A cyclen derivative, its preparation and use

Abstract

The present application relates to a kind of annelated derivative and its preparation method and use, specifically provide the compound or its pharmaceutically acceptable salt, stereoisomer as selective agonist of cannabinoid receptor CB2, wherein the compound has the structure of formula (I).

Description

TECHNICAL FIELD

[0001] The present application relates to a kind of and cyclic compound and its pharmaceutically acceptable salt, stereoisomer, nitrogen oxide, polymorph, hydrate, solvate, isotopically labeled, metabolite and its pharmaceutical composition in the preparation for preventing and treating the use of disease mediated by CB2 receptor. BACKGROUND

[0002] Pain, as the fifth vital sign, is the most common and most disturbing symptom in clinic, is an important factor affecting the quality of life and disability, and is one of the most important unmet medical needs. Limited by the limited efficacy and adverse reactions of existing analgesic drugs, the American Pain Society estimates that about 75% of patients do not receive effective pain treatment. Under the guidance of multi-mode analgesia, opioid drugs are widely used in moderate to severe pain, especially in postoperative analgesia. However, its significant adverse reactions such as nausea, vomiting, constipation, urinary retention and respiratory depression, as well as tolerance limit its clinical use, and the strong addiction restricts its use. Therefore, there is a great demand for new analgesic drugs with similar analgesic activity and reduced adverse reactions in clinic.

[0003] Extensive research has accumulated evidence that cannabinoid receptors widely distributed in the human body are involved in central and peripheral analgesia mediated by the endocannabinoid system, as well as anti-inflammatory and other regulations. Cannabinoid receptors include cannabinoid CB1 receptors (mainly distributed in the central nervous system, low level expression in the terminal of peripheral neurons) and cannabinoid CB2 receptors (mainly expressed in peripheral circulating immune cells). CB1 and CB2 receptor agonists have been shown to be involved in acute and chronic pain inhibition, and lack typical physical dependence symptoms. Among them, CB1 receptors are mainly distributed in the central nervous system, and bear the mental activity of cannabis compounds. Early agonists and antagonists developed for CB1 receptors are limited by mental adverse reactions, and the current research direction has shifted to the development of selective CB2 receptor agonists, which can avoid the mental side effects mediated by CB1 receptors while retaining effective analgesic activity. Extensive research has confirmed that CB2 receptor selective agonists have significant analgesic effect in various animal pain models such as preclinical neuropathic pain, inflammatory pain and acute pain, and no CB1 receptor related CNS adverse reactions have been observed. It is a potential new analgesic drug with low toxicity and high efficiency.

[0004] Therefore, based on existing domestic and foreign research, the present application seeks to develop a new structure of CB2 receptor selective agonist to provide better drugs for clinical application. SUMMARY

[0005] The purpose of the present application is to introduce a new type of selective agonist of cannabinoid receptor CB2.

[0006] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt, stereoisomer thereof, wherein the compound has the structure of Formula (I):

[0007]

[0008] wherein:

[0009] is selected from a phenyl ring or a 5-6 membered heteroaromatic ring;

[0010] U is selected from N or CH;

[0011] W is selected from S, O, S=O, S(=O)2, or CR a R b ; Y is selected from O, NR c or CR d R e ;

[0012] R a and R b are independently selected from hydrogen, halogen, or C 1-4 alkyl, wherein the C 1-4 alkyl is unsubstituted or substituted with one or more substituents each independently selected from halogen, cyano, or hydroxyl;

[0013] or R a and R b together with the atoms to which they are attached form a 3-6 membered hydrocarbon ring or a 4-6 membered heterocyclic ring, wherein the 3-6 membered hydrocarbon ring or the 4-6 membered heterocyclic ring is unsubstituted or substituted with one or more substituents each independently selected from halogen, cyano, C 1-4 alkyl, or halogenated C 1-4 alkyl;

[0014] R c is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or 4-6 membered heterocyclyl, wherein the C 1-4 alkyl, C 3-6 cycloalkyl, or 4-6 membered heterocyclyl is unsubstituted or substituted with one or more substituents each independently selected from halogen, cyano, hydroxyl, C 1-4 alkyl, -O-(C 1-4 alkyl), or halogenated C 1-4 alkyl;

[0015] R d and R e are independently selected from hydrogen, C 1-4 alkyl, wherein the C 1-4alkyl is unsubstituted or independently in each occurrence substituted with one or more substituents selected from halogen, cyano, or hydroxy; or R d and R e together with the atom to which they are attached form a 3-6 membered hydrocarbon ring or a 4-6 membered heterocyclic ring, wherein the 3-6 membered hydrocarbon ring or the 4-6 membered heterocyclic ring is unsubstituted or independently in each occurrence substituted with one or more substituents selected from halogen, cyano, or hydroxy;

[0016] Q is selected from O, NR f , S=O, or S(=O)2;

[0017] R f is selected from hydrogen, C 1-4 alkyl, or C 3-6 cycloalkyl, wherein the C 1-4 alkyl or C 3-6 cycloalkyl is unsubstituted or independently in each occurrence optionally substituted with one or more substituents selected from halogen, cyano, or hydroxy;

[0018] R 1 is selected from hydrogen, halogen, cyano, C 1-4 alkyl, -CH2OC 1-4 alkyl, haloC 1-4 alkyl, or C 3-6 cycloalkyl;

[0019] R 2 is independently in each occurrence selected from hydrogen, halogen, cyano, -COOH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, -OR z , -N(R z )2, -C(=O)-C 1-4 alkyl, -C(=O)-NH-C 1-4 alkyl, -C(=O)-N(C 1-4 alkyl)2, -NHC(=O)-C 1-4 alkyl, -NHC(=O)-O C 1-4 alkyl, -NHC(=O)-N(C 1-4 alkyl)2, -NHS(=O)2-C 1-4 alkyl, -NHS(=O)-(C 1-4 alkyl)2, -N=S(=O)-(C 1-4 alkyl)2, or -P(=O)-(C 1-4 alkyl)2, wherein the C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6 Cycloalkyl or 4-8 membered heterocyclyl is unsubstituted or substituted with one or more substituents each independently selected from halogen, cyano, hydroxy, =0, -0-(C 1-4 alkyl), haloC 1-4 alkyl, -NH2, -NH-(C 1-4 alkyl), -N(C 1-4 alkyl)2, or C 1-4 alkyl;

[0020] or, any two R 2 together with the atoms to which they are attached form a 5-7 membered hydrocarbon ring or a 5-7 membered heterocyclic ring, wherein said 5-7 membered hydrocarbon ring or 5-7 membered heterocyclic ring is unsubstituted or substituted with one or more substituents each independently selected from halogen, cyano, hydroxy, =0, -0-(C 1-6 alkyl), haloC 1-4 alkyl, or C 1-4 alkyl;

[0021] R z at each occurrence is each independently selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or 4-6 membered heterocyclyl, wherein said C 1-4 alkyl, C 3-6 cycloalkyl, or 4-6 membered heterocyclyl is unsubstituted or substituted with one or more substituents each independently selected from halogen, cyano, hydroxy, =0, -0-(C 1-6 alkyl), haloC 1-6 alkyl, or C 1-6 alkyl;

[0022] or two R z together with the atoms to which they are attached form a 4-6 membered heterocyclic ring; wherein said 4-6 membered heterocyclic ring is unsubstituted or substituted with one or more substituents each independently selected from halogen, cyano, hydroxy, =0, -0-(C 1-6 alkyl), -NH2, -NH-(C 1-6 alkyl), -N(C 1-6 alkyl)2, haloC 1-6 alkyl, or C 1-6 alkyl;

[0023] n is 0, 1, 2, or 3.

[0024] In certain preferred embodiments, the present application is directed to a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer,

[0025] W is selected from S, O, S=0, S(=0)2, or CR a R b ; R aand R b is independently selected from hydrogen, halogen, C 1-4 alkyl, or R a and R b together with the atoms to which they are attached form a 3-4 membered hydrocarbon ring or a 4 membered heterocyclic ring;

[0026] Preferably, W is selected from S, O, -CH2-,

[0027] More preferably, W is selected from S, O, -CH2- or

[0028] In certain preferred embodiments, the present application is directed to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer,

[0029] When W is selected from S, O, S=0 or S(=0)2, Y is selected from CR d R e ; R d and R e are independently selected from hydrogen, C 1-4 alkyl or haloC 1-4 alkyl; or R d and R e together with the atoms to which they are attached form a 3-6 membered hydrocarbon ring or a 4-6 membered heterocyclic ring;

[0030] Preferably, when W is selected from S or O, Y is selected from CR d R e ; R d and R e are independently selected from hydrogen, methyl, ethyl or fluoromethyl; or R d and R e together with the atoms to which they are attached form a cyclopropyl or oxetanyl;

[0031] More preferably, when W is selected from S or O, Y is selected from CR d R e ; R d and R e are independently selected from hydrogen or methyl.

[0032] In certain preferred embodiments, the present application is directed to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer,

[0033] When W is selected from -CH2-, Y is selected from O, NR c or CR d R e ; R c is selected from hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl, wherein said C1-4 alkyl or C 3-6 cycloalkyl is unsubstituted or substituted independently by one or more substituents selected from halogen, cyano, hydroxy or C 1-4 alkyl; R d and R e are independently selected from hydrogen, methyl, ethyl or fluoromethyl; or R d and R e together with the atom to which they are attached form a cyclopropyl or oxetanyl group;

[0034] Preferably, when W is selected from -CH2-, Y is selected from O, NR c or CR d R e ; R c is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl; R d and R e are independently selected from hydrogen, methyl, ethyl or fluoromethyl;

[0035] More preferably, when W is selected from -CH2- or Y is selected from O, NR c or CR d R e ; R c is selected from hydrogen, methyl or ethyl; R d and R e are independently selected from hydrogen or methyl.

[0036] In certain preferred embodiments, the present application is directed to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer,

[0037] Q is selected from O, NR f or S(=O)2; R f is selected from hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl, wherein said C 1-4 alkyl or C 3-6 cycloalkyl is unsubstituted or substituted independently by one or more substituents selected from hydrogen, halogen or hydroxy;

[0038] Preferably, Q is selected from O, NR f or S(=O)2; R f is selected from hydrogen, methyl, ethyl, isopropyl or fluoromethyl;

[0039] More preferably, Q is selected from O.

[0040] In certain preferred embodiments, the present application is directed to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer,

[0041] selected from substituted or unsubstituted 5-6 membered heteroaromatic ring;

[0042] Preferably, selected from pyridine, pyrimidine, pyrazine, pyridazine, pyrazole, oxazole, isoxazole, thiophene or thiazole;

[0043] More preferably, selected from pyridine, pyrimidine or pyrazine;

[0044] Further preferably selected from

[0045] In certain preferred embodiments, the present application is directed to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, metabolite, or prodrug thereof,

[0046] R 1 selected from hydrogen, C 1-4 alkyl, -CH2OC 1-4 alkyl, haloC 1-4 alkyl or C 3-6 cycloalkyl;

[0047] Preferably, R 1 is selected from hydrogen, methyl, ethyl, isopropyl, -CH2OMe, fluoromethyl, difluoromethyl or cyclopropyl;

[0048] More preferably, R 1 is selected from hydrogen, methyl, -CH2OMe, fluoromethyl or difluoromethyl;

[0049] In certain preferred embodiments, the present application is directed to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, metabolite, or prodrug thereof,

[0050] R 2 at each occurrence, is each independently selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, -OR z , -N(R z )2, -C(=O)-C 1-4 alkyl, -C(=O)-NH-C 1-4 alkyl, -C(=O)-N(C 1-4 alkyl)2, -NHC(=O)-C 1-4 alkyl, -NHC(=O)-OC 1-4 alkyl, -NHS(=O)-(C 1-4 alkyl)2or -P(=O)-(C 1-4 alkyl)2, wherein said C 1-4 alkyl, C 3-6cycloalkyl or 4-8 membered heterocyclyl is unsubstituted or substituted with one or more substituents each independently selected from -F, cyano, hydroxyl, =0, -OMe, -CF3, -CHF2, -CFH2, -NH2, -NH-CH2-, 1-3 haloC 1-3 alkyl, -NH2, -NH-CH2-, 1-4 alkyl, -N(CH2-, 1-4 alkyl)2or C 1-4 alkyl;

[0051] R 2 is each independently selected at each occurrence from hydrogen, F, Cl, Br, cyano, C 1-3 alkyl, cyclopropyl, cyclobutyl, oxetanyl, -OR z , -N(R z )2, -C(=0)Me, -C(=0)-NH-CH2-, 1-4 alkyl, -C(=0)-N(CH2-, 1-4 alkyl)2, wherein said C 1-3 alkyl, cyclopropyl, cyclobutyl or 4-8 membered heterocyclyl is unsubstituted or substituted with one or more substituents each independently selected from -F, cyano, hydroxyl, =0, -OMe, -CF3, -CHF2, -CFH2, -NH2, -NH-CH2-, 1-4 alkyl, -N(CH2-, 1-4 alkyl)2or C 1-4 alkyl;

[0052] R 2 is each independently selected at each occurrence from F, Cl, Br, cyano, C 1-3 alkyl, cyclopropyl, cyclobutyl, oxetanyl, -OR z , -N(R z )2, -C(=0)Me, -C(=0)-NHMe or -C(=0)-NMe2, wherein said C 1-3 alkyl, cyclopropyl, cyclobutyl or oxetanyl is unsubstituted or substituted with one or more substituents each independently selected from -F, cyano, hydroxyl, -OMe, -CF3, -CF2H, -CFH2or methyl.

[0053] In certain preferred embodiments, the present compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer,

[0054] any 2 R 2 together with the atoms to which they are attached form a 5-7 membered hydrocarbon ring or 5-7 membered heterocyclic ring, wherein said 5-7 membered hydrocarbon ring or 5-7 membered heterocyclic ring is unsubstituted or substituted with one or more substituents each independently selected from F, cyano, hydroxyl, =0, -OMe, -CF3, -CF2H, -CFH2or methyl.

[0055] preferably, any two R 2 together with the atom to which they are attached form a 5-membered hydrocarbon ring or a 5-membered oxygen heterocycle, wherein the 5-membered hydrocarbon ring or the 5-membered oxygen heterocycle is unsubstituted or substituted independently with one or more substituents selected from F, cyano, -OMe, -CF3, or methyl;

[0056] more preferably, any two R 2 together with the atom to which they are attached form a 5-membered hydrocarbon ring, wherein the 5-membered hydrocarbon ring is unsubstituted or substituted independently with one or more substituents selected from F, cyano, -OMe, or methyl.

