Compound as voltage-gated sodium channel inhibitor and use thereof

Abstract

The present invention relates to a voltage-gated sodium channel Nav1.8 selective inhibitor and the use thereof in the preparation of a related drug. The drug is used for treating diseases responsive to the inhibition of voltage-gated sodium channel NaV1.8, such as chronic pain, enterodynia, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or arrhythmia. Specifically, the present invention relates to a compound as shown in formula (X), and an isomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

Description

Compounds as voltage-gated sodium channel inhibitors and uses thereof

[0001] This application claims priority to:

[0002] CN202410483482.4, filing date: April 19, 2024; CN202411125232.X, filing date: August 15, 2024. TECHNICAL FIELD

[0003] The present application relates to the field of chemical medicine, in particular to a compound as voltage-gated sodium channel inhibitor and application thereof. BACKGROUND

[0004] Pain has an indispensable protective effect on normal life activities of the body. As an alarm signal, it reminds the body to pay attention to potential dangers, but at the same time, pain is also a common clinical symptom. After the external stimulus that causes pain disappears, strong or persistent pain will cause physiological function disorder and seriously affect the life quality of living beings.

[0005] Pain originates from nociceptors in the peripheral nervous system, which are free nerve endings widely distributed in the skin, muscles, joints and internal organs of the whole body. They can convert the heat, mechanical or chemical stimuli they feel into nerve impulses (action potentials) and transmit them to their cell body part located in the dorsal root ganglion (DRG) via afferent nerve fibers, and finally to the high-level nerve center, causing pain. The generation and conduction of action potentials in neurons depend on voltage-gated sodium ion channels (NaV) on the cell membrane. When the cell membrane is depolarized, the sodium ion channel is activated, the channel is opened, and the sodium ion influx occurs, which makes the cell membrane further depolarized, leading to the generation of action potential. Therefore, inhibiting abnormal sodium ion channel activity is helpful for the treatment and relief of pain.

[0006] NaV1.8 is mainly expressed in sensory ganglion of peripheral nervous system, such as dorsal root ganglion (DRG), small DRG neurons expressing NaV1.8 include pain receptors involved in pain signaling. NaV1.8 mediates large amplitude action potentials in small neurons of dorsal root ganglion, is necessary for rapid repetitive action potentials in pain receptors and spontaneous activity of damaged neurons, knockdown of NaV1.8 in rats has been achieved by using antisense DNA or small interfering RNA and achieved almost complete reversal of neuropathic pain in spinal nerve ligation and chronic compression injury models, so NaV1.8 channel is considered to be a promising target for analgesics, which is expected to play a role in diseases such as neuropathic pain, inflammatory pain and postoperative / spontaneous pain, and since NaV1.8 is mainly limited to sensory pain neurons, selective NaV1.8 inhibitors can avoid the adverse events commonly seen in non-selective NaV blockers.

[0007] In addition to pain, NaV1.8 channels are also considered to be related to diseases such as multiple sclerosis, arrhythmia, cough, and pruritus. Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system, and its exact pathogenesis has yet to be elucidated. The cerebellar Purkinje fibers of normal people do not express NaV1.8 channels, and the expression of cerebellar NaV1.8 is up-regulated in multiple sclerosis patients. In the cardiovascular system, NaV1.8 has been shown to be expressed in cardiac nerves such as Purkinje fibers, and is considered to be a potential therapeutic target for cardiovascular diseases such as arrhythmia. NaV1.8 is expressed in the vagal nerve plexus associated with cough, and the level of Nav1.8 phosphorylation and expression increases during pathological cough, and is involved in the cough reflex. In the itch sensation of mammals, histamine and other pruritogenic factors released by lymphocytes, mast cells and the like can activate NaV1.8 channels, and knocking out NaV1.8 in mice can effectively alleviate histamine and endothelin-induced pruritic behavior.

[0008] Currently, NaV1.8 selective inhibitors, VX-150 and Suzetrigine of VERTEX company, have achieved positive effects in clinical trials of patients with acute pain, diabetic peripheral neuropathic pain, etc., but there is no product on the market at present. Developing a highly selective voltage-gated sodium channel NaV1.8 inhibitor drug has very important significance in clinical practice. SUMMARY

[0009] The present invention provides a compound, or a pharmaceutical composition thereof, which can act as a NaV1.8 selective inhibitor. The present invention further relates to the use of the compound, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a disease and / or a condition by the compound inhibiting NaV1.8. The present invention still further describes a method of synthesizing the compound. The compounds of the present invention show excellent biological activity and pharmacokinetic properties.

[0010] In particular, in one aspect, a compound is disclosed, which is a compound as shown in Formula (X), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound as shown in Formula (X),

[0011] wherein:

[0012] Ring A is phenyl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl;

[0013] each R e is independently D, F, Cl, Br, I, CN, hydroxyl, nitro, -N(R a )2, -(C 1-6 alkylene)N(R a )2, -S(O)(=NH)C 1-6 alkyl, -C(O)OR a , -C(O)N(R a )2, -(C 1-6 alkylene)C(O)N(R a )2, -C(O)R a , -S(O)2NR a , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 1-6 alkylene, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio, C 3-6The cycloalkyl and 3-6 membered heterocyclic groups may be optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, oxo, hydroxy, C 1-3 Alkyl, C 1-3 Alkylamino, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl and C 1-3 substituted by an alkoxy substituent;

[0014] Each R a are independently H, D, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, the C 1-6 Alkyl, C 1- 6 alkoxy, C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups may be optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, oxo and C 1-3 Alkyl is substituted by a substituent; R 1 、R 2 、R 3 、R 4 and R 5 Each independently represents H, D, F, Cl, Br, I, CN, hydroxyl, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups may be optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, CN, nitro, amino, hydroxy, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl and C 1-3 substituted by an alkoxy substituent;

[0015] or R 3 and R 5 Together with the attached carbon atom, it forms C 3-6 Cycloalkyl;

[0016] R 6 CN, -S(O)C 1-6 Alkyl, -S(O)2C1-6 alkyl, -CH=N-O-C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkylthio or -L1-L2-R c , said C 1-6 alkyl, C 2-6 alkynyl and C 1-6 alkylthio can be independently optionally substituted with 1, 2 or 3 substituents selected from the group consisting of D, F, Cl, Br, I, oxo and hydroxy;

[0017] L1is a bond, O or S;

[0018] L2is a bond, C 1-6 alkylene or -(C 1-6 alkylene)-C 1-6 alkoxy, said C 1-6 alkylene and C 1-6 alkoxy can be independently optionally substituted with 1, or 3 substituents selected from the group consisting of D, F, Cl, Br, I, oxo and hydroxy;

[0019] R c is -O-N=, -P(O)(C 1-6 alkyl)2, C 2-6 alkynyl or -O-(3-8 membered heterocyclyl), said C 1-6 alkyl, C 2-6 alkynyl and 3-8 membered heterocyclyl can be independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from the group consisting of D, F, Cl, Br, I, hydroxy, oxo, nitro, amino, alkylamino, C 1- 6alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

[0020] R 7 and R 8 are each independently H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclyl can be optionally substituted with 1, 2 or 3 substituents selected from the group consisting of D, F, Cl, Br, I, CN, hydroxy, amino, nitro and C 1-3 alkoxy.

[0021] n is 0, 1, 2 or 3.

[0022] wherein ring A can be phenyl, pyridazine, pyrazine, pyridine or pyrimidine.

[0023] In some embodiments, it is a compound as shown in Formula (I), (II), or (III), or a stereoisomer, geometric isomer, tautomer, nitroso, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound shown in Formula (I), (II), or (III),

[0024] wherein:

[0025] X is CR 10 or N; Y is CR 13 or N;

[0026] R 9 and R 10 each independently is H, D, F, Cl, Br, I, CN, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy;

[0027] R 11 , R 12 and R 13 each independently is H, D, F, Cl, Br, I, CN, hydroxyl, nitro, -N(R a )2, -(C 1-6 alkylene)N(R a ) 2、 -S(O)(=NH)C 1-6 alkyl, -C(O)OR a , -C(O)N(R a )2, -(C 1-6 alkylene)C(O)N(R a )2, -C(O)R a , -S(O)2NR a , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl, said C 1-6 alkylene, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio, C 3-6 cycloalkyl and 3-6 membered heterocyclyl can be optionally substituted with 1, 2, or 3 substituents selected from D, F, CI, Br, I, CN, hydroxyl, amino, nitro, oxo, hydroxyl, C 1-3 alkyl, C 1-3 alkylamino, C 1-3 haloalkyl, C 1-3 hydroxyalkyl and C 1-3 alkoxy;

[0028] each R a is independently H, D, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 1-6 alkyl, C 1- 6alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclyl can be optionally substituted with 1, 2, or 3 substituents selected from D, F, CI, Br, I, CN, hydroxyl, amino, nitro, oxo, and C 1-3 alkyl.

[0029] In some embodiments, wherein R 1 , R 2 , R 3 , R 4 and R 5 each independently is H, D, F, CI, Br, I, hydroxyl, methyl, ethyl, CH2F, CHF2, CF3, -CH2OCH3, or -CH2OH.

[0030] In some embodiments, wherein R 9 , R 10 and R 11 each independently is H, D, F, CI, Br, I, CN, amino, nitro, methyl, ethyl, methoxy, trifluoromethyl, or trifluoromethoxy;

[0031] R 12 and R 13 each independently is H, D, F, CI, Br, I, CN, hydroxyl, amino, nitro, methyl, ethyl, CH2F, CHF 2、 -OCH3, -OCH2CH3, -C(O)NH2, -C(O)NHOH, -C(O)NHOCH3, -CH2OH, -CH(OH)CH2OH, -C(O)NHCH3, -CH(OH)(CH3)2, -S(O)(=NH)CH3、 -S(O)2NH2,

[0032] In some embodiments, wherein R 7 and R 8 each independently is H, D, F, Cl, Br, I, hydroxyl, methyl, ethyl, CH2F, CHF2, or CF3.

[0033] In some embodiments, wherein R 6 is CN, -S(O)C 1-3 alkyl, -S(O)2C 1-3 alkyl-CH=N-O-C 1-3 alkyl, -C 2-6 alkynyl, C 1-3 alkylthio, or -L1-L2-R c , said C 1-3 alkyl, C 1-3 alkylthio, and C 2-6 alkynyl can be independently optionally substituted with 1, 2, or 3 substituents selected from the group consisting of D, F, Cl, Br, I, oxo, and hydroxyl;

[0034] L1is a bond, O, or S;

[0035] L2is a bond, C 1-3 alkylene, or -(C 1-3 alkylene)-C 1-3 alkoxy;

[0036] R c is -O-N=, -P(O)(CH3)2, C 2-6 alkynyl, or -O-(3-8 membered heterocyclyl); said C 2-6 alkynyl and 3-8 membered heterocyclyl can be independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from the group consisting of D, F, Cl, Br, I, hydroxyl, oxo, nitro, amino, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl.

[0037] In some embodiments, wherein R 6 is CN, -S(O)CH3, -S(O)2CH3, -P(O)(CH3) 2、

[0038] In some embodiments, the compounds disclosed herein have a structure represented by formula (IV) or (V):

[0039] Among them, R c C 2-6 Alkynyl, the C 2-6 Alkynyl groups may be independently optionally substituted by 1, 2, 3, 4, 5 or 6 groups selected from D, F, Cl, Br, I, hydroxy, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 The cycloalkyl group and the 3- to 6-membered heterocyclic group are substituted.

[0040] In some embodiments, it is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug having one of the following structures:

[0041] In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) of the present invention, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0042] In one aspect, the present invention discloses the use of the compound and pharmaceutical composition in the preparation of a medicament for treating a disease responsive to inhibition of the voltage-gated sodium channel NaV1.8, wherein the disease is chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Chuck-Mare-Douglas syndrome, incontinence, pathological cough, or cardiac arrhythmia.

[0043] The foregoing description only summarizes certain aspects of the present invention, but is not intended to limit the present invention to these aspects. These and other aspects will be described in more detail and fully below.

[0044] Definitions and General Terms

[0045] The present application will be put into context by the listing of specific documents to which the embodiments identified correspond. The examples are accompanied by graphical illustrations of structural and chemical formulas. The present application is intended to encompass all alternatives, modifications and equivalents that can be included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many such equivalents. The present application is not intended to be limited to the described methods and materials. There are many documents and similar materials that are distinct from or contrary to the present application application, including but not limited to definitions of terms, usage of terms, described techniques, or the scope as controlled by the present application application.

[0046] The following definitions will apply unless otherwise defined herein. For purposes of the present application, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific gravity is to be determined in accordance with those values given in the Handbook of Chemistry and Physics for elements presented in their conventional solid state at. 20 °C and 1 atm. It is to be understood that for compounds, whenever appropriate, the specific gravity is to be determined in accordance with those values given in the Handbook of Chemistry and Physics for the specific compound or its individual components.

[0047] The term "comprising" is used in the inclusive sense, i.e., to mean including, but not limited to.

[0048] Compounds as described herein can optionally be substituted with one or more substituents, such as described herein for the compounds of the application, or as exemplified in the Examples, subgroups, and classes of compounds encompassed by the application. It will be appreciated that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." In general, the term "optionally" means that any given structure can be substituted or unsubstituted. Unless otherwise indicated, an optionally substituted group can have a substitution at each substitutable position of the group. When a given structure is substituted with more than one non-hydrogen substituent it will be appreciated that the substituents can be the same or different.wherein the substituents can be, but are not limited to, hydrogen, F, Cl, Br, I, nitro, cyano, oxo (=0), hydroxy, alkyl, hydroxyalkyl, alkylamino, aminoalkyl, haloalkoxy, cycloalkyl, amino, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, cycloalkyloxy, alkoxy, alkoxyalkyl, haloalkyl, -COOH, -alkylene-C(=0)0-alkyl, -alkylene-S(=0)2-alkyl, -alkylene-S(=0)2-amino, -S(=0)2-alkyl, -S(=0)2-amino, -S(=0)2OH, -0-alkylene-C(=0)0-alkyl, -0-alkylene-S(=0)2-alkyl, -0-alkylene-S(=0)2-amino, -0-alkylene-S(=0)2OH, -C(=0)NH2, -C(=0)NH-alkyl, -C(=0)N(alkyl)-alkyl, -C(=0)NHS(=0)2-alkyl, -C(=0)NHS(=0)2-amino, -C(=0)NHS(=0)2OH, -N(haloalkyl)-alkyl, -N(alkyl)-S(=0)2-alkyl, -NHS(=0)2-alkyl, -NHS(=0)2-haloalkyl, -N(alkyl)S(=0)2-haloalkyl, -N(alkyl)S(=0)2-alkylamino, -NHC(=0)-alkyl, -NHC(=0)-haloalkyl, -N(alkyl)C(=0)-haloalkyl, -N(alkyl)C(=0)-alkylamino, -N(alkyl)C(=0)0-alkyl, -NHC(=0)0-alkyl, -NHC(=0)0-haloalkyl, -N(alkyl)C(=0)0-haloalkyl, -N(alkyl)C(=0)0-aminoalkyl, -NHC(=0)-NH2, -NHC(=0)NH-(alkyl), -NHC(=0)NH(haloalkyl), -NHC(=0)N(alkyl)-alkyl, -OC(=0)-alkyl, -OC(=0)-amino, -OC(=0)-alkylamino, -OC(=0)-aminoalkyl, -OC(=0)-alkoxy, -C(=0)N(alkyl)S(=0)2-alkyl, -C(=0)N(alkyl)S(=0)2-amino, -C(=0)NH-S(=0)2OH, -C(=NH)NH2, -C(=NH)NH-alkyl, -C(=NH)N(alkyl)-alkyl, -C(=N-alkyl)-NH2, -C(=0)NH-alkylene-S(=0)2OH, -C(=0)NHC(=0)OH, -C(=0)NHC(=0)0-alkyl, -C(=0)N(alkyl)C(=0)0-alkyl, -C(=0)NH-alkylene-C(=0)OH, and -C(=0)NH-alkylene-C(=0)0-alkyl, and the like.

[0049] The term "alkyl" as used herein includes saturated straight or branched chain monovalent hydrocarbon radicals of 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, or 1 to 2 carbon atoms, wherein the alkyl group can be independently optionally substituted with one or more substituents as described herein. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), t-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l-butyl (-CH2CH2CH(CH3)2), 2-methyl-l-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, and n-octyl, and the like. The term "alkyl" and its prefix "alk" as used herein includes both straight chain and branched saturated carbon chains.

[0050] The term "alkylene" denotes a saturated, divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a straight- or branched-chain hydrocarbon radical. Unless otherwise specified, an alkylene radical contains 1 to 12 carbon atoms. In some embodiments, the alkylene radical contains 1 to 6 carbon atoms; in other embodiments, the alkylene radical contains 1 to 4 carbon atoms; in yet other embodiments, the alkylene radical contains 1 to 3 carbon atoms; and in still other embodiments, the alkylene radical contains 1 to 2 carbon atoms. Examples of such include methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like.

[0051] The term "alkenyl" denotes a straight- or branched-chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, in which at least one position is unsaturated, i.e., one C-C is sp 2 The term "alkenyl" denotes a straight- or branched-chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, in which at least one position is unsaturated, i.e., one C-C is sp

[0052] The term "alkynyl" denotes a straight- or branched-chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, in which at least one position is unsaturated, i.e., one C-C is sp

[0053] The term "heteroatom" denotes one or more O, S, N, P, and Si, including any oxidation state form of C, N, S, and P; primary, secondary, tertiary amine and quaternary ammonium salt forms; or forms in which the hydrogen on a nitrogen atom in a heterocycle is replaced, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl); or forms in which a -CH2- in a heterocycle is oxidized to form -C(=O)-.

[0054] The term "halogen" means F, Cl, Br, or I.

[0055] The term "deuterium" means heavy hydrogen, D.

[0056] The term "unsaturated" as used in the present application means that the moiety contains one or more degrees of unsaturation.

[0057] The term "alkoxy" or "alkyloxy" as used herein refers to an alkyl group, as defined herein, attached to the remainder of the molecule through an oxygen atom. In some embodiments, the alkoxy group is a C 1-4 alkoxy; examples of which include, but are not limited to, methoxy, ethoxy, propyloxy, and butyloxy, and the like. The alkoxy group can be independently unsubstituted or substituted with one or more substituents described herein.

[0058] The term "alkylthio" or "alkylsulfanyl" as used herein refers to an alkyl group, as defined herein, attached to the remainder of the molecule through a sulfur atom. In some embodiments, the alkylthio group is a C 1-4 alkylthio; examples of which include, but are not limited to, methylthio, ethylthio, propylthio, and butylthio, and the like. The alkylthio group can be independently unsubstituted or substituted with one or more substituents described herein.

[0059] The term "alkylamino" or "alkylamino" as used herein refers to an alkyl group, as defined herein, attached to the remainder of the molecule through an N atom. In some embodiments, the alkylamino group is a C 1-4 alkylamino; examples of which include, but are not limited to, methylamino, ethylamino, propylamino, and butylamino, and the like. The alkylamino group can be independently unsubstituted or substituted with one or more substituents described herein.

[0060] The term "cycloalkyl" or "cycloalkane" means a monovalent or multivalent monocyclic, bicyclic or tricyclic carbocyclic ring system containing 3 to 12 carbon atoms, which is either a saturated ring or a ring containing one or more unsaturated linkages, but never an aromatic ring. The "cycloalkyl" or "cycloalkane" can also be a bridged ring and a spiro ring. In one embodiment, the cycloalkyl group contains 3 to 10 carbon atoms; in another embodiment, the cycloalkyl group contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. Examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl, and the like. The cycloalkyl group can be independently unsubstituted or substituted with one or more substituents described herein.

[0061] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein to mean a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring system containing between three and twelve ring atoms, none of which is an aromatic ring, at least one of which is a heteroatom. The "heterocyclyl" or "heterocycle" can also be a bridged ring heterocycle and a spirocyclic heterocycle. In one embodiment, the "heterocyclyl" or "heterocycle" contains between three and ten ring atoms; in one embodiment, the "heterocyclyl" or "heterocycle" contains between three and eight ring atoms; in another embodiment, the "heterocyclyl" or "heterocycle" contains between five and eight ring atoms; in yet another embodiment, the "heterocyclyl" or "heterocycle" contains between three and six ring atoms; in still another embodiment, the "heterocyclyl" or "heterocycle" contains between five and six ring atoms; in a further embodiment, the "heterocyclyl" or "heterocycle" contains between four and six ring atoms; unless otherwise specified, the heterocyclyl group can be carbon-based or nitrogen-based, with the heteroatoms having the meaning as described herein. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, aziridinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxoanyl, homopiperazinyl, homopiperidinyl, oxazepinyl, thiazepinyl, oxazinanyl, thiazinanyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, 2-oxabicyclo[2.1.1]hexane, and 1,2,3,6-tetrahydropyridinyl. Examples of heterocyclyl groups in which a -CH2- group is replaced by a -C(=O)- group include, but are not limited to: 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinonyl, 3,5-dioxopiperidinyl, pyrimidinedionyl, and 5,6-dihydropyridin-2(lH)-onyl. Examples of heterocyclyl groups in which a sulfur atom is oxidized include, but are not limited to: sulfolanyl and 1,1-dioxothiomorpholinyl. The heterocyclyl groups described can be optionally substituted with one or more substituents described herein. diazepinyl thiazepinyl thioxoanyl, homopiperazinyl, homopiperidinyl, oxazepinyl, thiazepinyl, oxazinanyl, thiazinanyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, 2-oxabicyclo[2.1.1]hexane, and 1,2,3,6-tetrahydropyridinyl. Examples of heterocyclyl groups in which a -CH2- group is replaced by a -C(=O)- group include, but are not limited to: 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinonyl, 3,5-dioxopiperidinyl, pyrimidinedionyl, and 5,6-dihydropyridin-2(lH)-onyl. Examples of heterocyclyl groups in which a sulfur atom is oxidized include, but are not limited to: sulfolanyl and 1,1-dioxothiomorpholinyl. The heterocyclyl groups described can be optionally substituted with one or more substituents described herein.

[0062] The term "aryl" denotes a monocyclic, bicyclic, and tricyclic carbocyclic ring system containing six to fourteen ring atoms, or six to twelve ring atoms, or six to ten ring atoms, wherein at least one ring is aromatic, wherein each ring contains three to seven atoms in the ring, and has one or more attachment points to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring." Examples of aryl groups can include phenyl, naphthyl, and anthryl. The aryl groups described can be independently optionally substituted with one or more substituents described herein.

[0063] The term "heteroaryl" denotes a monocyclic, bicyclic and tricyclic ring system containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring contains 5-7 atoms in the ring and has one or more points of attachment to the remainder of the molecule. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, a 5-10 atom containing heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from O, S and N, wherein the nitrogen atom can be further oxidized.

[0064] Examples of heteroaryl groups include, but are not limited to: furanyl, imidazolyl (such as N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazolyl (such as 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (such as N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl, pyrimidinyl (such as 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl, thiazolyl (such as 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (such as 5-tetrazolyl), triazolyl, thiophenyl (such as 2-thiophenyl, 3-thiophenyl), pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl; also included are bicyclic rings, but are by no means limited to these: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxolanyl, indolinyl, isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazo[l,2-a]pyridinyl, pyrazolo[l,5-a]pyridinyl, pyrazolo[l,5-a]pyrimidinyl, imidazo[l,2-b]pyridazinyl, [l,2,4]triazolo[4,3-b]pyridazinyl, [l,2,4]triazolo[l,5-a]pyrimidinyl and [l,2,4]triazolo[l,5-a]pyridinyl, and the like.

[0065] The term "haloalkyl" or "haloalkoxy" denotes an alkyl or alkoxy group substituted with one or more halogen atoms, examples include, but are not limited to, trifluoromethyl, trifluoromethoxy and the like.

[0066] The term "halocycloalkyl" refers to a cycloalkyl group substituted with one or more halogen atoms. Examples include, but are not limited to, 1,1-difluorocyclopropane, 1-chloro-2-fluorocyclopropane, and the like.

[0067] As described herein, a substituent group is attached to a ring by a bond to form a ring system, which indicates that the substituent group can be substituted at any substitutable position on the ring. For example, formula (a) indicates that the substituent group R can be substituted at any substitutable position on the pyridine ring.

[0068] As described herein, a wavy line intersecting a bond in a chemical structure represents the point in the chemical structure at which the atom to which the wavy bond is attached is attached to the remainder of the molecule or to the remainder of a fragment of a molecule.

[0069] In addition, it should be noted that, unless otherwise explicitly stated, the descriptions used throughout this document, “each ... and ... are independently,” “... and ... are each independently,” and “... and ... are respectively independently,” are interchangeable and should be understood in a broad sense. They may mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0070] Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., enantiomers, diastereomers, geometric isomers, or conformational isomers): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, individual stereochemical isomers of the compounds of the present invention, or mixtures of such enantiomers, diastereomers, geometric isomers, or conformational isomers thereof, are within the scope of the present invention.

[0071] Unless otherwise indicated, the structural formulas and compounds described herein include all isomeric forms (e.g., enantiomers, diastereomers, geometric isomers, or conformers), N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs. Therefore, individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of the present invention are also within the scope of the present invention. Furthermore, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.

[0072] A "metabolite" refers to a product produced through metabolism of a specified compound of the present application or a pharmaceutically acceptable salt, analog, or derivative thereof in the body of a mammal, which exhibits the same or substantially the same activity as the compound of Formula (I) in vivo or in vitro. Metabolites of a compound can be identified using techniques known in the art and can be tested using tests described herein or otherwise known. Such products can be found, for example, in plasma, interstitial fluid, or other biological fluids or tissues. Metabolite products can result from, for example, a process of oxidation, reduction, hydrolysis, am idation, deam idation, esterification, deesterification, or enzymatic cleavage. Accordingly, the present application includes metabolites of compounds of the present application, including those produced in vivo, following administration of the compound to a mammal.

[0073] The definitions and conventions used in the present application for stereochemistry are generally in accordance with those set out in S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present application can contain asymmetric or chiral centers, and therefore exist in different stereoisomers or geometric isomers. All stereoisomers and geometric isomers of the compounds of the present application, including but not limited to, diastereomeric, enantiomeric, atropisic isomers, and mixtures thereof, such as racemates, are intended to be within the scope of the present application. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D, L, or R, S are used to denote the absolute configuration of the molecule. The prefixes d and 1 or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound, that is, the (-) or 1 form is levo-rotary. The (+) or d form is dextro-rotary. The chemical structures of these isomers are identical, but their orientations in the solid state differ. A specific stereoisomer can be referred to as an enantiomer if its structure is not superimposable on that of the other of the same substance. Mixtures of enantiomers are often called racemates, while mixtures of non-enantiomeric isomers are not referred to as racemates. A racemic mixture of D- and L- isomers can be prepared from a racemic acid or acid chloride, or from a racemic alcohol. A racemic mixture of D- and L- isomers can also be resolved into its component enantiomers by a variety of known techniques. These techniques take advantage of the fact that some non-racemic compounds interact differently with two different enantiomeric isomers of another compound. For example, a racemic mixture of D- and L- isomers can be resolved using a chiral resolving agent, which will react (or bind) with one enantiomer while not reacting (or binding) substantially with the other. For example, a racemic mixture of D- and L- isomers can be resolved using a chiral resolving agent, which will react (or bind) with one enantiomer while not reacting (or binding) substantially with the other. One of skill in the art will recognize that the choice of resolving agent will depend on the specific substituents in the compounds. Suitable resolving agents for use in the present application include, but are not limited to, the optically active forms of compounds such as those described in U.S. Patent No. 6,750,1 13, which is incorporated herein by reference. The resolved compounds can then be recovered by any suitable method, for example, by cleavage from the resolving agent or by fractional crystallization or chromatography. The resolved compounds can be converted to other enantiomeric isomers by known techniques, such as those described in U.S. Patent No. 6,750,1 13, which is incorporated herein by reference.

[0074] The term "tautomer" or "tautomeric forms" refers to isomers of different energy that can interconvert by a low energy barrier. For example, prototropic tautomers (i.e., tautomers that shift protons) include tautomeric interconversions by proton migration, such as keto-enol and imine-enamine isomerization. Atom-valence (valence) tautomers include interconversions that reorganize bonding electrons.

[0075] As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the application. Pharmaceutically acceptable salts are well known in the art, for examples, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable non-toxic acid addition salts include, but are not limited to, salts of mineral acids such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates; salts of organic acids such as acetates, oxalates, maleates, tartarates, citrates, succinates, malonates; or salts of acidic amino acids such as asparagates, glutamates; or salts of other methods such as ion exchange as described in the literature. Other pharmaceutically acceptable salts include adipates, ascorbates, 2-hydroxyethanesulfonates, alginates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, glycolates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, valerates and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C 1-4 Water or oil-soluble or dispersible products can be obtained by quaternization. Alkali metals or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed by the addition of inorganic or organic acids to a free amine group of the compound. Such salts are known to the art, for example, see S. M. Berge et al., "Pharmaceutical Salts," J. Pharmaceutical Sciences, 66: 1-19, 1977. 1-8 Sulfates and sulfonates.

[0076] The term "hydrate" as used herein refers to an association including solvent molecules other than water.

[0077] The term "solvate" as used herein refers to an association including one or more solvent molecules and a compound of the application. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.

