respective claims.

7. The compound of formula I according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein ​ 。 ​ ​ ​ ​

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