[0057] In certain preferred embodiments, the present compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer,

[0058] R z are each independently at each occurrence optionally selected from C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or 4-6 membered oxygen heterocyclyl, wherein the C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or 4-6 membered oxygen heterocyclyl is unsubstituted or substituted independently with one or more substituents selected from F, cyano, hydroxyl, =0, -OMe, -CF3, or methyl; or two R z together with the atom to which they are attached form a 4-6 membered heterocycle, which is unsubstituted or substituted independently with one or more substituents selected from F, cyano, hydroxyl, -OMe, -CF3, or methyl;

[0059] preferably, R z are each independently at each occurrence optionally selected from methyl, ethyl, isopropyl, -CF3, -CF2H, cyclopropyl, cyclobutyl, or oxetanyl, wherein the cyclopropyl, cyclobutyl, or oxetanyl is unsubstituted or substituted independently with one or more substituents selected from F, hydroxyl, or methyl; or two R z together with the nitrogen atom to which they are attached form a 4- or 5-membered heterocycle, which is unsubstituted or substituted independently with one or more substituents selected from F, hydroxyl, or methyl;

[0060] more preferably, R z are each independently at each occurrence optionally selected from methyl, ethyl, isopropyl, -CF3, -CF2H, cyclopropyl, cyclobutyl, or oxetanyl; or two R z together with the nitrogen atom to which they are attached form an azetidine, which is unsubstituted or substituted independently with one or more substituents selected from F, hydroxyl, or methyl.

[0061] In some preferred embodiments, the compound of formula (I) of the present invention, or its pharmaceutically acceptable salt or stereoisomer,

[0062]

[0063] Selected from

[0064] U is selected from N or CH;

[0065] When W is selected from S or O, Y is selected from CR. d R e ;R d and R e Independently selected from hydrogen or methyl;

[0066] When W is selected from -CH2- or When Y is selected from O and NR c or CR d R e ;R c Selected from hydrogen, methyl, or ethyl; R d and R e Independently selected from hydrogen or methyl;

[0067] Q is selected from O, NCH3, or S(=O)2;

[0068] R 1 Selected from hydrogen, methyl, -CH2OMe, fluoromethyl or difluoromethyl;

[0069] R 2 Each time it appears, it is independently selected from F, Cl, Br, cyano, and C. 1-3 Alkyl, cyclopropyl, cyclobutyl, oxetyl, -OR z -N(R) z )2, -C(=O)Me, -C(=O)-NHMe or -C(=O)-NMe2, wherein C 1-3 The alkyl, cyclopropyl, cyclobutyl, or oxecyclobutyl groups are unsubstituted or are each independently substituted by one or more substituents selected from -F, cyano, hydroxy, -OMe, -CF3, -CF2H, -CFH2, or methyl.

[0070] R z Each R is independently and optionally selected from methyl, ethyl, isopropyl, -CF3, -CF2H, cyclopropyl, cyclobutyl, or oxecyclobutyl; or two Rs. z Together with the nitrogen atom to which it is attached, they form azahexacyclobutane, which is unsubstituted or independently substituted by one or more substituents selected from F, hydroxyl or methyl;

[0071] n is 1 or 2.

[0072] In certain preferred embodiments, the present application provides a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer thereof, wherein the compound is selected from:

[0073]

[0074]

[0075]

[0076] In certain preferred embodiments, the compound is selected from:

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083] In another aspect, the present application provides a preparation method for preparing the above-mentioned compound, comprising the following steps:

[0084]

[0085] Step 1: nucleophilic substitution reaction of compound IM-1 and compound IM-2 under the action of a base to generate compound IM-3;

[0086] Step 2: halide in compound IM-3 is prepared into boronic acid or boronic ester compound IM-4 through Suzuki-Miyara reaction or metal halogen exchange and then reacted with boronic ester;

[0087] Step 3: compound IM-4 and compound IM-5 are coupled to generate a compound of Formula (I);

[0088] X1 is I, Br or Cl, X2 is I, Br, Cl or C 1-3 alkylsulfonate (for example trifluoromethanesulfonate); R L is I, Br, Cl or a sulfonate-based leaving group (such as OMs, OTs, etc.); R B is a boronic acid group or a boronic ester group;

[0089] In the above method steps, U, W, Y, Q, R 1 2 , ring A and n are as defined herein above.

[0090] In another aspect, the present application also relates to a pharmaceutical composition comprising: an effective dose of any of the compounds of the present application or a pharmaceutically acceptable salt, stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient; further comprising one or more other therapeutic agents.

[0091] In yet another aspect, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer thereof, or a pharmaceutical composition of the compounds of the present application, in the manufacture of a medicament for the prevention and treatment of diseases mediated by CB2receptors.

[0092] In another aspect, the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer thereof, or a pharmaceutical composition of the compounds of the present application, for the manufacture of a medicament for the treatment or prevention of pain, inflammatory diseases, autoimmune diseases or neurodegenerative diseases.

[0093] In certain preferred embodiments, the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer thereof, or a pharmaceutical composition of the compounds of the present application, for the manufacture of a medicament for the treatment or prevention of neuropathic pain, ulcerative colitis or Crohn's disease related abdominal pain disorders.

[0094] Definitions

[0095] Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. References herein to technical terms are intended to refer to the technical field as commonly understood by those skilled in the art, including variations or substitutions of techniques or replacements of equivalent techniques that would be apparent to those skilled in the art. Although the following terms are believed to be understood by those skilled in the art, the following definitions are set forth to better explain the present application.

[0096] The terms "comprising", "containing", "having" "including" or "involving", and other variants as used herein are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0097] As used herein, the term "alkylene" denotes a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0098] ​As used herein, the term "alkyl" defines a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6 carbon atoms. For example, as used herein, the term "C 1-6 "alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, or n-hexyl) optionally substituted with 1 or more (such as 1 to 3) suitable substituents such as halogen (when the group is referred to as "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C 1-4 "alkyl" refers to a linear or branched group of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl).

[0099] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon group which contains one double bond and has 2-5 carbon atoms (C 2-5 "alkenyl"). The alkenyl group is, for example, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the present application contain an alkenylene group, the compounds can exist in pure E (entgegen) form, pure Z (zusammen) form, or any mixture thereof.

[0100] As used herein, the term "alkynyl" means a linear or branched monovalent hydrocarbon group which contains one triple bond and has 2-5 carbon atoms (C 2-5 "alkynyl"). The alkynyl group is, for example, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2-methyl-2-propynyl, and 4-methyl-3-pentynyl.

[0101] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic including a spiro, fused, or bridged system (such as bicyclo[l.l.l]pentyl, bicyclo[2.2.l]heptyl, bicyclo[3.2.l]octyl, or bicyclo[5.2.0]nonyl, etc.) optionally substituted with one or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-6"Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which is optionally substituted with 1 or more (such as up to 3) suitable substituents, for example, methyl-substituted cyclopropyl.

[0102] As used herein, the terms "cycloalkyl" and "cycloalkylene" refer to saturated (i.e., "cycloalkyl" and "cycloalkylene") or unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings of, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including, but not limited to, (cyclo)propyl, (cyclo)butyl, (cyclo)pentyl, (cyclo)hexyl, (cyclo)heptyl, (cyclo)octyl, (cyclo)nonyl, (cyclo)hexenyl, and the like.

[0103] As used herein, the terms "heterocyclyl" and "heterocyclylene" refer to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) cyclic group having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring atoms, at least one of which is a heteroatom selected from N, O, and S, and the remainder of which are C. For example, a "3-10 membered (hetero)cyclyl" is a saturated or partially unsaturated (hetero)cyclyl group having 2-9 (e.g., 2, 3, 4, 5, 6, 7, 8, or 9) ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. Examples of heterocyclyl and heterocyclylene groups include, but are not limited to, (hetero)oxiranyl, (hetero)aziridinyl, (hetero)azetidinyl, (hetero)oxetanyl, (hetero)tetrahydrofuranyl, (hetero)dioxolinyl, (hetero)pyrrolidinyl, (hetero)pyrrolidinonyl, (hetero)imidazolidinyl, (hetero)pyrazolidinyl, (hetero)pyrazolinyl, (hetero)tetrahydropyranyl, (hetero)piperidinyl, (hetero)morpholinyl, (hetero)dithianyl, (hetero)thiomorpholinyl, (hetero)piperazinyl, or (hetero)trithianyl. Heterocyclyl and heterocyclylene groups can be optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0104] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0105] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and at least one nitrogen atom in a ring, and optionally may also contain one or more (e.g., one, two, three, or four) ring members selected from N, O, C=O, S, S=O, and S(=O)2, which are connected to the remainder of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atom, wherein the nitrogen-containing heterocycle is optionally fused to a benzene ring, and is connected to the remainder of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any remaining carbon atom in the fused benzene ring. The term "substitution" refers to the replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a selection from the indicated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0106] If a substituent is described as being "selected independently from" a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0107] As used herein, the term "one or more" means one or more under reasonable conditions, such as two, three, four, five, or ten.

[0108] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0109] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom of the substituted ring.

[0110] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium). 2 H), tritium ( 3 H); carbon isotopes (e.g., ... 11 C 13 C and 14 C); isotopes of chlorine (e.g.) 36 CI); isotopes of fluorine (e.g. 18 F); isoforms of iodine (e.g. 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and15 N); isotopes of oxygen (e.g. 15 O, 17 O and 18 O); isotopes of phosphorus (e.g. 32 P); and isotopes of sulfur (e.g. 35 S).

[0111] The term "stereoisomers" denotes isomers having the same molecular formula but differing in the arrangement of atoms or groups in space. In compounds with one or more asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers are possible. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the application can exist as mixtures of two or more different forms in rapid equilibrium, often referred to as tautomers. Representative examples of tautomers include keto-enol, phenol-keto, nitroso-oxime, imine-enamine, and the like. It is to be understood that the scope of the application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0112] Carbon-carbon bond of a compound of the application can be depicted herein using a solid line (—), a solid wedge or a dashed wedge A solid line is used to depict a bond to an asymmetric carbon atom to indicate that all possible stereoisomers (e.g., particular enantiomers, racemic mixtures, etc.) are included. A solid or dashed wedge is used to depict the stereoisomer shown as present. When present in a racemic mixture, solid and dashed wedges are used to define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise indicated, the compounds of the application are intended to exist as tautomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, atropisomers, and mixtures thereof. The compounds of the application can exhibit more than one type of isomerism, and consist of mixtures (e.g., racemic mixtures and diastereomeric pairs) thereof.

[0113] The application encompasses all possible crystalline forms or polymorphs of the compounds of the application, which can be a single polymorph or a mixture of more than one polymorph in any proportion.

[0114] It will also be appreciated that certain of the compounds of the present application can exist in free form, or as appropriate, in the form of a pharmaceutically acceptable derivative thereof. In this context, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, stereoisomers, nitroxides, polymorphs, hydrates, solvates, isotopically labeled derivatives, or metabolites or prodrugs thereof, which upon administration to a patient in need thereof, are capable of providing (directly or indirectly) a compound of this application, or a metabolite or residue thereof. Accordingly, as used herein, reference to a "compound of the present application" is meant to also encompass all such forms of the compound.

[0115] Pharmaceutically acceptable salts of the compounds of the present application include acid addition salts and base addition salts thereof.

[0116] Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include hydrochloride, acetate, aspartate, benzoate, bicarbonate / carbonate, gluceptate, gluconate, nitrate, orotate, palmitate, and other similar salts.

[0117] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, magnesium salts, and other similar salts.

[0118] A review of suitable salts is given in "Handbook of Pharmaceutical Salts: Properties, Selection and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Those of skill in the art of preparing pharmaceutically acceptable salts of compounds are well known.

[0119] As used herein, the term "ester" means an ester derived from the various generic compounds of the present application, which includes physiologically hydrolysable esters (which can be hydrolyzed under physiological conditions to release a free acid or alcohol form of a compound of the present application). The compounds of the present application can also be esters themselves.

[0120] The compounds of the present application can exist in the form of solvates, preferably hydrates, in which the compounds of the present application contain as a structural element of the crystal lattice of the compound a polar solvent, in particular, for example, water, methanol or ethanol. The amount of polar solvent, in particular water, can be present in stoichiometric or non-stoichiometric amounts.

[0121] One skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires an available lone pair of electrons to oxidize to an oxide; one skilled in the art will recognize which nitrogen-containing heterocycles are capable of forming N-oxides. One skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art. These include oxidation of the heterocycle or tertiary amine with peroxy acids such as peroxyacetic acid and meta-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: T. L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392. A. R. Katritzky and A. J. Boulton, Eds., Academic Press.

[0122] Also included within the scope of the application are metabolites of the compounds of the application, i.e., substances formed in vivo upon administration of the compounds of the application. Such products can result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the application includes metabolites of compounds of the application, including those produced by the in vivo action of mammalian tissue enzymes on the compounds of the application.

[0123] This invention further includes, within its scope, prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity, which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that are readily converted in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of the invention can be prepared, for example, by replacing suitable functional groups present in the compounds of the invention with certain portions known to those skilled in the art as “pro-moiety” (e.g., “Design of Prorugs,” H. Bundgaard (Elsevier, 1985)).

[0124] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in T.W. Greene & P. ​​G. W. M. Uts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art. Detailed Implementation

[0125] Example

[0126] The present invention will be further described in detail below with reference to the embodiments, but this is not intended to limit the present invention. Any equivalent substitutions made in the art based on the disclosure of the present invention shall fall within the protection scope of the present invention.

[0127] The structure of the compound was determined by mass spectrometry (MS) or nuclear magnetic resonance (NMR). 1 It was determined by HNMR.

[0128] Nuclear magnetic resonance (NMR) 1 HNMR shift (δ) is given in parts per million (ppm); nuclear magnetic resonance (NMR) 1 The ¹H NMR (hydrocarbon NMR) measurements were performed using a Bruker Avance-400 NMR spectrometer. The solvent was deuterated chloroform (CDCl₃), and the internal standard was tetramethylsilane (TMS). Chemical shifts were expressed in terms of 10⁻¹⁰ NMR values.-6 (ppm) as a unit.