[0078] The term "ester" as used herein refers to in vivo hydrolysable esters of a compound of Formula (I) containing a hydroxy group. Such esters are, for example, pharmaceutically acceptable esters of the parent alcohol on hydrolysis in human or animal subjects. Groups which form in vivo hydrolysable esters of a compound of Formula (I) containing a hydroxy group include, but are not limited to, phosphonooxy, acetyloxy methoxy, 2,2-dimethylpropionyloxy methoxy, alkanoyl, benzoyl, phenylacetyl, alkoxycarbonyl, dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl groups and the like.

[0079] The term "nitroso" as used herein refers to the oxidation of one or more than one nitrogen atom to form an N-oxide when the compound contains several amine functions. Particular examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen heterocycles. N-oxides can be formed by treatment of the corresponding amines with an oxidizing agent, for example, hydrogen peroxide or a peracid (for example, peroxo carboxylic acid) (see Advanced Organic Chemistry, Wiley Interscience, 4thEdition, Jerry March, pages 358-359). In particular, N-oxides can be prepared by the method of L. W. Deady (Syn. Comm. 1977, 7, 509-514), for example, by reacting the amine compound with meta-chloroperoxybenzoic acid (MCPBA) in an inert solvent (for example, dichloromethane).

[0080] The term "prodrug" as used herein refers to a compound that is converted into a compound of Formula (I) in vivo. Such conversion is achieved by the hydrolysis of the prodrug in the blood or by enzymatic conversion in the blood or tissues to the parent structure. Prodrugs of the application can be esters, and in the present application esters that can act as prodrugs are benzoate esters, aliphatic (C 1-24esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the present application containing a hydroxyl group can be acylated to give a prodrug form of the compound. Other prodrug forms include phosphates, such as those compounds which are phosphorylated on a hydroxyl group of the parent. A complete discussion of prodrugs is found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S. J. Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0081] As used herein, the terms "a," "an," "the," and like terms used in the context of the present application, particularly in the claims, are to be construed to cover both the singular and the plural, unless otherwise indicated by the context.

[0082] General Synthetic Procedures

[0083] To describe the present application, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not meant to limit the present application in any manner.

[0084] Generally, the compounds of the present application can be prepared by the methods illustrated herein, unless otherwise indicated by the context of the description, wherein the definitions of substituents are as described herein. The following reaction schemes and examples are intended to further illustrate the present application.

[0085] Those skilled in the art will appreciate that the chemical reactions described herein can be performed by using conventional methods in the art such as those described in Contemporary Organic Synthesis, W. Davies, Ed., VCH Publishers (1996); Rodd's Chemistry of Carbon Compounds, 3rd Edition, Vol. 1, 2, 3, and 4, Elsevier (1989); Organic Reactions, John Wiley and Sons (1973); March's Advanced Organic Chemistry, 5th Ed., Wiley-Interscience (2001); and Carruthers' Chemistry of Functional Groups, John Wiley and Sons (1987); and the first nine volumes of Comprehensive Organic Synthesis, Pierssennier et al. Ed.; Pergamon Press (1991). It is understood that where existing treatments exist for a given chemical reaction, those existing treatments can be used in the practice of the application. It is further recognized that the application is not limited to any particular methodology in carrying out the chemical reactions.

[0086] The starting materials, reagents, and the like used in the following examples are either commercially available or synthesized by known literature procedures unless otherwise indicated.

[0087] The apparatus and conditions for the detection are described as follows: 1H NMR spectra were recorded on a Bruker 500MHz NMR spectrometer. 1 H NMR spectra were recorded in CDCl3, DMSO-d6, CD3OD or acetone-d6 (in ppm) with TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When multiplets occur, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), br s (broadened singlet), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, J, are reported in Hertz (Hz).

[0088] Low resolution mass spectrometry (MS) data were measured on an Agilent G6125C quadrupole HPLC-MS (column type: XBridge BEH C18, 4.6 x 50 mm, 2.5 microns, 6 min, 1 mL / min flow rate. Mobile phase: 0-95% (CH3CN) in (H2O:CH3CN = 90:10 containing 0.1% formic acid), electrospray ionization (ESI), DAD detection at 210 nm / 254 nm.

[0089] Compounds are named according to the principles of nomenclature in the art or using software, and commercially available compounds are named using the supplier's catalog name. DETAILED DESCRIPTION

[0090] The present application will be described below with reference to specific examples, it should be noted that these examples are merely descriptive and do not limit the present application in any way.

[0091] Example 1

[0092] Preparation of compound 1-2

[0093] Compound 1-1 (40 g, 253 mmol) was dissolved in THF (200 mL) under nitrogen atmosphere, methyl lithium lithium bromide ethyl ether solution (506 mL, 759 mmol) was slowly added dropwise at zero degree, and the temperature was slowly raised to room temperature after the dropwise addition was completed, and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to 0°C, water (200 mL) was added dropwise to quench the reaction, and stirred for 1 hour, then extracted with dichloromethane (200 mL x 5), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and distilled at 60-100°C until no fraction was dropped, and the remaining in the bottle was THF solution of compound 1-2.

[0094] 1 H NMR (400 MHz, CDCl3): δ 2.36 (s, 3H), 1.52 (s, 3H).

[0095] Preparation of compound 1-3

[0096] The preparation route of compound 1-3 is as follows:

[0097] Compound 1-4 (33.2 mL, 299.40 mmol), compound 1-5 (61.90 g, 329.34 mmol), potassium carbonate (140.68 g, 1017.96 mmol), cuprous oxide (1.30 g, 8.98 mmol) were sequentially added to toluene (1000 mL), and under nitrogen atmosphere, tetraphenylphosphonium palladium (10.38 g, 8.98 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The reaction solution was concentrated, water (500 mL) was added, extracted with ethyl acetate (500 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compound 1-6.

[0098] Compound 1-6 (29 g, 126 mmol) was dissolved in THF (250 mL), and aqueous lithium hydroxide (144.9 mL, 289.74 mmol, 2 mol / L) was added. The reaction solution was warmed to 50°C and stirred for 1 h. After the reaction was completed, the mixture was cooled to room temperature, washed with dichloromethane (200 mL x 1), and the aqueous phase was adjusted to pH = 1 with dilute hydrochloric acid (1 mol / L) and extracted with dichloromethane (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 1-3.

[0099] Preparation of compound 1-7

[0100] Compound 1-3 (7.72 g, 38.2 mmol) was dissolved in acetonitrile (80 mL) under a nitrogen atmosphere, and carbonyldiimidazole (6.50 g, 40.08 mmol) was added at 0°C. After the mixture was stirred for 1 h, potassium carbonate (6.59 g, 47.7 mmol) and compound 1-2 (26.6 g, 38.2 mmol, 22.4% content) were sequentially added, the reaction solution was warmed to 35°C, and stirred for 10 h. After the reaction was completed, the solids were removed by suction filtration, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 1-7.

[0101] 1 H NMR (400 MHz, CDCl3): δ 7.00-6.87 (m, 2H), 3.92 (d, J = 2.1 Hz, 3H), 2.05 (s, 3H), 1.76 (s, 3H).

[0102] Preparation of compound 1-8

[0103] Palladium on carbon (3 g, 10% content) was added to 17.5 mL of isopropanol under a nitrogen atmosphere, and compound 1-7 (3 g, 9.31 mmol) was added with stirring at room temperature. The reaction solution was stirred for 30 h at 30°C under a hydrogen atmosphere (225 psi). The reaction solution was filtered with diatomite, and the filter cake was washed with 100 mL of isopropanol and 20 mL of dichloromethane, respectively, concentrated under reduced pressure, and dried twice with 50 mL of toluene to obtain compound 1-8.

[0104] 1 H NMR (400 MHz, CDCl3): δ 7.00-6.93 (m, 1H), 6.92-6.84 (m, 1H), 4.49 (d, J = 9.0 Hz, 1H), 4.04 (d, J = 2.9 Hz, 3H), 2.96-2.83 (m, 1H), 1.72 (s, 3H), 0.81 (dd, J = 2.1, 4.9 Hz, 3H);

[0105] m / z (ESI): [M+H]+ = 325.1.

[0106] Preparation of compound 1-9

[0107] Compound 1-9 was prepared by slowly adding diisobutylaluminum hydride (13.0 mL, 13.0 mmol, 1 mol / L solution in toluene) dropwise to a solution of compound 1-8 (2.8 g, 8.64 mmol) in 30 mL of toluene at -30 °C under a nitrogen atmosphere. After the addition was complete, the reaction was stirred at -30 °C for 1.5 h. After the reaction was complete, the reaction was diluted with 100 mL of ethyl acetate, warmed to 0 °C, quenched by the dropwise addition of saturated aqueous ammonium chloride, stirred for 0.5 h, filtered through celite, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 1-9.

[0108] 1 H NMR (400 MHz, CDCl3): δ 6.95-6.89 (m, 1H), 6.89-6.80 (m, 1H), 5.80 (t, J = 3.5 Hz, 1H), 4.00 (d, J = 2.6 Hz, 3H), 3.88-3.78 (m, 1H), 2.99-2.84 (m, 2H), 1.65 (s, 3H), 0.90-0.77 (m, 3H).

[0109] Preparation of compound 1-10

[0110] Compound 1-10 was prepared by adding compound 1-9 (2.4 g, 7.36 mmol), 4-dimethylaminopyridine (1.35 g, 11.03 mmol), and acetic anhydride (1.0 mL, 11.0 mmol) sequentially to 40 mL of dichloromethane with stirring at room temperature. The reaction was stirred at 20 °C for 1 h. After the reaction was complete, the reaction was quenched by slowly pouring into 30% aqueous ammonium chloride solution (100 mL). The organic phase was washed with 10% aqueous sodium carbonate solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 1-10.

[0111] 1 H NMR (400 MHz, CDCl3): δ 7.00-6.91 (m, 1H), 6.91-6.81 (m, 1H), 6.56 (d, J = 2.3 Hz, 1H), 4.01-3.99 (m, 3H), 3.96 (dd, J = 2.0, 8.9 Hz, 1H), 2.96-2.86 (m, 1H), 2.11 (s, 3H), 1.62 (s, 3H), 0.87 (dd, J = 1.9, 7.6 Hz, 3H).

[0112] Preparation of compound 1-11

[0113] Compound 1-10 (2.6 g, 7.06 mmol) was added to 40 mL of dichloromethane under nitrogen atmosphere, and then the reaction solution was cooled to -30 °C. Trimethylsilyl cyanide (2.8 mL, 21.2 mmol) was slowly added to the reaction solution, and stirred for 5 minutes. Then, boron trifluoride etherate (7.8 mL, 28.2 mmol) was added dropwise, and the reaction solution was stirred at -30-0 °C for 2 hours. After the reaction was completed, potassium hydroxide aqueous solution (2 mol / L, 100 mL) was slowly added dropwise, and the mixture was extracted with dichloromethane (50 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-11.

[0114] 1 H NMR (400 MHz, CDCl3): δ 6.93-6.85 (m, 1H), 6.78-6.76 (m, 1H), 5.08-5.01 (m, 1H), 4.26-4.21 (m, 1H), 4.08-4.05 (m, 3H), 2.89-2.81 (m, 1H), 1.64 (s, 3H), 0.83-0.79 (m, 3H).

[0115] Preparation of compound 1-12

[0116] Compound 1-11 (2.4 g, 7.16 mmol) was added to 20 mL of ethanol, and then potassium hydroxide aqueous solution (20 mL, 2 mol / L) was added dropwise with stirring. The reaction solution was warmed to 75 °C and stirred for 16 hours. After the reaction was completed, the solution was cooled and diluted with 100 mL of water. The ethanol was removed by concentration under reduced pressure. The concentrated solution was partitioned with 50 mL of ethyl acetate, and the aqueous phase was adjusted to pH = 5 with 6M hydrochloric acid. The aqueous phase was extracted with ethyl acetate (50 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase column chromatography (mobile phase A: water (0.1% formic acid)-B: acetonitrile; elution gradient: B: 70%-80%; elution for 15 minutes) to obtain compound 1-12.

[0117] 1 H NMR (400 MHz, DMSO-d6) δ 13.13-12.80 (m, 1H), 7.22-7.16 (m, 1H), 7.16-7.09 (m, 1H), 4.98 (d, J = 10.4 Hz, 1H), 4.08 (dd, J = 7.9, 10.8 Hz, 1H), 3.93 (d, J = 2.1 Hz, 3H), 2.73-2.60 (m, 1H), 1.53 (s, 3H), 0.74-0.64 (m, 3H).

[0118] m / z (ESI): [M-H] - = 353.2.

[0119] Preparation of compound 1-13

[0120] Compound 1-12 (2.1 g, 5.93 mmol) was added to 4 mL of toluene, after stirring and warming to 60°C, R-phenethylamine (0.86 g, 7.11 mmol) in 4 mL of toluene was slowly added dropwise, after the addition was completed, the reaction temperature was reduced to 50°C, and stirring was performed for 1 hour, the reaction temperature was slowly reduced to 20°C, and stirring was performed at 20°C for 8 hours, filtration was performed, the filter cake was washed with 5 mL of toluene, and drying was performed to obtain compound 1-13.

[0121] 1 H NMR (400 MHz, MeOD): δ 7.50-7.41 (m, 5H), 7.13 (ddd, J = 2.1, 6.0, 8.6 Hz, 1H), 6.96-6.87 (m, 1H), 4.73 (d, J = 10.4 Hz, 1H), 4.48-4.38 (m, 1H), 4.09 (dd, J = 8.3, 10.1 Hz, 1H), 3.96 (d, J = 2.1 Hz, 3H), 2.58-2.48 (m, 1H), 1.65-1.57 (m, 6H), 0.78-0.70 (m, 3H).

[0122] Preparation of compound 1-14

[0123] Compound 1-13 (2.25 g, 4.73 mmol) was added to a mixed solution of 20 mL of isopropyl alcohol and 40 mL of n-heptane, 40 mL of dichloromethane and 40 mL of an aqueous hydrochloric acid solution (2-mol / L) were sequentially added with stirring, the reaction liquid was stirred for half an hour, low-boiling-point solvents were removed by concentration under reduced pressure, 50 mL of ethyl acetate was added to the residual liquid, extraction was performed, the organic phase was washed with 20 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oil (1.76 g). Quinine (1.56 g, 4.80 mmol) was added to a 4 mL dichloromethane solution in which the above oil was dissolved, 4 mL of isopropyl alcohol was added, and the temperature was warmed to 70°C (low-boiling-point dichloromethane was distilled off), 12 mL of n-heptane was slowly added after the temperature of the reaction liquid was reduced to 65°C, stirring was performed at 65°C for 1 hour, the reaction liquid was slowly reduced to 20°C, stirring was performed at 20°C for 2 hours, filtration was performed, the filter cake was washed with isopropyl alcohol / n-heptane = 1 / 3 (3 mL), and drying under reduced pressure was performed to obtain compound 1-14.

[0124] 1H NMR (400 MHz, CDC13) δ 8.68 (d, J = 4.5 Hz, 1H), 7.84 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 4.4 Hz, 1H), 7.18 (dd, J = 2.6, 9.3 Hz, 1H), 7.10 (ddd, J = 1.8, 6.1, 8.4 Hz, 1H), 6.84 - 6.75 (m, 2H), 6.16 (s, 1H), 5.52 (ddd, J = 6.7, 10.4, 17.2 Hz, 1H), 5.06 - 4.92 (m, 2H), 4.85 (d, J = 10.1 Hz, 1H), 4.37 - 4.23 (m, 1H), 4.17 - 4.07 (m, 1H), 3.93 (d, J = 2.5 Hz, 3H), 3.70 (s, 3H), 3.39 - 3.24 (m, 2H), 3.07 - 2.91 (m, 2H), 2.60 - 2.48 (m, 1H), 2.58 (d, J = 1.5 Hz, 1H), 2.15 - 2.04 (m, 1H), 2.03 - 1.93 (m, 2H), 1.80 - 1.68 (m, 1H), 1.65 (s, 3H), 1.27 - 1.10 (m, 1H), 0.78 (dd, J = 1.8, 7.3 Hz, 3H).

[0125] Preparation of compound 1-15

[0126] To a solution of compound 1-14 (1.6 g, 2.36 mmol) in 20 mL of dichloromethane was added dropwise 20 mL of dilute hydrochloric acid (2.5 mol / L), and the mixture was stirred at 20 °C for half an hour, then allowed to stand to separate into two layers. To the organic phase was added 30 mL of dilute hydrochloric acid (2.5 mol / L) again, and the aqueous phase was extracted with dichloromethane (20 mL x 2). The combined organic phase was washed with 20 mL of water, dried over anhydrous sodium sulfate, and concentrated to give a white solid (600 mg). Under a nitrogen atmosphere, DMF (0.1 mL, 0.34 mmol) and oxalyl chloride (0.3 mL, 3.39 mmol) were added dropwise successively to a solution of the above white solid (600 mg, 1.69 mmol) in 10 mL of dichloromethane, and the reaction solution was warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure to give compound 1-15.

[0127] Preparation of compound 1-16

[0128] Compound 1-15 (200 mg, 0.54 mmol) was added slowly to a solution of 4-amino-2- pyridinecarboxylic acid methyl ester (163.3 mg, 1.07 mmol) and triethylamine (0.2 mL, 1.61 mmol) in 4 mL of dichloromethane under nitrogen atmosphere at 0 °C, the mixture was warmed to 20 °C and stirred for 2 h. After the reaction was completed, 20 mL of water was added to quench the reaction, extracted with dichloromethane (10 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by reverse phase column chromatography (mobile phase A: water (0.1% ammonia water) - B: acetonitrile; elution gradient: B: 70% - 80%; elution for 15 min) to give compound 1-16.

[0129] 1 H NMR (400 MHz, CDCl3): δ 8.64 (d, J = 5.4 Hz, 1H), 8.58 (s, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.94 (dd, J = 2.3, 5.5 Hz, 1H), 7.12 - 7.05 (m, 1H), 6.97 - 6.88 (m, 1H), 5.04 (d, J = 11.1 Hz, 1H), 4.21 - 4.06 (m, 2H), 2.84 - 2.70 (m, 1H), 1.70 (s, 3H), 1.56 (s, 4H), 0.86 - 0.75 (m, 3H);

[0130] m / z (ESI): [M+H] + = 489.2.

[0131] Preparation of compound 1-17

[0132] Compound 1-16 (210 mg, 0.43 mmol) was added to a solution of 7 mol / L ammonia / methanol (6.1 mL, 43.00 mmol), the reaction was carried out in a four-fluorine jar at 40 °C for 24 h. After the reaction was completed, the crude product was concentrated and purified by preparative high performance liquid chromatography (column type: Phenomenex luna C18 150*25mm*10um; mobile phase: [A: water (0.1% formic acid) - B: acetonitrile; elution gradient: B%: 40% - 70% elution for 10 min) to give compound 1-17.

[0133] 1H NMR (400 MHz, DMSO-d6): δ 10.74 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.07 (br d, J = 2.1 Hz, 1H), 7.83 (dd, J = 2.1, 5.5 Hz, 1H), 7.63 (s, 1H), 7.22 - 7.12 (m, 2H), 5.10 (d, J = 10.3 Hz, 1H), 4.25 (dd, J = 7.9, 10.1 Hz, 1H), 3.94 (d, J = 2.0 Hz, 3H), 2.83 - 2.71 (m, 1H), 1.61 (s, 3H), 0.73 (d, J = 6.5 Hz, 3H);

[0134] m / z (ESI): [M+H] + = 474.4.

[0135] Preparation of compound 1-18

[0136] Bromine (0.30 mL, 0.32 mmol) was slowly added to a solution of compound 1-17 (100 mg, 0.21 mmol) in 2 mL of dichloromethane at 0 °C under nitrogen atmosphere. After the addition was completed, the reaction was stirred at 0 °C for 2 hours. After the reaction was completed, the reaction was quenched by pouring into 50 mL of saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by thin layer silica gel preparation (dichloromethane / methanol = 10:1) to give compound 1-18.

[0137] 1 H NMR (400 MHz, DMSO-d6): δ 10.74 (s, 1H), 10.53 - 10.41 (m, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 7.83 (dd, J = 2.1, 5.5 Hz, 1H), 7.62 (br s, 1H), 7.03 (t, J = 7.1 Hz, 1H), 6.86 (q, J = 8.9 Hz, 1H), 5.10 (d, J = 10.3 Hz, 1H), 4.30 - 4.20 (m, 1H), 2.90 - 2.78 (m 1H), 2.54 (d, J = 1.0 Hz, 2H), 1.60 (s, 3H), 0.71 (d, J = 6.3 Hz, 3H);

[0138] m / z (ESI): [M+H] + = 460.2.

[0139] Preparation of example 1

[0140] Bromo propynyl (2.38 mg, 0.02 mmol) was added slowly dropwise to a solution of compound 1-18 (10 mg, 0.02 mmol) and potassium carbonate (13.8 mg, 0.02 mmol) in 1 mL of DMF under nitrogen atmosphere. After the addition was completed, the reaction was warmed to 60 °C for 2 hours. The reaction was cooled and filtered. The filtrate was purified by preparative high performance liquid chromatography (column type: Waters Xbridge 150*25mm*5um; mobile phase A: water (ammonium bicarbonate)-B: acetonitrile; elution gradient: B%: 42%-72% eluted in 11 minutes) to give Example 1.

[0141] 1 H NMR (400 MHz, CDCl3): δ 8.68 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 8.16 (dd, J = 2.2, 5.6 Hz, 1H), 7.94 (d, J = 2.1 Hz, 1H), 7.84 (s, 1H), 7.19-7.11 (m, 1H), 7.05-6.94 (m, 1H), 5.67-5.56 (m, 1H), 5.02 (d, J = 11.4 Hz, 1H), 4.93-4.74 (m, 2H), 4.26 (dd, J = 7.8, 11.3 Hz, 1H), 2.90-2.79 (m, 1H), 2.38 (t, J = 2.4 Hz, 1H), 1.72 (s, 3H), 0.86-0.77 (m, 3H);

[0142] m / z (ESI): [M+H] + = 498.2.

[0143] Example 2

[0144] 1-bromo-2-butynyl (14.5 mg, 0.11 mmol) was added slowly dropwise to a solution of compound 1-18 (50 mg, 0.11 mmol) and potassium carbonate (75.2 mg, 0.54 mmol) in 1 mL of DMF under nitrogen atmosphere. The reaction was warmed to 60 °C for 2 hours. After the reaction was completed, the reaction was cooled to room temperature, filtered, and the filtrate was purified by preparative high performance liquid chromatography (column type: Waters Xbridge 150*25mm*5um; mobile phase A: water (ammonium bicarbonate)-B: acetonitrile; elution gradient: B%: 50%-80% eluted in 9 minutes) to give Example 2.

[0145] 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.10 - 8.02 (m, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.28 - 7.14 (m, 2H), 5.12 (d, J = 10.4 Hz, 1H), 4.93 - 4.78 (m, 2H), 4.37 (dd, J = 7.6, 10.3 Hz, 1H), 2.90 - 2.70 (m, 1H), 1.75 (t, J = 2.4 Hz, 3H), 1.62 (s, 3H), 0.73 (d, J = 6.4 Hz, 3H);

[0146] m / z (ESI): [M+H] + = 512.2.

[0147] Example 3

[0148] Preparation of compound 3-1

[0149] Compound 1-18 (200 mg, 0.04 mmol) and triethylamine (0.1 mL, 0.65 mmol) were dissolved in 3 mL of dichloromethane under nitrogen atmosphere, the mixture was stirred at zero degree for 10 minutes, trifluoromethanesulfonic anhydride (72.3 μL, 0.44 mmol) was added dropwise, after the addition was completed, the reaction was continued at zero degree for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 3-1.

[0150] m / z (ESI): [M+H] + = 512.2.

[0151] Preparation of compound 3-2

[0152] Palladium (II) chloride 1,1'-bis(diphenylphosphino)ferrocene (6.19 mg, 0.01 mmol), cuprous iodide (3.22 mg, 0.02 mmol) and triethylamine (25.66 mg, 0.25 mmol) were sequentially added to 0.5 mL of DMF solvent containing compound 3-1 (50 mg, 0.08 mmol) and triisopropylsilyl acetylene (0.1 mL, 0.25 mmol), and the reaction solution was warmed to 100°C and stirred for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through short silica gel (washed with ethyl acetate), and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase column chromatography (0.1% formic acid system) to obtain compound 3-2.

[0153] 1 H NMR (400 MHz, CDC13): δ 8.61 (s, 1H), 8.47 (d, J = 5.6 Hz, 1H), 8.18 (dd, J = 2.1, 5.4 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 4.5 Hz, 1H), 7.18 (d, J = 5.7 Hz, 2H), 5.59 (d, J = 2.9 Hz, 1H), 5.03 (d, J = 11.2 Hz, 1H), 4.32 (dd, J = 8.2, 11.0 Hz, 2H), 2.97 (t, J = 7.6 Hz, 1H), 2.37 (s, 1H), 2.03 (d, J = 6.6 Hz, 1H), 1.68 (s, 3H), 1.10 (s, 18H), 0.87 - 0.81 (m, 3H);

[0154] m / z (ESI): [M+H] + = 624.2.

[0155] Preparation of Example 3

[0156] Under nitrogen atmosphere, cesium fluoride (30.38 mg, 0.20 mmol) was added to a solution of compound 3-2 (13 mg, 0.02 mmol) in 0.5 mL DMF, and the reaction was stirred at 25 °C for 1 hour. After the reaction was completed, it was filtered, and the filtrate was separated and purified by preparative high performance liquid (Waters Xbridge 150*25mm*5um; mobile phase A: water (ammonium bicarbonate)-B: acetonitrile; elution gradient: B%: 45%-75%; elution for 9 minutes) to obtain Example 3.

[0157] 1 H NMR (400 MHz, CDC13): δ 8.67 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.17 (dd, J = 2.0, 5.4 Hz, 1H), 7.94 (d, J = 1.6 Hz, 1H), 7.87 (s, 1H), 7.26 - 7.17 (m, 2H), 5.61 (d, J = 2.3 Hz, 1H), 5.06 (d, J = 11.0 Hz, 1H), 4.27 (dd, J = 7.9, 11.2 Hz, 1H), 3.64 (s, 1H), 2.97 (t, J = 7.6 Hz, 1H), 1.71 (s, 3H), 0.88 - 0.74 (m, 3H);

[0158] m / z (ESI): [M+H] + = 468.2.

[0159] Example 4

[0160] Preparation of compound 4-2

[0161] The synthetic route of compound 4-2 is as follows:

[0162] Compound 4-1 (3.00 g, 18.4 mmol) was added dropwise into a solution of 1,2-dibromoethane (14.5 g, 77.2 mmol) and triethylamine (5.60 mL, 40.5 mmol) in 50 mL of DMF under a nitrogen atmosphere, and the mixture was stirred at 20 °C for 16 hours. After the reaction was completed, the reaction solution was poured into 100 mL of water, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluted with petroleum ether) to obtain compound 4-2.

[0163] 1 H NMR (400 MHz, DMSO-d6): δ 7.87 (s, 4H), 4.45 (t, J = 6.0 Hz, 2H), 3.77-3.77 (m, 1H), 3.75 (t, J = 6.0 Hz, 1H).

[0164] Preparation of compound 4-3

[0165] Compound 4-2 (58.8 mg, 0.22 mmol) was added to a solution of compound 1-18 (100 mg, 0.22 mmol) and potassium carbonate (150 mg, 1.09 mmol) in 2 mL of DMF under a nitrogen atmosphere, and the reaction solution was warmed to 60 °C and stirred for 6.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was purified by reverse phase column chromatography (0.1% formic acid system) to obtain compound 4-3.

[0166] 1 H NMR (400 MHz, CDCl3): δ 8.75 (s, 1H), 8.35 (d, J = 5.6 Hz, 1H), 8.23 (dd, J = 2.4, 5.6 Hz, 1H), 7.80 (d, J = 2.0 Hz, 2H), 7.70 (s, 4H), 7.25-7.17 (m, 1H), 7.02-6.92 (m, 1H), 5.82-5.71 (m, 1H), 5.00 (d, J = 11.6 Hz, 1H), 4.74-4.62 (m, 2H), 4.51 (dd, J = 8.0, 10.4 Hz, 1H), 4.44-4.25 (m, 2H), 3.07-2.97 (m, 1H), 1.78 (s, 3H), 0.80 (dd, J = 2.0, 5.6 Hz, 3H);

[0167] m / z (ESI): [M+H] += 649.2.

[0168] Preparation of compound 4-4

[0169] Hydrazine hydrate (14.2 mg, 0.28 mmol) was added to a solution of compound 4-3 (90.0 mg, 0.14 mmol) in 3 mL of ethanol under nitrogen atmosphere, and the reaction was stirred at 65 °C for 1 hour. After the reaction was completed, the reaction was cooled to room temperature, filtered, and the filtrate was concentrated to obtain compound 4-4.

[0170] 1 H NMR (400 MHz, CDCl3): δ 8.70-8.64 (m, 1H), 8.47 (d, J = 5.6 Hz, 1H), 8.13 (dd, J = 2.4, 5.6 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.87-7.80 (m, 1H), 7.13-7.06 (m, 1H), 6.99 (d, J = 2.4 Hz, 1H), 5.62-5.56 (m, 1H), 5.02 (d, J = 11.2 Hz, 1H), 4.49-4.40 (m, 1H), 4.38-4.23 (m, 2H), 3.96-3.88 (m, 1H), 3.86-3.79 (m, 1H), 2.88-2.74 (m, 1H), 1.29-1.23 (m, 3H), 0.83-0.77 (m, 3H).

[0171] Preparation of example 4

[0172] Pyridine p-toluenesulfonate (0.27 mg) and paraformaldehyde (6.37 mg, 0.21 mmol) were added to a solution of compound 4-4 (55 mg, 0.11 mmol) in 3 mL of dichloromethane under nitrogen atmosphere, and the reaction was stirred at 40 °C for 4 hours. After the reaction was completed, water (20 mL) was added to the reaction, and extracted with ethyl acetate (10 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was separated and purified by preparative high performance liquid chromatography (column type: Waters Xbridge 150*25mm*5um; mobile phase A: water (ammonium bicarbonate)-B: acetonitrile; gradient: B: 48%-78% elution for 10 minutes) to obtain example 4.

[0173] 1H NMR (400 MHz, DMSO-d6): δ 10.69 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.4, 5.6 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.20-7.13 (m, 2H), 7.05 (d, J = 7.6 Hz, 1H), 6.58 (d, J = 7.6 Hz, 1H), 5.12 (d, J = 10.6 Hz, 1H), 4.43 (dd, J = 4.8, 6.8 Hz, 1H), 4.37-4.23 (m, 4H), 2.88-2.76 (m, 1H), 1.60 (s, 3H), 0.70 (d, J = 6.0 Hz, 3H);

[0174] m / z (ESI): [M+H] + = 531.2.

[0175] Example 5

[0176] Preparation of compound 5-2

[0177] The synthetic route of compound 5-2 is as follows:

[0178] Under nitrogen atmosphere, tert-butyldimethylsilyl chloride (865 mg, 5.74 mmol) was added to a solution of compound 5-1 (300 mg, 2.87 mmol) and imidazole (586 mg, 8.61 mmol) in 5 mL of DMF, and the reaction solution was stirred at 20 °C for 3 hours. After the reaction was completed, water (50 mL) was added to the reaction solution, extracted with ethyl acetate (25 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluted with petroleum ether) to obtain compound 5-2.

[0179] 1 H NMR (400 MHz, CDCl3): δ 4.37 (t, J = 2.0 Hz, 2H), 4.18 (t, J = 2.0 Hz, 2H), 0.92 (s, 9H), 0.13 (s, 6H).

[0180] Preparation of compound 5-3

[0181] A solution of compound 5-2 (28.6 mg, 0.13 mmol) in DMF (1 mL) was added slowly to a suspension of compound 1-18 (60 mg, 0.13 mmol) and potassium carbonate (90.3 mg, 0.65 mmol) in DMF (1 mL) under nitrogen atmosphere. The reaction was stirred at 60 °C for 2 hours. After the reaction was completed, the reaction was cooled to room temperature, filtered, and the filtrate was separated and purified by reverse phase preparative (mobile phase A: water (0.1% ammonia water) - B: acetonitrile; elution gradient: B: 100%; elution for 3 minutes) to give compound 5-3.

[0182] 1 H NMR (400 MHz, DMSO-d6): δ 10.73 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.95 (s, 4H), 7.84 (dd, J = 2.4, 5.6 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.26-7.17 (m, 2H), 5.12 (d, J = 10.4 Hz, 1H), 5.04-4.92 (m, 2H), 4.33 (dd, J = 7.6, 10.2 Hz, 1H), 4.28-4.22 (m, 2H), 1.61 (s, 3H), 0.77 (s, 9H), -0.06 (s, 6H);

[0183] m / z (ESI): [M+H] + = 642.3.

[0184] Preparation of Example 5

[0185] Compound 5-3 (25 mg, 0.04 mmol) was dissolved in hydrogen chloride methanol solution (2 mL, 2 mol / L) and stirred at 25 °C for 0.5 hours. After the reaction was completed, it was concentrated, diluted with 2 mL of methanol, adjusted to pH = 8 with ammonia water, and separated and purified by preparative high performance liquid chromatography (column type: Waters Xbridge 150*25mm*5um; mobile phase A: water (ammonium bicarbonate) - B: acetonitrile; elution gradient: B: 38%-68%; elution for 9 minutes) to give Example 5.

[0186] 1H NMR (400 MHz, DMSO-d6): δ 10.73 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.63 (br d, J = 1.6 Hz, 1H), 7.28 - 7.14 (m, 2H), 5.21 (t, J = 6.0 Hz, 1H), 5.11 (d, J = 10.4 Hz, 1H), 4.94 (d, J = 1.6 Hz, 2H), 4.34 (dd, J = 7.6, 10.4 Hz, 1H), 4.10 - 4.03 (m, 2H), 2.90 - 2.79 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 6.4 Hz, 3H);

[0187] m / z (ESI): [M+H] + = 528.2.

[0188] Example 6

[0189] Preparation of compound 6-2

[0190] Methyl lithium (5.3 mL, 8.41 mmol) was slowly added to 15 mL of tetrahydrofuran solution of compound 6-1 (1.0 g, 8.41 mmol) under nitrogen atmosphere at -78 °C. After the reaction solution was stirred at -78 °C for 5 minutes, acetone (6.2 mL, 84.06 mmol) was slowly added dropwise. After the addition was completed, the reaction solution was continuously stirred at -78 °C for 10 minutes. After the reaction was completed, 30 mL of saturated aqueous ammonium chloride solution was added for quenching. The aqueous phase was extracted with 30 mL of ethyl acetate (30 mL x 3). The combined organic phase was washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound 6-2.

[0191] 1 H NMR (400 MHz, CDCl3): δ 3.94 (s, 2H), 1.53 (s, 6H).

[0192] Preparation of Example 6

[0193] Potassium carbonate (63.18 mg, 0.46 mmol) and compound 6-2 (16.29 mg, 0.09 mmol) were added to a solution of compound 1-18 (50 mg, 0.09 mmol) in 1 mL of DMF under nitrogen atmosphere. The reaction was stirred at 60 °C for 2 hours. After the reaction was completed, the reaction was filtered, and the filtrate was purified by preparative high performance liquid chromatography (column type: Waters Xbridge 150*25mm*5um; mobile phase A: water (ammonium bicarbonate) - B: acetonitrile; elution gradient: B: 35%~65%; elution 10 minutes) to give Example 6.

[0194] 1 H NMR (400 MHz, DMSO-d6): δ 10.74 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.61 (d, J = 1.6 Hz, 1H), 7.24-7.15 (m, 2H), 5.31 (s, 1H), 5.12 (d, J = 10.6 Hz, 1H), 4.94 (s, 2H), 4.28 (dd, J = 7.2, 10.2 Hz, 1H), 2.85 (t, J = 7.2 Hz, 1H), 1.63 (s, 3H), 1.27 (s, 3H), 1.24 (s, 3H), 0.74 (d, J = 5.6 Hz, 3H);

[0195] m / z (ESI): [M+H] + = 556.3.

[0196] Example 7

[0197] 2-methyl-3-butyn-2-ol (0.1 mL, 0.89 mmol) and K2CO3 (451.27 mg, 3.27 mmol) were added to a solution of compound 1-18 (300 mg, 0.65 mmol) in DMF (6 mL) under nitrogen atmosphere. The reaction was reacted at 100 °C for 2 hours. Compound 2 (0.1 mL, 0.89 mmol) was added to the reaction, and the reaction was continued to react at 100 °C for 2 hours. After the reaction was completed, the reaction was cooled to room temperature and filtered. The filtrate was purified by reverse phase preparation (Waters Xbridge 150*25mm*5um, water (water (NH4HCO3)-ACN, 52%-82%, 16 min) to give Example 7.

[0198] 1H NMR (400 MHz, DMSO-d6): δ 10.76 (br s, 1H), 8.48 (d, J = 5.52 Hz, 1H), 8.25 (d, J = 1.88 Hz, 1H), 8.08 (d, J = 2.00 Hz, 1H), 7.82 (dd, J = 5.40, 1.88 Hz, 1H), 7.63 (br s, 1H), 7.16 - 7.29 (m, 2H), 5.09 (d, J = 10.52 Hz, 1H), 4.43 (dd, J = 10.32, 7.60 Hz, 1H), 3.54 (s, 1H), 2.80 (t, J = 7.20 Hz, 1H), 1.70 (s, 3H), 1.67 (s, 3H), 1.61 (s, 3H), 0.70 (br d, J = 5.12 Hz, 3H);

[0199] m / z (ESI): [M+H] + = 526.1.

[0200] Example 8

[0201] Preparation of compound 8-2

[0202] Methanesulfonic anhydride (0.80 mL, 6.42 mmol) was slowly added to a solution of compound 8-1 (300 mg, 4.28 mmol) and triethylamine (1.8 mL, 12.8 mmol) in dichloromethane (5 mL) under nitrogen atmosphere. The reaction was stirred at 20 °C for 2 hours. After the reaction was completed, the reaction was concentrated under reduced pressure, diluted with water (50 mL), extracted with ethyl acetate (25 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 8-2.

[0203] 1 H NMR (400 MHz, CDCl3): δ 5.30 (dq, J = 2.0, 6.8 Hz, 1H), 3.13 (s, 3H), 2.71 (d, J = 2.0 Hz, 1H), 1.67 (d, J = 6.8 Hz, 3H).

[0204] Preparation of Example 8

[0205] A solution of compound 8-2 (6.45 mg, 0.04 mmol) in DMF (0.5 mL) was slowly added to a solution of compound 1-18 (100 mg, 0.22 mmol) and potassium carbonate (150 mg, 1.09 mmol) in DMF (0.5 mL) under nitrogen atmosphere. The reaction was stirred at 60 °C for 16 h. After the reaction was completed, the reaction was filtered, and the filtrate was purified by reverse phase preparative purification (column: Waters Xbridge 150 x 25 mm x 5 um, water (NH4HCO3)-ACN, 40%-70%, 15 min) to give Example 8.

[0206] 1 H NMR (400 MHz, DMSO-d6): δ 10.70 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 2.0, 5.6 Hz, 1H), 7.62 (br d, J = 2.0 Hz, 1H), 7.27 - 7.14 (m, 2H), 5.25 (dq, J = 2.0, 6.4 Hz, 1H), 5.10 (d, J = 10.8 Hz, 1H), 4.31 (dd, J = 7.6, 10.8 Hz, 1H), 3.67 (d, J = 2.0 Hz, 1H), 2.85 - 2.73 (m, 1H), 1.66 - 1.57 (m, 6H), 0.77 (br d, J = 6.0 Hz, 3H);

[0207] m / z (ESI): [M+H] + = 512.2.

[0208] Example 9

[0209] To a solution of compound 1-18 (60 mg, 0.11 mmol) in 1,4-dioxane (2 mL) was added cyanomethylidene tri-n-butylphosphonium (132.4 mg, 0.55 mmol) and (S)-(-)-3-butyn-2-ol (38.45 mg, 0.55 mmol) under nitrogen atmosphere. The reaction was stirred at 40 °C for 16 h. After completion of the reaction, the reaction was quenched with water (40 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by preparative reverse phase HPLC (Column: Waters Xbridge 150 x 25 mm x 5 um; Condition: water (NH4HCO3) - ACN; Begin B: 43, End B: 73; Gradient Time (min): 10; 100% B Hold Time (min): 4, Flow Rate (ml / min): 25) to give Example 9.

[0210] 1 H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.63 (br s, 1H), 7.30 - 7.15 (m, 2H), 5.16 - 5.06 (m, 2H), 4.45 (dd, J = 7.2, 10.2 Hz, 1H), 3.41 (d, J = 2.0 Hz, 1H), 2.91 - 2.79 (m, 1H), 1.66 - 1.59 (m, 6H), 0.70 (d, J = 6.0 Hz, 3H);

[0211] m / z (ESI): [M+H] + = 512.1.

[0212] Example 10

[0213] Preparation of compound 10-2

[0214] Under nitrogen atmosphere, tert-butyldimethylsilyl chloride (1.92 g, 12.80 mmol) was added to a solution of compound 10-1 (0.50 mL, 6.40 mmol) and imidazole (1.31 g, 19.2 mmol) in DMF (10 mL), and the reaction was stirred at 20 °C for 16 h. After the reaction was completed, the reaction was quenched with water (100 mL), extracted with ethyl acetate (50 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was separated and purified by column chromatography (eluted with petroleum ether) to give compound 10-2.

[0215] 1 H NMR (400 MHz, CDCl3): δ 3.74 (t, J = 6.4 Hz, 2H), 2.68-2.59 (m, 2H), 1.57 (s, 1H), 0.93-0.90 (m, 9H), 0.10-0.07 (m, 6H).

[0216] Preparation of compound 10-3

[0217] Under nitrogen atmosphere, tris(dibenzylideneacetone)dipalladium (31.0 mg, 0.03 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (39.1 mg, 0.07 mmol) were added to a solution of compound 3-1 (200 mg, 0.34 mmol), compound 10-2 (130 mg, 0.68 mmol) and N,N-diisopropylethylamine (0.3 mL, 2.03 mmol) in 1,4-dioxane (4 mL), and the reaction was stirred at 100 °C for 16 h. After the reaction was completed, it was cooled to room temperature, quenched with water (50 mL), extracted with ethyl acetate (20 mL x 2), and the combined organic phase was washed with brine (20 mL) and separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was separated and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give compound 10-3.

[0218] 1H NMR (400 MHz, CDC13): δ = 8.71 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 8.16 (dd, J = 2.0, 5.6 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 4.0 Hz, 1H), 7.24-7.16 (m, 2H), 5.66 (d, J = 3.6 Hz, 1H), 5.06 (d, J = 11.2 Hz, 1H), 4.54 (dd, J = 8.0, 11.2 Hz, 1H), 3.73-3.65 (m, 2H), 3.15 (dq, J = 4.8, 7.2 Hz, 3H), 3.04-2.95 (m, 2H), 2.83 (m, 1H), 0.81 (s, 9H), 0.78-0.73 (m, 3H), 0.04 (d, J = 10.0 Hz, 6H);

[0219] m / z (ESI): [M+H] + = 634.1.

[0220] Preparation of Example 10

[0221] Compound 10-3 (95 mg, 0.15 mmol) was added to a solution of hydrochloric acid in methanol (2 N, 5 mL) under a nitrogen atmosphere, and the reaction was allowed to react at 17 °C for 0.5 h. After the reaction was completed, the reaction was concentrated under reduced pressure, and the residue was diluted with methanol (2 mL), adjusted to pH = 8 with ammonia water, and separated and purified by reverse phase preparative purification (column: Waters Xbridge 150*25 mm*5 um, water (NH4HCO3)-ACN, 38%-68%, 15 min) to obtain Example 10.

[0222] 1 H NMR (400 MHz, DMSO-d6): δ 10.68 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.09-8.03 (m, 1H), 7.83 (dd, J = 2.4, 5.6 Hz, 1H), 7.62 (br d, J = 2.0 Hz, 1H), 7.55-7.43 (m, 1H), 7.29 (dd, J = 5.2, 8.0 Hz, 1H), 5.17 (d, J = 10.4 Hz, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.69 (dd, J = 7.6, 10.4 Hz, 1H), 3.51-3.39 (m, 2H), 2.96-2.89 (m, 2H), 2.84 (t, J = 7.2 Hz, 1H), 1.64 (s, 3H), 0.70 (br d, J = 6.0 Hz, 3H);

[0223] m / z (ESI): [M+H] + = 520.2.

[0224] Example 11

[0225] Preparation of compound 11-2

[0226] Under nitrogen atmosphere, triethylamine (223.8 μL, 1.61 mmol) and 11-1 (81.67 mg, 0.54 mmol) were added to 4 mL of dichloromethane solution of compound 1-15 (200 mg, 0.54 mmol) successively, and the reaction solution was stirred at 25 °C for 1 hour. After the reaction was completed, the crude product was concentrated, and compound 11-2 was separated by reverse phase preparation (0.1% FA) purification.

[0227] m / z (ESI): [M+H] + = 489.1.

[0228] Preparation of compound 11-3

[0229] Under nitrogen atmosphere, boron tribromide (0.1 mL, 0.24 mmol) was slowly added dropwise to 2 mL of dichloromethane solution of compound 11-2 (80 mg, 0.16 mmol) at 0 °C, and the reaction solution was stirred at 25 °C for 1.5 hours. After the reaction was completed, 3 mL of dichloromethane was added for dilution, 4 mL of saturated aqueous sodium bicarbonate solution was added dropwise for quenching, and dichloromethane (5 mL x 3) was used for extraction. The combined organic phase was washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound 11-3 was separated by reverse phase preparation (0.1% FA) purification.

[0230] LC-MS (ESI): [M+H] + = 475.1.

[0231] Preparation of Example 11

[0232] Under nitrogen atmosphere, 3-bromopropynyl (12.54 mg, 0.11 mmol) was added to 1 mL of N,N-dimethylformamide solution of compound 11-3 (50 mg, 0.11 mmol) and K2CO3 (72.82 mg, 0.53 mmol), and the reaction solution was reacted at 60 °C for 2 hours. After the reaction was completed, the reaction solution was filtered after being cooled to room temperature, and Example 11 was obtained by reverse phase preparation purification (Waters Xbridge 150 x 25 mm x 5 um, water (water (NH4HCO3)-ACN, 45%-75% over 10 min)).

[0233] 1H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 8.34 (d, J = 5.52 Hz, 1H), 7.86 (d, J = 1.88 Hz, 1H), 7.49 (dd, J = 5.52, 2.12 Hz, 1H), 7.11-7.28 (m, 2H), 5.18 (s, 1H), 5.09 (d, J = 10.52 Hz, 1H), 4.86-4.99 (m, 2H), 4.33 (dd, J = 10.36, 7.52 Hz, 1H), 3.65 (t, J = 2.36 Hz, 1H), 2.84 (t, J = 7.44 Hz, 1H), 1.60 (s, 3H), 1.39 (s, 6H), 0.73 (d, J = 6.36 Hz, 3H);

[0234] m / z (ESI): [M+H] + = 513.1.

[0235] Example 12

[0236] Preparation of compound 12-2

[0237] Deuterium lithium aluminum hydride (2.6 mL, 5.12 mmol, 2M THF solution) was slowly added to a solution of compound 12-1 (1 g, 6.40 mmol) in 40 mL of tetrahydrofuran at 0 °C under nitrogen atmosphere, and the reaction was stirred at 0 °C for 1 hour. After the reaction was completed, 1 mL of deuterium water was added for quenching, and the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound 12-2.

[0238] 1 H NMR (400 MHz, CDCl3): δ 1.67 (s, 1H), 0.20-0.17 (m, 9H).

[0239] Preparation of compound 12-3

[0240] Under a nitrogen atmosphere, tributyl cyanomethyl phosphonium (176.54 mg, 0.77 mmol) and compound 12-2 (95.28 mg, 0.73 mmol) were sequentially added to a solution of compound 1-18 (80 mg, 0.15 mmol) in 2 mL of dioxane, and the reaction was stirred at 40 °C for 16 hours. After the reaction was completed, 10 mL of water was added for quenching, and the mixture was extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain compound 12-3.

[0241] 1H NMR (400 MHz, CDC13): δ 8.71-8.67 (m, 1H), 8.47 (d, J = 5.6 Hz, 1H), 8.18 (dd, J = 2.0, 5.6 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.88 (br d, J = 2.0 Hz, 1H), 7.17-7.11 (m, 1H), 6.99-6.93 (m, 1H), 5.62-5.56 (m, 1H), 5.04 (d, J = 11.2 Hz, 1H), 4.18 (dd, J = 6.8, 10.8 Hz, 1H), 2.91 (t, J = 7.6 Hz, 1H), 1.72 (s, 3H), 0.84-0.80 (m, 3H), 0.09 (s, 9H);

[0242] m / z (ESI): [M+H] + = 572.2.

[0243] Preparation of Example 12

[0244] Tetrabutylammonium fluoride (235 μL, 0.23 mmol, 1M THF solution) was added to a solution of compound 12-3 (60 mg, 0.08 mmol) in 2 mL of tetrahydrofuran under nitrogen atmosphere. The reaction was stirred at 22.5 °C for 1.5 hours. After the reaction was completed, it was quenched with 40 mL of water, extracted with ethyl acetate (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was separated by reverse phase preparative purification (Column: Waters Xbridge 150 x 25 mm x 5 um; Condition: water (NH4HCO3) - ACN; Begin B: 43, End B: 73; Gradient Time (min): 10; 100% B Hold Time (min): 4, Flow Rate (ml / min): 25) to give Example 12.

[0245] 1H NMR (400 MHz, DMSO-d6): δ 10.71 (br s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 2.0, 5.6 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.28 - 7.15 (m, 2H), 5.11 (d, J = 10.2 Hz, 1H), 4.33 (dd, J = 7.2, 10.2 Hz, 1H), 3.63 (s, 1H), 2.90 - 2.78 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 6.8 Hz, 3H);

[0246] m / z (ESI): [M+H]+ = 500.1. +

[0247] Example 13

[0248] Under nitrogen atmosphere, 4-bromo-n-butynyl (193.81 mg, 1.46 mmol) and potassium carbonate (225.64 mg, 1.63 mmol) were added into 3 mL DMF solution of compound 1-18 (150 mg, 0.33 mmol) successively, and the reaction solution was reacted at 80 °C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and filtered, and the filtrate was purified by reversed-phase preparation (Waters Xbridge 150x25mmx5um, water(water(NH4HCO3)-ACN, 48%-78%, 25 min) to obtain Example 13.

[0249] 1 H NMR (400 MHz, DMSO-d6): δ 10.71 (br s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 2.0, 5.6 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.28 - 7.15 (m, 2H), 5.11 (d, J = 10.2 Hz, 1H), 4.33 (dd, J = 7.2, 10.2 Hz, 1H), 3.63 (s, 1H), 2.90 - 2.78 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 6.8 Hz, 3H);

[0250] m / z (ESI): [M+H]+ = 512.1.​

[0251] Example 14

[0252] Preparation of compound 14-2

[0253] Sodium hydride (14.5 mg, 0.36 mmol) was slowly added to a solution of compound 14-1 (0.4 mL, 8.06 mmol) in 5 mL of DMF under nitrogen protection at 0 °C. After the reaction solution was stirred at 0 °C for half an hour, bromopropargyl (642 mg, 5.40 mmol) was added dropwise. After the addition was completed, the reaction solution was warmed to 50 °C and continued to stir for 16 hours. After the reaction was completed, the reaction solution was added dropwise to ice saturated ammonium chloride (0.0 mL) for quenching. Ethyl acetate (20 mL*2) was used for extraction. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. Compound 14-2 was obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) separation and purification.

[0254] 1 H NMR (400 MHz, DMSO-d6): δ 4.65 (t, J = 5.4 Hz, 1H), 4.13 (d, J = 2.4 Hz, 2H), 3.53-3.47 (m, 2H), 3.47-3.43 (m, 2H), 3.41 (t, J = 2.4 Hz, 1H).

[0255] Preparation of Example 14

[0256] Under nitrogen atmosphere, tributyl cyanomethyl phosphonium (131 mg, 0.54 mmol) was added to a solution of compound 1-18 (50.0 mg, 0.11 mmol) and compound 14-2 (54.5 mg, 0.54 mmol) in 2 mL of dioxane. The reaction solution was warmed to 40 °C and reacted for 2 hours. After the reaction was completed, the reaction solution was quenched with 50 mL of water. Ethyl acetate (20 mL*2) was used for extraction. The combined organic phase was washed with brine (20 mL) and separated. The aqueous phase was extracted with ethyl acetate (20 mL) again. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Example 14 was obtained by reverse phase preparation purification (column: Waters Xbridge 150*25mm*5um, water(NH4HCO3)-ACN, 40%-70%, 15min).

[0257] 1H NMR (400 MHz, DMSO-d6): δ 10.70 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.22-7.12 (m, 2H), 5.11 (d, J = 10.8 Hz, 1H), 4.36-4.27 (m, 2H), 4.27-4.21 (m, 1H), 4.19 (t, J = 2.4 Hz, 2H), 3.75 (td, J = 2.8, 5.2 Hz, 2H), 3.44 (t, J = 2.4 Hz, 1H), 2.91-2.80 (m, 1H), 1.62 (s, 3H), 0.71 (d, J = 6.0 Hz, 3H);

[0258] m / z (ESI): [M+H] + = 542.2.

[0259] Example 15

[0260] Preparation of compound 15-2

[0261] Compound 15-1 (1 g, 14.27 mmol) was dissolved in tetrahydrofuran (10 mL) and n-butyllithium (6.8 mL, 17.12 mmol, 2.5 M) was slowly added dropwise under a nitrogen atmosphere at -78 °C. The reaction solution was stirred at -78 °C for 1 h, and then paraformaldehyde (2.06 g, 22.83 mmol) was added. The reaction solution was slowly warmed to 25 °C and stirred for 16 h. After the reaction was completed, the reaction solution was cooled to 0 °C, quenched with saturated aqueous ammonium chloride solution (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 15-2.

[0262] 1 H NMR (400 MHz, DMSO-d6): δ 5.19 (t, J = 5.2 Hz, 1H), 4.12-4.08 (m, 4H), 3.25 (s, 3H).

[0263] Preparation of Example 15

[0264] Compound 15-2 (48.49 mg, 0.48 mmol) and tributyl phosphine cyanide (116.90 mg, 0.48 mmol) were added to a solution of compound 1-18 (50 mg, 0.10 mmol) in dioxane (2 mL) under nitrogen atmosphere. The reaction was stirred at 40 °C for 12 h. After completion of the reaction, the reaction was quenched with water (40 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase preparative purification (Column: Waters Xbridge 150 x 25 mm x 5 um; water (NH4HCO3) - ACN; Begin B: 40, End B: 70; Gradient Time (min): 10; 100% B Hold Time (min): 4, Flow Rate (ml / min): 25) to obtain Example 15.

[0265] 1 H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.28 - 7.15 (m, 2H), 5.12 (d, J = 10.4 Hz, 1H), 5.06 - 4.93 (m, 2H), 4.34 (dd, J = 7.2, 10.4 Hz, 1H), 4.12 - 4.01 (m, 2H), 3.13 (s, 3H), 2.88 - 2.80 (m, 1H), 1.61 (s, 3H), 0.73 (d, J = 6.0 Hz, 3H);

[0266] m / z (ESI): [M+H] + = 542.2.

[0267] Example 16

[0268] Preparation of compound 16-2

[0269] To a solution of compound 16-1 (5 g, 71.34 mmol), 4-dimethylaminopyridine (0.87 g, 7.13 mmol) and triethylamine (19.8 mL, 142.67 mmol) in dichloromethane (50 mL) was added tert-butyldiphenylsilyl chloride (21.57 g, 78.47 mmol) at 0 °C under nitrogen atmosphere. The reaction was warmed to 25 °C and stirred for 12 h. After completion of the reaction, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution (50 mL). The aqueous phase was extracted with dichloromethane (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 16-2.

[0270] 1 H NMR (400 MHz, CDCl3): δ 7.77 (td, J = 1.3, 7.9 Hz, 2H), 7.70 (td, J = 1.3, 7.9 Hz, 2H), 7.51-7.37 (m, 6H), 4.53-4.42 (m, 1H), 2.35 (dd, J = 0.6, 2.0 Hz, 1H), 1.41 (dd, J = 0.9, 6.4 Hz, 3H), 1.10 (d, J = 1.0 Hz, 9H).

[0271] Preparation of compound 16-3

[0272] Methyl lithium ethyl ether solution (15.2 mL, 24.31 mmol, 1.6 M) was slowly added to a solution of compound 16-2 (5 g, 16.21 mmol) in tetrahydrofuran (100 mL) at -70 °C under nitrogen atmosphere. The reaction was stirred at -70 °C for 1 h. Then, paraformaldehyde (0.73 g, 24.31 mmol) was added to the reaction mixture in portions. The mixture was warmed to 22 °C and stirred for 12 h. After completion of the reaction, the reaction was quenched by the dropwise addition of saturated aqueous ammonium chloride solution (50 mL) at 0 °C. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 16-3.

[0273] 1 H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 6.6 Hz, 2H), 7.70 (d, J = 6.5 Hz, 2H), 7.48-7.35 (m, 6H), 4.54 (q, J = 6.4 Hz, 1H), 4.10-4.06 (m, 2H), 1.42 (d, J = 6.5 Hz, 3H), 1.21-1.14 (m, 1H), 1.08 (s, 9H).

[0274] Preparation of compound 16-4

[0275] Under nitrogen atmosphere, tributyl cyanomethyl phosphonium bromide (236.44 mg, 0.98 mmol) was added to a solution of 1-18 (150 mg, 0.33 mmol) and compound 16-3 (1105.38 mg, 3.27 mmol) in 1,4-dioxane (1.5 mL), the reaction was stirred at 25 °C for 12 h. After the reaction was completed, the reaction was filtered, the filtrate was purified by reverse phase column (0.1% formic acid system) to obtain compound 16-4.

[0276] 1 H NMR (400 MHz, CDCl3): δ 8.69 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 8.14 (dd, J = 2.1, 5.5 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.89-7.84 (m, 1H), 7.68 (dd, J = 1.5, 7.9 Hz, 2H), 7.61 (dd, J = 1.3, 7.9 Hz, 2H), 7.45-7.32 (m, 7H), 7.15-7.08 (m, 1H), 7.00-6.90 (m, 1H), 5.65 (d, J = 4.1 Hz, 1H), 5.01 (d, J = 11.3 Hz, 1H), 4.76 (q, J = 15.1 Hz, 2H), 4.42 (q, J = 6.5 Hz, 1H), 2.89-2.78 (m, 1H), 1.64 (s, 3H), 1.29-1.27 (m, 3H), 1.01 (s, 9H), 0.82-0.77 (m, 3H);

[0277] m / z (ESI): [M+H] + = 780.2.