[0129] Mass spectrometry (MS) was measured using a FINNIGAN LCQ Ad (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX).

[0130] Thin layer silica gel plates were used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.

[0131] Column chromatography was generally performed using Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0132] In the absence of special instructions in the present application, the reactions mentioned in the present application were all carried out under N2protection or nitrogen atmosphere.

[0133] In the present application, the term "N2protection" or "nitrogen atmosphere" means, for example, connecting the reaction bottle to a 1L volume of nitrogen balloon.

[0134] In the absence of special instructions in the present application, the solutions mentioned in the reactions of the present application are aqueous solutions.

[0135] In the present application, the term "room temperature" means a temperature between 10°C and 25°C.

[0136] The abbreviations as used herein have the following meanings:

[0137]

[0138] Example A: Preparation of intermediate 6-bromo-2H-benzo[b][l,4]thiazin-3(4H)-one (Int-1)

[0139] First step: Preparation of 2-((4-bromo-2-nitrophenyl)thio)acetic acid (Int-1c)

[0140] 4-bromo-1-fluoro-2-nitrobenzene (Int-1a) (10.0 g, 45.5 mmol), Int-1b (5.00 g, 54.3 mmol), K2CO3(15.7 g, 113.8 mmol) were dissolved in DMF (200 mL), and after the addition was completed, the reaction was carried out at 25°C for 16 hours. After the reaction was completed, the reaction solution was lowered to 0°C, water was added to the reaction system, 5M aqueous hydrochloric acid was used to adjust the pH to 2-3, ethyl acetate was added, the liquid was separated, the aqueous phase was extracted with ethyl acetate three times, the organic phases were combined, washed with water and saturated brine once each, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain the crude product of the title compound (Int-1c) (18.0 g).

[0141] MS m / z (ES): 292.0 [M+H] +

[0142] Second Step: Preparation of compound 2-((2-amino-4-bromophenyl)thio)acetic acid (Int-1d)

[0143] The compound Int-1c crude (18.0 g, 45.5 mmol) was dissolved in ammonia water (200 mL), at 25 °C, FeSO4·7H2O (63.2 g, 227 mmol) was dissolved in 200 mL water, added to the reaction system, reacted at 25 °C for 18 hours. After the reaction was completed, the reaction system was filtered, toluene was added to the filtrate and concentrated to obtain the crude product of the title compound (Int-1d) (30.0 g).

[0144] MS m / z (ES): 262.0 [M+H] +

[0145] Third Step: Preparation of compound 6-bromo-2H-benzo[b][1,4]thiazin-3(4H)-one (Int-1)

[0146] The compound Int-1d crude (30 g, 45.45 mmol) was dissolved in TFA (200 mL), after the addition was completed, the temperature was raised to 75 °C and reacted for 3.5 hours. After the reaction was completed, the reaction system was concentrated to obtain a brown oil, which was purified by silica gel column (petroleum ether / ethyl acetate = 1 / 0~5 / 1) to obtain the title compound (Int-1) (10.2 g, three-step yield 92%).

[0147] MS m / z (ES): 244.0 [M+H] +

[0148] Example B: Preparation of intermediate 4-(2-(3-methylmorpholin)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one (Int-2)

[0149]

[0150] First Step: Preparation of compound 2-(3-methylmorpholin)ethan-1-ol (Int-2c)

[0151] Int-2c (2.20 g, 15.2 mmol) was dissolved in dichloromethane (300 mL), the reaction system was slowly cooled to 0 °C under N2protection, triethylamine (4.61 g, 45.5 mmol), 4-dimethylaminopyridine (185 mg, 1.52 mmol) were added, after the addition of p-toluenesulfonyl chloride (3.46 g, 18.2 mmol), the reaction was warmed to 25 °C. After the reaction was complete, water and ethyl acetate were added to the reaction system, the liquid was separated, the aqueous phase was extracted with ethyl acetate three times, the organic phases were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give brown title compound Int-2d (3 g) as a crude product.

[0152] MS m / z (ES): 300.1 [M+H] +

[0153] Second step: Preparation of compound 2-(3-methylmorpholinyl)ethyl-4-methylbenzenesulfonate (Int-2d)

[0154] Int-2c (2.20 g, 15.2 mmol) was dissolved in dichloromethane (300 mL), the reaction system was slowly cooled to 0 °C under N2protection, triethylamine (4.61 g, 45.5 mmol), 4-dimethylaminopyridine (185 mg, 1.52 mmol) were added, after the addition of p-toluenesulfonyl chloride (3.46 g, 18.2 mmol), the reaction was warmed to 25 °C. After the reaction was complete, water and ethyl acetate were added to the reaction system, the liquid was separated, the aqueous phase was extracted with ethyl acetate three times, the organic phases were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give brown title compound Int-2d (3 g) as a crude product.

[0155] MS m / z (ES): 300.1 [M+H] +

[0156] Third step: Preparation of compound 6-bromo-4-(2-(3-methylmorpholinyl)ethyl)-2H- benzo[b][1,4]thiazin-3(4H)-one (Int-2e)

[0157] Int-2d (3.00 g, 15.2 mmol), Int-1 (0.92 g, 3.79 mmol) and Cs2CO3(4.94 g, 15.2 mmol), KI (0.25 g, 1.51 mmol) were dissolved in N,N-dimethylformamide (50 mL), after the addition, the reaction was warmed to 50 °C. After the reaction was complete, water and ethyl acetate were added to the reaction system, the liquid was separated, the aqueous phase was extracted with ethyl acetate three times, the organic phases were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a brown oil, which was purified by silica gel preparative plate (petroleum ether / ethyl acetate = 3 / 1) to give title compound Int-2e (0.97 g, 69% yield for three steps.

[0158] MS m / z (ES): 371.1 [M+H] +

[0159] Fourth Step: Preparation of compound 4-(2-(3-methylmorpholinyl)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one (Int-2)

[0160] Compound Int-2e (0.97 g, 2.61 mmol), bis(pinacolato)diboron (1.32 g, 5.22 mmol) and KOAc (0.77 g, 7.83 mmol) were dissolved in 1,4-dioxane (25 mL), Pd(dppf)Cl2(0.19 g, 0.26 mmol) was added under N2protection, and the reaction was heated to 90 °C after the addition was completed. After the reaction was completed, the reaction solution was filtered and concentrated to obtain a brown crude product of the title compound (Int-2) (2.8 g). The obtained crude product was used directly in the next step without further purification.

[0161] MS m / z (ES): 419.1 [M+H] +

[0162] Example C: Preparation of compound 4-(2-(3-methylmorpholinyl)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Int-3)

[0163]

[0164] First Step: Preparation of compound 2-(3-methylmorpholinyl)ethyl methanesulfonate (Int-3d-1) and 4-(2-chloroethyl)-3-methylmorpholine (Int-3d-2)

[0165] Compound Int-2c crude product (2.90 g, 19.8 mmol) was dissolved in dichloromethane (50 mL), and triethylamine (4.61 g, 45.5 mmol) was added slowly under N2protection while the reaction system was slowly cooled to 0 °C in an ice water bath. After the addition was completed, MsCl (3.40 g, 29.7 mmol) was added dropwise, and the reaction was performed at 0 °C for 1 hour. After the reaction was completed, water was added to the reaction system, and the mixture was separated. The aqueous phase was extracted with dichloromethane three times, and the combined organic phase was washed with water and saturated brine once each, dried over anhydrous sodium sulfate, and filtered under suction. The filtrate was concentrated to obtain a crude mixture of compounds Int-3d-1 and Int-3d-2 (4.4 g). The obtained crude mixture was used directly in the next step without further purification.

[0166] MS m / z (ES): 224.0 [M+H]+

[0167] Step 2: Preparation of compound 6-bromo-4-(2-(3-methylmorpholinyl)ethyl)-2H- benzo[b][l,4]oxazin-3(4H)-one (Int-3f)

[0168] A mixture of crude compound Int-3d-l and Int-3d-2 (4.4 g, 19.8 mmol), Int-3e (2.3 g, 9.9 mmol) and Cs2CO3(6.5 g, 19.8 mmol) was dissolved in N,N- dimethylformamide (50 mL), after addition, the reaction was carried out at 25 °C for 8 hours. After the reaction was completed, water and ethyl acetate were added to the reaction system, the liquid was separated, the aqueous phase was extracted with ethyl acetate three times, the organic phases were combined, washed with water and saturated brine once, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a brown oil. Purification on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) gave compound Int-3f (1.9 g) in a two-step yield of 27%.

[0169] MS m / z (ES): 355.0 [M+H] +

[0170] Step 3: Preparation of compound 4-(2-(3-methylmorpholinyl)ethyl)-6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-benzo[b][l,4]oxazin-3(4H)-one (Int-3)

[0171] Compound Int-3f (1.9 g, 5.36 mmol), bis(pinacolato)diboron (1.77 g, 6.97 mmol) and KOAc (1.57 g, 16.08 mmol) were dissolved in 1,4-dioxane (50 mL), Pd(dppf)Cl2(392 mg, 0.54 mmol) was added under N2protection, and the reaction was carried out at 90 °C for 3 hours. After the reaction was completed, the reaction solution was filtered and concentrated to obtain brown crude compound Int-3 (4 g). The obtained crude product was used directly in the next reaction without further purification.

[0172] MS m / z (ES): 403.0 [M+H] +

[0173] Example D: Preparation of intermediate (R)-4-(2-(3-methylmorpholinyl)ethyl)-6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-benzo[b][l,4]oxazin-3(4H)-one (Int-4)

[0174]

[0175] The crude compound Int-4 was synthesized using a similar procedure described in Example B, except that compound Int-4a was used instead of compound Int-2a in Example B. The resulting crude product was used directly in the next step without further purification.

[0176] MS m / z (ES): 419.2 [M+H] +

[0177] Example E: Preparation of intermediate 1-(2-(3-methylmorpholinyl)ethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (Int-5)

[0178]

[0179] The crude compound Int-5 was synthesized using a similar procedure described in Example B, except that compound Int-5a was used instead of compound Int-1 in Example B. The resulting crude product was used directly in the next step without further purification.

[0180] MS m / z (ES): 404.2 [M+H] +

[0181] Example F: Preparation of intermediate (S)-4-(2-(3-methylmorpholinyl)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one (Int-6)

[0182]

[0183] The crude compound Int-6 was synthesized using a similar procedure described in Example B, except that compound Int-6a was used instead of compound Int-2a in Example B. The resulting crude product was used directly in the next step without further purification.

[0184] MS m / z (ES): 419.2 [M+H] +

[0185] Example G: Preparation of compound 1-(2-morpholinoethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-one (Int-7)

[0186]

[0187] The crude compound Int-8 was synthesized using similar method described in example B except using compound Int-8a instead of compound Int-1 in example B. The resulting crude was used in the next step without further purification.

[0188] MS m / z (ES): 406.2 [M+H] +

[0189] Example H: Preparation of intermediate 1-(2-(3-methylmorpholinyl)ethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-one (Int-8)

[0190]

[0191] The crude compound Int-8 was synthesized using similar method described in example B except using compound Int-8a instead of compound Int-1 in example B. The resulting crude was used in the next step without further purification.

[0192] MS m / z (ES): 420.2 [M+H] +

[0193] Example I: Preparation of intermediate 1-(2-morpholinoethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (Int-9)

[0194]

[0195] The crude compound Int-9 was synthesized using similar method described in example B except using compound Int-7a instead of compound Int-2d, Int-9a instead of compound Int-1 in example B. The resulting crude was used in the next step without further purification.

[0196] MS m / z (ES): 387.2 [M+H] +

[0197] Example J: Preparation of intermediate 4,4-dimethyl-1-(2-(3-methylmorpholinyl)ethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (Int-10)

[0198]

[0199] The crude compound Int-10 was synthesized using a similar procedure described in Example B except using compound Int-10a instead of compound Int-1 in Example B. The resulting crude compound was used directly in the next step without further purification.

[0200] MS m / z (ES): 431.2 [M+H] +

[0201] Example K: Preparation of intermediate 4-(2-morpholinoethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one (Int-11)

[0202]

[0203] The crude compound Int-11 was synthesized using a similar procedure described in Example B except using compound Int-7a instead of compound Int-2d in Example B. The resulting crude compound was used directly in the next step without further purification.

[0204] MS m / z (ES): 405.2 [M+H] +

[0205] Example 1: Preparation of compound 6-(5-fluoropyridin-2-yl)-4-(2-(3-methylmorpholino)ethyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (1)

[0206]

[0207] First Step: Preparation of compound 6-(5-fluoropyridin-2-yl)-4-(2-(3-methylmorpholino)ethyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (1)

[0208] The crude compound Int-2 (80 mg, 0.20 mmol), 1a (70 mg, 0.40 mmol) and CsF (91 mg, 0.60 mmol) were dissolved in 1,4-dioxane (3 mL) solution, Pd(dppf)Cl2(14 mg, 0.02 mmol) was added under N2protection, after adding, the temperature was increased to 95 °C for reaction. After the reaction was completed, water and ethyl acetate were added to the reaction system, separated, the aqueous phase was extracted with ethyl acetate for three times, the combined organic phase was washed with water and saturated brine for one time, dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated to obtain a brown crude product, which was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to obtain compound 1 (9 mg) with a purity of 99.60%.

[0209] MS m / z (ES): 388.1 [M+H] +

[0210] 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 2.8 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.10 (dd, J = 8.8, 4.4 Hz, 1H), 7.85 (ddd, J = 8.8, 8.8, 2.8 Hz, 1H), 7.72 (dd, J = 8.0, 1.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 4.18 - 4.07 (m, 2H), 3.65 - 3.57 (m, 1H), 3.54 (s, 2H), 3.51 (dd, J = 10.8, 3.2 Hz, 1H), 3.40 - 3.34 (m, 1H), 3.00 - 2.85 (m, 2H), 2.82 - 2.74 (m, 1H), 2.42 - 2.25 (m, 3H), 0.77 (d, J = 6.0 Hz, 3H).