[0278] Preparation of example 16

[0279] Under nitrogen atmosphere, ammonium fluoride (189.98 mg, 5.13 mmol) was added to a solution of compound 16-4 (200 mg, 0.26 mmol) in methanol (4 mL), the reaction was stirred at 25 °C for 12 h. After the reaction was completed, the reaction was filtered, the filtrate was purified by reverse phase preparation (Phenomenex luna C18 150 x 40 mm x 15 um; mobile phase: water (FA)-ACN; B%: 42%-72%, 15 min) to obtain example 16.

[0280] 1H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 8.49 (d, J = 5.4 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H), 8.07 (d, J = 2.1 Hz, 1H), 7.84 (dd, J = 2.2, 5.6 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.27 - 7.14 (m, 2H), 5.32 (d, J = 5.4 Hz, 1H), 5.12 (d, J = 10.5 Hz, 1H), 4.93 (s, 2H), 4.40 - 4.22 (m, 2H), 2.90 - 2.81 (m, 1H), 1.62 (s, 3H), 1.20 (d, J = 6.5 Hz, 3H), 0.74 (d, J = 6.6 Hz, 3H);

[0281] m / z (ESI): [M+H] + = 542.2.

[0282] Example 17

[0283] Preparation of compound 17-2

[0284] Compound 17-2 was prepared according to the method described in the preparation of compound 17-1, using compound 17-1 (2 g, 28.53 mmol) and tert-butyldiphenylsilyl chloride (8.63 g, 31.39 mmol) as the starting materials.

[0285] 1 H NMR (400 MHz, CDCl3): δ 7.77 (dd, J = 1.3, 7.8 Hz, 2H), 7.73 - 7.68 (m, 2H), 7.48 - 7.36 (m, 6H), 4.47 (dq, J = 2.0, 6.5 Hz, 1H), 2.35 (d, J = 2.1 Hz, 1H), 1.41 (d, J = 6.5 Hz, 3H), 1.10 (s, 9H).

[0286] Preparation of compound 17-3

[0287] Methyl lithium ethyl ether solution (4.9 mL, 7.78 mmol, 1.6 M) was slowly added to a solution of compound 17-2 (1.6 g, 5.19 mmol) in tetrahydrofuran (30 mL) at -70 °C under nitrogen atmosphere. After the reaction solution was stirred at -70 °C for 1 h, paraformaldehyde (0.47 g, 15.56 mmol) was added to the reaction solution in portions. The mixture was warmed to 27 °C and stirred for 12 h. After the reaction was completed, the reaction solution was cooled to 0 °C, and saturated aqueous ammonium chloride solution (15 mL) was added dropwise to quench the reaction. The aqueous phase was extracted with ethyl acetate (20 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 17-3.

[0288] 1 H NMR (400 MHz, CDCl3): δ 7.77 (dd, J = 1.1, 7.6 Hz, 2H), 7.73-7.68 (m, 2H), 7.49-7.35 (m, 6H), 4.60-4.50 (m, 1H), 4.09 (d, J = 1.4 Hz, 2H), 1.42 (d, J = 6.5 Hz, 3H), 1.08 (s, 9H).

[0289] Preparation of compound 17-4

[0290] Under nitrogen atmosphere, tri-butyl cyanomethyl phosphonium (157.62 mg, 0.65 mmol) was added to a solution of 1-18 (100 mg, 0.22 mmol) and compound 17-3 (736.92 mg, 2.18 mmol) in 1,4-dioxane (1 mL), and the reaction solution was stirred at 25 °C for 12 h. The reaction solution was filtered, and the filtrate was purified by reverse phase column chromatography (0.1% formic acid system) to give compound 17-4.

[0291] 1H NMR (400 MHz, CDC13): δ 8.61 (s, 1H), 8.36 (d, J = 5.6 Hz, 1H), 8.08 (dd, J = 2.2, 5.6 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.84-7.79 (m, 1H), 7.61 (dd, J = 1.3, 7.9 Hz, 2H), 7.58-7.52 (m, 2H), 7.39-7.23 (m, 7H), 7.09-7.02 (m, 1H), 6.94-6.83 (m, 1H), 5.56 (br d, J = 3.5 Hz, 1H), 4.94 (d, J = 11.3 Hz, 1H), 4.80-4.58 (m, 2H), 4.35 (q, J = 6.5 Hz, 1H), 2.79-2.67 (m, 1H), 1.55 (s, 3H), 1.20 (s, 3H), 0.95 (s, 9H), 0.70 (dd, J = 1.9, 5.3 Hz, 3H);

[0292] m / z (ESI): [M+H] + = 780.3.

[0293] Preparation of Example 17

[0294] Ammonium fluoride (132.98 mg, 3.59 mmol) was added to a solution of compound 17-4 (140 mg, 0.18 mmol) in methanol (3 mL) under nitrogen atmosphere, and the reaction was stirred at 25 °C for 12 hours. After the reaction was completed, the reaction was filtered, and the filtrate was purified by reverse phase preparative purification (Phenomenex luna C18 150*25 mm*10 um; mobile phase: water (FA)-ACN; B%: 42%-72%, 15 min) to obtain Example 17.

[0295] 1 H NMR (400 MHz, DMSO-d6): δ 10.73 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.1 Hz, 1H), 7.84 (dd, J = 2.1, 5.5 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.28-7.15 (m, 2H), 5.32 (d, J = 5.4 Hz, 1H), 5.12 (d, J = 10.5 Hz, 1H), 4.94 (s, 2H), 4.40-4.23 (m, 2H), 2.90-2.79 (m, 1H), 1.63 (s, 3H), 1.15 (d, J = 6.6 Hz, 3H), 0.74 (d, J = 6.1 Hz, 3H);

[0296] m / z (ESI): [M+H] 542.1. + = 542.1.

[0297] Preparation of Example 18

[0298] Preparation of compound 18-2

[0299] Deuterium lithium aluminum hydride (0.34 g, 8.15 mmol) was added slowly in batches to a solution of compound 18-1 (1 g, 10.19 mmol) in diethyl ether (15 mL) at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 1 h. Deuterium water (1 mL) was added to quench the reaction. The reaction was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give compound 18-2.

[0300] 1 H NMR (400 MHz, CDCl3): d 1.85 (s, 3H).

[0301] Preparation of Example 18

[0302] Tert-butyl cyanomethylphosphonium bromide (231.18 mg, 0.96 mmol) and compound 18-2 (138.12 mg, 1.92 mmol) were added to a solution of compound 1-18 (100 mg, 0.19 mmol) in dioxane (1 mL) under nitrogen atmosphere. The reaction was stirred at 40 °C for 16 h. After the reaction was completed, the reaction was quenched by water (30 mL). The reaction was extracted by ethyl acetate (30 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative reversed-phase chromatography (Column: Waters Xbridge 150 x 25 mm x 5 um; Condition: water (NH4HCO3) - ACN; Begin B: 43, End B: 73; Gradient Time (min): 15; 100% B Hold Time (min): 4, Flow Rate (ml / min): 25) to give Example 18.

[0303] 1H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.28 - 7.14 (m, 2H), 5.12 (d, J = 10.8 Hz, 1H), 4.37 (dd, J = 7.2, 10.8 Hz, 1H), 2.90 - 2.79 (m, 1H), 1.75 (s, 3H), 1.62 (s, 3H), 0.73 (d, J = 6.0 Hz, 3H);

[0304] m / z (ESI): [M+H] + = 514.1.

[0305] Example 19

[0306] Preparation of compound 19-2

[0307] Compound 19-2 was prepared according to the method described in the preparation of compound 19-1, using compound 19-2 as the starting material.

[0308] 1 H NMR (400 MHz, CDCl3): δ 4.44 (s, 2H), 3.79 (s, 3H), 0.92 (s, 9H), 0.14 (s, 6H).

[0309] Preparation of compound 19-3

[0310] Deuterium lithium aluminum hydride (0.29 g, 7.01 mmol) was added slowly in batches to a solution of compound 19-2 (2.00 g, 8.76 mmol) in tetrahydrofuran (100 mL) at -70 °C under nitrogen atmosphere. The mixture was stirred at -70 °C for 2 h, then warmed to 0 °C, 1 mL deuterium water was added slowly to quench the reaction, and the mixture was stirred for 10 min before warming to 25 °C. After drying, filtering, and concentrating the filtrate under reduced pressure to dryness, the crude product was obtained. Purification by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) gave compound 19-3.

[0311] 1 H NMR (400 MHz, DMSO-d6): δ 5.12 (s, 1H), 4.32 (s, 2H), 0.87 (s, 9H), 0.08 (s, 6H).

[0312] Preparation of compound 19-4

[0313] Methanesulfonic anhydride (194 mg, 1.11 mmol) was added slowly to a solution of compound 19-3 (300 mg, 1.48 mmol) and triethylamine (0.6 mL, 4.45 mmol) in dichloromethane (3 mL) under nitrogen atmosphere. The reaction was stirred at 25 °C for 2 h. After the reaction was completed, 20 mL water was added to quench the reaction, and the aqueous phase was extracted with dichloromethane (10 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to give compound 19-4.

[0314] 1 H NMR (400 MHz, DMSO-d6): δ 5.12 (s, 1H), 4.32 (s, 2H), 0.87 (s, 9H), 0.08 (s, 6H).

[0315] Preparation of compound 19-5

[0316] Compound 19-4 (183 mg, 0.65 mmol) was added to a solution of compound 1-18 (100 mg, 0.22 mmol) and potassium carbonate (150 mg, 1.09 mmol) in N-N, dimethylformamide (2 mL) under nitrogen atmosphere. The reaction was stirred at 60 °C for 12 h. After the reaction was completed, the reaction was diluted with 20 mL water, and the aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to give a crude product. Purification by reverse phase preparation (0.1% FA / ACN, 80% to 90% over 10 min) gave compound 19-5.

[0317] 1H NMR (400 MHz, CDC13): δ 8.66 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 8.16 (dd, J = 2.4, 5.6 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.88-7.81 (m, 1H), 7.16-7.10 (m, 1H), 7.03-6.91 (m, 1H), 5.58 (br s, 1H), 5.02 (d, J = 11.2 Hz, 1H), 4.21 (d, J = 1.6 Hz, 2H), 2.93-2.84 (m, 1H), 1.71 (s, 3H), 0.85 (s, 9H), 0.83-0.78 (m, 3H), 0.02 (s, 6H);

[0318] m / z (ESI): [M+H] + = 644.3.

[0319] Preparation of Example 19

[0320] A solution of compound 19-5 (60.0 mg, 0.09 mmol) in 3 mL of hydrochloric acid / methanol (2M) was stirred at 25 °C for 0.5 h under nitrogen atmosphere. After the reaction was completed, the crude product was concentrated under reduced pressure. Example 19 was obtained by separation and purification by reverse phase column (column: Waters Xbridge 150 x 25 mm x 5 um, 30% to 60% over 10 min).

[0321] 1 H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 2.4, 5.6 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.26-7.14 (m, 2H), 5.19 (t, J = 6.0 Hz, 1H), 5.11 (d, J = 10.4 Hz, 1H), 4.34 (dd, J = 7.6, 10.4 Hz, 1H), 4.06 (d, J = 4.0 Hz, 2H), 2.92-2.80 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H);

[0322] m / z (ESI): [M+H] + = 530.1.

[0323] Example 20

[0324] Preparation of Example 20

[0325] Under a nitrogen atmosphere, deuterated water (0.2 mL, 9.30 mmol) and potassium carbonate (15.42 mg, 0.11 mmol) were added to a 1 mL acetonitrile solution containing 50 mg of Example 12 (0.09 mmol). The reaction was stirred at 24°C for 12 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was isolated and purified using a reverse phase preparative chromatography (column: Phenomenex 150 × 25 mm × 10 μm, Condition: water (FA)-CAN; Begin B: 48, End B: 78, Gradient Time (min): 11, 100% B Hold Time (min): 4, Flow Rate (ml / min): 2) to obtain Example 20.

[0326] 1 H NMR (400MHz, DMSO-d6): δ10.71(s,1H),8.49(d,J=5.4Hz,1H),8.27(d,J=2.0Hz,1H),8.06(d,J=2.4Hz,1H),7.83(dd,J=2.4,5.4Hz,1H),7.62(d ,J=2.0Hz,1H),7.28-7.14(m,2H),5.12(d,J=10.2Hz,1H),4.33(dd,J=7.6,10.2Hz,1H),2.90-2.78(m,1H),1.62(s,3H),0.74(d,J=6.0Hz,3H);

[0327] m / z(ESI):[M+H] + =501.1.

[0328] Example 21

[0329] Preparation of compound 21-1

[0330] Under nitrogen atmosphere, compound 1-15 (200 mg, 0.54 mmol) was added to methanol (2 mL), and the mixture was stirred at 25°C for 2 hours. The reaction solution was concentrated to dryness to obtain compound 21-1.

[0331] m / z(ESI):[M+H] + =369.0.

[0332] Preparation of compound 21-2

[0333] To a solution of compound 21-1 (2.00 g, 5.43 mmol) in dichloromethane (40 mL) was added boron tribromide (2.04 g, 8.15 mmol) dropwise at 0 °C. The mixture was stirred at 25 °C for 1.5 h. To the reaction mixture was added saturated aqueous sodium bicarbonate solution (20 mL) slowly dropwise. The mixture was extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was separated and purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give compound 21-2.

[0334] m / z (ESI): [M+H] + = 355.1.

[0335] Preparation of compound 21-3

[0336] Propargyl bromide (0.34 g, 2.82 mmol) was added to a suspension of compound 21-2 (1.00 g, 2.82 mmol) and potassium carbonate (1.95 g, 14.11) in DMF (10 mL). The mixture was stirred at 60 °C for 2 h. The reaction mixture was filtered and the filtrate was purified by reverse phase column chromatography (0.1% formic acid system) to give compound 21-3.

[0337] m / z (ESI): [M+H] + = 393.1.

[0338] Preparation of compound 21-4

[0339] To a solution of compound 21-3 (930 mg, 2.37 mmol) in THF (12 mL), methanol (4 mL) and water (4 mL) was added lithium hydroxide (497.33 mg, 11.85 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (30 mL) and adjusted to pH 4 with dilute hydrochloric acid (1 mol / L). The mixture was extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give compound 21-4.

[0340] m / z (ESI): [M-H] - = 377.0.

[0341] Preparation of compound 21-5

[0342] To a solution of compound 21-4 (70 mg, 0.19 mmol) in DCM (2 mL) was added DMF (2.9 μL, 0.04 mmol) and oxalyl chloride (31.8 μL, 0.37 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated to give compound 21-5.

[0343] Preparation of compound 21-6

[0344] Preparation of compound 21-8

[0345] Di-tert-butyl dicarbonate (2.8 mL, 13.1 mmol) and triethylamine (1.8 mL, 13.1 mmol) were added to a solution of compound 21-7 (1.00 g, 6.57 mmol) and 4-dimethylaminopyridine (0.40 g, 3.29 mmol) in 10 mL of dichloromethane under nitrogen atmosphere. The reaction was stirred at 26 °C for 16 hours. Di-tert-butyl dicarbonate (2.8 mL, 13.1 mmol) was added and the reaction was stirred at 40 °C for another 16 hours. After the reaction was completed, the reaction was diluted with 200 mL of water, the aqueous phase was extracted with dichloromethane (100 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give compound 21-8.

[0346] 1 H NMR (400 MHz, CDCl3): δ 8.57 (d, J = 5.6 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.71 (dd, J = 2.0, 5.6 Hz, 1H), 7.00 (s, 1H), 4.00 (s, 3H), 1.54 (s, 9H);

[0347] m / z (ESI): [M+H] + = 253.0.

[0348] Preparation of compound 21-9

[0349] M-chloroperbenzoic acid (965.69 mg, 4.76 mmol, 85% content) was slowly added to a solution of compound 21-8 (600 mg, 2.38 mmol) in 10 mL of dichloromethane at 0 °C, and the reaction was stirred at 26 °C for 16 hours. After the reaction was completed, the reaction was filtered, and the filtrate was slowly added to 50 mL of saturated aqueous sodium sulfite solution to quench, and after the reaction was negative by starch iodide test, the aqueous phase was extracted with dichloromethane (20 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 100% methanol elution) to give compound 21-9.

[0350] 1H NMR (400 MHz, CDC13): δ 8.13 (d, J = 7.2 Hz, 1H), 7.86 (s, 1H), 7.53 (d, J = 4.8 Hz, 1H), 3.96 (s, 3H), 1.51 (s, 9H);

[0351] m / z (ESI): [M+H] + = 269.0.

[0352] Preparation of compound 21-6

[0353] Compound 21-6 was prepared by slowly adding trifluoroacetic acid (2.00 mL, 26.9 mmol) to a solution of compound 21-9 (170 mg, 0.63 mmol) in 2 mL of dichloromethane under nitrogen atmosphere. The mixture was stirred at 25 °C for 2 hours and then concentrated. The residue was adjusted to pH 10 with triethylamine and purified by reverse phase preparative (0.1% FA / ACN, 100% water over 3 min).

[0354] Preparation of compound 21-10

[0355] Compound 21-10 was prepared by adding compound 21-5 (70.0 mg, 0.18 mmol) to a solution of compound 21-6 (148 mg, 0.88 mmol) and triethylamine (0.1 mL, 0.88 mmol) in 0.5 mL of dichloromethane under nitrogen atmosphere. The reaction was stirred at 25 °C for 1.5 hours. After completion of the reaction, the reaction was quenched with 20 mL of water. The aqueous phase was extracted with dichloromethane (10 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by reverse phase preparative (0.1% FA / ACN, 50% to 60% over 5 min) to give compound 21-10.

[0356] m / z (ESI): [M+H] + = 529.2.

[0357] Preparation of example 21

[0358] Example 21 was prepared by adding compound 21-10 (70.0 mg, 0.13 mmol) to 10 mL of ammonium hydroxide (7 M) under nitrogen atmosphere. The reaction was stirred at 25 °C for 16 hours and then concentrated to give a crude product. The crude product was purified by reverse phase preparative (column: Waters Xbridge 150 x 25 mm x 5 um, 32% to 62% over 11 min) to give example 21.

[0359] 1H NMR (400 MHz, DMSO-d6): δ = 10.78 (s, 1H), 10.59 (d, J = 4.4 Hz, 1H), 8.52 (d, J = 3.2 Hz, 1H), 8.31 (d, J = 7.2 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 7.88 (dd, J = 3.2, 7.2 Hz, 1H), 7.26-7.16 (m, 2H), 5.10 (d, J = 10.4 Hz, 1H), 4.98-4.85 (m, 2H), 4.32 (dd, J = 7.6, 10.4 Hz, 1H), 3.63 (t, J = 2.4 Hz, 1H), 2.88-2.66 (m, 1H), 1.62 (s, 3H), 0.73 (d, J = 6.0 Hz, 3H);

[0360] m / z (ESI): [M+H] + = 514.1.

[0361] Examples 22, 23

[0362] Preparation of compound 22-2

[0363] Cesium carbonate (20.55 g, 63.08 mmol), [1,1-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane (1.29 g, 1.58 mmol) were added to a mixture solution of compound 22-1 (5 g, 31.54 mmol) and potassium ethylene trifluoroborate (5.07 g, 37.85 mmol) in 150 mL of 2-methyltetrahydrofuran and 15 mL of water under nitrogen atmosphere, the reaction solution was warmed to 90 °C and stirred for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated, 50 mL of water was added to the residue to dilute, extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by reverse phase preparation (0.1% FA system) and silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1~2 / 1) in sequence to obtain compound 22-2.

[0364] 1 H NMR (400 MHz, CDCl3): δ 9.39 (d, J = 2.4 Hz, 1H), 8.44 (dd, J = 2.4, 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 6.91 (dd, J = 10.8, 17.6 Hz, 1H), 6.46 (d, J = 17.6 Hz, 1H), 5.75 (d, J = 10.8 Hz, 1H).

[0365] Preparation of compound 22-3

[0366] A solution of osmium tetroxide (63.55 mg, 0.25 mmol) in 4.3 mL of water was added slowly to a mixture of N-methylmorpholine N-oxide (4353.92 mg, 37.17 mmol), compound 22-2 (1860.00 mg, 12.39 mmol), 4.3 mL of water and 16 mL of acetone under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 25 °C for another 3 hours. After the reaction was completed, the reaction solution was cooled to 0 °C, quenched by adding 50 mL of saturated aqueous sodium sulfite solution, stirred for 15 minutes, and then the aqueous phase was extracted with 50 mL of ethyl acetate (15 times). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to obtain compound 22-3.

[0367] 1 H NMR (400 MHz, DMSO-d6): δ 9.29 (d, J = 2.4 Hz, 1H), 8.58 (dd, J = 2.8, 8.8 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 5.76 (d, J = 5.2 Hz, 1H), 4.79 (t, J = 6.0 Hz, 1H), 4.72 (q, J = 5.2 Hz, 1H), 3.78-3.69 (m, 1H), 3.62-3.53 (m, 1H).

[0368] Preparation of compound 22-4

[0369] Under nitrogen atmosphere, p-toluenesulfonic acid (120 mg, 0.67 mmol) and 2,2-dimethoxypropane (2.1 mL, 16.70 mmol) were added to a mixture of compound 22-3 (1230.00 mg, 6.68 mmol) in 20 mL of 2-methyltetrahydrofuran and 20 mL of acetone, and the reaction solution was stirred at 25 °C for 16 hours. After the reaction was completed, 10 mL of saturated aqueous sodium bicarbonate solution was added to quench the reaction, 50 mL of water was added to dilute the solution, and the aqueous phase was extracted with 50 mL of ethyl acetate (3 times). The combined organic phase was washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 22-4.

[0370] 1H NMR (400 MHz, DMSO-d6): δ 9.32 (d, J = 2.4 Hz, 1H), 8.63 (dd, J = 2.4, 8.4 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 5.27 (t, J = 6.4 Hz, 1H), 4.45 (dd, J = 7.2, 8.4 Hz, 1H), 3.91 (dd, J = 6.0, 8.4 Hz, 1H), 1.46 (s, 3H), 1.43 (s, 3H);

[0371] m / z (ESI): [M+H] + = 224.9.

[0372] Preparation of compound 22-5

[0373] Under argon atmosphere, 10% palladium carbon catalyst (wet) (100 mg) was added to a solution of compound 22-4 (700 mg, 3.12 mmol) in 28 mL of ethyl acetate, after hydrogen replacement for three times, the reaction solution was stirred at 25 °C for 6 hours under hydrogen (15 psi) atmosphere. After the reaction was completed, the reaction solution was filtered through diatomite, and the filtrate was concentrated under reduced pressure to obtain compound 22-5.

[0374] Preparation of compound 22-6

[0375] Under nitrogen atmosphere, triethylamine (559.4 μL, 4.02 mmol) was added to a solution of compound 1-15 (500 mg, 1.34 mmol) and compound 22-5 (260.56 mg, 1.34 mmol) in 10 mL of dichloromethane, and the reaction solution was reacted at 25 °C for 1 hour. After the reaction was completed, 10 mL of water was added to dilute the reaction solution, and the aqueous phase was extracted with dichloromethane (15 mL x 3), and the combined organic phase was washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 ~ 2 / 1) to obtain compound 22-6.

[0376] 1H NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 8.70 (dd, J = 2.4, 5.2 Hz, 1H), 8.05 (ddd, J = 2.4, 5.2, 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.22-7.10 (m, 2H), 5.17-4.99 (m, 2H), 4.32 (dd, J = 6.8, 8.0 Hz, 1H), 4.23 (dd, J = 7.6, 10.4 Hz, 1H), 3.94 (d, J = 2.0 Hz, 3H), 3.81 (dd, J = 6.8, 8.0 Hz, 1H), 2.79-2.72 (m, 1H), 1.60 (s, 3H), 1.41 (s, 3H), 1.38 (s, 3H), 0.73 (d, J = 6.0 Hz, 3H);

[0377] m / z (ESI): [M+H] + = 531.2.

[0378] Preparation of compound 22-7

[0379] Bromotrimethylsilane (0.8 mL, 1.67 mmol) was slowly added to compound 22-6 (590 mg, 1.11 mmol) in 12 mL of dichloromethane under nitrogen atmosphere at 0°C, and the reaction was stirred at 25°C for 1.5 hours. After the reaction was completed, 10 mL of saturated sodium bicarbonate solution was added to quench the reaction, and the aqueous phase was extracted with 20 mL of dichloromethane (3 times), and the combined organic phase was washed with 40 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) and reverse phase column chromatography (0.1% formic acid system) to obtain compound 22-7.

[0380] 1H NMR (400 MHz, DMSO-d6): δ 10.49 (br s, 1H), 8.66 (dd, J = 2.4, 9.2 Hz, 1H), 8.35 (s, 1H), 7.99 (dt, J = 2.4, 8.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.01 (t, J = 6.8 Hz, 1H), 6.80 (q, J = 8.8 Hz, 1H), 5.57 - 5.20 (m, 1H), 5.10 (d, J = 10.4 Hz, 1H), 4.89 - 4.59 (m, 1H), 4.53 (dd, J = 4.4, 6.8 Hz, 1H), 4.22 (dd, J = 7.6, 10.0 Hz, 1H), 3.62 (dd, J = 4.0, 10.8 Hz, 2H), 2.83 (t, J = 7.2 Hz, 1H), 1.58 (s, 3H), 0.70 (d, J = 6.0 Hz, 3H);

[0381] m / z (ESI): [M+H] + = 477.2.

[0382] Preparation of Examples 22, 23

[0383] Bromopropynyl (32.6 μL, 0.38 mmol) was slowly added to a solution of compound 22-7 (90 mg, 0.19 mmol) and potassium carbonate (130.54 mg, 0.94 mmol) in 1.5 mL of N-N, dimethylformamide under nitrogen atmosphere, the reaction was warmed to 60 °C and stirred for 2 hours. After the reaction was completed, the reaction was cooled to room temperature, filtered, and the filtrate was purified by reverse phase preparative purification (Waters Xbridge 150 x 25 mm x 5 um; mobile phase: water (NH4HCO3) - ACN; B%: 40% - 60%, 25 min) to give a mixture of Example 22 and Example 23; the mixture was separated by SFC (Column: DAICEL CHIRALCEL OX (250 mm x 30 mm x 10 um); Condition: CO2-EtOH (0.1% NH3H2O); B%: 15 - 15; Gradient Time (min): 6.2; 100% B Hold Time (min): 0; Flow Rate (ml / min): 150) to give two single isomers.

[0384] Example 22 (retention time = 1.505 min):

[0385] 1H NMR (400 MHz, DMSO-d6): δ 10.36 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 2.4, 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.27 - 7.15 (m, 2H), 5.33 (d, J = 4.4 Hz, 1H), 5.10 (d, J = 10.4 Hz, 1H), 4.92 (dd, J = 2.4, 4.0 Hz, 2H), 4.64 (t, J = 5.6 Hz, 1H), 4.53 (td, J = 4.4, 6.8 Hz, 1H), 4.31 (dd, J = 7.6, 10.4 Hz, 1H), 3.66 (t, J = 2.4 Hz, 1H), 3.62 (ddd, J = 4.4, 6.0, 10.8 Hz, 1H), 3.43 (td, J = 6.4, 11.2 Hz, 1H), 2.83 (t, J = 7.6 Hz, 1H), 1.60 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H);

[0386] m / z (ESI): [M+H] = 515.3. +

[0387] Example 23 (retention time = 1.649 minutes):

[0388] 1 H NMR (400 MHz, DMSO-d6): δ 10.36 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 2.4, 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.27 - 7.15 (m, 2H), 5.33 (d, J = 4.4 Hz, 1H), 5.10 (d, J = 10.4 Hz, 1H), 4.92 (dd, J = 2.4, 4.0 Hz, 2H), 4.64 (t, J = 5.6 Hz, 1H), 4.53 (td, J = 4.4, 6.8 Hz, 1H), 4.31 (dd, J = 7.6, 10.4 Hz, 1H), 3.66 (t, J = 2.4 Hz, 1H), 3.62 (ddd, J = 4.4, 6.0, 10.8 Hz, 1H), 3.43 (td, J = 6.4, 11.2 Hz, 1H), 2.83 (t, J = 7.6 Hz, 1H), 1.60 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H);

[0389] m / z (ESI): [M+H] = 515.2. +

[0390] Examples 24, 25

[0391] ​​Preparation of compound 24-1

[0392] Compound 24-1 was prepared according to the following reaction scheme: Under nitrogen atmosphere, cyanomethylene tri-n-butylphosphonium (7.15 g, 29.64 mmol) was added to a solution of compound 21-2 (2.10 g, 5.93 mmol) and compound 12-2 (3.86 g, 29.64 mmol) in 80 mL of dioxane, and the reaction was stirred at 40 °C for 16 h. After the reaction was completed, the reaction was cooled to room temperature, quenched with 100 mL of water, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1-30 / 1) to give compound 24-1.

[0393] 1 H NMR (400 MHz, CDCl3): δ 6.98-6.92 (m, 1H), 6.92-6.86 (m, 1H), 4.92 (d, J = 10.4 Hz, 1H), 4.28-4.19 (m, 1H), 3.71 (s, 3H), 2.91-2.69 (m, 1H), 1.65 (s, 3H), 0.81-0.74 (m, 3H), 0.15 (s, 9H).

[0394] Preparation of compound 24-2

[0395] Under nitrogen atmosphere, a solution of lithium hydroxide (1.01 g, 24.1 mmol) in 8 mL of water was added dropwise to a solution of compound 24-1 (2.25 g, 4.82 mmol) in 24 mL of tetrahydrofuran and 8 mL of methanol, and the reaction was stirred at 26 °C for 1 h. After the reaction was completed, the low-boiling-point solvent was removed by concentration under reduced pressure, and the residue was adjusted to pH 5 with 2M dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (20 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-ethyl acetate / methanol = 5 / 1) to give compound 24-2.

[0396] 1 H NMR (400 MHz, DMSO-d6): δ 7.24-7.08 (m, 2H), 4.76 (d, J = 10.4 Hz, 1H), 4.16-4.05 (m, 1H), 3.64 (s, 1H), 2.74-2.66 (m, 1H), 1.51 (s, 3H), 0.67 (d, J = 6.0 Hz, 3H);

[0397] m / z (ESI): [M-H] - = 379.1.

[0398] Preparation of compound 24-3

[0399] Oxalyl chloride (67.7 μL, 0.79 mmol) was added slowly dropwise to a solution of compound 24-2 (100 mg, 0.26 mmol) and N,N-dimethylformamide (2.0 μL, 0.03 mmol) in 2 mL of dichloromethane under nitrogen atmosphere. The reaction was stirred at 26 °C for 2 hours. After the reaction was completed, the reaction was concentrated under reduced pressure to obtain compound 24-3.

[0400] Preparation of compound 24-5

[0401] A solution of compound 24-3 (100 mg, 0.25 mmol) in 1 mL of dichloromethane was added dropwise to a solution of compound 24-4 (70.3 mg, 0.5 mmol) and triethylamine (0.1 mL, 0.75 mmol) in 1 mL of dichloromethane under nitrogen atmosphere. The reaction was stirred at 26 °C for 1 hour. After the reaction was completed, the reaction was diluted with 50 mL of water. The aqueous phase was extracted with dichloromethane (20 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 ~ 5 / 1) to obtain compound 24-5.

[0402] 1 H NMR (400 MHz, CDCl3): δ 8.39-8.28 (m, 2H), 7.52 (d, J = 2.0 Hz, 1H), 7.16-7.11 (m, 1H), 7.09 (dd, J = 2.0, 5.6 Hz, 1H), 7.03-6.95 (m, 1H), 4.99 (d, J = 11.2 Hz, 1H), 4.20 (s, 1H), 2.88-2.76 (m, 1H), 2.54 (s, 3H), 2.37 (s, 1H), 1.70 (s, 3H), 0.84-0.76 (m, 3H);

[0403] m / z (ESI): [M+H] + = 503.2.

[0404] Preparation of Examples 24, 25

[0405] Iodobenzene diacetate (216.7 mg, 0.67 mmol) was added to a solution of compound 24-5 (160 mg, 0.32 mmol) and ammonium acetate (39.27 mg, 0.51 mmol) in 4 mL of methanol under nitrogen atmosphere. The reaction was stirred at 26 °C for 1 h. After the reaction was completed, the reaction was diluted with 20 mL of water and the low boiling point solvent was removed by concentration under reduced pressure. The aqueous phase was extracted with ethyl acetate (10 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by reverse phase preparation (0.1% NH4OH, 40% to 50% over 10 min) and then separated by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm), CO2-EtOH (0.1% NH3·H2O), 25% over 4.1 min, flow rate: 60 mL / min) to give two single isomers.

[0406] Example 24 (retention time = 1.265 min):

[0407] 1 H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 2.0, 5.6 Hz, 1H), 7.30-7.13 (m, 2H), 5.13 (d, J = 10.4 Hz, 1H), 4.39-4.27 (m, 2H), 3.63 (s, 1H), 3.11 (s, 3H), 2.89-2.78 (m, 1H), 1.61 (s, 3H), 0.74 (d, J = 6.4 Hz, 3H);

[0408] m / z (ESI): [M+H] + = 534.1.

[0409] Example 25 (retention time = 1.412 min):

[0410] 1H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 2.0, 5.6 Hz, 1H), 7.29 - 7.14 (m, 2H), 5.13 (d, J = 10.4 Hz, 1H), 4.39 - 4.28 (m, 2H), 3.63 (s, 1H), 3.11 (d, J = 1.2 Hz, 3H), 2.90 - 2.78 (m, 1H), 1.61 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H);

[0411] m / z (ESI): [M+H] + = 534.1.

[0412] Example 26

[0413] Preparation of compound 26-2

[0414] Compound 26-1 (380 mg, 2.55 mmol) was added to 10 mL of ammonium hydroxide solution (6 M) under nitrogen atmosphere, and the reaction solution was stirred at 25 °C for 20 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 ~ 1 / 1, dichloromethane / methanol = 20 / 1 ~ 10 / 1) to obtain compound 26-2.

[0415] 1 H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 2.0, 5.6 Hz, 1H), 7.29 - 7.14 (m, 2H), 5.13 (d, J = 10.4 Hz, 1H), 4.39 - 4.28 (m, 2H), 3.63 (s, 1H), 3.11 (d, J = 1.2 Hz, 3H), 2.90 - 2.78 (m, 1H), 1.61 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H);

[0416] Preparation of compound 26-3

[0417] Compound 26-3 was prepared according to the method described in the preparation of compound 26-2. Under nitrogen atmosphere, imidazole (40.97 mg, 0.60 mmol) and tert-butyldimethylsilyl chloride (68.02 mg, 0.45 mmol) were added to a solution of compound 26-2 (50.0 mg, 0.30 mmol) in 1 mL of N,N-dimethylformamide, and the reaction was stirred at 25 °C for 12 hours. After the reaction was completed, 20 mL of water was added to quench the reaction, and the aqueous phase was extracted with 20 mL of ethyl acetate (20 mL x 2). The combined organic phase was washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 ~ 0 / 1) to obtain compound 26-3.

[0418] 1 H NMR (400 MHz, DMSO-d6): δ 7.61 (brs, 1H), 7.21 (brs, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.58 (dd, J = 2.4, 8.0 Hz, 1H), 5.14 (s, 2H), 4.65 (s, 2H), 0.86 (s, 9H), 0.04 (s, 6H).

[0419] Preparation of compound 26-4

[0420] Compound 26-4 was prepared according to the method described in the preparation of compound 26-2. Under nitrogen atmosphere, compound 26-3 (53.97 mg, 0.19 mmol) and triethylamine (87.1 μL, 0.63 mmol) were added to a solution of compound 24-3 (50.0 mg, 0.13 mmol) in 2 mL of dichloromethane, and the reaction was stirred at 25 °C for 1 hour. After the reaction was completed, 20 mL of water was added to quench the reaction, and the aqueous phase was extracted with 20 mL of dichloromethane (20 mL x 2). The combined organic phase was washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 ~ 1 / 1) to obtain compound 26-4.

[0421] 1H NMR (400 MHz, CDC13): δ 8.47 (s, 1H), 8.03-7.93 (m, 2H), 7.75 (d, J = 2.4 Hz, 1H), 7.29 (s, 1H), 7.20-7.15 (m, 1H), 7.02-6.94 (m, 1H), 5.68 (br s, 1H), 5.00 (d, J = 11.2 Hz, 1H), 4.78 (s, 2H), 4.25 (dd, J = 7.6, 11.2 Hz, 1H), 2.88-2.75 (m, 1H), 2.38 (s, 1H), 1.71 (s, 3H), 0.88 (s, 9H), 0.83-0.78 (m, 3H), 0.10 (s, 6H);

[0422] m / z (ESI): [M+H] + = 643.3.

[0423] Preparation of Example 26

[0424] Tetrabutylammonium fluoride tetrahydrofuran solution (133.4 μL, 0.13 mmol, 1M) was added to a solution of compound 26-4 (60.0 mg, 0.09 mmol) in 1 mL of tetrahydrofuran under nitrogen atmosphere, and the reaction was allowed to react at 25 °C for 0.5 hours. After the reaction was completed, the crude product was concentrated, purified by reverse phase preparation (Phenomenex luna C18 150 x 25 mm x 10 um; mobile phase: water (FA) - ACN; B%: 45% - 75%, 25 min) and twice by reverse phase preparation (Waters Xbridge 150 x 25 mm x 5 um; mobile phase: water (NH4HCO3) - ACN; B%: 42% - 72%, 25 min) to obtain Example 26.

[0425] 1 H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 7.86 (br s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 2.0, 8.0 Hz, 1H), 7.48-7.37 (m, 2H), 7.27-7.12 (m, 2H), 5.24 (br s, 1H), 5.07 (d, J = 10.4 Hz, 1H), 4.53 (d, J = 3.6 Hz, 2H), 4.32 (dd, J = 7.6, 10.4 Hz, 1H), 3.64 (s, 1H), 2.83 (t, J = 7.2 Hz, 1H), 1.60 (s, 3H), 0.73 (d, J = 6.0 Hz, 3H);

[0426] m / z (ESI): [M-H]- + = 511.1.

[0427] Example 27

[0428] Preparation of compound 27-1

[0429] Under nitrogen atmosphere, triethylamine (365.5 μL, 2.63 mmol) was added to a solution of compound 24-3 (103.67 mg, 0.26 mmol) in dichloromethane (1 mL), followed by dropwise addition of a solution of methyl 4-aminopyridine-2-carboxylate (80.01 mg, 0.53 mmol) in dichloromethane (0.5 mL), and the reaction was stirred at 26 °C for 2 hours. After completion of the reaction, the reaction was diluted with 30 mL of water, and the aqueous phase was extracted with dichloromethane (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 27-1.

[0430] 1 H NMR (400 MHz, CDC13): δ 8.63 (d, J = 5.6 Hz, 1H), 8.58 (s, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.93 (dd, J = 5.6, 2.0 Hz, 1H), 7.05-7.19 (m, 1H), 6.93-7.05 (m, 1H), 5.03 (d, J = 11.2 Hz, 1H), 4.21-4.32 (m, 1H), 4.01 (s, 3H), 2.73-2.94 (m, 1H), 2.38 (s, 1H), 1.72 (s, 3H), 0.76-0.87 (m, 3H);

[0431] m / z (ESI): [M-H] - = 511.1.

[0432] Preparation of Example 27

[0433] Potassium cyanide (2 mg, 0.03 mmol) and aqueous hydroxylamine (0.5 mL, 8.16 mmol, 50% aqueous solution) were added successively to a solution of compound 27-1 (30 mg, 0.06 mmol) in 0.5 mL of methanol and 0.5 mL of tetrahydrofuran under a nitrogen atmosphere. The reaction solution was stirred at 26 °C for 12 hours. After the reaction was completed, the reaction solution was poured into 20 mL of saturated aqueous sodium bicarbonate solution and quenched, extracted with dichloromethane (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase preparation (Column Phenomenex luna C18 150*25mm*10um; mobile phase: water (TFA)-ACN; B%: 28%-58%, 14 min) to obtain Example 27.

[0434] 1 H NMR (400 MHz, DMSO-d6): δ 11.38 (s, 1H), 10.70 (s, 1H), 8.45 (d, J = 5.6 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 5.6, 2.0 Hz, 1H), 7.07-7.38 (m, 2H), 5.11 (d, J = 10.4 Hz, 1H). 4.10-4.45 (m, 1H), 3.63 (s, 2H), 2.84 (s, 1H), 1.62 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H);

[0435] m / z (ESI): [M+H] + = 516.1.

[0436] Example 28

[0437] Preparation of compound 28-1

[0438] Under a nitrogen atmosphere, triethylamine (348.6 μL, 2.51 mmol) and 4- aminopyridine-2-carbonitrile (59.75 mg, 0.50 mmol) were added successively to a solution of compound 24-3 (100 mg, 0.25 mmol) in 1 mL of dichloromethane, and the reaction solution was stirred at 26 °C for 2 hours. After the reaction was completed, 10 mL of water was added for dilution, extracted with dichloromethane (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by thin layer silica gel preparation (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 28-1.

[0439] 1H NMR (400 MHz, CDC13): δ 8.67-8.53 (m, 2H), 8.08-7.99 (m, 1H), 7.70-7.60 (m, 1H), 7.16-7.07 (m, 1H), 7.06-6.91 (m, 1H), 5.13-4.94 (m, 1H), 4.31-4.18 (m, 1H), 2.91-2.78 (m, 1H), 2.44-2.36 (m, 1H), 1.75-1.67 (m, 3H), 0.86-0.76 (m, 3H);

[0440] m / z (ESI): [M+H] + = 482.1.

[0441] Preparation of Example 28

[0442] Hydroxylamine hydrochloride (7.69 mg, 0.11 mmol) and sodium carbonate (23.47 mg, 0.22 mmol) were added to a solution of compound 28-1 (41 mg, 0.09 mmol) in 2 mL of ethanol under nitrogen atmosphere. The reaction was stirred at 25 °C for 1 hour. After the reaction was completed, the filtrate was adjusted to pH 5 with 2N hydrochloric acid and purified by reversed-phase preparation (Column Phenomenex luna C18 150*25mm*10um Condition water (FA)-CAN Begin B 43 End B 73 Gradient Time (min) 11 100% B Hold Time (min) 4 Flow Rate (ml / min) 25) to obtain Example 28.

[0443] 1 H NMR (400 MHz, DMSO-d6): δ 10.74-10.50 (m, 1H), 9.93-9.75 (m, 1H), 8.47-8.37 (m, 1H), 8.22-8.08 (m, 1H), 7.69-7.56 (m, 1H), 7.32-7.06 (m, 2H), 5.93-5.65 (m, 2H), 5.22-4.91 (m, 1H), 4.48-4.15 (m, 1H), 3.67-3.58 (m, 1H), 2.89-2.78 (m, 1H), 1.70-1.53 (m, 3H), 0.87-0.59 (m, 3H);

[0444] m / z (ESI): [M+H] + = 515.2.

[0445] Example 29

[0446] Preparation of Example 29

[0447] Under nitrogen atmosphere, triethylamine (139.4 μL, 1.00 mmol) was added to a solution of compound 24-3 (100 mg, 0.25 mmol) in 0.5 mL of dichloromethane, followed by the addition of 4-aminopyridine-2-sulfonamide (45.17 mg, 0.26 mmol), and the mixture was stirred at 26 °C for 2 hours. After the reaction was completed, 20 mL of water was added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by reverse phase preparation (Column Waters Xbridge 150*25 mm*5 um; mobile phase: water(NH3H2O)-ACN; B%: 38%-68%, 12 min) to give Example 29.

[0448] 1 H NMR (400 MHz, DMSO-d6): δ 10.52 (s, 1H), 8.09-8.31 (m, 1H), 7.75 (dt, J = 7.6, 2.0 Hz, 1H), 7.44-7.61 (m, 2H), 7.36 (s, 2H), 7.08-7.28 (m, 2H), 5.10 (d, J = 10.4 Hz, 1H), 4.34 (dd, J = 10.32, 7.44 Hz, 1H), 3.64 (s, 1H), 2.85 (s, 1H), 1.62 (s, 3H), 0.63-0.83 (m, 3H);

[0449] m / z (ESI): [M+H] + = 535.2.

[0450] Examples 30, 31

[0451] Preparation of compound 30-1

[0452] Under nitrogen atmosphere, a solution of compound 24-3 (300 mg, 0.75 mmol) in 2 mL of dichloromethane was added dropwise to a solution of 3-(methylthio)aniline (35.16 mg, 0.25 mmol) and triethylamine (0.3 mL, 2.26 mmol) in 2 mL of dichloromethane, and the mixture was stirred at 26 °C for 2 hours. After the reaction was completed, 50 mL of water was added to dilute the reaction mixture, and the aqueous phase was extracted with dichloromethane (20 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1-5 / 1) to give compound 30-1.

[0453] 1H NMR (400 MHz, CDC13): δ 8.30 (s, 1H), 7.57-7.51 (m, 1H), 7.26-7.20 (m, 2H), 7.20-7.14 (m, 1H), 7.03-6.94 (m, 2H), 5.00 (d, J = 11.2 Hz, 1H), 4.28 (dd, J = 7.6, 11.2 Hz, 1H), 2.88-2.76 (m, 1H), 2.47 (s, 3H), 2.37 (s, 1H), 1.70 (s, 3H), 0.84-0.76 (m, 3H);

[0454] m / z (ESI): [M+H] + = 502.1.

[0455] Preparation of Examples 30, 31

[0456] Diacetoxyiodobenzene (407 mg, 1.26 mmol) was added to a solution of compound 30-1 (300 mg, 0.60 mmol) and ammonium acetate (73.8 mg, 0.96 mmol) in 5 mL of methanol under nitrogen atmosphere. The reaction was stirred at 26 °C for 1 hour. After the reaction was completed, the low boiling point solvent was removed by concentration under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 ~ 0 / 1) and reverse phase preparation (0.1% FA / ACN, 50% to 60% over 5 min) to obtain a mixture of Example 30 and Example 31. The mixture was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um), CO2-EtOH (0.1% NH3H2O), 30% to 30% over 2.7 min, 60 mL / min) to obtain two single isomers.

[0457] Example 30 (retention time = 0.915 min):

[0458] 1 H NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H), 8.24 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.58-7.49 (m, 1H), 7.27-7.14 (m, 2H), 5.09 (d, J = 10.4 Hz, 1H), 4.33 (dd, J = 7.6, 10.4 Hz, 1H), 4.22-4.15 (m, 1H), 3.64 (s, 1H), 3.02 (s, 3H), 2.92-2.77 (m, 1H), 1.61 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H);

[0459] m / z (ESI): [M+H] + = 533.3.

[0460] Example 31 (retention time = 1.165 min):

[0461] 1 H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 8.24 (t, J = 1.8 Hz, 1H), 7.88-7.82 (m, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.58-7.49 (m, 1H), 7.30-7.11 (m, 2H), 5.09 (d, J = 10.4 Hz, 1H), 4.33 (dd, J = 7.6, 10.4 Hz, 1H), 4.19 (s, 1H), 3.64 (s, 1H), 3.02 (d, J = 0.8 Hz, 3H), 2.90-2.77 (m, 1H), 1.61 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H);

[0462] m / z (ESI): [M+H] + = 533.2.

[0463] Example 32

[0464] Preparation of compound 32-2

[0465] Tert-butyldimethylsilyl chloride (865 mg, 5.74 mmol) was added to a solution of compound 32-1 (300 mg, 2.87 mmol) and imidazole (586 mg, 8.61 mmol) in 5 mL of N,N-dimethylformamide under nitrogen atmosphere, and the reaction was allowed to react at 20 °C for 3 hours. After the reaction was completed, it was quenched with 50 mL of water, extracted with ethyl acetate (25 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (eluted with petroleum ether) to obtain compound 32-2.

[0466] 1 H NMR (400 MHz, CDCl3): δ 4.37 (t, J = 2.0 Hz, 2H), 4.18 (t, J = 2.0 Hz, 2H), 0.92 (s, 9H), 0.13 (s, 6H).

[0467] Preparation of compound 32-3

[0468] A solution of compound 32-2 (28.6 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) was added slowly to a solution of compound 1-18 (60 mg, 0.13 mmol) and potassium carbonate (90.3 mg, 0.65 mmol) in 1 mL of N,N-dimethylformamide under nitrogen atmosphere, and the reaction was stirred at 60 °C for 2 hours. After the reaction was completed, the reaction was cooled and filtered. The filtrate was separated and purified by reverse phase preparative separation (column: Waters Xbridge 150 x 25 mm x 5 um, water (NH4HCO3)-ACN, 38%-68% over 9 min) to obtain compound 32-3.

[0469] Preparation of Example 32

[0470] Compound 32-3 (25 mg, 0.04 mmol) was dissolved in methanolic hydrochloric acid (2 mL, 2M) and stirred at 25 °C for 0.5 hours. After the reaction was completed, it was concentrated, diluted with 2 mL of methanol, adjusted to pH = 8 with ammonia water, and separated and purified by reverse phase preparative separation (column: Waters Xbridge 150 x 25 mm x 5 um, water (NH4HCO3)-ACN, 38%-68% over 9 min) to obtain Example 32.

[0471] 1 H NMR (400 MHz, DMSO-d6): δ 10.73 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.28-7.14 (m, 2H), 5.21 (t, J = 6.0 Hz, 1H), 5.11 (d, J = 10.4 Hz, 1H), 4.94 (d, J = 1.6 Hz, 2H), 4.34 (dd, J = 7.6, 10.4 Hz, 1H), 4.10-4.03 (m, 2H), 2.91-2.79 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 6.4 Hz, 3H);

[0472] m / z (ESI): [M+H] + = 528.2.

[0473] Example 33

[0474] Preparation of Example 33

[0475] Pd(dppf)Cl2CH2Cl2(13.81 mg, 0.02 mmol), CuI (6.48 mg, 0.03 mmol), triethylamine (117.5 μL, 0.85 mmol) and compound 33-1 (142.23 mg, 1.69 mmol) were added to a solution of compound 3-1 (100 mg, 0.17 mmol) in 2 mL of N,N-dimethylformamide under nitrogen atmosphere. The reaction was stirred at 100 °C for 16 hours. After completion of the reaction, the reaction was cooled to room temperature, quenched with 40 mL of water, extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by preparative reverse phase HPLC (Column: Waters Xbridge 150 x 25 mm x 5 um; Condition: water (NH4HCO3) - ACN; Begin B: 38, End B: 68; Gradient Time (min): 10; 100% B Hold Time (min): 4, Flow Rate (ml / min): 25) to give Example 33.

[0476] 1 H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.49 (d, J = 5.4 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 2.0, 5.4 Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.53 - 7.45 (m, 1H), 7.28 (dd, J = 4.0, 8.8 Hz, 1H), 5.69 (s, 1H), 5.22 (d, J = 10.2 Hz, 1H), 4.36 (dd, J = 7.6, 10.2 Hz, 1H), 2.96 (t, J = 7.6 Hz, 1H), 1.64 (s, 3H), 1.51 (s, 6H), 0.75 - 0.68 (m, 3H);

[0477] m / z (ESI): [M-17] + = 508.2.

[0478] Example 34

[0479] Preparation of compound 34-2

[0480] Benzoyl chloride (322.7 μL, 2.78 mmol) and triethylamine (478.0 μL, 3.44 mmol) were added to a 10 mL dichloromethane solution of compound 34-1 (500 mg, 2.65 mmol) under nitrogen atmosphere, and the reaction solution was stirred at 25 °C for 12 hours. After the reaction was completed, it was quenched with 30 mL of an aqueous sodium hydroxide solution (1 N), and the aqueous phase was extracted with dichloromethane (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 34-2.

[0481] 1 H NMR (400 MHz, CDCl3): δ 8.79 (s, 2H), 8.14 (dd, J = 1.2, 8.0 Hz, 2H), 7.63-7.56 (m, 1H), 7.50-7.44 (m, 2H), 5.53 (s, 2H);

[0482] m / z (ESI): [M+H] + = 294.4.

[0483] Preparation of compound 34-3

[0484] Cesium carbonate (607.20 mg, 1.86 mmol), (±)-2,2-bis(diphenylphosphino)-1,1- binaphthyl (178.53 mg, 0.29 mmol), palladium acetate (32.18 mg, 0.14 mmol), and benzophenone imine (312 mg, 1.72 mmol) were added to a 10 mL toluene solution of compound 34-2 (440 mg, 1.43 mmol) under nitrogen atmosphere, and the reaction solution was stirred at 120 °C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with 60 mL of water, extracted with ethyl acetate (30 mL x 3), and the combined organic phase was washed with 50 mL of a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 34-3.

[0485] 1 H NMR (400 MHz, CDCl3): δ 8.18 (s, 2H), 8.14-8.10 (m, 2H), 7.81-7.74 (m, 2H), 7.58-7.55 (m, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.48-7.42 (m, 4H), 7.38-7.32 (m, 3H), 7.13 (dd, J = 2.0, 7.2 Hz, 2H), 5.47 (s, 2H);

[0486] m / z (ESI): [M+H]+ = 394.1.

[0487] Preparation of compound 34-4

[0488] Hydroxylamine hydrochloride (250.83 mg, 3.61 mmol) and sodium acetate (434.27 mg, 5.29 mmol) were added to a solution of compound 34-3 (600 mg, 1.20 mmol) in 10 mL of methanol under nitrogen atmosphere, and the reaction solution was stirred at 25 °C for 7 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether / ethyl acetate = 5 / 1 ~ 1 / 1) to obtain compound 34-4.

[0489] 1 H NMR (400 MHz, CDCl3): δ 8.22 (s, 2H), 8.12 (d, J = 7.2 Hz, 2H), 7.60-7.54 (m, 1H), 7.48-7.41 (m, 2H), 5.47 (s, 2H);

[0490] m / z (ESI): [M+23] + = 252.1.

[0491] Preparation of compound 34-5

[0492] Under nitrogen atmosphere, 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120.62 mg, 0.32 mmol), N,N-diisopropylethylamine (69.9 μL, 0.42 mmol) and compound 34-4 (64.93 mg, 0.25 mmol) were added to a solution of compound 21-4 (80 mg, 0.21 mmol) in 2 mL of N,N-dimethylformamide, and the reaction solution was stirred at 25 °C for 16 hours. After the reaction was completed, it was quenched with 40 mL of water, extracted with ethyl acetate (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether / ethyl acetate = 5 / 1 ~ 3 / 1) to obtain compound 34-5.

[0493] 1H NMR (400 MHz, CDC13): δ 8.97 (s, 2H), 8.38 (s, 1H), 8.16-8.09 (m, 2H), 7.63-7.55 (m, 1H), 7.50-7.41 (m, 2H), 7.17-7.09 (m, 1H), 7.04-6.94 (m, 1H), 5.53 (s, 2H), 5.04 (d, J = 11.2 Hz, 1H), 4.93-4.87 (m, 1H), 4.83-4.78 (m, 1H), 4.26 (dd, J = 7.6, 11.2 Hz, 1H), 2.89-2.81 (m, 1H), 2.44 (t, J = 2.4 Hz, 1H), 1.70 (s, 3H), 0.84-0.79 (m, 3H);

[0494] m / z (ESI): [M+H] + = 590.2.

[0495] Preparation of Example 34

[0496] Lithium hydroxide (38.05 mg, 0.91 mmol) was added to a solution of compound 34-5 (110 mg, 0.18 mmol) in 3 mL of methanol under nitrogen atmosphere. The reaction was stirred at 25 °C for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure. Example 34 was isolated by reverse phase preparation purification (Column: Waters Xbridge 150 x 25 mm x 5 um; Condition: water (NH4HCO3) - ACN; Begin B: 23, End B: 53; Gradient Time (min): 10; 100% B Hold Time (min): 4, Flow Rate (ml / min): 25).

[0497] 1H NMR (400 MHz, DMSO-d6): δ 10.46 (s, 1H), 8.98 (s, 2H), 7.27-7.16 (m, 2H), 5.26 (t, J = 6.0 Hz, 1H), 5.15 (d, J = 10.4 Hz, 1H), 4.98-4.85 (m, 2H), 4.55 (d, J = 6.0 Hz, 2H), 4.32 (dd, J = 7.2, 10.2 Hz, 1H), 3.67 (t, J = 2.0 Hz, 1H), 2.89-2.78 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H);

[0498] m / z (ESI): [M+H] + = 486.1.

[0499] Example 35

[0500] Preparation of compound 35-2

[0501] Under nitrogen atmosphere, triethylamine (94.1 mg, 0.93 mmol), tert-butyldimethyl(2- propynyloxy)silane (317 mg, 1.86 mmol), (diphenylphosphino)ferrocenepalladium chloride (13.6 mg, 0.02 mmol) and cuprous iodide (7.08 mg, 0.04 mmol) were added successively into a solution of compound 3-1 (110 mg, 0.19 mmol) in 2 mL of N,N-dimethylformamide. The reaction was stirred at 80 °C for 48 hours. After the reaction was completed, the reaction was cooled to room temperature. The reaction was diluted with 30 mL of water and extracted with ethyl acetate (15 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was separated and purified by reverse phase preparative (0.1% FA / ACN, 80% to 90% over 5 min) to give compound 35-2.

[0502] m / z (ESI): [M-H]- + = 612.2

[0503] Preparation of example 35

[0504] Under nitrogen atmosphere, compound 35-2 (14 mg, 0.02 mmol) was added into a solution of 2M hydrochloric acid in methanol (2 mL). The reaction was stirred at 25 °C for 0.5 hours. After the reaction was completed, the reaction was concentrated to dryness to give a crude product. The crude product was separated and purified by reverse phase preparative (column: Phenomenex luna C18 150 x 25 mm x 10 um, 35% to 65% over 9 min) and (column: Waters Xbridge 150 x 25 mm x 5 um, 35% to 65% over 11 min) to give example 35.

[0505] 1H NMR (400 MHz, DMSO-d6): δ 10.78 (br s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.27 (s, 1H), 8.08-8.03 (m, 1H), 7.83 (d, J = 3.6 Hz, 1H), 7.60 (s, 1H), 7.52-7.45 (m, 1H), 7.30 (dd, J = 4.4, 8.5 Hz, 1H), 5.67-5.45 (m, 1H), 5.20 (d, J = 10.4 Hz, 1H), 4.42 (s, 2H), 4.36 (dd, J = 7.6, 10.3 Hz, 1H), 3.04-2.92 (m, 1H), 1.62 (s, 3H), 0.71 (d, J = 6.4 Hz, 3H);

[0506] m / z (ESI): [M+H] + = 498.2.