[0211] Example 2: Preparation of compound 6-(6-fluoropyridin-2-yl)-4-(2-(3- methylmorpholino)ethyl)-2H-benzo[b][l,4]thiazin-3(4H)-one (2)

[0212]

[0213] First step: Preparation of compound 6-(6-fluoropyridin-2-yl)-4-(2-(3- methylmorpholino)ethyl)-2H-benzo[b][l,4]thiazin-3(4H)-one (2)

[0214] Using a similar method as described in Example 1, crude compound 2 was synthesized except that compound 2a was used instead of compound la in Example 1. The resulting crude product was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 2 (9 mg) with a purity of 89.99%.

[0215] MS m / z (ES): 388.1 [M+H] +

[0216] 1H NMR (400 MHz, DMSO-d6) δ 8.16 - 8.05 (m, 2H), 7.99 (dd, J = 7.6, 2.8 Hz, 1H), 7.75 (dd, J = 8.4, 2.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.16 (dd, J = 8.0, 2.8 Hz, 1H), 4.12 (t, J = 6.4 Hz, 2H), 3.64 - 3.58 (m, 1H), 3.56 (s, 2H), 3.55 - 3.48 (m, 1H), 3.42 - 3.30 (m, 1H), 3.00 - 2.89 (m, 2H), 2.85 - 2.78 (m, 1H), 2.42 - 2.30 (m, 3H), 0.81 (d, J = 6.4 Hz, 3H).

[0217] Example 3: Preparation of compound 6-(6-chloropyridin-2-yl)-4-(2-(3- methylmorpholino)ethyl)-2H-benzo[b][l,4]thiazin-3(4H)-one (3)

[0218]

[0219] First step: Preparation of compound 6-(6-chloropyridin-2-yl)-4-(2-(3- methylmorpholino)ethyl)-2H-benzo[b][l,4]thiazin-3(4H)-one (3)

[0220] Using a similar method as described in Example 1, except using compound 3a instead of compound la in Example 1, the crude compound 3 was synthesized. The obtained crude was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 3 (8.91 mg) with purity 99.77%.

[0221] MS m / z (ES): 404.1 [M+H] +

[0222] 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 2.0 Hz, 1H), 8.04 (dd, J = 7.2, 0.8 Hz, 1H), 7.97 (t, J = 7.6 Hz, 1H), 7.74 (dd, J = 8.0, 1.6 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 4.11 (t, J = 6.8 Hz, 2H), 3.66 - 3.60 (m, 1H), 3.56 (s, 2H), 3.53 (dd, J = 10.8, 3.2 Hz, 1H), 3.41 - 3.34 (m, 1H), 3.02 - 2.88 (m, 2H), 2.87 - 2.80 (m, 1H), 2.45 - 2.34 (m, 3H), 0.84 (d, J = 6.4 Hz, 3H).

[0223] Example 4: Preparation of compound 6-(4-(2-(3-methylmorpholino)ethyl)-3-oxa-3,4-dihydro- 2H-benzo[b][l,4]thiazin-6-yl)pyrazine-2-carbonitrile (4)

[0224]

[0225] First step: Preparation of compound 6-(4-(2-(3-methylmorpholino)ethyl)-3-oxa-3,4- dihydro-2H-benzo[b][l,4]thiazin-6-yl)pyrazine-2-carbonitrile (4)

[0226] Using a similar method described in Example 1, except using compound 4a instead of compound la in Example 1, the crude compound 4 was synthesized. The resulting crude compound was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 4 (16.67 mg) with purity 98.20%.

[0227] MS m / z (ES): 396.1 [M+H] +

[0228] 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 9.18 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.88 (dd, J = 8.0, 1.6 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 4.13 (t, J = 6.4 Hz, 2H), 3.66 - 3.60 (m, 1H), 3.58 (s, 2H), 3.53 (dd, J = 10.6, 3.6 Hz, 1H), 3.41 - 3.34 (m, 1H), 3.02 - 2.88 (m, 2H), 2.85 - 2.77 (m, 1H), 2.45 - 2.30 (m, 3H), 0.82 (d, J = 6.0 Hz, 3H).

[0229] Example 5: Preparation of compound 6-(6-(difluoromethyl)pyridin-2-yl)-4-(2-(3- methylmorpholino)ethyl)-2H-benzo[b][l,4]thiazin-3(4H)-one (5)

[0230]

[0231] First step: Preparation of compound 6-(6-(difluoromethyl)pyridin-2-yl)-4-(2-(3- methylmorpholino)ethyl)-2H-benzo[b][l,4]thiazin-3(4H)-one (5)

[0232] The crude compound 5 was synthesized using a similar method described in Example 1 except that compound 5a was used instead of compound la in Example 1. The resulting crude product was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 5 (13.80 mg) with purity 96.02%.

[0233] MS m / z (ES): 420.1 [M+H] +

[0234] 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 7.6 Hz, 1H), 8.16 - 8.08 (m, 2H), 7.80 (dd, J = 8.4, 1.6 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 6.99 (t, J = 54.8 Hz, 1H), 4.13 (t, J = 6.4 Hz, 2H), 3.63 - 3.58 (m, 1H), 3.56 (s, 2H), 3.54 - 3.49 (m, 1H), 3.39 - 3.33 (m, 1H), 2.98 - 2.87 (m, 2H), 2.85 - 2.79 (m, 1H), 2.44 - 2.31 (m, 3H), 0.82 (d, J = 6.0 Hz, 3H).

[0235] Example 6: Preparation of compound 6-methyl-5-(4-(2-(3-methylmorpholino)ethyl)-3-oxa-3,4-dihydro-2H- benzo[b][l,4]thiazin-6-yl)picolinonitrile (6)

[0236]

[0237] First step: Preparation of compound 6-methyl-5-(4-(2-(3-methylmorpholino)ethyl)-3-oxa-3,4-dihydro-2H- benzo[b][l,4]thiazin-6-yl)picolinonitrile (6)

[0238] Using a similar method as described in Example 1, except using compound 6a instead of compound la in Example 1, the crude compound 6 was synthesized. The resulting crude product was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 6 (9.79 mg) with purity 95.28%.

[0239] MS m / z (ES): 409.1 [M+H] +

[0240] 1H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.14 (dd, J = 8.0, 1.6 Hz, 1H), 4.21 - 4.12 (m, 1H), 4.12 - 4.03 (m, 1H), 3.60 - 3.51 (m, 3H), 3.47 (dd, J = 10.6, 3.2 Hz, 1H), 3.28 - 3.20 (m, 1H), 2.92 - 2.79 (m, 2H), 2.75 - 2.69 (m, 1H), 2.52 (s, 3H), 2.35 - 2.19 (m, 3H), 0.71 (d, J = 6.0 Hz, 3H).

[0241] Example 7: Preparation of compound N-methyl-6-(4-(2-(3-methylmorpholino)ethyl)-3-oxa-3,4-dihydro-2H- benzo[b][l,4]thiazin-6-yl)nicotinamide (7)

[0242]

[0243] First step: Preparation of compound N-methyl-6-(4-(2-(3-methylmorpholino)ethyl)-3-oxa-3,4-dihydro-2H- benzo[b][l,4]thiazin-6-yl)nicotinamide (7)

[0244] Using a similar method described in Example 1, crude compound 7 was synthesized except that compound 7a was used instead of compound la in Example 1. The resulting crude product was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 7 (11.25 mg) with a purity of 93.43%.

[0245] MS m / z (ES): 427.1 [M+H] +

[0246] 1H NMR (400 MHz, DMSO-d6) 9.05 (d, J = 8.0 Hz, 1H), 8.69 (q, J = 4.4 Hz, 1H), 8.30 - 8.23 (m, 2H), 8.12 (d, J = 8.4 Hz, 1H), 7.81 (dd, J = 8.0, 1.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 4.13 (t, J = 6.4 Hz, 2H), 3.66 - 3.59 (m, 1H), 3.55 (s, 2H), 3.52 (dd, J = 10.8, 3.2 Hz, 1H), 3.40 - 3.33 (m, 1H), 3.01 - 2.87 (m, 2H), 2.82 (d, J = 4.4 Hz, 3H), 2.82 - 2.76 (m, 1H), 2.42 - 2.28 (m, 3H), 0.79 (d, J = 6.0 Hz, 3H).

[0247] Example 8: Preparation of compound N-methyl-6-(4-(2-(3-methylmorpholino)ethyl)-3-oxa-3,4-dihydro-2H- benzo[b][l,4]thiazin-6-yl)picolinamide (8)

[0248]

[0249] First step: Preparation of compound N-methyl-6-(4-(2-(3-methylmorpholino)ethyl)-3-oxa-3,4-dihydro-2H- benzo[b][l,4]thiazin-6-yl)picolinamide (8)

[0250] The compound 8a crude (80 mg, 0.20 mmol), 8b (70 mg, 0.40 mmol) and Cs2CO3(195 mg, 0.60 mmol) were dissolved in 1,4-dioxane (3 mL), Pd(dppf)Cl2(14 mg, 0.02 mmol) was added under N2protection, and after the addition, the reaction was warmed to 95 °C. After the reaction was completed, water and ethyl acetate were added to the reaction system, separated, the aqueous phase was extracted with ethyl acetate three times, the organic phase was combined, washed with water and saturated brine once, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a brown crude product, which was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 8 (24.11 mg) with a purity of 99.42%.

[0251] MS m / z (ES): 427.1 [M+H] +

[0252] 1H NMR (400 MHz, DMSO-d6) δ 8.87 (q, J = 4.8 Hz, 1H), 8.23 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.07 (t, J = 8.0 Hz, 1H), 8.01 - 7.94 (m, 2H), 7.55 (d, J = 8.0 Hz, 1H), 4.36 - 3.18 (m, 2H), 3.55 (s, 2H), 3.54 - 3.44 (m, 2H), 3.32 - 3.21 (m, 1H), 2.93 - 2.83 (m, 5H), 2.83 - 2.74 (m, 1H), 2.39 - 2.24 (m, 3H), 0.73 (d, J = 6.4 Hz, 3H).

[0253] Example 9: Preparation of compound N,N-dimethyl-6-(4-(2-(3-methylmorpholino)ethyl)-3-oxa-3,4-dihydro-2H- benzo[b][l,4]thiazin-6-yl)picolinamide (9)

[0254]

[0255] First step: Preparation of compound N,N-dimethyl-6-(4-(2-(3-methylmorpholino)ethyl)-3-oxa-3,4-dihydro-2H- benzo[b][l,4]thiazin-6-yl)picolinamide (9)

[0256] Using a similar method described in Example 8, except using compound 9a instead of compound 8a in Example 8, the crude compound 9 was synthesized. The obtained crude compound was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 9 (23.1 mg) with purity 93.18%.

[0257] MS m / z (ES): 441.1 [M+H] +

[0258] 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 1.6 Hz, 1H), 8.08 (dd, J = 8.0, 1.2 Hz, 1H), 8.01 (t, J = 8.0 Hz, 1H), 7.76 (dd, J = 8.4, 1.6 Hz, 1H), 7.55 - 7.49 (m, 2H), 4.11 (t, J = 6.8 Hz, 2H), 3.62 - 3.56 (m, 1H), 3.54 (s, 2H), 3.51 (dd, J = 10.8, 3.2 Hz, 1H), 3.38 - 3.31 (m, 1H), 3.03 (s, 3H), 3.00 (s, 3H), 2.98 - 2.86 (m, 2H), 2.80 - 2.74 (m, 1H), 2.45 - 2.28 (m, 3H), 0.79 (d, J = 6.0 Hz, 3H).

[0259] Example 10: Preparation of compound 2-methyl-2-(5-(4-(2-(3-methylmorpholino)ethyl)-3-oxa-3,4-dihydro-2H- benzo[b][l,4]thiazin-6-yl)pyridin-2-yl)propanenitrile hydrochloride (10)

[0260]

[0261] First step: Preparation of compound 2-methyl-2-(5-(4-(2-(3-methylmorpholino)ethyl)-3-oxa-3,4-dihydro-2H- benzo[b][l,4]thiazin-6-yl)pyridin-2-yl)propanenitrile hydrochloride (10)

[0262] The crude compound 10 was synthesized using a similar procedure described in Example 8 except that compound 10a was used instead of compound 8a in Example 8. The resulting crude was purified on a silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give the free form of compound 10 which was dissolved in acetonitrile (2 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 M, 0.05 mL, 0.20 mmol) was added dropwise under ice water bath. After stirring for one hour under ice water bath, the reaction mixture was concentrated to dryness, water (8 mL) was added, and the hydrochloride salt of compound 10 was obtained after lyophilization (25.46 mg) with a purity of 95.43%.

[0263] MS m / z (ES): 437.1 [M+H] +

[0264] 1H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J = 2.4 Hz, 1H), 8.19 (dd, J = 8.4, 2.4 Hz, 1H), 7.78 (d, J = 1.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.43 (dd, J = 8.0, 2.0 Hz, 1H), 4.29 - 4.11 (m, 2H), 3.59 - 3.52 (m, 3H), 3.50 - 3.45 (m, 1H), 3.30 - 3.23 (m, 1H), 2.94 - 2.83 (m, 2H), 2.81 - 2.73 (m, 1H), 2.37 - 2.24 (m, 3H), 1.75 (s, 6H), 0.73 (d, J = 6.0 Hz, 3H).

[0265] Example 11: Preparation of compound 4-(2-(3-(methyloxymethyl)morpholino)ethyl)-6-(6- (trifluoromethoxy)pyridin-2-yl)-2H-benzo[b][l,4]thiazin-3(4H)-one (11)

[0266]

[0267] First step: Preparation of compound 2-(3-(methyloxymethyl)morpholino)ethan-l-ol (11c)

[0268] Dissolve 3-(methyloxymethyl)morpholine hydrochloride (11a) (100 mg, 0.60 mmol), 11b (309 mg, 1.81 mmol), K2CO3(249 mg, 1.80 mmol) in acetonitrile (4 mL), after adding, warm to 90 °C to react. After the reaction is complete, the reaction solution is cooled to room temperature, filtered and concentrated to obtain a light yellow oil of crude compound 11c (133 mg, light yellow oil), which is used directly in the next step without further purification.