[0507] Examples 36, 37

[0508] Preparation of compound 36-2

[0509] Compound 36-1 (35.34 mg, 0.25 mmol) was added to a solution of compound 21-5 (100 mg, 0.25 mmol) and triethylamine (105.1 μL, 0.76 mmol) in 2 mL of dichloromethane under nitrogen atmosphere, and the reaction solution was reacted at 25 °C for 1 hour. After the reaction was completed, 3 mL of water was added to dilute and quench the reaction, the aqueous phase was extracted with dichloromethane (10 mL x 3), the combined organic phase was washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by reverse phase preparation (0.1% formic acid system) to obtain compound 36-2.

[0510] 1 H NMR (400 MHz, CDCl3): δ 8.38-8.29 (m, 2H), 7.51 (d, J = 1.6 Hz, 1H), 7.09 (dd, J = 1.6, 5.6 Hz, 1H), 7.03-6.96 (m, 1H), 4.99 (d, J = 11.2 Hz, 1H), 4.92-4.86 (m, 1H), 4.83-4.77 (m, 1H), 4.25 (dd, J = 7.8, 11.2 Hz, 1H), 2.88-2.77 (m, 1H), 2.54 (s, 3H), 2.38 (t, J = 2.4 Hz, 1H), 1.70 (s, 3H), 0.80 (dd, J = 1.6, 7.4 Hz, 3H);

[0511] m / z (ESI): [M+H] += 501.1.

[0512] Preparation of Example 36, 37

[0513] Diacetyloiodobenzene (40.80 mg, 0.13 mmol), ammonium acetate (7.39 mg, 0.10 mmol) were added successively to a solution of compound 36-2 (30 mg, 0.06 mmol) in 1 mL of methanol under nitrogen atmosphere. The reaction was stirred at 25 °C for 18 hours. After the reaction was completed, the reaction mixture was concentrated to give the crude product, which was purified by reverse phase preparative purification (Waters Xbridge 150×25mm×5um; mobile phase: water (NH4HCO3)-ACN; B%: 43%-63%, 25 min) to give a mixture of Example 36 and Example 37; the mixture was separated by SFC (Column DAICEL CHIRALPAK AD (250×50mm×10um); Condition: CO2-EtOH (0.1% NH3H2O); B%: 20-20; Gradient Time (min): 3.6; 100% B Hold Time (min): 0; FlowRate (ml / min): 120) to give two single isomers.

[0514] Example 36 (retention time = 1.273 min):

[0515] 1 H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 2.0, 5.6 Hz, 1H), 7.27-7.17 (m, 2H), 5.13 (d, J = 10.4 Hz, 1H), 4.95-4.89 (m, 2H), 4.37-4.30 (m, 2H), 3.64 (t, J = 2.4 Hz, 1H), 3.11 (d, J = 0.8 Hz, 3H), 2.84 (t, J = 7.2 Hz, 1H), 1.61 (s, 3H), 0.74 (d, J = 6.4 Hz, 3H);

[0516] m / z (ESI): [M+H] + = 532.1.

[0517] Example 37 (retention time = 1.420 min):

[0518] 1H NMR (400 MHz, DMSO-d6): δ 10.89 (s, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 2.0, 5.6 Hz, 1H), 7.27-7.16 (m, 2H), 5.13 (d, J = 10.4 Hz, 1H), 4.92 (t, J = 2.8 Hz, 2H), 4.39-4.29 (m, 2H), 3.64 (t, J = 2.4 Hz, 1H), 3.11 (d, J = 0.8 Hz, 3H), 2.87-2.80 (m, 1H), 1.61 (s, 3H), 0.74 (d, J = 5.6 Hz, 3H);

[0519] m / z (ESI): [M+H] + = 532.2.

[0520] Example 38

[0521] Preparation of Example 38

[0522] Tris(dibenzylideneacetone)dipalladium (7.74 mg, 0.01 mmol), 4,5- bisdiphenylphosphin-9,9-dimethylxanthene (4.89 mg, 0.01 mmol), N,N- diisopropylethylamine (41.9 μL, 0.25 mmol) were added successively into 2 mL of 2-methoxyethyl ether solution of compound 3-1 (50 mg, 0.08 mmol) and dimethyl phosphine oxide (13.20 mg, 0.17 mmol) under nitrogen atmosphere, the reaction was heated to 100 °C and stirred for 15 hours. After the reaction was completed, the reaction was cooled to room temperature, filtered through a short silica gel column (ethyl acetate washing), and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase preparation (Waters Xbridge 150 x 25 mm x 5 um; mobile phase: water (NH4HCO3)-ACN; B%: 23%-53%, 25 min) to obtain Example 38.

[0523] 1H NMR (400 MHz, DMSO-d6): δ 10.60 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.28 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 2.1 Hz, 1H), 7.83 (dd, J = 2.2, 5.6 Hz, 1H), 7.72 - 7.59 (m, 2H), 7.46 - 7.39 (m, 1H), 5.48 (dd, J = 7.1, 10.8 Hz, 1H), 5.15 (d, J = 10.8 Hz, 1H), 2.90 (t, J = 7.4 Hz, 1H), 1.85 - 1.76 (m, 6H), 1.58 (s, 3H), 0.76 (d, J = 6.5 Hz, 3H);

[0524] m / z (ESI): [M+H] 520.2. +

[0525] Example 39

[0526] Preparation of Example 39

[0527] Triethylamine (139.4 μL, 1.00 mmol) was added to a solution of compound 24-3 (100 mg, 0.25 mmol) in 0.5 mL of dichloromethane under nitrogen atmosphere, followed by the addition of 4-aminopyridine-2-sulfonamide (45.17 mg, 0.26 mmol), and the mixture was stirred at 26 °C for 2 hours. After the reaction was completed, 20 mL of water was added for quenching, and extraction was performed with dichloromethane (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reversed phase preparation (Column Waters Xbridge 150*25mm*5um; mobile phase: water(NH3H2O)-ACN; B%: 38%-68%, 12 min) to obtain Example 39.

[0528] 1 H NMR (400 MHz, DMSO-d6): δ 10.52 (s, 1H), 8.09 - 8.31 (m, 1H), 7.75 (dt, J = 7.6, 2.0 Hz, 1H), 7.44 - 7.61 (m, 2H), 7.36 (s, 2H), 7.08 - 7.28 (m, 2H), 5.10 (d, J = 10.4 Hz, 1H), 4.34 (dd, J = 10.32, 7.44 Hz, 1H), 3.64 (s, 1H), 2.85 (s, 1H), 1.62 (s, 3H), 0.63 - 0.83 (m, 3H);

[0529] m / z (ESI): [M+H] 520.2.​+ = 535.2.

[0530] Example 40

[0531] Preparation of compound 40-2

[0532] Under nitrogen atmosphere, triethylamine (57.5 μL, 0.41 mmol) and compound 40-1 (43.28 mg, 0.21 mmol) were added to a solution of compound 24-3 (55.0 mg, 0.14 mmol) in 1 mL of dichloromethane, and the reaction was stirred at 25 °C for 1 h. After the reaction was completed, the reaction was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 40-2.

[0533] 1 H NMR (400 MHz, CDC13): δ 8.51 (s, 1H), 7.82-7.77 (m, 3H), 7.20-7.12 (m, 1H), 7.03-6.94 (m, 1H), 5.02 (d, J = 11.2 Hz, 1H), 4.26 (dd, J = 7.6, 11.2 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 2.90-2.78 (m, 1H), 2.37 (s, 1H), 1.71 (s, 3H), 0.85-0.78 (m, 3H);

[0534] m / z (ESI): [M+H] + = 572.2.

[0535] Preparation of Example 40

[0536] Under nitrogen atmosphere, compound 40-2 (50.0 mg, 0.08 mmol) was dissolved in 5 mL of ammonium methylate (7 M) solution, and the reaction was stirred at 60 °C for 17 h. After the reaction was completed, the reaction was concentrated under reduced pressure to obtain a crude product, which was separated and purified by reverse phase preparation (Column Phenomenex luna C18 150 x 25 mm x 10 um; mobile phase: water (FA) - ACN; B%: 43% - 73%, 11 min) to obtain Example 40.

[0537] 1H NMR (400 MHz, METHANOL-d4): δ 8.54 (s, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 2.0, 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.23-7.13 (m, 1H), 7.09-6.99 (m, 1H), 5.08 (d, J = 10.8 Hz, 1H), 4.43 (dd, J = 8.0, 10.2 Hz, 1H), 2.93 (s, 1H), 2.90-2.84 (m, 1H), 1.68 (s, 3H), 0.83 (d, J = 5.6 Hz, 3H);

[0538] m / z (ESI): [M+H] + = 542.2.

[0539] Example 41

[0540] Preparation of Example 41

[0541] MCPBA (55.0 mg, 0.32 mmol) was added to a solution of compound 24-5 (80 mg, 0.16 mmol) in 3 mL of dichloromethane at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 2 h. After the reaction was completed, the reaction was quenched by slowly adding to 50 mL of saturated aqueous sodium sulfite solution. After the aqueous phase was negative by starch-iodine test, the mixture was extracted with dichloromethane (20 mL x 2). The combined organic phase was washed with 20 mL of saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The product was purified by reverse phase preparative column (column: Waters Xbridge CI 8 150*25mm*5um; mobile phase: [A: H20 (10 mM NH4HCO3); B: ACN]; B%: 48.00%-78.00%, 15.00 min; flow rate: 25.00 ml / min) to give Example 41.

[0542] 1 H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1H), 8.63 (d, J = 5.6 Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H), 7.91 (dd, J = 2.0, 5.6 Hz, 1H), 7.30-7.15 (m, 2H), 5.14 (d, J = 10.4 Hz, 1H), 4.33 (dd, J = 7.6, 10.4 Hz, 1H), 3.62 (s, 1H), 3.24 (s, 3H), 2.90-2.77 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 6.4 Hz, 3H);

[0543] m / z (ESI): [M+H] 171.2. + = 535.2.

[0544] Example 42

[0545] Preparation of compound 42-2

[0546] Compound dimethyl phosphine oxide (676.69 mg, 8.67 mmol), potassium phosphate (3.07 g, 14.45 mmol), tris(dibenzylideneacetone)dipalladium (317.58 mg, 0.35 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (401.34 mg, 0.69 mmol) were added to a solution of compound 42-1 (1.0 g, 5.78 mmol) in 20 mL of N,N-dimethylformamide under nitrogen atmosphere, the reaction was heated to 140 °C for 16 hours. After the reaction was completed, the reaction was cooled to room temperature, filtered, the filter cake was washed with 10 mL of ethyl acetate twice, the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to separate compound 42-2.

[0547] 1 H NMR (400 MHz, DMSO-d6): δ 8.09 (d, J = 5.6 Hz, 1H), 7.10 (dd, J = 2.4, 7.2 Hz, 1H), 6.52 (td, J = 2.0, 5.6 Hz, 1H), 6.34 (s, 2H), 1.56 (s, 3H), 1.53 (s, 3H);

[0548] m / z (ESI): [M+H] 171.2. + = 535.2.

[0549] Preparation of example 42

[0550] Compound 42-2 (42.93 mg, 0.21 mmol) and triethylamine (57.5 μL, 0.41 mmol) were added to a solution of compound 24-3 (55 mg, 0.14 mmol) in 1 mL of dichloromethane under nitrogen atmosphere, the reaction was reacted at 25 °C for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure, and purified by reverse phase preparation (chromatographic column Waters Xbridge C18 150 x 25 mm x 5 um, aqueous-organic phase H2O (10 mM NH4HCO3)-ACN, B%: 33%-63%, 15 min) to obtain example 42.

[0551] 1H NMR (400 MHz, DMSO-d6): δ 10.74 (s, 1H), 8.61 (d, J = 5.6 Hz, 1H), 8.21 (dd, J = 2.0, 6.4 Hz, 1H), 7.77 (td, J = 2.0, 5.6 Hz, 1H), 7.27 - 7.13 (m, 2H), 5.12 (d, J = 10.6 Hz, 1H), 4.33 (dd, J = 7.2, 10.2 Hz, 1H), 3.65 (s, 1H), 2.91 - 2.77 (m, 1H), 1.70 - 1.51 (m, 9H), 0.74 (d, J = 6.0 Hz, 3H);

[0552] m / z (ESI): [M+H] + = 533.2.

[0553] Example 43

[0554] Preparation of compound 43-3

[0555] Compound 43-2 (2.69 g, 20.34 mmol), triphenylphosphine (5.34 g, 20.34 mmol) and diisopropyl azodicarboxylate (4.0 mL, 20.34 mmol) were added to a solution of compound 43-1 (1.9 g, 13.56 mmol) in 30 mL of toluene under nitrogen atmosphere, and the reaction solution was heated to 80 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound 43-3.

[0556] 1 H NMR (400 MHz, CDCl3): δ 8.39 (d, J = 5.6 Hz, 1H), 7.61 (dd, J = 2.0, 5.6 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 4.57 - 4.39 (m, 3H), 4.17 (dd, J = 6.4, 8.4 Hz, 1H), 3.88 (dd, J = 6.0, 8.4 Hz, 1H), 1.47 (s, 3H), 1.41 (s, 3H).

[0557] Preparation of compound 43-4

[0558] Iron powder (2.42 g, 43.42 mmol) and ammonium chloride (2.32 g, 43.42 mmol) were added to a solution of compound 43-3 (2.3 g, 8.68 mmol) in 20 mL of ethanol and 4 mL of water under nitrogen atmosphere, and the reaction was heated to 80 °C for 2 hours. After the reaction was completed, the reaction was cooled to room temperature, diluted with 40 mL of ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain compound 43-4.

[0559] 1 H NMR (400 MHz, DMSO-d6): δ 7.59 (d, J = 6.0 Hz, 1H), 6.17 (dd, J = 2.0, 6.0 Hz, 1H), 5.93 (s, 2H), 5.81 (d, J = 1.6 Hz, 1H), 4.37-4.29 (m, 1H), 4.20-4.09 (m, 2H), 4.03 (dd, J = 6.4, 8.0 Hz, 1H), 3.69 (dd, J = 6.4, 8.0 Hz, 1H), 1.33 (s, 3H), 1.28 (s, 3H);

[0560] m / z (ESI): [M+H] + = 225.2.

[0561] Preparation of compound 43-5

[0562] Compound 43-5 (86.97 mg, 0.38 mmol) and triethylamine (104.6 μL, 0.75 mmol) were added to a solution of compound 24-3 (100 mg, 0.25 mmol) in 1 mL of dichloromethane under nitrogen atmosphere, and the reaction was allowed to react at 25 °C for 1 hour. After the reaction was completed, it was quenched with 20 mL of water and extracted with dichloromethane (20 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain compound 43-5.

[0563] 1H NMR (400 MHz, CDC13): δ 8.37 (s, 1 H), 8.03 (d, J = 6.4 Hz, 1 H), 7.17-7.10 (m, 1 H), 7.06-6.95 (m, 3 H), 4.98 (d, J = 11.2 Hz, 1 H), 4.49-4.42 (m, 1 H), 4.37-4.30 (m, 2 H), 4.25 (dd, J = 8.0, 11.3 Hz, 1 H), 4.12 (dd, J = 6.0, 8.4 Hz, 1 H), 3.85 (dd, J = 6.0, 8.4 Hz, 1 H), 2.89-2.77 (m, 1 H), 2.37 (s, 1 H), 1.69 (s, 3 H), 1.45 (s, 3 H), 1.39 (s, 3 H), 0.83-0.78 (m, 3 H);

[0564] m / z (ESI): [M+H] + = 587.2.

[0565] Preparation of Example 43

[0566] Under nitrogen atmosphere, trifluoroacetic acid (0.2 mL, 2.69 mmol) was added to a solution of compound 43-5 (50 mg, 0.08 mmol) in 2 mL of dichloromethane, and the reaction was allowed to react at 26 °C for 1 hour. After the reaction was completed, the reaction was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase preparation (column: Waters Xbridge C18 150*25mm*5um; mobile phase: [A: H20 (10 mM NH4HCO3); B: ACN]; B%: 40.00%-70.00%, 15.00 min; flow rate: 25.00 ml / min) to obtain Example 43.

[0567] 1H NMR (400 MHz, DMSO-d6): δ 10.49 (s, 1H), 8.01 (d, J = 5.6 Hz, 1H), 7.26-7.19 (m, 1H), 7.17-7.10 (m, 3H), 5.08 (d, J = 10.4 Hz, 1H), 4.87 (d, J = 5.2 Hz, 1H), 4.60 (t, J = 5.6 Hz, 1H), 4.32 (dd, J = 7.6, 10.0 Hz, 1H), 4.22 (dd, J = 4.4, 10.8 Hz, 1H), 4.09 (dd, J = 6.0, 10.8 Hz, 1H), 3.75 (qd, J = 5.6, 10.8 Hz, 1H), 3.63 (s, 1H), 3.40 (t, J = 5.6 Hz, 2H), 2.90-2.77 (m, 1H), 1.59 (s, 3H), 0.73 (d, J = 6.0 Hz, 3H);

[0568] m / z (ESI): [M+H] + = 547.2.

[0569] Example 44

[0570] Preparation of Example 44

[0571] Compound 24-3 (424 mg, 1.06 mmol) was dissolved in dichloromethane (6 mL) under nitrogen atmosphere, triethylamine (0.5 mL, 3.6 mmol) was added, followed by compound 44-1 (127 mg, 1.06 mmol), the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction was quenched by adding 20 mL of saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane (3 x 20 mL), the combined organic phase was washed with saturated brine (1 x x 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 ~ 1 / 1) to obtain Example 44.

[0572] LC-MS (ESI): [M+H] + = 482.1.

[0573] Example 45

[0574] Preparation of Example 45

[0575] Compound 45-1 (17.95 mg, 0.16 mmol) and triethylamine (87.1 μL, 0.63 mmol) were dissolved in DMF (1 mL), stirred at room temperature for 5 minutes, then a solution of compound 24-3 (50 mg, 0.13 mmol) in DMF (1 mL) was slowly added dropwise into the mixture, stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was added to water (10 ml), the mixture was extracted with ethyl acetate (10 ml x 3), the organic phase was washed with saturated aqueous sodium chloride solution (10 ml x 3), dried over anhydrous sodium sulfate, and the organic phase was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin layer silica gel preparation (dichloromethane:methanol = 10:1) and reverse phase preparation (Phenomenex luna C18 150 x 25 mm x 10 um); flow rate: 25 mL / min; gradient: 47%-67% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to obtain Example 45.

[0576] 1 H NMR (400 MHz, CDCl3): δ 8.42-8.27 (m, 1H), 7.15-6.94 (m, 3H), 6.75-6.62 (m, 2H), 5.06-4.93 (m, 1H), 4.36-4.20 (m, 1H), 2.88-2.78 (m, 1H), 2.47-2.40 (m, 1H), 1.36-1.18 (m, 3H), 0.80 (d, J = 5.2 Hz, 3H);

[0577] m / z (ESI): [M+H] + = 473.1.

[0578] Example 46

[0579] Preparation of Example 46

[0580] Sodium methoxide methanol (0.01 mL, 0.05 mmol) was added to a solution of Example 44 (100 mg, 0.21 mmol) in 5 mL of methanol under nitrogen atmosphere. The reaction was stirred at room temperature for 2 hours, then ammonium chloride (23 mg, 0.42 mmol) was added and the reaction was stirred at 40 °C for 12 hours. The reaction was concentrated and the crude was purified by reverse phase preparative HPLC (Phenomenex luna C18 150 x 25 mm x 10 um; flow rate: 25 mL / min; gradient: 23% - 53% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to give Example 46.

[0581] 1 H NMR (400 MHz, DMSO-d6): δ 8.61 (d, J = 5.6 Hz, 1H), 8.47-8.44 (m, 2H), 7.89-7.87 (m, 1H), 7.23-7.21 (m, 2H), 5.19 (d, J = 10.8 Hz, 1H), 4.38-4.33 (m, 1H), 3.66 (s, 1H), 2.89-2.81 (m, 1H), 1.62 (s, 3H), 0.75 (d, J = 6.0 Hz, 3H);

[0582] m / z (ESI): [M+H] + = 499.1.

[0583] Example 47

[0584] Preparation of Example 47

[0585] Example 44 (100 mg, 0.21 mmol) was dissolved in 2 mL of 1,4-dioxane under nitrogen atmosphere. Triethylamine (0.058 mL, 0.42 mmol) and dimethylamine hydrochloride (33.87 mg, 0.42 mmol) were added sequentially and the reaction was stirred at 90 °C for 16 hours. The reaction was concentrated and the crude was purified by reverse phase preparative HPLC (Phenomenex luna C18 150 x 25 mm x 10 um; flow rate: 25 mL / min; gradient: 24% - 54% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to give Example 47.

[0586] 1 H NMR (400 MHz, DMSO-d6): δ 11.55-11.48 (m, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.44 (s, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.78-7.76 (m, 1H), 7.30-7.26 (m, 1H), 7.23-7.17 (m, 1H), 5.26 (d, J = 10.4 Hz, 1H), 4.37-4.33 (m, 1H), 3.66 (s, 1H), 3.02 (s, 6H), 2.87-2.78 (m, 1H), 1.61 (s, 3H), 0.75 (d, J = 6.4 Hz, 3H);

[0587] m / z (ESI): [M+H] + = 527.2.

[0588] Example 48

[0589] Preparation of compound 48-1

[0590] Compound 12-2 (500 mg, 3.85 mmol), imidazole (800 mg, 11.76 mmol) and tert- butyldiphenylsilyl chloride (2.4 g, 8.73 mmol) were dissolved in anhydrous DCM (30 mL) and stirred at room temperature for 12 hours. The reaction was concentrated to get the crude product which was purified by silica gel column chromatography (eluted with petroleum ether) to get compound 48-1.

[0591] Preparation of compound 48-2

[0592] Compound 48-1 (900 mg, 2.44 mmol) and potassium carbonate (1.1 g, 7.96 mmol) were dissolved in DMF (12 mL) and stirred at room temperature for 24 hours. The reaction was added into ethyl acetate (100 mL), washed once with water (30 mL) and once with saturated brine (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated to get the crude product which was purified by silica gel column chromatography to get compound 48-2.

[0593] 1 H NMR (400 MHz, CDCl3): δ 7.56-7.59 (m, 1H), 7.26-7.50 (m, 1H), 2.24 (s, 1H), 1.12-1.34 (m, 9H).

[0594] Preparation of compound 48-3

[0595] Compound 48-2 (370 mg, 1.25 mmol) was dissolved in THF (1 mL) under nitrogen atmosphere at -50 °C, n-butyllithium n-hexane solution (1.0 mL, 2.50 mmol) was added slowly, and stirred for 0.5 h. Deuterated iodomethane (370 mg, 2.55 mmol) in THF (1 mL) was added, and stirred for 1 h. The reaction was quenched by pouring into saturated aqueous ammonium chloride (100 mL), and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 48-3.

[0596] 1 H NMR (400 MHz, CDC13): δ 7.77-7.79 (m, 1H), 7.44-7.50 (m, 1H), 1.12-1.34 (m, 9H).

[0597] Preparation of compound 48-4

[0598] Compound 48-3 (370 mg, 1.18 mmol) was dissolved in tetrabutylammonium fluoride in tetrahydrofuran (5 mL, 5.00 mmol), and stirred at room temperature for 0.5 h. The reaction was diluted with ethyl acetate (100 mL), and then washed once with water (100 mL) and once with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 48-4.

[0599] Preparation of example 48

[0600] Triphenylphosphine (70 mg, 0.11 mmol), compound 1-18 (50 mg, 0.11 mmol), and compound 48-4 (10 mg, 0.13 mmol) were dissolved in THF (1.5 mL) under nitrogen atmosphere, and diisopropyl azodicarboxylate (30 mg, 0.15 mmol) was added under ice water bath. The reaction was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (20 mL), and the mixture was washed with water (10 mL x 2) and once with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by reverse phase preparative HPLC (Phenomenex luna C18 150 x 25 mm x 10 um; flow rate: 25 mL / min; gradient: 48% - 78% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to give example 48.

[0601] m / z (ESI): [M+H]+ = 517.1.

[0602] Example 49

[0603] Preparation of Example 49

[0604] Example 24 (50 mg, 0.09 mmol) was placed in a 50 mL single-necked flask, DCM (3 mL) was added at room temperature, argon was replaced, trimethyloxonium tetrafluoroborate (7 mg, 0.05 mmol) was added to the solution, and stirring was performed at room temperature for 6 hours. The reaction solution was rotary-evaporated to obtain a crude product, which was purified by thin-layer silica gel chromatography (petroleum ether: ethyl acetate = 1:1) to obtain Example 49.

[0605] 1 H NMR (400 MHz, DMSO-d6): δ 10.91 (s, 1H), 8.62 (d, J = 5.5 Hz, 1H), 8.32 (d, J = 1.9 Hz, 1H), 7.86 (dd, J = 5.5, 2.1 Hz, 1H), 7.32-7.12 (m, 2H), 5.14 (d, J = 10.4 Hz, 1H), 4.34 (dd, J = 10.4, 7.5 Hz, 1H), 3.63 (s, 1H), 3.16 (s, 3H), 2.93-2.76 (m, 1H), 2.45 (s, 3H), 1.62 (s, 3H), 0.74 (d, J = 6.2 Hz, 3H);

[0606] m / z (ESI): [M+H] + = 548.4.

[0607] Example 50

[0608] Preparation of Compound 50-1

[0609] A solution of boron tribromide in dichloromethane (12.7 mL, 25.4 mmol) was slowly dropped into a solution of compound 1-12 (4.5 g, 12.7 mmol) in 60 mL of dichloromethane under a nitrogen atmosphere, and the reaction solution was warmed to 25 °C and stirred for 1 hour. After the reaction was completed, the reaction solution was poured into 100 mL of saturated aqueous sodium bicarbonate solution, extracted once with 50 mL of dichloromethane, and the organic phase was discarded. The aqueous phase was adjusted to a pH of 3-4 with (30 mL, 3M) dilute hydrochloric acid, and extracted with dichloromethane (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 50-1.

[0610] 1H NMR (400 MHz, DMSO-d6): δ 7.11-6.96 (m, 1H), 6.92-6.70 (m, 1H), 4.97 (d, J = 10.4 Hz, 1H), 4.09 (dd, J = 10.4, 7.6 Hz, 1H), 2.73 (s, 1H), 1.52 (s, 3H), 0.67 (d, J = 6.0 Hz, 3H).

[0611] Preparation of compound 50-2

[0612] Under nitrogen atmosphere, 2,2,2-trichloro-1-[(2-methylpropan-2-yl)oxy]ethan-1-imine (10.82 g, 49.52 mmol) was added into a solution of compound 50-1 (3.37 g, 9.90 mmol) in 35 mL of dichloromethane, and the reaction solution was stirred at 25 °C for 1 h. After the reaction was completed, 20 mL of water was added for quenching, and the mixture was extracted with dichloromethane (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-5 / 1) to give compound 50-2.

[0613] 1 H NMR (400 MHz, DMSO-d6): δ 7.04 (t, J = 6.8 Hz, 1H), 6.91-6.74 (m, 1H), 4.90 (d, J = 10.4 Hz, 1H), 4.04 (dd, J = 10.8, 7.2 Hz, 1H), 2.70 (t, J = 7.6 Hz, 1H), 1.52 (d, J = 2.0 Hz, 5H), 1.27 (s, 9H), 0.70 (d, J = 5.6 Hz, 3H).

[0614] Preparation of compound 50-3

[0615] Under nitrogen atmosphere, triflic anhydride (4.409 g, 15.63 mmol) was added into a solution of triethylamine (3.163 g, 31.26 mmol) and compound 50-2 (4.130 g, 10.42 mmol) in 40 mL of dichloromethane at 0 °C, and the reaction solution was reacted at 0 °C for 2 h. After the reaction was completed, the reaction solution was poured into 100 mL of water, and the aqueous phase was extracted with dichloromethane (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1-2 / 1) to give compound 50-3.

[0616] 1H NMR (400 MHz, CDC13): δ 7.35-7.13 (m, 2H), 4.79 (d, J = 9.6 Hz, 1H), 4.23-4.03 (m, 1H), 2.78 (t, J = 7.6 Hz, 1H), 1.63 (s, 3H), 1.35 (s, 9H), 1.23-1.30 (m, 2H), 0.90-0.78 (m, 3H).

[0617] Preparation of compound 50-4

[0618] Potassium vinylfluoroborate (2.23 g, 16.65 mmol), cesium carbonate (5.426 g, 16.65 mmol) and RuPhos Pd G3 (696 mg, 0.83 mmol) were added successively to a solution of compound 50-3 (4.4 g, 8.33 mmol) in 9 mL water and 45 mL toluene under nitrogen atmosphere, and the reaction solution was heated to 85 °C for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with 50 mL water, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1-5 / 1) to obtain compound 50-4.

[0619] 1 H NMR (400 MHz, CDC13): δ 7.35-7.13 (m, 2H), 4.79 (d, J = 9.6 Hz, 1H), 4.23-4.03 (m, 1H), 2.78 (t, J = 7.6 Hz, 1H), 1.63 (s, 3H), 1.35 (s, 9H), 1.23-1.30 (m, 2H), 0.90-0.78 (m, 3H).

[0620] Preparation of compound 50-5

[0621] Ozone was passed into a solution of compound 50-4 (3.287 g, 8.09 mmol) in 50 mL dichloromethane, and after the reaction solution turned blue, nitrogen was passed to blow the solution to restore yellow, and triphenylphosphine (3.18 g, 12.13 mmol) was added. The reaction solution was slowly heated to 25 °C and reacted for 12 hours. After the reaction was completed, the reaction solution was rotary evaporated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1-10 / 1) to obtain compound 50-5.

[0622] 1H NMR (400 MHz, CDC13): δ 10.52 (s, 1H), 7.47-7.38 (m, 1H), 7.27 (s, 2H), 4.88 (d, J = 10.6 Hz, 1H), 4.76-4.63 (m, 1H), 2.87 (s, 1H), 1.68 (s, 3H), 1.32 (s, 9H), 0.78-0.69 (m, 3H).

[0623] Preparation of compound 50-6

[0624] Sodium borohydride (92.64 mg, 2.45 mmol) was slowly added to a solution of compound 50-5 (0.5 g, 1.22 mmol) in 6 mL of tetrahydrofuran at 0 °C under nitrogen atmosphere. The reaction was stirred at 25 °C for 1 hour. After the reaction was completed, 10 mL of saturated ammonium chloride aqueous solution was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-5 / 1) to obtain compound 50-6.

[0625] Preparation of compound 50-7

[0626] Sodium hydride (102 mg, 2.56 mmol, 60% content) was slowly added to a solution of compound 50-6 (350 mg, 0.85 mmol) in 6 mL of tetrahydrofuran at 0 °C under nitrogen atmosphere. After being stirred for 10 minutes, (3-bromoprop-1-ynyl)trimethylsilane (244 mg, 1.28 mmol) was added. The reaction was stirred at 25 °C for 6 hours. After the reaction was completed, 5 mL of saturated ammonium chloride aqueous solution was added to quench the reaction. The aqueous phase was extracted with 0.5 M hydrochloric acid to adjust the pH to 3-4. The aqueous phase was extracted with dichloromethane (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-1 / 1) to obtain compound 50-7.

[0627] Preparation of compound 50-8

[0628] N,N-dimethylformamide (2.3 μL, 0.03 mmol) and oxalyl chloride (114.52 mg, 0.90 mmol) were sequentially added to a solution of compound 50-7 (118 mg, 0.30 mmol) in 4 mL of dichloromethane under nitrogen atmosphere. The reaction was reacted at 25 °C for 1 hour to obtain a solution containing compound 50-8, which was directly used in the next reaction.

[0629] Preparation of compound 50-9

[0630] To the reaction solution of the above step (pH > 8) was added triethylamine (416.2 μL, 2.99 mmol) under nitrogen atmosphere, followed by the addition of 4-aminopyridine-2-carboxylic acid methyl ester (136.68 mg, 0.90 mmol), and the reaction solution was stirred at 25 °C for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1-1 / 2) to obtain compound 50-9.

[0631] Preparation of Example 50

[0632] Compound 50-9 (74 mg, 0.14 mmol) was added to a 7.0 M ammonia methanol solution (3 mL, 21 mmol) under nitrogen atmosphere, and the reaction solution was reacted at 25 °C for 12 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase preparation (column: Boston Green ODS 150*30 mm*5 um; mobile phase: [A: H2O (0.225% FA); B: ACN]; B%: 48.00%-78.00%, 11.00 min; flow rate: 25.00 mL / min) to obtain Example 50.

[0633] 1 H NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.05 (s, 1H), 7.81 (dd, J = 5.6, 2.0 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.51-7.37 (m, 1H), 7.35-7.23 (m, 1H), 5.16 (d, J = 10.8 Hz, 1H), 4.65 (d, J = 2.0 Hz, 2H), 4.40-4.30 (m, 1H), 4.24 (dd, J = 4.4, 2.4 Hz, 2H), 3.55 (s, 1H), 3.52-3.49 (m, 1H), 2.82 (s, 1H), 1.64 (s, 3H), 0.83-0.64 (m, 3H);

[0634] m / z (ESI): [M+H] + = 512.1.

[0635] Example 51

[0636] Preparation of Example 51

[0637] Compound 1-18 (200 mg, 0.44 mmol) was dissolved in DMF (2 mL), potassium carbonate (180.50 mg, 1.31 mmol) and chloromethyl methyl sulfide (126.13 mg, 1.31 mmol), potassium iodide (72.27 mg, 0.44 mmol) were added, the reaction was stirred at 25 °C for 1 h. The reaction was added to 20 mL aqueous solution, extracted with dichloromethane, separated, the organic phase was washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by reverse phase preparative purification ((Phenomenex luna C18 150 x 25 mm x 10 um); flow rate: 25 mL / min; gradient: 52% - 72% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to give Example 51.

[0638] 1 H NMR (400 MHz, DMSO-d6): δ 10.71 (s, 1H), 8.49 (d, J = 6.0 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 2.0, 5.6 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.21 (d, J = 6.4 Hz, 2H), 5.48 - 5.38 (m, 1H), 5.37 - 5.31 (m, 1H), 5.12 (d, J = 10.4 Hz, 1H), 4.38 (dd, J = 7.6, 10.0 Hz, 1H), 2.83 (t, J = 7.6 Hz, 1H), 2.22 (s, 3H), 1.62 (s, 3H), 0.73 (d, J = 6.0 Hz, 3H);

[0639] m / z (ESI): [M+H] + = 520.1.

[0640] Example 52

[0641] Preparation of Example 52

[0642] Compound 52-1 (70 mg, 0.26 mmol), compound 1-18 (120 mg, 0.26 mmol), potassium carbonate (110 mg, 0.80 mmol) and sodium iodide (50 mg, 0.33 mmol) were dissolved in DMF (5 mL) and stirred at room temperature for 12 hours. The reaction was quenched by pouring into water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by reverse phase preparative HPLC (Phenomenex luna C18 150 x 25 mm x 10 um; flow rate: 25 mL / min; gradient: 45% - 75% B over 15 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to give Example 52.

[0643] 1 H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.08 (s, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.64 (s, 1H), 7.61 - 7.52 (m, 1H), 7.43 - 7.35 (m, 1H), 5.17 (d, J = 10.2 Hz, 1H), 4.79 - 4.71 (m, 1H), 4.26 - 4.18 (m, 1H), 2.73 - 4.64 (m, 1H), 1.60 (s, 3H), 0.78 - 0.70 (m, 3H);

[0644] m / z (ESI): [M+H] + = 534.0.

[0645] Examples 53, 54

[0646] Preparation of compound 53-1

[0647] A solution of ethynylmagnesium bromide in tetrahydrofuran (1.9 mL, 0.96 mmol, 0.5 M) was added slowly dropwise to a solution of 50-5 (300 mg, 0.73 mmol) in THF (10 mL) at 0 °C, and the reaction was allowed to warm to 25 °C naturally. After 2 h, the reaction was quenched by slowly adding an aqueous solution of ammonium chloride (3 mL) at 0 °C, diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 5:1 to 3:1) to give compound 53-1.

[0648] Preparation of compound 53-2

[0649] Diethylamine sulfide trifluoride (0.1 mL, 607.73 μmol) was added slowly dropwise to a solution of 53-1 (220 mg, 506.45 μmol) in DCM (5 mL) at -20 °C, and the reaction was allowed to warm to 25 °C naturally. After 2 h, the reaction was quenched by slowly adding saturated sodium bicarbonate, extracted with dichloromethane (5 mL x 3), and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1 to 3:1) to give compound 53-2.

[0650] Preparation of compound 53-3

[0651] Compound 53-2 (195 mg, 0.45 mmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction was stirred at 25 °C for 1 h. The reaction was directly concentrated to give compound 53-3.

[0652] Preparation of compound 53-4

[0653] Compound 53-3 (150 mg, 0.39 mmol) and DMF (3.1 μL, 0.04 mmol) were dissolved in DCM (5 mL), and oxalyl chloride (169.4 μL, 1.97 mmol) was slowly added under ice bath. The reaction was stirred at room temperature for 3 h. The reaction was concentrated to give compound 53-4.

[0654] Preparation of compound 53-5

[0655] Compound 53-4 (140 mg, 0.35 mmol) was dissolved in DCM (0.5 mL), and triethylamine (0.2 mL, 1.76 mmol) and methyl 4-aminopyridine-2-carboxylate (53.42 mg, 0.35 mmol) were slowly added under ice bath. The reaction was stirred at room temperature for 3 h. The reaction was concentrated, and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1) to give compound 53-5.

[0656] Preparation of Examples 53, 54

[0657] Compound 53-5 (20 mg, 0.04 mmol) and aminomethanol (16.55 mg, 0.97 mmol) were dissolved in MeOH (0.5 mL) and the reaction was stirred at 25 °C for 3 hours. The reaction was concentrated and the crude was purified by reverse phase preparative (Phenomenex luna C18 150 x 25 mm x 10 um); flow rate: 25 mL / min; gradient: 49% - 69% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to give two isomers.

[0658] Example 53 (smaller retention time):

[0659] 1 H NMR (400 MHz, DMSO-d6): δ 10.56 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.82 (dd, J = 2.0, 5.2 Hz, 1H), 7.67 - 7.56 (m, 2H), 7.40 - 7.35 (m, 1H), 6.85 - 6.69 (m, 1H), 5.16 (d, J = 10.0 Hz, 1H), 4.46 (t, J = 9.2 Hz, 1H), 4.28 (dd, J = 2.0, 5.0 Hz, 1H), 2.94 - 2.85 (m, 1H), 1.66 (s, 3H), 0.76 (d, J = 7.2 Hz, 3H);

[0660] m / z (ESI): [M+H] + = 500.2.

[0661] Example 54 (larger retention time):

[0662] 1H NMR: (400 MHz, DMSO-d6): δ 10.58 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 1.2 Hz, 1H), 7.86 (dd, J = 2.2, 5.6 Hz, 1H), 7.65-7.56 (m, 2H), 7.40 (dd, J = 4.2, 8.8 Hz, 1H), 6.93-6.77 (m, 1H), 5.23 (d, J = 10.0 Hz, 1H), 4.63 (t, J = 9.2 Hz, 1H), 4.09 (dd, J = 2.2, 5.0 Hz, 1H), 2.67-2.61 (m, 1H), 1.67 (s, 3H), 0.69 (d, J = 6.4 Hz, 3H);

[0663] m / z (ESI): [M+H] + = 500.2.

[0664] Example 55

[0665] Preparation of compound 52-1

[0666] Under nitrogen atmosphere, n-butyllithium n-hexane (33 mL, 82.50 mmol) solution was slowly added to compound 55-1 (13.3 mL, 71.28 mmol) in THF (80 mL) at -70 °C. After stirring for 1 hour, compound 55-2 (23 g, 109.62 mmol) was slowly added to the reaction system. The temperature was restored to 20 °C and stirring was continued for 15 hours. The reaction solution was poured into ice ammonium chloride aqueous solution (100 mL), and the mixture was extracted with petroleum ether (200 mL x 2). After the organic phases were combined, they were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a crude product. The crude product was dissolved in 50 mL of petroleum ether and filtered through silica gel powder (10 cm thick), and the filtrate was concentrated to dryness to obtain compound 52-1.

[0667] Preparation of compound 55-3

[0668] Compound 52-1 (10 g, 37.15 mmol) was dissolved in tetrahydrofuran (10 mL) and water (40 mL), and after the addition of indium powder (6 g, 52.26 mmol), it was ultrasonically vibrated for 8 hours. Aqueous formaldehyde solution (16 g, 197.14 mmol) was added to the reaction solution, and stirring was continued for 32 hours. The reaction solution was diluted with ethyl acetate (300 mL), filtered, and the filtrate was allowed to stand to separate into layers. The upper ethyl acetate layer was separated and washed once more with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 55-3.

[0669] Preparation of compound 55-4

[0670] Compound 55-3 (500 mg, 2.27 mmol) and pyridine (0.5 mL, 6.18 mmol) were dissolved in DCM (10 mL), trifluoromethanesulfonic anhydride (0.5 mL, 3.01 mmol) was added slowly under ice-bath, and the mixture was stirred in a warm room for 1 hour. The reaction solution was diluted with ethyl acetate (200 mL), washed with water (100 mL x 2), saturated brine (100 mL) successively, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 55-4.

[0671] Preparation of example 55

[0672] Compound 55-4 (130 mg, 0.37 mmol) and compound 1-18 (170 mg, 0.37 mmol) were dissolved in DMF (5 mL), and potassium carbonate (180 mg, 1.30 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase preparation (Phenomenex luna C18 150 x 25 mm x 10 um; flow rate: 25 mL / min; gradient: 42% - 72% B over 15 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to obtain example 55.

[0673] m / z (ESI): [M+H] + = 548.1.

[0674] Examples 56, 57

[0675] Preparation of compound 56-1

[0676] Under a nitrogen atmosphere, triethylamine (1.1 mL, 7.87 mmol) was added to 24-3 (314 mg, 0.79 mmol) in 3 mL of dichloromethane, followed by the addition of a solution of compound 22-5 (198.83 mg, 1.02 mmol) in 3 mL of DCM, and the mixture was stirred at 26 degrees for 2 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 56-1.

[0677] Preparation of Examples 56, 57

[0678] Trifluoroacetic acid (800.8 μL, 10.78 mmol) was added to a solution of compound 56-1 (300 mg, 0.54 mmol) in 9 mL of dichloromethane under nitrogen atmosphere. The reaction was stirred at 25 °C for 2 hours. The reaction was concentrated to give the crude product. Purification by reverse phase preparative (Waters Xbridge 150*25mm*5um, water(water(NH4HCO3)-ACN, 38%-68% over 12 min) gave a mixture of Example 56 and Example 57. The mixture was separated by SFC (column: DAICEL CHIRALCEL OX (250mm*30mm, 10um); mobile phase: [A: CO2; B: EtOH (0.1% NH3H2O)]; B%: 15.00%-15.00%, 60.00 min; flow rate: 150.00 g / min) to give two single isomers.

[0679] Example 56 (retention time = 1.497 min)

[0680] 1 H NMR (400 MHz, DMSO-d6): δ 10.36 (s, 1H), 8.71-8.56 (m, 1H), 8.09-7.88 (m, 1H), 7.50-7.37 (m, 1H), 7.29-7.08 (m, 2H), 5.44-5.29 (m, 1H), 5.16-5.04 (m, 1H), 4.70-4.60 (m, 1H), 4.57-4.48 (m, 1H), 4.40-4.26 (m, 1H), 3.70-3.57 (m, 2H), 3.49-3.39 (m, 1H), 2.91-2.75 (m, 1H), 1.61 (s, 3H), 0.81-0.63 (m, 3H);

[0681] m / z (ESI): [M+H] + = 517.3.

[0682] Example 57 (retention time = 1.655 min)

[0683] 1H NMR (400 MHz, DMSO-d6): δ 10.37 (s, 1H), 8.72-8.59 (m, 1H), 7.97 (dd, J = 2.4, 8.6 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.29-7.10 (m, 2H), 5.34 (d, J = 4.8 Hz, 1H), 5.10 (d, J = 10.5 Hz, 1H), 4.64 (br t, J = 5.8 Hz, 1H), 4.59-4.47 (m, 1H), 4.31 (dd, J = 7.5, 10.3 Hz, 1H), 3.71-3.57 (m, 2H), 3.44 (td, J = 5.9, 11.4 Hz, 1H), 2.83 (t, J = 7.3 Hz, 1H), 1.61 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H);

[0684] m / z: [M+H]+ + = 517.1.

[0685] Examples 58, 59

[0686] Preparation of compound 58-1

[0687] To a solution of compound 50-1 (500 mg, 1.47 mmol) in DCM (5 mL) was added DMF (10 mg, 0.15 mmol) and oxalyl chloride (0.4 mL, 4.41 mmol). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated, and then triethylamine (0.6 mL, 4.35 mmol) and the above concentrated solution were added successively to a solution of compound 56-5 (337.89 mg, 1.74 mmol) in 10 mL of dichloromethane under nitrogen atmosphere. The reaction was stirred at 26 °C for 16 hours. After the reaction was completed, 30 mL of water was added for dilution, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 ~ 1 / 1) to give compound 58-1.

[0688] 1H NMR (400 MHz, CDC13): δ = 8.56 (d, J = 2.4 Hz, 1H), 8.41 (s, 1H), 8.13 (dd, J = 2.4, 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 6.8 Hz, 1H), 6.83-6.72 (m, 1H), 6.31 (s, 1H), 5.18 (t, J = 6.8 Hz, 1H), 5.14-5.03 (m, 1H), 4.44 (t, J = 7.6 Hz, 1H), 3.91 (t, J = 7.6 Hz, 1H), 2.92-2.79 (m, 1H), 1.70 (s, 3H), 1.51 (d, J = 14.4 Hz, 6H), 0.87-0.78 (m, 3H);

[0689] m / z (ESI): [M+H] + = 517.2.

[0690] Preparation of compound 58-2

[0691] Trifluoromethanesulfonic anhydride (83.5 μL, 0.50 mmol) was added to a solution of compound 58-1 (280 mg, 0.61 mmol) in 4 mL of dichloromethane at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 2 hours. After the reaction was completed, 20 mL of water was added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 ~ 2 / 1) to give compound 58-2.

[0692] Preparation of compound 58-3

[0693] Ethynyl[tris(propan-2-yl)]silane (0.2 mL, 0.77 mmol), cuprous iodide (3.0 mg, 0.02 mmol), triethylamine (23.4 mg, 0.23 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (8.46 mg, 0.01 mmol) were sequentially added to a solution of compound 58-2 (50 mg, 0.08 mmol) in 1.5 mL of N,N-dimethylformamide under nitrogen atmosphere. The reaction was stirred at 100 °C for 16 hours. After the reaction was completed, the reaction was cooled to room temperature, diluted with 20 mL of water and 20 mL of ethyl acetate, filtered, and the filtrate was extracted with ethyl acetate (10 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by thin layer silica gel preparation (petroleum ether / ethyl acetate = 3 / 1) to give compound 58-3.

[0694] Preparation of compound 58-4

[0695] Under nitrogen atmosphere, trifluoroacetic acid (262 μL, 3.53 mmol) was added to a solution of compound 58-3 (120 mg, 0.18 mmol) in 2 mL of dichloromethane, and the reaction was stirred at 25 °C for 0.5 h. After the reaction was completed, saturated sodium bicarbonate was slowly added to the reaction to adjust pH = 7, and the aqueous phase was extracted with dichloromethane (20 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 58-4.

[0696] Preparation of Examples 58 and 59

[0697] Under nitrogen atmosphere, cesium fluoride (284 mg, 1.87 mmol) was added to a solution of compound 58-4 (120 mg, 0.19 mmol) in 2 mL of N,N-dimethylformamide, and the reaction was stirred at 25 °C for 0.5 h. After the reaction was completed, the reaction was filtered, and the filtrate was purified by reverse phase preparation (0.1% FA / ACN, 55%-65% over 5 min) to give a mixture of Example 58 and Example 59. The mixture was separated by SFC (column: DAICEL CHIRALCEL OX (250 mm*30 mm, 10 um); mobile phase: [A: CO2; B: EtOH (0.1% NH3H2O)]; B%: 20.00%-20.00%, 4.00 min; flow rate: 150.00 g / min) to give two single isomers:

[0698] Example 58 (retention time = 1.587 min)

[0699] 1 H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1H), 8.64 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 2.4, 8.6 Hz, 1H), 7.61-7.50 (m, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.30 (dd, J = 4.4, 8.4 Hz, 1H), 5.34 (d, J = 4.8 Hz, 1H), 5.18 (d, J = 10.0 Hz, 1H), 5.03 (s, 1H), 4.64 (t, J = 6.0 Hz, 1H), 4.53 (td, J = 4.0, 6.8 Hz, 1H), 4.38 (dd, J = 7.8, 10.0 Hz, 1H), 3.68-3.58 (m, 1H), 3.43 (td, J = 6.0, 11.6 Hz, 1H), 2.97-2.84 (m, 1H), 1.60 (s, 3H), 0.73 (br d, J = 6.0 Hz, 3H);

[0700] m / z (ESI): [M+H]+ = 485.2.

[0701] Example 59 (retention time = 1.726 min)

[0702] 1 H NMR (400 MHz, DMSO-d6): δ 10.45 (s, 1H), 8.70-8.65 (m, 1H), 8.02-7.95 (m, 1H), 7.61-7.49 (m, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 4.4, 8.4 Hz, 1H), 5.35 (d, J = 4.8 Hz, 1H), 5.20 (d, J = 10.0 Hz, 1H), 5.02 (s, 1H), 4.65 (t, J = 6.0 Hz, 1H), 4.58-4.49 (m, 1H), 4.39 (dd, J = 7.8, 9.8 Hz, 1H), 3.68-3.59 (m, 1H), 3.48-3.41 (m, 1H), 2.96-2.82 (m, 1H), 1.60 (s, 3H), 0.73 (br d, J = 6.0 Hz, 3H);

[0703] m / z: [M+H]+ + = 485.2.

[0704] Example 60

[0705] Preparation of compound 60-2

[0706] Compound 60-1 (0.64 g, 5.60 mmol) was added dropwise into a solution of cuprous iodide (0.1 g, 0.51 mmol), ethynyltrimethylsilane (0.7 mL, 5.09 mmol) in acetonitrile (5 mL) under nitrogen atmosphere. The reaction was stirred at 25 °C for 16 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 60-2.

[0707] Preparation of compound 60-3

[0708] Deuterated lithium aluminum hydride (0.13 g, 3.04 mmol) was added slowly in batches to a solution of compound 60-2 (0.7 g, 3.80 mmol) in 20 mL THF at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 1 h. After the reaction was completed, 1.5 mL deuterated water was added slowly at 0 °C to quench the reaction. After stirring for 10 min, the reaction was warmed to 26 °C and dried by adding anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 60-3.

[0709] Preparation of compound 60-4

[0710] Under nitrogen atmosphere, cyanomethylidene tributylphosphonium (210.17 mg, 0.87 mmol) was added to a solution of compound 1-18 (80 mg, 0.17 mmol) and compound 60-3 (170. mg, 1.39 mmol) in 2 mL of dioxane, the reaction was heated to 40 degree and stirred for 16 hours. After the reaction was completed, the reaction was cooled to room temperature, diluted with 10 mL of water, extracted with ethyl acetate (5 mL x 3) for three times, the combined organic phase was washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 ~ 1 / 1) to obtain compound 60-4.

[0711] Preparation of example 60

[0712] Under nitrogen atmosphere, tetrabutylammonium fluoride tetrahydrofuran solution (0.17 mL, 0.17 mmol) was added to a solution of compound 60-4 (50 mg, 0.09 mmol) in 1 mL of THF, the reaction was reacted at 25 degrees for 1 hour. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (5 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by reverse phase preparation ((Phenomenex luna C18 150 x 25 mm x 10 um); flow rate: 25 mL / min; gradient: 42% - 72% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to obtain example 60.

[0713] 1 H NMR (400 MHz, DMSO-d6): δ 10.81-10.60 (m, 1H), 8.55-8.46 (m, 1H), 8.33-8.26 (m, 1H), 8.11-8.01 (m, 1H), 7.90-7.80 (m, 1H), 7.69-7.58 (m, 1H), 7.27-7.07 (m, 2H), 5.19-5.05 (m, 1H), 4.44-4.26 (m, 1H), 2.92-2.79 (m, 2H), 2.70-2.60 (m, 2H), 1.72-1.57 (m, 3H), 0.79-0.64 (m, 3H);

[0714] m / z (ESI): [M+H] + = 514.0.

[0715] Example 61

[0716] Preparation of compound 61-1

[0717] To a solution of compound 50-5 (500 mg, 1.22 mmol) in tetrahydrofuran (5 mL) was added iodine (396.70 mg, 2.45 mmol) and ammonia water (2.5 mL, 30% content), and the reaction was stirred at 30 °C for 10 hours. The reaction was quenched with 30 mL of water, extracted with ethyl acetate (30 mL x 2), and the combined organic phase was washed with saturated sodium sulfite aqueous solution (30 mL x 2), saturated sodium chloride aqueous solution (30 mL x 1) successively, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound 61-1.

[0718] 1 H NMR (400 MHz, CDCl3): δ = 7.45 (q, J = 9.0 Hz, 1H), 7.24 (dd, J = 4.3, 8.8 Hz, 1H), 4.82 (d, J = 9.2 Hz, 1H), 4.15-4.12 (m, 1H), 2.94-2.89 (m, 1H), 1.66 (s, 3H), 1.39 (s, 9H), 0.88-0.79 (m, 3H).

[0719] Preparation of compound 61-2

[0720] To a solution of compound 61-1 (300 mg, 0.74 mmol) in DCM (10 mL) was added trifluoroacetic acid (2.00 mL), and the reaction was stirred at 20 °C for 5 hours. After the reaction was completed, the reaction was directly concentrated under reduced pressure to obtain compound 61-2.

[0721] m / z (ESI): [M-H] - = 348.0.

[0722] Preparation of compound 61-3

[0723] Compound 61-2 (260 mg, 0.74 mmol) and methyl 4-aminopicolinate (169.90 mg, 1.12 mmol) were dissolved in acetonitrile (5 mL), and N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (313.31 mg, 1.12 mmol) was added. The reaction was stirred at 20 °C for 16 h. The reaction was diluted with 30 mL of water and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 7) to give compound 61-3.

[0724] m / z (ESI): [M+H] 484.2. + = 484.2.

[0725] Preparation of Example 61

[0726] Compound 61-3 (100 mg, 0.21 mmol) was added to an ammonium hydroxide solution (2 mL, 6 M) and stirred at 20 °C for 16 h. After the reaction was completed, the reaction was directly concentrated under reduced pressure. The resulting crude product was purified by reverse phase preparative (Phenomenex luna C18 150 x 25 mm x 10 um; flow rate: 25 mL / min; gradient: 42% - 62% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to give Example 61.

[0727] 1 H NMR (400 MHz, DMSO-d6): d 10.68 (s, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.95 - 7.87 (m, 1H), 7.85 (dd, J = 2.0, 5.6 Hz, 1H), 7.62 (br s, 1H), 7.49 (dd, J = 4.4, 8.8 Hz, 1H), 5.26 (d, J = 9.2 Hz, 1H), 4.31 (t, J = 8.8 Hz, 1H), 2.91 (t, J = 7.6 Hz, 1H), 1.62 (s, 3H), 0.79 (d, J = 6.4 Hz, 3H);

[0728] m / z (ESI): [M+H] 469.0. + = 469.0.

[0729] Experimental Example 1 Manual Patch Clamp Method for Detecting Inhibitory Activity of the Compound of the Invention on Voltage-gated Sodium Channel NaV1.8

[0730] Cell Culture and Passage: CHO cells stably expressing human NaV1.8 were cultured in Ham's F-12 medium containing 10% fetal bovine serum and 10 μg / mL Blasticidin, 200 μg / mL Hygromycin B, and 100 μg / mL Zeocin. The cell culture temperature was 37°C, and the carbon dioxide concentration was 5%. During cell passage, the old medium was removed and washed once with PBS, and then a 0.25% -Trypsin-EDTA solution was added and incubated at 37°C. When the cells were observed to detach from the bottom of the dish, an appropriate amount of 37°C preheated complete medium was added. After the cells were blown off the bottom of the dish, they were transferred to a sterile centrifuge tube, centrifuged at 1000 rpm for 5 min to collect the cells, and then the cells were seeded in a 6 cm cell culture dish (2.5 x 10 5 cells / dish, 5 mL of medium) for amplification or maintenance of culture. To maintain the electrophysiological activity of the cells, the cell density should not be less than 80%.

[0731] Before patch clamp detection, 0.25% -Trypsin-EDTA solution was added to the CHO cells stably expressing human NaV1.8 to separate and count the cells, and 6.5 x 10 3 cells were attached to a coverslip and cultured in a 24-well plate (final volume 500 μL), and detection was performed after 18 hours.

[0732] Preparation of Compound Sample: The test compound was prepared as a 100 mM stock solution with dimethyl sulfoxide (DMSO), and then diluted with an extracellular solution (140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2·2H2O, 10 mM D-Glucose, 10 mM HEPES, 1.25 mM NaH2PO4·2H2O, NaOH to adjust pH = 7.4) containing 100 nM tetrodotoxin (TTX) to different concentrations of working solutions. The concentration of DMSO in each working solution was 0.1%. The test working solution was sonicated for 20 min before detection.

[0733] Patch clamp recording: The patch clamp recording was performed as follows. First, the capillary glass tube was pulled into a recording electrode using a microelectrode puller. Then, the recording electrode was filled with the internal solution (50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, 20 mM EGTA, CsOH to adjust pH = 7.2). The recording electrode was then mounted into a microelectrode holder. The recording electrode was guided to contact the cell under an inverted microscope. A negative pressure was applied to form a GΩ seal. Fast capacitance compensation was performed at this time. Then, a negative pressure was applied to break the cell membrane and form a whole-cell recording mode. Finally, slow capacitance compensation was performed and the relevant parameters were recorded. No leakage compensation was performed.

[0734] When the sodium current was stable, the drug was administered. Each drug concentration was tested for 5 min (or until the current was stable) before the next concentration was tested. The coverslips with cells were placed in a recording bath under an inverted microscope. The blank control external solution and the working solution of the test compound were gravity perfused through the recording bath from low to high concentrations to act on the cells. The liquid exchange was performed using a peristaltic pump during recording. The current detected in the external solution without the compound was used as the control for each cell. Each concentration was tested twice independently. All electrophysiological experiments were performed at room temperature. Specifically, two concentrations (for preliminary screening) or five concentrations (for calculating the IC 50 value) were set for each test compound. The inhibitory activity of the test compound on NaV1.8 sodium channels was determined by calculating the relative percentage of the peak current generated by the cells treated with the test compound to the peak current generated by the control cells.