[0269] MS m / z (ES): 176.1 [M+H] +

[0270] Second step: Preparation of compound 2-(3-(methyloxymethyl)morpholino)ethyl 4- methylbenzenesulfonate (11d)

[0271] The crude compound 11c (133 mg, 0.60 mmol) was dissolved in dichloromethane (4 mL), the reaction system was slowly cooled to 0 °C under N2protection, triethylamine (182 mg, 1.80 mmol), 4-dimethylaminopyridine (7 mg, 0.06 mmol), p-toluenesulfonyl chloride (137 mg, 0.72 mmol) were added, and the reaction was warmed to 25 °C after addition. After the reaction was completed, water and ethyl acetate were added to the reaction system, the liquid was separated, the aqueous phase was extracted with ethyl acetate three times, the organic phases were combined, washed with water and saturated brine once, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain brown crude compound 11d (200 mg, brown oil), which was used directly in the next step without further purification.

[0272] MS m / z (ES): 330.1 [M+H] +

[0273] Step 3: Preparation of compound 6-bromo-4-(2-(3-(methoxymethyl)morpholino)ethyl)- 2H-benzo[b][1,4]thiazin-3(4H)-one (11e)

[0274] The crude compound 11d (200 mg, 0.60 mmol), Int-1 (36 mg, 0.15 mmol) and Cs2CO3(195 mg, 0.60 mmol), KI (10 mg, 0.06 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the reaction was warmed to 50 °C after addition. After the reaction was completed, water and ethyl acetate were added to the reaction system, the liquid was separated, the aqueous phase was extracted with ethyl acetate three times, the organic phases were combined, washed with water and saturated brine once, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain brown oil, and the obtained crude product was purified by silica gel preparative plate (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 11e (45 mg, white solid), with a three-step yield of 75%.

[0275] MS m / z (ES): 401.1 [M+H] +

[0276] Step 4: Preparation of compound 4-(2-(3-(methoxymethyl)morpholino)ethyl)-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one (11f)

[0277] Compound 11e (45 mg, 0.11 mmol), bis-pinacol diborane (56 mg, 0.22 mmol) and KOAc (32 mg, 0.33 mmol) were dissolved in 1,4-dioxane (5 mL), Pd(dppf)Cl2(7 mg, 0.01 mmol) was added under N2protection, and the mixture was heated to 90 °C after the addition was completed. After the reaction was completed, the reaction solution was filtered and concentrated to obtain brown crude compound 11f (300 mg, brown oil), which was used directly in the next step without further purification.

[0278] MS m / z (ES): 449.2 [M+H] +

[0279] Fifth step: Preparation of compound 4-(2-(3-(methoxymethyl)morpholino)ethyl)-6-(6- (trifluoromethoxy)pyridin-2-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one (11)

[0280] Compound 11f (300 mg, 0.11 mmol), 11g (43 mg, 0.22 mmol) and Cs2CO3(107 mg, 0.33 mmol) were dissolved in 1,4-dioxane (5 mL), Pd(dppf)Cl2(7 mg, 0.01 mmol) was added under N2protection, and the mixture was heated to 95 °C after the addition was completed. After the reaction was completed, water and ethyl acetate were added to the reaction system, the mixture was separated, the aqueous phase was extracted with ethyl acetate three times, the combined organic phase was washed with water and saturated brine once, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a brown crude product. The crude product was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to obtain compound 11 (2.06 mg) with a purity of 80.55%.

[0281] MS m / z (ES): 484.1 [M+H] +

[0282] 1H NMR (400 MHz, DMSO-d6) δ 8.13 (t, J = 8.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.75 (dd, J = 8.4, 2.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 4.27 - 4.17 (m, 1H), 4.12 - 4.04 (m, 1H), 3.56 (s, 2H), 3.55 - 3.46 (m, 4H), 3.22 - 3.12 (m, 3H), 3.02 (s, 3H), 2.79 - 2.71 (m, 1H), 2.47 - 2.39 (m, 2H), 2.35 - 2.29 (m, 1H).

[0283] Example 12: Preparation of compound 4-(2-(3-methylmorpholino)ethyl)-6-(6- (trifluoromethoxy)pyridin-2-yl)-2H-benzo[b][l,4]oxazin-3(4H)-one (12)

[0284]

[0285] First Step: Preparation of compound 4-(2-(3-methylmorpholino)ethyl)-6-(6- (trifluoromethoxy)pyridin-2-yl)-2H-benzo[b][l,4]oxazin-3(4H)-one (12)

[0286] The compound Int-3 crude (80 mg, 0.20 mmol), 11 g (70 mg, 0.40 mmol) and CsF (91 mg, 0.60 mmol) were dissolved in 1,4-dioxane (3 mL), Pd(dppf)Cl2(14 mg, 0.02 mmol) was added under N2protection, and after addition, the reaction was warmed to 95 °C. After the reaction was completed, water and ethyl acetate were added to the reaction system, separated, the aqueous phase was extracted with ethyl acetate three times, the combined organic phase was washed with water and saturated brine once, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a brown crude product. The crude product was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 12 (9.7 mg) with a purity of 99.42%.

[0287] MS m / z (ES): 438.1 [M+H] +

[0288] 1H NMR (400 MHz, DMSO-d6) δ 8.09 (t, J = 8.0 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.74 (dd, J = 8.4, 2.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 4.71 (s, 2H), 4.18 - 4.00 (m, 2H), 3.67 - 3.60 (m, 1H), 3.53 (dd, J = 10.8, 3.2 Hz, 1H), 3.42 - 3.36 (m, 1H), 3.01 - 2.87 (m, 2H), 2.87 - 2.79 (m, 1H), 2.46 - 2.32 (m, 3H), 0.79 (d, J = 6.0 Hz, 3H).

[0289] Example 13: Preparation of compound 4-(2-(3-methylmorpholino)ethyl)-6-(pyrazin-2-yl)- 2H-benzo[b][l,4]oxazin-3(4H)-one (13)

[0290]

[0291] First step: Preparation of compound 4-(2-(3-methylmorpholino)ethyl)-6-(pyrazin-2-yl)- 2H-benzo[b][l,4]oxazin-3(4H)-one (13)

[0292] Using a similar method described in Example 12, crude compound 13 was synthesized except that compound 13a was used instead of compound 11g in Example 12. The resulting crude product was purified on a silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 13 (11.8 mg) with a purity of 97.23%.

[0293] MS m / z (ES): 355.1 [M+H] +

[0294] 1H NMR (400 MHz, DMSO-d6) δ 9.28 (d, J = 1.6 Hz, 1H), 8.69 (s, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 8.8, 2.0 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 4.72 (s, 2H), 4.20 - 4.04 (m, 2H), 3.68 - 3.61 (m, 1H), 3.53 (dd, J = 11.2, 3.2 Hz, 1H), 3.42 - 3.36 (m, 1H), 2.99 - 2.89 (m, 2H), 2.88 - 2.81 (m, 1H), 2.43 - 2.34 (m, 3H), 0.78 (d, J = 6.0 Hz, 3H).

[0295] Example 14: Preparation of compound 2-methyl-6-(4-(2-(3-methylmorpholino)ethyl)-3-oxo-3,4-dihydro-2H- benzo[b][l,4]oxazol-6-yl)pyridine- 1 -oxide hydrochloride (14)

[0296]

[0297] First step: Preparation of compound 2-bromo-6-methylpyridine- 1 -oxide (14b)

[0298] Compound 14a (400 mg, 2.3 mmol), mCPBA (465 mg, 2.7 mmol) were dissolved in dichloromethane (7 mL), after addition, 25 °C reaction for 16 hours. After the reaction was completed, saturated aqueous sodium thiosulfate solution (7 mL) was added to quench the reaction, then saturated aqueous sodium bicarbonate solution was used to adjust the pH to 7-8 under ice water bath, separated, the aqueous phase was extracted with dichloromethane three times, the combined organic phase was washed with water, saturated brine once, dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated to give brown crude 14b (400 mg), which was used directly without further purification.

[0299] MS m / z (ES): 187.8 [M+H] +

[0300] Second step: Preparation of compound 2-methyl-6-(4-(2-(3-methylmorpholino)ethyl)-3-oxo-3,4-dihydro-2H- benzo[b][l,4]oxazol-6-yl)pyridine- 1 -oxide hydrochloride (14)

[0301] The crude product of compound 14 was synthesized using a similar procedure described in example 12, except compound 14b was used instead of compound 11g in example 12. The resulting crude product was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give the free form of compound 14, which was dissolved in acetonitrile (2 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 M, 0.05 mL, 0.20 mmol) was added dropwise under ice water bath. After stirring for one hour under ice water bath, the reaction system was concentrated to dryness, water (8 mL) was added, and the hydrochloride salt of compound 14 was obtained after lyophilization (8.9 mg) with a purity of 99.67%.

[0302] MS m / z (ES): 384.0 [M+H] +

[0303] 1 H NMR (400 MHz, DMSO) δ 11.35 (br, 1H), 7.80 (s, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.57 (d, J = 6.8 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 4.84 - 4.72 (m, 2H), 4.51 - 4.31 (m, 2H), 4.04 - 3.80 (m, 3H), 3.70 - 3.49 (m, 2H), 3.49 - 3.39 (m, 1H), 3.38 - 3.20 (m, 3H), 2.48 (s, 3H), 1.26 (d, J = 6.4 Hz, 3H).

[0304] Example 15: Preparation of compound 5-(4-(2-(3-methylmorpholino)ethyl)-3-oxo-3,4- dihydro-2H-benzo[b][l,4]thiazin-6-yl)picolinonitrile (15)

[0305]

[0306] First step: Preparation of compound 5-(4-(2-(3-methylmorpholino)ethyl)-3-oxo-3,4- dihydro-2H-benzo[b][l,4]thiazin-6-yl)picolinonitrile (15)

[0307] The crude product of compound 15 was synthesized using a similar procedure described in example 8, except compound 15a was used instead of compound 8a in example 8. The resulting crude product was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 15 (39.1 mg) with a purity of 99.03%.

[0308] MS m / z (ES): 395.1 [M+H] +

[0309] 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 1.6 Hz, 1H), 8.42 (dd, J = 8.4, 2.4 Hz, 1H), 8.29 - 8.22 (m, 2H), 7.85 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 4.20 - 4.08 (m, 2H), 3.64 - 3.58 (m, 1H), 3.57 (s, 2H), 3.50 (dd, J = 11.2, 3.2 Hz, 1H), 3.38 - 3.30 (m, 1H), 2.95 - 2.86 (m, 2H), 2.81 - 2.73 (m, 1H), 2.38 - 2.28 (m, 3H), 0.76 (d, J = 6.4 Hz, 3H).

[0310] Example 16: Preparation of compound 4-(2-(3-methylmorpholino)ethyl)-6-(6- (trifluoromethyl)pyrazin-2-yl)-2H-benzo[b][l,4]thiazin-3(4H)-one (16)

[0311]

[0312] First step: Preparation of compound 4-(2-(3-methylmorpholino)ethyl)-6-(6- (trifluoromethyl)pyrazin-2-yl)-2H-benzo[b][l,4]thiazin-3(4H)-one (16)

[0313] Using a similar method described in Example 8, except using compound 16a instead of compound 8a in Example 8, the crude compound 16 was synthesized. The resulting crude product was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 16 (52.49 mg) with purity 95.38%.

[0314] MS m / z (ES): 439.1 [M+H] +

[0315] 1H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 9.16 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.89 (dd, J = 8.4, 2.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 4.14 (t, J = 6.8 Hz, 2H), 3.61 - 3.56 (m, 1H), 3.58 (s, 2H), 3.51 (dd, J = 10.8, 3.2 Hz, 1H), 3.38 - 3.30 (m, 1H), 2.99 - 2.87 (m, 2H), 2.84 - 2.77 (m, 1H), 2.45 - 2.31 (m, 3H), 0.81 (d, J = 6.0 Hz, 3H).

[0316] Example 17: Preparation of compound 6-(6-methoxypyridin-2-yl)-4-(2-(3- methylmorpholino)ethyl)-2H-benzo[b][l,4]thiazin-3(4H)-one (17)

[0317]

[0318] First step: Preparation of compound 6-(6-methoxypyridin-2-yl)-4-(2-(3- methylmorpholino)ethyl)-2H-benzo[b][l,4]thiazin-3(4H)-one (17)

[0319] The crude compound 17 was synthesized using a similar method described in Example 8, except that compound 17a was used instead of compound 8a in Example 8. The resulting crude product was purified on a silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 17 (6.64 mg) with a purity of 97.77%.

[0320] MS m / z (ES): 400.0 [M+H] +

[0321] 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 1.6 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.76 (dd, J = 8.0, 1.6 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 4.20 - 4.09 (m, 2H), 3.96 (s, 3H), 3.61 - 3.56 (m, 1H), 3.54 (s, 2H), 3.50 (dd, J = 11.2, 3.2 Hz, 1H), 3.38 - 3.30 (m, 1H), 2.97 - 2.85 (m, 2H), 2.81 - 2.74 (m, 1H), 2.41 - 2.28 (m, 3H), 0.78 (d, J = 6.4 Hz, 3H).

[0322] Example 18: Preparation of compound 6-(4-(2-(3-methylmorpholino)ethyl)-3-oxo-3,4- dihydro-2H-benzo[b][l,4]thiazin-6-yl)picolinonitrile (18)

[0323]

[0324] First step: Preparation of compound 6-(4-(2-(3-methylmorpholino)ethyl)-3-oxo-3,4- dihydro-2H-benzo[b][l,4]thiazin-6-yl)picolinonitrile (18)

[0325] Using a similar method described in Example 8, except using compound 18a instead of compound 8a in Example 8, the crude compound 18 was synthesized. The resulting crude was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 18 (39.98 mg) with purity 99.60%.

[0326] MS m / z (ES): 395.1 [M+H] +

[0327] 1H NMR (400 MHz, DMSO-d6) δ 8.37 (dd, J = 8.4, 1.2 Hz, 1H), 8.20 - 8.14 (m, 2H), 8.01 (dd, J = 7.6, 0.8 Hz, 1H), 7.79 (dd, J = 8.0, 1.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 4.12 (t, J = 6.8 Hz, 2H), 3.64 (dt, J = 11.2, 3.2 Hz, 1H), 3.57 (s, 2H), 3.53 (dd, J = 11.2, 3.2 Hz, 1H), 3.40 - 3.34 (m, 1H), 3.00 - 2.89 (m, 2H), 2.83 (dt, J = 11.6, 3.2 Hz, 1H), 2.46 - 2.30 (m, 3H), 0.85 (d, J = 6.0 Hz, 3H).