[0735] Voltage stimulation protocol for whole-cell patch clamp recording of NaV1.8 sodium current: After forming a whole-cell seal, the cell voltage was clamped at -120 mV. First, the voltage was stepped from -130 mV to -10 mV at 10 mV, and maintained for 5 s, and then a 0 mV depolarization pulse was applied to obtain the half-inactivation voltage (Vhalf). The resting state and half-inactivated state of the sodium current were detected using a double-pulse mode. First, a first depolarization pulse (TP1) was applied to 0 mV for 50 ms to detect the resting state sodium current. Then, the voltage was adjusted to Vhalf and maintained for 5 s, followed by a return of the voltage to -120 mV for 20 ms, and then a second depolarization pulse (TP2) was applied to 0 mV for 50 ms to detect the half-inactivated sodium current. Finally, it was returned to the clamping voltage -120 mV. The data was collected every 20 ms to observe the effect of the drug on the peak current of the sodium current in the two different states.

[0736] Example compounds on Na V1.8 channel inhibitory activity was determined by the above-mentioned test, and the inhibition rate and IC 50 See Table 1 and Table 2.

[0737] Table 1, Example compound on NaV1.8 channel inhibitory activity (inhibition rate)

[0738] Table 2, Example compound on NaV1.8 channel inhibitory activity (IC 50 )

[0739] The experimental results show that the example compounds of the present application have good inhibitory effect on NaV1.8.

[0740] Experimental Example 2: In vivo pharmacokinetic study of rats by single intravenous injection or oral administration by gavage.

[0741] Experimental method: 6 male SD rats weighing 200-300g were divided into two groups, one group was orally administered 5mg / kg, and the other group was administered 1mg / kg by tail vein. The animals orally administered were fasted overnight and fed 4 hours after administration, and the animals administered by intravenous injection were free to eat. Blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24h after administration, and plasma samples were pretreated, detected by LC / MS / MS in MRM mode, and the appropriate standard curve was established to quantify the target compound in plasma samples to obtain the drug concentration-time curve. The WinNonlin software was used to calculate the pharmacokinetic parameters of non-compartment membrane type, and the experimental results are shown in the following table:

[0742] Table 3, Pharmacokinetic parameters of example compounds of the present application in rats

[0743] The experimental results show that the example compounds of the present application have high blood drug concentration, high exposure and low clearance in rats, and have obvious pharmacokinetic advantages.

[0744] Experimental Example 3: In vivo pharmacokinetic study of mice by single intravenous injection or oral administration by gavage.

[0745] Experimental method: 20-30 g male C57BL / 6 mice were taken, 6 for each group, one group was 5 mg / kg single dose of tail vein, one group was 1 mg / kg single dose of oral administration. Two groups of animals were free to eat. Blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration, and the plasma samples were pretreated, detected by LC / MS / MS in MRM mode, and the appropriate standard curve was established to quantify the target compound in the plasma sample to obtain the drug concentration-time curve. The non-compartment model of WinNonlin software was used to calculate the pharmacokinetic parameters, and the experimental results are shown in the following table:

[0746] Table 4, the mouse pharmacokinetic parameters of the compound of the present application

[0747] The experimental results show that the compound of the present application has high blood concentration and high exposure in mice, and has pharmacokinetic advantages.

[0748] Experimental example 4: in vivo pharmacokinetic study of dogs by single intravenous injection or oral administration by gavage.

[0749] Experimental method: 9-11 kg male beagle dogs were taken, 6 for each group, one group was 0.5 mg / kg single dose of tail vein, one group was 1 mg / kg single dose of oral administration. The animals of intravenous injection administration group were free to eat, and the animals of oral administration group were fasted overnight, and the food was restored 4 hours after administration. The intravenous injection administration group was blood collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24 and 48 h after administration, and the oral administration group was blood collected at 0.25, 0.5, 1, 2, 4, 8, 24, 32 and 48 h after administration, and the plasma samples were pretreated, detected by LC / MS / MS in MRM mode, and the appropriate standard curve was established to quantify the target compound in the plasma sample to obtain the drug concentration-time curve. The non-compartment model of WinNonlin software was used to calculate the pharmacokinetic parameters, and the experimental results are shown in the following table:

[0750] Table 5, the canine pharmacokinetic parameters of the compound of the present application

[0751] The experimental results show that the compound of the present application has low clearance rate, high exposure and high oral bioavailability in dogs, and has pharmacokinetic advantages.

[0752] Experimental example 5: in vivo pharmacokinetic study of monkeys by single intravenous injection or oral administration by gavage.

[0753] Take 3.0-3.3 kg male cynomolgus monkeys 6, divided into two groups, one group 1 mg / kg single intravenous administration, one group 2 mg / kg single oral administration. The animals in the intravenous injection group were free to eat, and the animals in the oral administration group were fasted overnight and resumed eating 4 hours after administration. The animals in the intravenous injection group were bled at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24 and 48 hours after administration, and the animals in the oral administration group were bled at 0.25, 0.5, 1, 2, 4, 8, 24, 32 and 48 hours after administration. After pretreatment, the plasma samples were detected by LC / MS / MS in MRM mode, and the appropriate standard curve was established to quantify the target compound in the plasma sample to obtain the drug concentration-time curve. The pharmacokinetic parameters were calculated by non-compartment model using WinNonlin software, and the experimental results are shown in the following table:

[0754] Table 6, the pharmacokinetic parameters of the compound of the present application in monkeys

[0755] The experimental results show that the compound of the present application has low clearance rate, high exposure and high oral bioavailability in dogs, and has pharmacokinetic advantages

[0756] Experimental Example 6: Solubility of the compound of the present application.

[0757] Experimental method: Take 15 μL of 10 mM DMSO stock solution, add 485 μL of phosphate buffer (PBS pH 7.4), simulated fasted intestinal fluid (FaSSIF pH 6.5), simulated fed intestinal fluid (FeSSIF pH 5.0) and simulated fasted gastric fluid (FaSSGF pH 1.6) respectively in a 96-well plate (n=2), the final concentration is 300 μM (containing 3% DMSO). After adding a stirring rod to each well, seal, and oscillate in a constant temperature oscillator at 25°C 1100 rpm for 2h. After oscillation, filter the sample in a filter plate using a vacuum filter. Take 5 μL of the filtrate, add 5 μL of DMSO, then add the appropriate amount of ultrapure water and acetonitrile mixture (1:1) containing internal standard to dilute the corresponding multiple, mix well and then LC-MS / MS sample analysis. Take 5 μL of 300 μM DMSO standard solution, add 5 μL of different buffers, then add the appropriate amount of ultrapure water and acetonitrile mixture (1:1) containing internal standard to dilute the corresponding multiple, mix well, and LC-MS / MS analysis with the sample. The experimental results are shown in the following table.

[0758] The solubility values of the test sample and the standard control are calculated according to the following formula:

[0759] Table 7, the solubility of the compound of the present application

[0760] The experimental results show that the compounds of the embodiments of the present application have good solubility in FaSSIF, FESSIF and FaSSGF solutions.

[0761] Experimental Example 7: CYP inhibition of the compounds of the present application.

[0762] Experimental method: the specific probe substrate of CYP450 isoenzyme is incubated with human liver microsomes and different concentrations of compounds, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) is added to start the reaction. After the reaction is completed, the sample is treated and the concentration of the metabolite produced by the probe substrate is quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS) method, so as to calculate the IC 50 value. The experimental results are shown in the following table:

[0763] Table 8, effect of the compounds of the embodiments of the present application on the activity of human liver microsomal cytochrome P450

[0764] The experimental results show that the compounds of the embodiments of the present application have weak inhibition on cytochrome P450 isoenzyme, and the risk of drug-drug interaction is low.

[0765] Experimental Example 8: liver microsomal metabolic stability of the compounds of the present application.

[0766] Experimental method: in a 100 mM pH 7.4 phosphate buffer system, appropriate volumes of human, monkey, dog, rat or mouse liver microsomes (protein final concentration 0.5 mg / mL) and reduced nicotinamide adenine dinucleotide phosphate (NADPH, final concentration 1 mM) are mixed, and after pre-incubation at 37°C for 10 min, appropriate volumes of target compounds (final concentration 1 μM) are added to start the reaction, and the organic solvent is not more than 1%. At 0.5, 5, 15, 30 and 60 min after the reaction, the same volume of incubation solution is taken, and an appropriate amount of internal standard-containing ice acetonitrile solution is added to terminate the reaction. After centrifugation at 3220 g for 40 min, the supernatant is diluted with ultrapure water, and LC / MS / MS is used for quantitative analysis. The peak area ratio of 0.5 min target compound to internal standard is taken as 100%, and the relative percentage of the remaining time points of the target compound is calculated. The natural logarithm of the remaining percentage of the target compound at each time point is linearly regressed with the incubation time to obtain the slope (k), and the half-life is calculated by the formula t 1 / 2 = -0.693 / k. The experimental results are shown in the following table:

[0767] Table 9, liver microsomal metabolic stability of the compounds of the embodiments of the present application

[0768] The experimental results show that the compounds of the embodiments of the application are relatively stable in liver microsomes of various species.

[0769] Experimental Example 9: Hepatocyte metabolic stability of the compounds of the application.

[0770] Experimental method: human, monkey, dog, rat or mouse hepatocytes (cell density 0.5 x 10 6 cells / mL) and target compounds (final concentration 1 μM) were mixed and incubated in a 37°C incubator with shaking for 120 min, with no more than 1% organic solvent. The same volume of incubation solution was taken at 0.5, 15, 30, 60, 90 and 120 min, respectively, and the reaction was terminated by adding an appropriate amount of ice acetonitrile solution containing an internal standard. After centrifugation at 3220 g for 45 min, the supernatant was diluted with ultrapure water, and LC / MS / MS was used for quantitative analysis. The peak area ratio of the target compound to the internal standard at 0.5 min was taken as 100%, and the relative percentage of the target compound at the other time points was calculated. The natural logarithm of the relative percentage of the target compound at each time point and the incubation time were subjected to linear regression analysis to obtain the slope (k), and the half-life was calculated by the formula t 1 / 2 = -0.693 / k. The experimental results are shown in the following table:

[0771] Table 10: Hepatocyte metabolic stability of the compounds of the embodiments of the application

[0772] The experimental results show that the compounds of the embodiments of the application are relatively stable in hepatocytes of various species.

[0773] Experimental Example 10: Plasma protein binding rate of the compounds of the application.

[0774] Experimental method: 10 mM DMSO stock solution was diluted with DMSO to obtain a 1 mM working solution. 3 μL of the test substance working solution was added to 597 μL of pre-incubated plasma, and mixed thoroughly. The final concentration of the test substance in the plasma was 5 μM. The final organic solvent content of the incubation system was 0.5%. Immediately after mixing, 50 μL of the incubation system was transferred to a new 96-well plate as the 0-point sample, which was treated in the same way as the incubated sample.

[0775] After the equilibrium dialysis plate and dialysis membrane were assembled, 120 μL of the test substance plasma sample and pH 7.4 phosphate buffer were added to the two sides of the dialysis membrane, respectively, and the membrane was sealed. The dialysis membrane was incubated in a 37°C incubator with 5% CO2 at 300 rpm on a vortex shaker for 6 h. After incubation, the membrane was removed, and 50 μL of the sample was taken from each chamber and transferred to a new 96-well plate. The remaining incubation system was also incubated under the same conditions for a corresponding period of time for the stability test of the test substance. After incubation, 50 μL of the incubation system was transferred and treated in the same way as the dialysis-incubated plasma sample.

[0776] To the withdrawn buffer sample, 50 μL of blank plasma was added, and to the withdrawn plasma sample, an equal volume of blank buffer was added, vortexed for 2 minutes, and 400 μL of quenching agent (containing 0.5 μM tolbutamide in acetonitrile) was added to precipitate the protein. All samples were vortexed for 10 minutes, and then centrifuged at 3000 g, 4°C for 30 minutes. 100 μL of supernatant was transferred to a new 96-well plate and centrifuged again at 3000 g, 4°C for 30 minutes. 150 μL of supernatant was transferred to a new 96-well plate, an equal volume of pure water was added, and mixed, and used for LC-MS / MS analysis.

[0777] All data were calculated by Microsoft Excel. The peak area was determined by the extracted ion chromatogram. The free percentage and the bound percentage were calculated by the ratio of the peak area of the test substance to the internal standard, and the calculation formula was as follows:

[0778] The bound percentage (%) = 100 - the free percentage, and the experimental results are shown in the following table:

[0779] Table 11, Plasma protein binding rate of the compound of the present application

[0780] Experimental Example 11: Pharmacodynamic test of Example 3, 12 and 24

[0781] 1. Purpose of the experiment

[0782] Male SD rats and male C57 BL / 6J mice were selected to establish a plantar incision pain model, and the analgesic effect of the compound of the present application was evaluated by determining the changes in the mechanical pain threshold of the animals.

[0783] 2. Experimental drugs

[0784] Example 3, Example 12 and Example 24. Add 5% DMSO, 10% solutol, 85% saline in turn, vortex to mix until clear.

[0785] 3. Experimental materials and experimental methods

[0786] 3.1 Species, strain, age, and gender of experimental animals

[0787] SD rats, 6-8 weeks old, male; C57 BL / 6J mice, 6-8 weeks old, male.

[0788] 3.2 Grouping of experimental animals

[0789] After adaptive feeding of SD rats, the rats were grouped as follows:

[0790] C57 BL / 6J mice were acclimated and then grouped as follows:

[0791] 3.3 Experimental Methods

[0792] Plantar Incisional Pain Model: The experimental animals were anesthetized and fixed in a prone position on the operating table. The lateral hind limb was flattened with the sole upwards and fixed with surgical tape. The skin and fascia were incised with a sterile scalpel blade to make a longitudinal incision from the heel to the tip of the toes. The tip of a curved forceps was inserted under the lateral edge of the flexor digitorum brevis muscle and pushed into the medial side of the muscle to lift the muscle. A longitudinal incision was made in the muscle with a scalpel to ensure that the muscle belly was cut in half. The skin was sutured with 7-0 suture thread and sterilized. The animals were returned to their original place and allowed to recover from the surgery overnight. Oral gavage administration was performed, and mechanical pain measurement was performed 3 hours after administration of the drug to the animals.

[0793] Mechanical Pain Measurement (Ascending Method): The experimental animals were placed on a mechanical pain metal mesh frame for 30-60 min, and after the animals were no longer inquisitive, exploratory, and relatively calm, the test began. The experimental animals were stimulated with Von-Frey fiber silk to bend the fiber silk slowly and gently on the plantar of the hind limb after the animals were calm. The animals were observed for 2-3 s for foot withdrawal response. The animals were stimulated with fiber silk of increasing weight in order. Each fiber silk was stimulated 5 times, with at least 10 s between each stimulation. If the positive response was less than 3 times, the above operation was repeated with the next larger fiber silk. When 3 or more positive responses were observed in the test for the first time, the fiber silk was the pain threshold for the animal (each animal was tested twice, and the average value was taken). If the animals lifted their feet, avoided, or licked their feet in response to the stimulus, it was marked as positive (x), and foot withdrawal response due to physical activity was not counted. If there was no such response, it was marked as negative (o).

[0794] Fiber silk weight: rats 0.6, 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 15.0 (g), and the cut-off value was 15.0 g; mice 0.16, 0.40, 0.60, 1.00, 1.40, 2.00 (g), and the cut-off value was 2.00 g.

[0795] 3.4 Data Analysis

[0796] After the data was summarized and statistically analyzed, the mean and standard error were analyzed using SPSS data statistical software (version R26.0.0.0), and according to the SPSS statistical results, the images were drawn using Graph Pad software (version 8.0.2), and the data was tested using one-way ANOVA and t-test.

[0797] Threshold Increase Percentage (%) = [(Gt (G0- G1) / G0] x 100 (%), wherein G0is the baseline paw withdrawal threshold of the animal and G1is the paw withdrawal threshold of the animal after administration of the compound. t G0is the baseline paw withdrawal threshold of the animal and G1is the paw withdrawal threshold of the animal after administration of the compound.

[0798] 4、Results

[0799] The analgesic effects of Example 3, Example 12 and Example 24 in the rat incisional paw pain model are shown in Table 12. The analgesic effects of Example 3, Example 12 and Example 24 in the mouse incisional paw pain model are shown in Table 13.

[0800] Table 12 Analgesic effects of compounds of the disclosure in the rat incisional paw pain model

[0801] Table 13 Analgesic effects of compounds of the disclosure in the mouse incisional paw pain model

[0802] 5、Conclusion

[0803] The baseline paw withdrawal threshold of the rats before surgery was 5.0 ± 0.1 g. After surgery, 3 hours after administration, the paw withdrawal threshold of the Example 3 compound at 30 mg / kg was 7.1 ± 0.2 g, which was significantly higher than the paw withdrawal threshold of the vehicle control group by 97.2% (p < 0.0001); the paw withdrawal thresholds of the Example 12 compound at 15 and 30 mg / kg were 7.0 ± 0.3 g and 7.5 ± 0.2 g, respectively, which were significantly higher than the paw withdrawal threshold of the vehicle control group by 94.4% (p < 0.0001) and 108.3% (p < 0.0001), respectively. The paw withdrawal threshold of the Example 12 compound at 30 mg / kg was slightly higher than the paw withdrawal threshold at 15 mg / kg, and the analgesic effect tended to be saturated; the paw withdrawal threshold of the Example 24 compound at 30 mg / kg was 8.1 ± 0.3 g, which was significantly higher than the paw withdrawal threshold of the vehicle control group by 125% (p < 0.0001), and the analgesic effect was significantly higher than the paw withdrawal threshold of the Example 3 compound at 30 mg / kg (p < 0.05).

[0804] The baseline pain thresholds of mice before surgery were as follows: 3 hours after surgery, the pain threshold of Example 3 at 60 mg / kg was 0.70±0.05 g, a significant increase of 94.4% (p<0.01) compared to the pain threshold of the vehicle control group; the pain threshold of Example 12 at 60 mg / kg was 0.78±0.06 g, a significant increase of 116.7% (p<0.001) compared to the pain threshold of the vehicle control group; and the pain thresholds of Example 24 at 30 and 15 mg / kg were 0.74±0.08 g and 0.54±0.04 g, respectively, significantly increasing by 105.6% (p<0.001) and 50.0% compared to the pain threshold of the vehicle control group. The pain threshold of Example 24 at 30 mg / kg was significantly higher than that at 15 mg / kg (p<0.05), demonstrating a clear dose-dependent analgesic effect.

[0805] Experimental Example 12: Example 61 Pharmacological Efficacy Test

[0806] 1. Experimental Purpose

[0807] The mechanical allodynia test was used to evaluate the efficacy of the compounds in the mouse plantar incision pain model.

[0808] 2. Experimental drugs

[0809] The compound of Example 61 was added in sequence with 5% DMSO, 10% solutol, and 85% saline, and vortexed to mix until clear.

[0810] 3. Experimental Materials and Methods

[0811] 3.1 Experimental Animal Species, Strain, Age, and Gender: C57 BL / 6 mice, 6-8 weeks old, male.

[0812] 3.2 Experimental Animal Grouping

[0813] After adaptive breeding, C57 BL / 6 mice were divided into the following groups:

[0814] 3.3 Experimental methods

[0815] Plantar incision pain modeling: Use isoflurane to anesthetize the animal, and squeeze the animal's toes to confirm that the animal is fully anesthetized before surgery. Apply eye ointment to the animal's eyes to prevent the animal's cornea from drying out. Use iodine tincture and 70% ethanol to disinfect the sole of the left foot three times, and start the surgery after the skin is dry. Starting from 2mm from the heel, make an incision about 5mm long longitudinally toward the toe. After cutting the skin, lift the flexor digitorum brevis muscle and cause longitudinal blunt injury. Suture the wound and disinfect. After the animal is fully awake (free to move), put the animal back in the cage. 10 animals did not undergo mouse incision pain surgery, as a contrast.

[0816] Mechanical hyperalgesia test (up-down method): One day after modeling, mechanical hyperalgesia test was performed on the left hind paw of all model mice at 1 hour, 3 hours and 6 hours after administration. The mice were placed individually in a Plexiglas box with a mesh floor to allow access to the hind paws. The mice were allowed to acclimate for 15 minutes prior to testing. After acclimation, the mice were tested on the plantar surface of the left hind paw using von Frey filaments. The von Frey filaments included 8 testing forces: 2.36 (0.02 g), 2.44 (0.04 g), 2.83 (0.07 g), 3.22 (0.16 g), 3.61 (0.4 g), 3.84 (0.6 g), 4.08 (1 g), 4.17 (1.4 g). During testing, the filament was applied perpendicular to the skin and bent for 6-8 seconds. A flinch was scored as a response if the animal quickly withdrew its paw. A flinch was also scored if the animal withdrew its paw as the filament was removed from the skin. If the animal moved or walked, no response was scored and the test was repeated. The first test was performed using 3.22 (0.16 g). If the animal responded, the next test was performed using the next lower force. If the animal did not respond, the next test was performed using the next higher force. The maximum force was 4.17 (1.4 g). The results were recorded in the following table as X for a response and O for no response.

[0817] Mechanical hyperalgesia was expressed as paw withdrawal threshold (PWT) in the mouse behavioral test and was calculated according to the following formula:

[0818] 50% response threshold (g) = (10 (Xf+kδ) ) / 10,000

[0819] Xf = final test filament value used in the test

[0820] k = table value (see Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994 Jul; 53(1): 55-63.)

[0821] delta = mean difference

[0822] 3.4 Data analysis

[0823] After the data was summarized, Prism (Graph pad software, Inc.) software was used to analyze the data and one-way ANOVA was used to test the data.

[0824] 4. Results

[0825] The analgesic effect of Example 61 in the mouse incisional plantar pain model is shown in Table 14.

[0826] Table 14 Analgesic effect of compounds of the present disclosure in the mouse incisional plantar pain model

[0827] Note: Data represent Mean ± SEM, * vs vehicle control, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

[0828] 5. Conclusion

[0829] The compound of Example 61 showed significant analgesic effect in the mouse incisional plantar pain model at different time points after administration, and showed obvious dose dependence.

[0830] In the description of the present specification, the description referring to the terms "one embodiment", "some embodiments", "an example", "a specific example", or "some examples" and the like means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present application. In the present specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Also, the specific features, structures, materials or characteristics described can be combined in any appropriate manner in any one or more embodiments or examples. Furthermore, the person skilled in the art can combine and combine the different embodiments or examples described in the present specification and the features of the different embodiments or examples, without contradiction.

Claims

1. A compound which is a compound of Formula (X) or a stereoisomer, geometric isomer, tautomer, nitroso, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of Formula (X), wherein: Ring A is phenyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl; Each R e are independently H, D, F, Cl, Br, I, CN, hydroxy, nitro, -N(R a )2、-(C 1-6 Alkylene)N(R a )2, -S(O)(=NH)C 1-6 Alkyl, -C(O)OR a 、-C(O)N(R a )2、-(C 1-6 Alkylene)C(O)N(R a )2、-C(O)R a 、-S(O)2NR a 、 C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, which C 1-6 alkylene, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio, C 3-6 cycloalkyl and 3-6 membered heterocyclyl can optionally be substituted with 1, 2 or 3 substituents selected from the group consisting of D, F, CI, Br, I, CN, hydroxy, amino, nitro, oxo, hydroxy, C 1-3 alkyl, C 1-3 alkylamino, C 1-3 haloalkyl, C 1-3 hydroxyalkyl and C 1-3 alkoxy; each R is independently H, D, hydroxyl, C a independently H, D, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl can be optionally substituted with 1, 2, or 3 substituents selected from the group consisting of D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, oxo, and C 1-3 alkyl; R 1 , R 2 , R 3 , R 4 and R 5 are each independently H, D, F, CI, Br, I, CN, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, which C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl can optionally be substituted with 1, 2 or 3 substituents selected from the group consisting of D, F, CI, Br, I, CN, nitro, amino, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl and C 1-3 alkoxy; or R 3 and R 5 together with the carbon atom to which they are attached form C 3-6 cycloalkyl; R 6 CN, -S(O)C 1-6 alkyl, -S(O)2C 1-6 alkyl, -CH=N-O-C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkylthio or -L1-L2-R c , said C 1-6 alkyl, C 2-6 alkynyl and C 1-6 alkylthio can be independently optionally substituted with 1, 2 or 3 substituents selected from the group consisting of D, F, Cl, Br, I, oxo and hydroxy; L1is a bond, O, or S; L2is a bond, C 1-6 alkylene or -(C 1-6 alkylene)-C 1-6 alkoxy, said C 1-6 alkylene and C 1-6 alkoxy can be independently optionally substituted with 1, or 3 substituents selected from the group consisting of D, F, Cl, Br, I, oxo, and hydroxy; R c -O-N=, -P(O)(C 1-6 alkyl)2, C 2-6 alkenyl, or -O-(3-8 membered heterocyclyl), said C 1-6 alkyl, C 2-6 alkenyl, and 3-8 membered heterocyclyl can be independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from the group consisting of D, F, Cl, Br, I, hydroxy, oxo, nitro, amino, alkylamino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; R 7 and R 8 each independently H, D, F, CI, Br, I, CN, hydroxyl, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclyl can be optionally substituted with 1, 2, or 3 substituents selected from D, F, CI, Br, I, CN, hydroxyl, amino, nitro, and C 1-3 alkoxy. n is 1, 2, or 3.

2. The compound of claim 1, wherein, Ring A is phenyl, pyridazine, pyrazine, pyridine, or pyrimidine.

3. The compound of claim 1, which is a compound of Formula (I), (II), or (III), or a stereoisomer, geometric isomer, tautomer, nitroso, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of Formula (I), (II), or (III), wherein: X is CR 10 or N; Y is CR 13 or N; R 9 and R 10 each independently H, D, F, Cl, Br, I, CN, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy; R 11 , R 12 , and R 13 are each independently H, D, F, CI, Br, I, CN, hydroxyl, nitro, -N(R a )2, -(C 1-6 alkylene)N(R a ) 2、 -S(O)(=NH)C 1-6 alkyl, -C(O)OR a , -C(O)N(R a )2, -(C 1-6 alkylene)C(O)N(R a )2, -C(O)R a , -S(O)2NR a , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, which C 1-6 alkylene, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio, C 3-6 cycloalkyl and 3-6 membered heterocyclyl can optionally be substituted with 1, 2 or 3 substituents selected from the group consisting of D, F, CI, Br, I, CN, hydroxy, amino, nitro, oxo, hydroxy, C 1-3 alkyl, C 1-3 alkylamino, C 1-3 haloalkyl, C 1-3 hydroxyalkyl and C 1-3 alkoxy; each R is independently H, D, hydroxyl, C a is independently H, D, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl can be optionally substituted with 1, 2, or 3 substituents selected from the group consisting of D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, oxo, and C 1-3 alkyl.

4. The compound of any one of claims 1-3, wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, D, F, CI, Br, I, hydroxyl, methyl, ethyl, CH2F, CHF2, CF3, -CH2OCH3, or -CH2OH.

5. The compound of any one of claims 1-4, wherein R 9 , R 10 , and R 11 are each independently H, D, F, CI, Br, I, CN, amino, nitro, methyl, ethyl, methoxy, trifluoromethyl, or trifluoromethoxy. R 12 and R 13 each independently H, D, F, CI, Br, I, CN, hydroxyl, amino, nitro, methyl, ethyl, CH2F, CHF2, -OCH3, -OCH2CH3, -C(O)NH2, -C(O)NHOH, -C(O)NHOCH3, -CH2OH, -CH(OH)CH2OH, -C(O)NHCH3, -CH(OH)(CH3)2, -S(O)(=NH)CH3, -S(O)2NH2, 6. The compound of any one of claims 1-5, wherein R 7 and R 8 each independently is H, D, F, Cl, Br, I, hydroxyl, methyl, ethyl, CH2F, CHF2, or CF3.

7. The compound according to any one of claims 1 to 6, wherein R 6 is CN, -S(O)C 1-3 alkyl, -S(O)2C 1-3 alkyl-CH=N-O-C 1-3 alkyl, -C 2-6 alkenyl, C 1-3 alkynyl, C c alkylthio or -L1-L2-R 1-3 , said C 1-3 alkyl, C 2-6 alkynyl can be independently optionally substituted with 1, 2 or 3 substituents selected from the group consisting of D, F, Cl, Br, I, oxo and hydroxy; L1is a bond, O, or S; L2is a bond, C 1-3 alkylene or -(C 1-3 alkylene)-C 1-3 alkoxy; R c -O-N=, -P(O)(CH3)2, C 2-6 alkynyl or -O-(3-8 membered heterocyclyl); said C 2-6 alkynyl and 3-8 membered heterocyclyl are independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from the group consisting of D, F, Cl, Br, I, hydroxy, oxo, nitro, amino, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 3-6 cycloalkyl and 3-6 membered heterocyclyl.

8. The compound of any one of claims 1-7, wherein R6 is CN, -S(O)CH3, -S(O)2CH3, -C≡CH, -P(O)(CH3) 2、 9. The compound of claims 1-8, having the structure of formula (IV) or (V): wherein R c C 2-6 alkynyl, said C 2-6 The alkynyl group can be independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from the group consisting of D, F, Cl, Br, I, hydroxy, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl.

10. A compound which is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitroso, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound having one of the following structures:

11. A pharmaceutical composition comprising a compound of any one of claims 1-10; optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

12. Use of a compound of any one of claims 1-10 or a pharmaceutical composition of claim 11 for the manufacture of a medicament for the treatment of a disease responsive to the inhibition of voltage-gated sodium channel NaV1.

8.

13. The use according to claim 12, wherein the disease is chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.

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