[0328] Example 19: Preparation of compound 4-(2-(3-methylmorpholino)ethyl)-6-(6- (oxetan-3-yloxy)pyridin-2-yl)-2H-benzo[b][l,4]thiazin-3(4H)-one (19)

[0329]

[0330] First step: Preparation of compound 2-bromo-6-(oxetan-3-yloxy)pyridine (19c)

[0331] The crude compound 19a (500 mg, 2.8 mmol), 19b (233 mg, 3.1 mmol) were dissolved in tetrahydrofuran (5 mL), after the addition, the reaction system was cooled to 0 °C, tBuOK (408 mg, 3.6 mmol) was added, after the addition, the reaction was carried out at 0 °C for 2 hours. After the reaction was completed, water and ethyl acetate were added to the reaction system, the liquid was separated, the aqueous phase was extracted with ethyl acetate three times, the organic phases were combined, washed with water and saturated brine once, dried over anhydrous sodium sulfate, and then filtered under suction. The filtrate was concentrated to obtain brown crude 19c (540 mg).

[0332] MS m / z (ES): 229.8 [M+H] +

[0333] Second step: Preparation of compound 4-(2-(3-methylmorpholino)ethyl)-6-(6- (oxetan-3-yloxy)pyridin-2-yl)-2H-benzo[b][l,4]thiazin-3(4H)-one (19)

[0334] Using a similar method described in Example 1, except using compound 19c instead of compound 1a in Example 1, the crude compound 19 was synthesized. The obtained crude was purified by silica gel preparative plate (methylene chloride / methanol = 20 / 1) to give compound 19 (17.10 mg) with purity 98.01%.

[0335] MS m / z (ES): 442.0 [M+H] +

[0336] 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 1.6 Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 7.70 (dd, J = 8.0, 1.6 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 5.73 - 5.65 (m, 1H), 4.97 (td, J = 6.8, 4.4 Hz, 2H), 4.64 (dt, J = 6.8, 5.2 Hz, 2H), 4.18 (t, J = 6.4 Hz, 2H), 3.59 (dt, J = 11.2, 3.2 Hz, 1H), 3.54 (s, 2H), 3.50 (dd, J = 10.8, 3.2 Hz, 1H), 3.38 - 3.31 (m, 1H), 2.96 (dd, J = 10.8, 8.8 Hz, 1H), 2.87 (dt, J = 13.6, 6.8 Hz, 1H), 2.77 (dt, J = 12.0, 2.8 Hz, 1H), 2.41 - 2.30 (m, 3H), 0.76 (d, J = 6.0 Hz, 3H).

[0337] Example 20: Preparation of compound (R)-6-(4-(2-(3-methylmorpholino)ethyl)-3-oxo-3,4-dihydro-2H- benzo[b][l,4]thiazin-6-yl)pyridine cyanide (20)

[0338]

[0339] First step: Preparation of compound (R)-6-(4-(2-(3-methylmorpholino)ethyl)-3-oxo-3,4-dihydro-2H- benzo[b][l,4]thiazin-6-yl)pyridine cyanide (20)

[0340] A mixture of compound Int-4 crude (80 mg, 0.20 mmol), 18a (70 mg, 0.40 mmol) and CsF (91 mg, 0.60 mmol) was dissolved in 1,4-dioxane (3 mL) solution, Pd(dppf)Cl2(14 mg, 0.02 mmol) was added under N2protection, after the addition, the reaction was heated to 95 °C. After the reaction was completed, water and ethyl acetate were added to the reaction system, separated, the aqueous phase was extracted with ethyl acetate three times, the combined organic phase was washed with water and saturated brine once, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to give a brown crude product. Purification of the obtained on a silica gel preparative plate (dichloromethane / methanol = 20 / 1) gave compound 20 (30.58 mg) with a purity of 96.80%.

[0341] MS m / z (ES): 395.0 [M+H] +

[0342] 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (dd, J = 8.4, 1.2 Hz, 1H), 8.20 - 8.14 (m, 2H), 8.01 (dd, J = 7.6, 0.8 Hz, 1H), 7.79 (dd, J = 8.0, 1.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 4.12 (t, J = 6.8 Hz, 2H), 3.64 (dt, J = 11.2, 3.2 Hz, 1H), 3.57 (s, 2H), 3.53 (dd, J = 11.2, 3.2 Hz, 1H), 3.40 - 3.34 (m, 1H), 3.00 - 2.89 (m, 2H), 2.83 (dt, J = 11.6, 3.2 Hz, 1H), 2.46 - 2.30 (m, 3H), 0.85 (d, J = 6.0 Hz, 3H).

[0343] Example 21: Preparation of compound 1-(2-(3-methylmorpholino)ethyl)-7-(6- (trifluoromethoxy)pyridin-2-yl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (21)

[0344]

[0345] First step: Preparation of compound 1-(2-(3-methylmorpholino)ethyl)-7-(6- (trifluoromethoxy)pyridin-2-yl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (21)

[0346] The crude product of compound 21 was synthesized using a similar procedure described in Example 1 except using compound Int-5 instead of compound Int-2 in Example 1, compound 11g instead of compound 1a in Example 1. The resulting crude product was purified on silica gel pre-plate (methylene chloride / methanol = 20 / 1) to give compound 21 (10.47 mg) with a purity of 97.91%.

[0347] MS m / z (ES): 439.0 [M+H] +

[0348] 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 2.0 Hz, 1H), 8.18 - 8.07 (m, 3H), 7.28 (dd, J = 7.6, 1.2 Hz, 1H), 4.92 (s, 2H), 4.16 - 3.98 (m, 2H), 3.61 (dt, J = 11.2, 3.2 Hz, 1H), 3.52 (dd, J = 10.8, 3.2 Hz, 1H), 3.41 - 3.32 (m, 1H), 2.99 - 2.87 (m, 2H), 2.83 (dt, J = 11.6, 2.8 Hz, 1H), 2.43 - 2.30 (m, 3H), 0.78 (d, J = 6.0 Hz, 3H).

[0349] Example 22: Preparation of (S)-6-(4-(2-(3-methylmorpholino)ethyl)-3-oxo-3,4- dihydro-2H-benzo[b][l,4]thiazin-6-yl)pyridine cyanide (22)

[0350]

[0351] First Step: Preparation of (S)-6-(4-(2-(3-methylmorpholino)ethyl)-3-oxo-3,4- dihydro-2H-benzo[b][l,4]thiazin-6-yl)pyridine cyanide (22)

[0352] The crude product of compound 22 was synthesized using a similar procedure described in Example 8 except using compound Int-6 instead of compound Int-2 in Example 8, compound 18a instead of compound 8a in Example 8. The resulting crude product was purified on silica gel pre-plate (methylene chloride / methanol = 20 / 1) to give compound 22 (30.58 mg) with a purity of 96.80%.

[0353] MS m / z (ES): 395.0 [M+H] +

[0354] 1H NMR (400 MHz, DMSO-d6) δ 8.37 (dd, J = 8.4, 1.2 Hz, 1H), 8.20 - 8.14 (m, 2H), 8.01 (dd, J = 7.6, 0.8 Hz, 1H), 7.79 (dd, J = 8.0, 1.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 4.12 (t, J = 6.8 Hz, 2H), 3.64 (dt, J = 11.2, 3.2 Hz, 1H), 3.57 (s, 2H), 3.53 (dd, J = 11.2, 3.2 Hz, 1H), 3.40 - 3.34 (m, 1H), 3.00 - 2.89 (m, 2H), 2.83 (dt, J = 11.6, 3.2 Hz, 1H), 2.46 - 2.30 (m, 3H), 0.85 (d, J = 6.0 Hz, 3H).

[0355] Example 23: Preparation of compound 6-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-4-(2-(3- methylmorpholino)ethyl)-2H-benzo[b][l,4]thiazin-3(4H)-one (23)

[0356]

[0357] First step: Preparation of compound 6-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-4-(2-(3- methylmorpholino)ethyl)-2H-benzo[b][l,4]thiazin-3(4H)-one (23)

[0358] The crude compound 23 was synthesized using a similar method described in example 8, except that compound 23a was used instead of compound 8a in example 8. The resulting crude product was purified on a silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 23 (16.74 mg) with a purity of 98.75%.

[0359] MS m / z (ES): 410.0 [M+H] +

[0360] 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 2.0 Hz, 1H), 7.76 - 7.67 (m, 3H), 7.47 (d, J = 8.0 Hz, 1H), 4.13 - 4.03 (m, 2H), 3.63 (dt, J = 11.2, 2.8 Hz, 1H), 3.55 - 3.52 (m, 1H), 3.53 (s, 2H), 3.43 - 3.37 (m, 1H), 3.03 - 2.88 (m, 6H), 2.81 (dt, J = 11.6, 2.8 Hz, 1H), 2.44 - 2.33 (m, 3H), 2.12 - 2.05 (m, 2H), 0.85 (d, J = 6.4 Hz, 3H).

[0361] Example 24: Preparation of compound 6-(4-(2-(4-methylpiperazin-1-yl)ethyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)pyridine cyanide (24)

[0362]

[0363] First to third steps: Preparation of compound 4-(2-(4-methylpiperazin-1-yl)ethyl)-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one (24d)

[0364] The crude compound 24d was synthesized using similar method described in the second to fourth steps of Example 11 except using compound 24a instead of compound 11c in Example 11. The resulting crude was used directly in the next step without further purification.

[0365] Fourth step: Preparation of compound 6-(4-(2-(4-methylpiperazin-1-yl)ethyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)pyridine cyanide (24)

[0366] The crude compound 24 was synthesized using similar method described in Example 1 except using compound 24d instead of compound Int-2 in Example 1, and compound 18a instead of compound 1a in Example 1. The resulting crude was purified on silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 24 (5.32 mg) with purity 99.48%.

[0367] MS m / z (ES): 394.0 [M+H] +

[0368] 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 8.4 Hz, 1H), 8.16 (t, J = 8.0 Hz, 1H), 8.12 (s, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 4.12 (t, J = 6.8 Hz, 2H), 3.56 (s, 2H), 2.54 - 2.45 (m, 6H), 2.36 - 2.18 (m, 4H), 2.10 (s, 3H).

[0369] Example 25: Preparation of compound N,2-dimethyl-5-(4-(2-(3-methylmorpholino)ethyl)-3- oxo-3,4-dihydro-2H-benzo[b][l,4]thiazin-6-yl)pyridine cyanide (25)

[0370]

[0371] First step: Preparation of compound N,2-dimethyl-5-(4-(2-(3-methylmorpholino)ethyl)-3- oxo-3,4-dihydro-2H-benzo[b][l,4]thiazin-6-yl)pyridine cyanide (25)

[0372] The crude compound 25 was synthesized using a similar method described in Example 8, except that compound 25a was used instead of compound 8a in Example 8. The resulting crude product was purified on a silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 25 (8.44 mg) with a purity of 98.46%.

[0373] MS m / z (ES): 441.2 [M+H] +

[0374] 1 H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 2.4 Hz, 1H), 8.46 (q, J = 4.8 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.45 (dd, J = 8.0, 2.0 Hz, 1H), 4.23 - 4.12 (m, 2H), 3.60 - 3.54 (m, 1H), 3.53 (s, 2H), 3.52 - 3.47 (m, 1H) 3.36 - 3.24 (m, 1H), 2.94 - 2.84 (m, 2H), 2.80 (d, J = 4.4 Hz, 3H), 2.80 - 2.75 (m, 1H), 2.56 (s, 3H), 2.38 - 2.24 (m, 3H), 0.75 (d, J = 6.4 Hz, 3H).

[0375] Example 26: Preparation of compound l-(2-morpholinoethyl)-7-(6- (trifluoromethoxy)pyridin-2-yl)-lH-pyrido[2,3-b][l,4]thiazin-2(3H)-one (26)

[0376]

[0377] First Step: Preparation of compound l-(2-morpholinoethyl)-7-(6- (trifluoromethoxy)pyridin-2-yl)-lH-pyrido[2,3-b][l,4]thiazin-2(3H)-one (26)

[0378] Using a similar procedure as described in Example 8, crude compound 26 was synthesized except that compound Int-7 was used instead of compound Int-2 in Example 8, and compound 11g was used instead of compound 8a in Example 8. The resulting crude compound was purified on a silica gel preparative plate (methylene chloride / methanol = 20 / 1) to give compound 26 (40.37 mg) with purity 99.98%.

[0379] MS m / z (ES): 441.0 [M+H] +

[0380] 1 H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.21 - 8.13 (m, 2H), 7.33 (dd, J = 7.2, 1.6 Hz, 1H), 4.11 (t, J = 6.8 Hz, 2H), 3.74 (s, 2H), 3.49 - 3.40 (m, 4H), 2.54 - 2.47 (m, 2H), 2.43 - 2.32 (m, 4H).

[0381] Example 27: Preparation of compound 6-(l-(2-morpholinoethyl)-2-oxo-2,3- dihydro-lH-pyrido[2,3-b][l,4]thiazin-7-yl)-3-(trifluoromethyl)pyridinecarbonitrile (27)

[0382]

[0383] First Step: Preparation of compound 6-(l-(2-morpholinoethyl)-2-oxo-2,3- dihydro-lH-pyrido[2,3-b][l,4]thiazin-7-yl)-3-(trifluoromethyl)pyridinecarbonitrile (27)

[0384] The crude product of compound 27 was synthesized using a similar method described in Example 8, except compound Int-7 was used instead of compound Int-2 in Example 8, and compound 27a was used instead of compound 8a in Example 8. The resulting crude product was purified by silica gel pre-plate (dichloromethane / methanol = 20 / 1) to give compound 27 (28.34 mg) with purity 99.05%.

[0385] MS m / z (ES): 450.0 [M+H] +

[0386] 1 H NMR (400 MHz, DMSO-d6) d 8.93 (d, J = 2.0 Hz, 1H), 8.67 (d, J = 8.8 Hz, 1H), 8.64 (d, J = 8.8 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 4.13 (t, J = 6.0 Hz, 2H), 3.78 (s, 2H), 3.49 - 3.40 (m, 4H), 2.54 - 2.47 (m, 2H), 2.45 - 2.36 (m, 4H).

[0387] Example 28: Preparation of compound 1-(2-(3-methylmorpholino)ethyl)-7-(6- (trifluoromethoxy)pyridin-2-yl)-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-one (28)

[0388]

[0389] First Step: Preparation of compound 1-(2-(3-methylmorpholino)ethyl)-7-(6- (trifluoromethoxy)pyridin-2-yl)-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-one (28)

[0390] The crude product of compound 28 was synthesized using a similar method described in Example 8, except compound Int-8 was used instead of compound Int-2 in Example 8, and compound 11g was used instead of compound 8a in Example 8. The resulting crude product was purified by silica gel pre-plate (dichloromethane / methanol = 20 / 1) to give compound 28 (7.89 mg) with purity 94.42%.

[0391] MS m / z (ES): 455.1 [M+H] +

[0392] 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 1.6 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.21 - 8.12 (m, 2H), 7.33 (dd, J = 6.8, 1.6 Hz, 1H), 4.19 - 4.12 (m, 1H), 4.11 - 4.03 (m, 1H), 3.74 (s, 2H), 3.56 - 3.49 (m, 1H), 3.46 (dd, J = 10.8, 3.2 Hz, 1H), 3.26 - 3.19 (m, 1H), 2.93 - 2.80 (m, 2H), 2.77 - 2.69 (m, 1H), 2.36 - 2.21 (m, 3H), 0.73 (d, J = 6.4 Hz, 3H).

[0393] Example 29: Preparation of compound 6-(l-(2-2-morpholinoethyl)-2-oxo-l,2,3,4- tetrahydroquinolin-7-yl)picolinitrile (29)

[0394]

[0395] First step: Preparation of compound 6-(l-(2-2-morpholinoethyl)-2-oxo-l,2,3,4- tetrahydroquinolin-7-yl)picolinitrile (29)

[0396] Using a similar method described in Example 8, crude compound 29 was synthesized except that compound Int-9 was used instead of compound Int-2 in Example 8, and compound 18a was used instead of compound 8a in Example 8. The obtained crude compound was purified on a silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 29 (28.34 mg) with a purity of 99.34%.

[0397] MS m / z (ES): 363.2 [M+H] +

[0398] 1 H NMR (400 MHz, DMSO) δ 8.35 (d, J = 7.6 Hz, 1H), 8.15 (t, J = 7.6 Hz, 1H), 8.00 (d, J = 6.8 Hz, 1H), 7.93 (s, 1H), 7.75 (dd, J = 7.6, 1.2 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 4.10 (t, J = 6.8 Hz, 2H), 3.66 - 3.48 (m, 4H), 2.98 - 2.86 (m, 2H), 2.58 (dd, J = 7.6, 5.2 Hz, 2H), 2.55 - 2.49 (m, 6H).

[0399] Example 30: Preparation of compound N,N-dimethyl-6-(4-(2-(3-methylmorpholino)ethyl)-3- oxo-3,4-dihydro-2H-benzo[b][l,4]thiazin-6-yl)nicotinamide (30)

[0400]

[0401] First step: Preparation of compound N,N-dimethyl-6-(4-(2-(3-methylmorpholino)ethyl)-3- oxo-3,4-dihydro-2H-benzo[b][l,4]thiazin-6-yl)nicotinamide (30)

[0402] The crude compound 30 was synthesized using a similar method described in Example 8, except that compound 30a was used instead of compound 8a in Example 8. The resulting crude product was purified on a silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 30 (6.65 mg) with a purity of 99.33%.

[0403] MS m / z (ES): 441.2 [M+H] +

[0404] 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 1.6 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.95 (dd, J = 8.4, 2.0 Hz, 1H), 7.80 (dd, J = 8.4, 2.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 4.20 - 4.09 (m, 2H), 3.61 (dt, J = 10.9, 3.0 Hz, 1H), 3.56 (s, 2H), 3.51 (dd, J = 11.2, 3.2 Hz, 1H), 3.41 - 3.37 (m, 1H), 3.02 (s, 3H), 2.98 (s, 3H), 2.97 - 2.85 (m, 2H), 2.79 (dt, J = 11.6, 2.8 Hz, 1H), 2.41 - 2.27 (m, 3H), 0.78 (d, J = 6.4 Hz, 3H).

[0405] Example 31: Preparation of compound 4-(2-(3-methylmorpholino)ethyl)-6-(5- (trifluoromethoxy)pyridin-2-yl)-2H-benzo[b][l,4]thiazin-3(4H)-one (31)

[0406]

[0407] First Step: Preparation of compound 4-(2-(3-methylmorpholinyl)ethyl)-6-(5- (trifluoromethoxy)pyridin-2-yl)-2H-benzo[b][l,4]thiazin-3(4H)-one (31)

[0408] The crude compound 31 was synthesized using a similar method described in Example 8, except using compound 31a instead of compound 8a in Example 8. The resulting crude product was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 31 (7.81 mg) with purity 98.32%.

[0409] MS m / z (ES): 454.1 [M+H] +

[0410] 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 2.8 Hz, 1H), 8.20 - 8.12 (m, 2H), 8.00 (dd, J = 8.8, 1.6 Hz, 1H), 7.75 (dd, J = 8.0, 1.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 4.21 - 4.05 (m, 2H), 3.60 (dt, J = 10.8, 3.2 Hz, 1H), 3.55 (s, 2H), 3.50 (dd, J = 10.8, 2.8 Hz, 1H), 3.38 - 3.30 (m, 1H), 2.97 - 2.88 (m, 2H), 2.78 (dt, J = 11.6, 2.8 Hz, 1H), 2.41 - 2.25 (m, 3H), 0.76 (d, J = 6.0 Hz, 3H).

[0411] Example 32: Preparation of compound 6-(4-(2-(3-methylmorpholinyl)ethyl)-3-oxo-3,4- dihydro-2H-benzo[b][l,4]thiazin-6-yl)nicotinonitrile (32)

[0412]

[0413] First Step: Preparation of compound 6-(4-(2-(3-methylmorpholinyl)ethyl)-3-oxo-3,4- dihydro-2H-benzo[b][l,4]thiazin-6-yl)nicotinonitrile (32)

[0414] The crude compound 32 was synthesized using a similar method described in Example 8, except using compound 32a instead of compound 8a in Example 8. The resulting crude product was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 32 (5.80 mg) with purity 96.07%.

[0415] MS m / z (ES): 395.1 [M+H]+

[0416] 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (dd, J = 2.0, 0.8 Hz, 1H), 8.42 (dd, J = 8.4, 2.4 Hz, 1H), 8.30 - 8.21 (m, 2H), 7.85 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 4.18 - 4.07 (m, 2H), 3.64 - 3.58 (m, 1H), 3.57 (s, 2H), 3.50 (dd, J = 10.8, 3.2 Hz, 1H), 3.38 - 3.31 (m, 1H), 2.98 - 2.85 (m, 2H), 2.78 (dt, J = 11.6, 2.8 Hz, 1H), 2.41 - 2.24 (m, 3H), 0.76 (d, J = 6.4 Hz, 3H).

[0417] Example 33: Preparation of compound 4-(2-(3-methylmorpholino)ethyl)-6-(5- (trifluoromethyl)pyridin-2-yl)-2H-benzo[b][l,4]thiazin-3(4H)-one (33)

[0418]

[0419] First step: Preparation of compound 4-(2-(3-methylmorpholino)ethyl)-6-(5- (trifluoromethyl)pyridin-2-yl)-2H-benzo[b][l,4]thiazin-3(4H)-one (33)

[0420] The crude compound 33 was synthesized using a similar method described in Example 8, except that compound 33a was used instead of compound 8a in Example 8. The resulting crude product was purified on a silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 33 (4.33 mg) with a purity of 97.22%.

[0421] MS m / z (ES): 438.1 [M+H] +

[0422] 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.32 (dd, J = 8.4, 2.4 Hz, 1H), 8.28 - 8.20 (m, 2H), 7.85 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 4.22 - 4.10 (m, 2H), 3.66 - 3.58 (m, 1H), 3.57 (s, 2H), 3.55 - 3.46 (m, 1H), 3.41 - 3.35 (m, 1H), 2.99 - 2.88 (m 2H), 2.84 - 2.74 (m, 1H), 2.40 - 2.28 (m, 3H), 0.78 (d, J = 6.4 Hz, 3H).

[0423] Example 34: Preparation of compound 4-(2-(3-methylmorpholino)ethyl)-6-(6- (trifluoromethyl)pyridin-3-yl)-2H-benzo[b][l,4]thiazin-3(4H)-one (34)

[0424]

[0425] First step: Preparation of compound 4-(2-(3-methylmorpholino)ethyl)-6-(6- (trifluoromethyl)pyridin-3-yl)-2H-benzo[b][l,4]thiazin-3(4H)-one (34)

[0426] The crude compound 34 was synthesized using a similar method described in Example 1 except that compound 34a was used instead of compound la in Example 1. The resulting crude product was purified on a silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 34 (7.94 mg) with a purity of 97.21%.

[0427] MS m / z (ES): 438.1 [M+H] +

[0428] 1H NMR (400 MHz, DMSO-d6) δ 9.12 (d, J = 2.0 Hz, 1H), 8.40 (dd, J = 8.0, 2.4 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 8.0, 1.6 Hz, 1H), 4.30 - 4.13 (m, 2H), 3.57 - 3.54 (m, 3H), 3.48 (dd, J = 10.8, 3.2 Hz, 1H), 3.25 (td, J = 9.6, 2.0 Hz, 1H), 2.95 - 2.81 (m, 2H), 2.81 - 2.73 (m, 1H), 2.38 - 2.21 (m, 3H), 0.73 (d, J = 6.4 Hz, 3H).

[0429] Example 35: Preparation of compound 2-methyl-5-(4-(2-(3-methylmorpholino)ethyl)-3-oxo-3,4-dihydro-2H- benzo[b][l,4]thiazin-6-yl)nicotinonitrile (35)

[0430]

[0431] First step: Preparation of compound 2-methyl-5-(4-(2-(3-methylmorpholino)ethyl)-3-oxo-3,4-dihydro-2H- benzo[b][l,4]thiazin-6-yl)nicotinonitrile (35)

[0432] Using a similar method described in Example 8, except using compound 35a instead of compound 8a in Example 8, the crude compound 35 was synthesized. The resulting crude compound was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 35 (6.90 mg) with purity 98.96%.

[0433] MS m / z (ES): 409.1 [M+H] +

[0434] 1H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 2.4 Hz, 1H), 8.63 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.0, 2.0 Hz, 1H), 4.27 - 4.15 (m, 2H), 3.58 - 3.52 (m, 3H), 3.48 (dd, J = 10.8, 3.2 Hz, 1H), 3.30 - 3.23 (m, 1H), 2.92 - 2.84 (m, 2H), 2.82 - 2.75 (m, 1H), 2.72 (s, 3H), 2.35 - 2.25 (m, 3H), 0.73 (d, J = 6.4 Hz, 3H).

[0435] Example 36: Preparation of compound 6-(4,4-dimethyl-l-(2-(3-methylmorpholino)ethyl)- 2-oxo-l,4-dihydro-2H-benzo[d][l,3]oxazol-7-yl)picolinonitrile (36)

[0436]

[0437] First Step: Preparation of compound 6-(4,4-dimethyl-l-(2-(3-methylmorpholino)ethyl)- 2-oxo-l,4-dihydro-2H-benzo[d][l,3]oxazol-7-yl)picolinonitrile (36)

[0438] Using a similar procedure as described in Example 8, crude compound 36 was synthesized except that compound Int-10 was used instead of compound Int-2 in Example 8, and compound 18a was used instead of compound 8a in Example 8. The resulting crude compound was purified on a silica gel preparative plate (methylene chloride / methanol = 20 / 1) to give compound 36 (24.56 mg) with a purity of 97.20%.

[0439] MS m / z (ES): 407.2 [M+H] +

[0440] 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 8.0 Hz, 1H), 8.17 (t, J = 7.6 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 7.84 (dd, J = 8.0, 1.6 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 4.19 - 4.14 (m, 1H), 4.11 - 4.02 (m, 1H), 3.71 - 3.63 (m, 1H), 3.54 (dd, J = 10.8, 2.8 Hz, 1H), 3.44 (td, J = 10.0, 2.4 Hz, 1H), 3.07 - 2.97 (m, 2H), 2.93 - 2.85 (m, 1H), 2.43 - 2.31 (m, 3H), 1.68 (s, 3H), 1.66 (s, 3H), 0.81 (d, J = 6.4 Hz, 3H).

[0441] Example 37: Preparation of compound l-(2-morpholinoethyl)-7-(5-(trifluoromethyl)pyridin-2-yl)-lH-pyrido[2,3-b][l,4]thiazin-2(3H)-one (37)

[0442]

[0443] First step: Preparation of compound l-(2-morpholinoethyl)-7-(5-(trifluoromethyl)pyridin-2-yl)-lH-pyrido[2,3-b][l,4]thiazin-2(3H)-one (37)

[0444] Using a similar method to that described in Example 8, crude compound 37 was synthesized, except that compound Int-7 was used instead of compound Int-2 in Example 8, and compound 37a was used instead of compound 8a in Example 8. The obtained crude compound was purified on a silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 37 (17.41 mg) with a purity of 99.42%.

[0445] MS m / z (ES): 425.1 [M+H] +

[0446] 1 H NMR (400 MHz, DMSO) δ 9.09 (s, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.48 (d, J = 1.6 Hz, 1H), 8.42 - 8.32 (m, 2H), 4.14 (t, J = 6.4 Hz, 2H), 3.76 (s, 2H), 3.51 - 3.40 (m, 4H), 2.51 - 2.45 (m, 2H), 2.43 - 2.32 (m, 4H).

[0447] Example 38: Preparation of compound 6-(4-(2-morpholinoethyl)-3-oxo-3,4- dihydro-2H-benzo[b][l,4]thiazin-6-yl)picolinonitrile (38)

[0448]

[0449] First Step: Preparation of compound 6-(4-(2-morpholinoethyl)-3-oxo-3,4- dihydro-2H-benzo[b][l,4]thiazin-6-yl)picolinonitrile (38)

[0450] Using a similar procedure as described in Example 8, crude compound 38 was synthesized except that compound Int-ll was used instead of compound Int-2 in Example 8, and compound 18a was used instead of compound 8a in Example 8. The resulting crude compound was purified on a silica gel pre-plate (methylene chloride / methanol = 20 / 1) to give compound 38 (41.9 mg, off-white solid) with purity 98.1%.

[0451] MS m / z (ES): 381.1 [M+H] +

[0452] 1 H NMR (400 MHz, DMSO) d 8.36 (d, J = 8.0 Hz, 1H), 8.22 - 8.11 (m, 2H), 8.01 (d, J = 7.6 Hz, 1H), 7.79 (dd, J = 8.4, 1.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 4.14 (t, J = 6.4 Hz, 2H), 3.57 (s, 2H), 3.55 - 3.48 (m, 4H), 2.54 (t, J = 6.8 Hz, 2H), 2.48 - 2.42 (m, 4H).

[0453] Example 39: Preparation of compound 6-(6-cyclopropylpyridin-3-yl)-4-(2-(3- methylmorpholino)ethyl)-2H-benzo[b][l,4]thiazin-3(4H)-one hydrochloride (39)

[0454]

[0455] First Step: Preparation of compound 6-(6-cyclopropylpyridin-3-yl)-4-(2-(3- methylmorpholino)ethyl)-2H-benzo[b][l,4]thiazin-3(4H)-one hydrochloride (39)

[0456] The crude compound 39 was synthesized using a similar procedure described in Example 8 except compound 39a was used instead of compound 8a in Example 8. The resulting crude was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give the free form of compound 39 (30.1 mg, 0.07 mmol), which was dissolved in acetonitrile (2 mL), and hydrogen chloride in 1,4-dioxane (4 M, 0.05 mL, 0.20 mmol) was added dropwise under ice water bath. After stirring for one hour under ice water bath, the reaction was concentrated to dryness, water (8 mL) was added, and the hydrochloride salt of compound 39 (30.72 mg) was obtained after lyophilization with 98.17% purity.

[0457] MS m / z (ES): 410.1 [M+H] +

[0458] 1 H NMR (400 MHz, DMSO-d6) δ 12.35 - 11.96 (m, 1H), 9.23 - 9.07 (m, 1H), 8.97 - 8.74 (m, 1H), 7.90 - 7.76 (m, 1H), 7.70 - 7.54 (m, 3H), 4.73 - 4.58 (m, 1H), 4.51 - 4.39 (m, 1H), 4.05 - 3.68 (m, 4H), 3.68 - 3.57 (m, 3H), 3.53 - 3.40 (m, 1H), 3.40 - 3.20 (m, 3H), 2.60 - 2.50 (m, 1H), 1.41 - 1.32 (m, 2H), 1.27 (d, J = 6.4 Hz, 3H), 1.26 - 1.18 (m, 2H).

[0459] Example 40: Preparation of compound 4-(2-(3-methylmorpholino)ethyl)-6-(6- methylpyridin-2-yl)-2H-benzo[b][l,4]thiazin-3(4H)-one (40)

[0460]

[0461] First step: Preparation of compound 4-(2-(3-methylmorpholino)ethyl)-6-(6- methylpyridin-2-yl)-2H-benzo[b][l,4]thiazin-3(4H)-one (40)

[0462] The crude compound 40 was synthesized using a similar procedure described in Example 8 except compound 40a was used instead of compound 8a in Example 8. The resulting crude was purified by silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 40 (41.6 mg) with 99.5% purity.

[0463] MS m / z (ES): 384.1 [M+H]+

[0464] 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 1.6 Hz, 1H), 7.83 - 7.75 (m, 2H), 7.73 (dd, J = 8.0, 1.6 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.23 (dd, J = 6.8, 2.0 Hz, 1H), 4.18 - 4.02 (m, 2H), 3.67 - 3.59 (m, 1H), 3.58 - 3.50 (m, 3H), 3.41 - 3.34 (m, 1H), 3.02 - 2.87 (m, 2H), 2.89 - 2.78 (m, 1H), 2.52 (s, 3H), 2.47 - 2.31 (m, 3H), 0.85 (d, J = 6.4 Hz, 3H).

[0465] Example 41: Preparation of compound 4-(2-(3-methylmorpholino)ethyl)-6-(4- (trifluoromethyl)pyrimidin-2-yl)-2H-benzo[b][l,4]thiazin-3(4H)-one (41)

[0466]

[0467] First Step: Preparation of compound 4-(2-(3-methylmorpholino)ethyl)-6-(4- (trifluoromethyl)pyrimidin-2-yl)-2H-benzo[b][l,4]thiazin-3(4H)-one (41)

[0468] Using similar method described in Example 8, crude compound 41 was synthesized except that compound 41a was used instead of compound 8a in Example 8. The resulting crude compound 41 was purified on silica gel preparative plate (dichloromethane / methanol = 20 / 1) to give compound 41 (16.17 mg, off-white solid) with purity 98.93%.

[0469] MS m / z (ES): 439.1 [M+H] +

[0470] 1H NMR (400 MHz, DMSO-d6) δ 9.28 (d, J = 5.2 Hz, 1H), 8.42 (d, J = 1.2 Hz, 1H), 8.08 (dd, J = 8.4, 1.2 Hz, 1H), 7.98 (d, J = 5.2 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 4.15 - 3.98 (m, 2H), 3.68 - 3.62 (m, 1H), 3.60 (s, 2H), 3.55 (dd, J = 10.4, 3.2 Hz, 1H), 3.46 - 3.39 (m, 1H), 3.05 - 2.92 (m, 2H), 2.87 - 2.79 (m, 1H), 2.49 - 2.31 (m, 3H), 0.86 (d, J = 6.4 Hz, 3H).

[0471] Pharmacological test evaluation

[0472] In vitro test of the effect of each compound of formula (I) on different receptor activities

[0473] 1. Test purpose: Using Flp-In-CHO-CB1, Flp-In-CHO-CB2 cell lines, and the established cAMP assay detection platform, the CB1, CB2 agonistic activities of each compound sample were detected.

[0474] 2 Test method:

[0475] 2.1 Cell culture and reagent preparation

[0476] a. Cell lines: Flp-In-CHO-CB1 (for detection of CB1 agonistic activity), Flp-In-CHO-CB2 (for detection of CB2 agonistic activity)

[0477] b. Complete culture medium: Ham's F12K + 10% fetal bovine serum + 1* penicillin streptomycin + 800 μg / ml hygromycin

[0478] c. Experimental buffer: 1* HBSS + 20 mM HEPES + 0.1% BSA + 500 μM IBMX

[0479] 2.2 Determination of the effect of each compound on CB1 receptor activity

[0480] 2.2.1 Cell culture and seed plate

[0481] a. The Flp-In-CHO-CB1 cell line was cultured in complete culture medium at 37°C in a 5% CO2 environment;

[0482] b. After TrypLE digestion, cells were resuspended in complete medium and seeded into 384 cell culture plates at a density of 8000 cells per well.

[0483] c. Cells were incubated overnight at 37°C, 5% CO2

[0484] 2.2.2 Detection of agonist activity

[0485] a. Prepare experimental buffer: 1 * HBSS, 0.1% BSA, 20 mM HEPES and 500 μΜ IBMX.

[0486] b. Dilute compounds in buffer, starting concentration 80 mM, 3-fold concentration gradient, total 10 concentrations.

[0487] c. Remove medium from 384 plates, add 15 μΐ of buffer per well.

[0488] d. Add 2.5 μΐ of compound per well, incubate at 37°C for 10 min.

[0489] e. Dilute forskolin to 8 μΜ (8*) in experimental buffer.

[0490] f. Add 2.5 μΐ of diluted 8* forskolin, incubate at 37°C for 30 min.

[0491] g. Thaw Eu-cAMP tracer and Ulight-anti-cAMP, dilute in cAMP detection buffer.

[0492] h. Add 10 μΐ of Eu-cAMP tracer to experimental wells, then add 10 μΐ of Ulight-anti-cAMP to experimental wells.

[0493] i. Centrifuge reaction plates at 200 g for 30 s at room temperature, allow to stand at 25°C for 1 h, then collect data using Envision

[0494] 2.3 Example compound activity assay on CB2 receptor

[0495] 2.3.1 Cell culture and seeding

[0496] a. Flp-In-CHO-CB2 cell line was cultured in complete medium at 37°C, 5% CO2.

[0497] b. After TrypLE digestion, cells were resuspended in complete medium and seeded into 384 cell culture plates at a density of 8000 cells per well.

[0498] 2.3.2 Detection of agonistic activity

[0499] a. Prepare experimental buffer: 1 * HBSS, 0.1% BSA, 20 mM HEPES and 500 μM IBMX.

[0500] b. Dilute the compounds with buffer, dilute the starting concentration 80 mM, 3-fold concentration gradient dilution, a total of 10 concentrations.

[0501] c. Add 2.5 μl of compound to each well, incubate at 37°C for 10 minutes.

[0502] d. Dilute forskolin to 16 μM (8*) with experimental buffer.

[0503] e. Add 2.5 μl of diluted 8* forskolin, incubate at 37°C for 30 minutes.

[0504] f. Freeze-thaw Eu-cAMP tracer and Ulight-anti-cAMP, dilute with cAMP detection buffer.

[0505] g. Add 10 μl of Eu-cAMP tracer to the experimental well, then add 10 μl of Ulight-anti-cAMP to the experimental well.

[0506] h. Centrifuge the reaction plate at 200g for 30s at room temperature, after 1h at 25°C, collect data using Envision

[0507] 2.4 Data analysis

[0508] 1) Z' factor = 1 - 3 * (SD Max + SD Min ) / (Mean Max - Mean Min );

[0509] 2) CV Max = (SD Max / Mean Max ) * 100%;

[0510] 3) CV Min = (SD Min / Mean Min ) * 100%;

[0511] 4) S / B = Singal / Background;

[0512] 5) Calculate the EC 50 of the compound using the GraphPad nonlinear fitting formula:

[0513] Y = Bottom + (Top-Bottom) / (1+10^((LogEC 50 -X)*HillSlope))

[0514] X: Compound concentration log value; Y: Activity %

[0515] 3. Test results

[0516] Table 1 Agonistic activity of example compounds on CB1, CB2

[0517]

[0518] 4. Conclusion

[0519] Most of the example compounds of the present application have significantly weaker agonistic activity on CB1 than on CB2, and have good selectivity.

[0520] The above merely describes the embodiments of the present application, which are specific and detailed, but should not be understood as a limitation on the patent scope of the present application. It should be noted that, for those skilled in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are all within the protection scope of the present application.

Claims

1. A compound having the structure of formula (I): in: Selected from 6-membered aromatic rings; U is selected from N or CH; W is selected from S or CR a R b Y is selected from CR d R e ; R a and R b Independently selected from hydrogen; R d and R e Independently selected from hydrogen; Q is selected from O; R 1 Selected from hydrogen, C 1-4 alkyl; R 2 Each time it appears, it is independently selected from halogen, cyano, and C. 1-4 Alkyl, C 3-6 cycloalkyl, -OR z Wherein C 1-4 The alkyl group is either unsubstituted or substituted independently by one or more substituents selected from halogens; R z Each time it appears, it is independently selected from C. 1-4 Alkyl, or 4-6 membered heterocyclic group, wherein the C 1-4 The alkyl group is either unsubstituted or substituted independently by one or more substituents selected from halogens; n is 1 or 2.

2. The compound of formula (I) according to claim 1, wherein, When W is selected from S, Y is selected from CR. d R e ;R d and R e Independently selected from hydrogen; When W is selected from -CH2-, Y is selected from CR. d R e ;R d and R e It is independently selected from hydrogen.

3. The compound according to claim 1 or 2, Selected from pyridine, pyrimidine, and pyrazine.

4. The compound according to claim 3, Selected from 5. The compound of formula (I) according to any one of claims 1-2, wherein, R 1 Selected from hydrogen and methyl; R 2 Each time it appears, it is independently selected from halogen, cyano, and C. 1-4 Alkyl, C 3-6 cycloalkyl, -OR z Wherein C 1-4 The alkyl group is either unsubstituted or substituted independently by one or more substituents selected from -F; R z Each time it appears, it is independently and arbitrarily selected from C. 1-3 Alkyl or 4-6 membered oxocyclic group, wherein the C 1-3 The alkyl group is either unsubstituted or substituted independently by one or more substituents selected from F.

6. The compound according to claim 5, R 2 Each time it appears, it is independently selected from F, Cl, Br, cyano, and C. 1-3 Alkyl, cyclopropyl, cyclobutyl, -OR z Wherein C 1-3 The alkyl group is either unsubstituted or substituted independently by one or more substituents selected from -F.

7. The compound according to claim 6, R 2 Each time it appears, it is independently selected from F, Cl, cyano, and C. 1-3 Alkyl, cyclopropyl, cyclobutyl, -OR z Wherein C 1-3 The alkyl group is either unsubstituted or substituted independently by one or more substituents selected from -F.

8. The compound according to claim 7, R z Each of the groups is independently and optionally selected from methyl, ethyl, -CF3 or oxecyclobutyl.

9. The compound of formula (I) according to any one of claims 1-2, wherein, Selected from U is selected from N or CH; When W is selected from S, Y is selected from CR. d R e ;R d and R e Independently selected from hydrogen; When W is selected from -CH2-, Y is selected from CR. d R e ;R d and R e Independently selected from hydrogen; Q is selected from O; R 1 Selected from hydrogen and methyl; R 2 Each time it appears, it is independently selected from F, Cl, cyano, and C. 1-3 Alkyl, cyclopropyl, cyclobutyl, -OR z Wherein C 1-3 The alkyl group is either unsubstituted or substituted independently by one or more substituents selected from -F; R z Each of the groups is independently and optionally selected from methyl, ethyl, -CF3 or oxecyclobutyl; n is 1 or 2.

10. A compound of formula (I) according to any one of claims 1-2, wherein the compound is selected from:

11. The compound according to claim 10, characterized in that... The compound is selected from:

12. A pharmaceutical composition comprising: An effective dose of the compound of formula (I) according to any one of claims 1-2, and a pharmaceutically acceptable carrier or excipient.

13. The composition according to claim 12, characterized in that... It also includes one or more other therapeutic agents.

14. Use of the compound of formula (I) according to any one of claims 1-2 in the preparation of a medicament for the prevention and treatment of diseases mediated by CB2 receptors; wherein the diseases mediated by CB2 receptors are pain, inflammatory diseases, autoimmune diseases or neurodegenerative diseases.

15. The use according to claim 14, characterized in that... The diseases mediated by the CB2 receptor refer to neuropathic pain, ulcerative colitis, or abdominal pain associated with Crohn's disease.

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