CN115724843A

CN115724843A - SOS1 inhibitors, pharmaceutical compositions comprising the same and uses thereof

Info

Publication number: CN115724843A
Application number: CN202211045868.4A
Authority: CN
Inventors: 张贵平; 李家鹏; 王奎锋; 王旭
Original assignee: Suzhou Genhouse Pharmaceutical Co ltd
Current assignee: Suzhou Genhouse Pharmaceutical Co ltd
Priority date: 2021-08-31
Filing date: 2022-08-30
Publication date: 2023-03-03

Description

SOS1 inhibitors, pharmaceutical compositions comprising the same and uses thereof

Technical Field

The present invention relates to SOS1 inhibitors, pharmaceutical compositions comprising the same, and their use for the prevention or treatment of disease.

Background

RAS-RAF-MEK-ERK is a classical tumor signaling pathway that is closely associated with the development of a variety of cancers. Ras is a group of closely related globular monomeric proteins (molecular weight 21 kDa) consisting of 189 amino acids, has gtpase activity, can bind to GDP or GTP, and plays a key role in cellular signaling pathways. SOS1 plays an important role in RAS activation, and can synergistically regulate related biological functions of cell proliferation, differentiation, apoptosis, inflammation and the like.

SOS (Son of seven less, SOS) is a guanine nucleotide exchange factor (GEF) that exists as two homologs of SOS1 and SOS 2. Where SOS1 is a multi-domain protein containing 1333 amino acids consisting of a histone fold, a Dbl (DH) and Pleckstrin (PH) homeodomain, a Ras Exchange Motif (REM), and a Cdc25 homolog and a polyproline domain. SOS1 can bind to joint proteins such as GRB2, and plays an important role in RAS-RAF-MEK-ERK signal pathway and PI3K-AKT-mTOR signal. SOS1 can catalyze the switch from KRAS-OFF to KRAS-ON conformation, and is an important bimolecular switch in cell signaling. Normally the KRAS protein binds primarily to GDP, and once KRAS-SOS1 binds, it results in decreased GTP hydrolysis or increased GTP loading, altering the steady state equilibrium of GDP and GTP binding, thereby leaving KRAS in an activated state.

Although selective KRAS G12C inhibitors have demonstrated clinical therapeutic efficacy in KRAS G12C mutant cancers, G12C mutations account for only about 15% of KRAS-driven malignancies. It is therefore important to develop a related study of SOS1 inhibitors that bind to the SOS1 catalytic domain, block the interaction of SOS1 with KRAS, and shift the equilibrium in the pathway to the KRAS-GDP binding form, resulting in the KRAS-OFF state. Thereby reducing the signal transduction of MAPK kinase pathway and inhibiting the proliferation of tumor cells.

Disclosure of Invention

The present application provides compounds useful as SOS1 inhibitors, which have excellent inhibitory activity against SOS 1. In addition, the compounds of the present invention also have excellent properties of good physicochemical properties (e.g., solubility, physical and/or chemical stability), good pharmacokinetic properties (e.g., improved bioavailability, good metabolic stability, suitable half-life and duration of action), good safety (less toxicity (e.g., reduced cardiotoxicity) and/or fewer side effects), less susceptibility to drug resistance, and the like.

One aspect of the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein the compound has the structure of formula (I):

wherein:

represents a single bond or a double bond, with the proviso that when it represents a double bond, R ³ And R ^4’ Is absent;

ring A is C _6-10 An aromatic or 5-14 membered heteroaromatic ring;

l is-O- (CH) ₂ ) _m -、-S-(CH ₂ ) _m -、-S(＝O)-(CH ₂ ) _m -or-S (= O) ₂ -(CH ₂ ) _m -；

R ¹ Each occurrence independently selected from halogen, -OH、-NH ₂ 、-CN、-NO ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-to 10-membered heterocyclic group, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 Aralkyl, -C (= O) R ^a 、-OC(＝O)R ^a 、-C(＝O)OR ^a 、-OR ^a 、-SR ^a 、-S(＝O)R ^a 、-S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^a R ^b 、-NR ^a R ^b 、-C(＝O)NR ^a R ^b 、-NR ^a -C(＝O)R ^b 、-NR ^a -C(＝O)OR ^b 、-NR ^a -S(＝O) ₂ -R ^b 、-NR ^a -C(＝O)-NR ^a R ^b 、-C _1-6 alkylene-OR ^a 、-C _1-6 alkylene-NR ^a R ^b and-O-C _1-6 alkylene-NR ^a R ^b ；

When n > 1, two adjacent R ¹ Together with the group to which they are attached optionally together form C _3-6 Hydrocarbon ring, 3-to 10-membered heterocyclic ring, C _6-10 An aromatic or 5-14 membered heteroaromatic ring;

R ² is selected from C _1-6 Alkyl radical, C _3-10 Cycloalkyl and 3-10 membered heterocyclyl;

R ³ 、R ⁴ 、R ^4’ and R ⁵ Each independently selected from H, halogen, -OH, -NH ₂ 、-CN、-NO ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-to 10-membered heterocyclic group, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 Aralkyl, -C (= O) R ^a 、-OC(＝O)R ^a 、-C(＝O)OR ^a 、-OR ^a 、-SR ^a 、-S(＝O)R ^a 、-S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^a R ^b 、-NR ^a R ^b 、-C(＝O)NR ^a R ^b 、-NR ^a -C(＝O)R ^b 、-NR ^a -C(＝O)OR ^b 、-NR ^a -S(＝O) ₂ -R ^b 、-NR ^a -C(＝O)-NR ^a R ^b 、-C _1-6 alkylene-OR ^a 、-C _1-6 alkylene-NR ^a R ^b and-O-C _1-6 alkylene-NR ^a R ^b ；

Or R ⁴ And R ^4’ Together with the carbon atom to which they are attached

Provided that at this time point,

represents a single bond;

R ^a and R ^b Each occurrence is independently selected from H, C _1-6 Alkyl radical, C _3-10 Cycloalkyl, 3-to 10-membered heterocyclic group, C _6-10 Aryl, 5-14 membered heteroaryl and C _6-12 Aralkyl group;

m is an integer of 0, 1,2 or 3;

n is an integer of 0, 1,2, 3 or 4;

the above alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, hydrocarbon ring, heterocyclyl, heterocycle, aryl, heteroaryl ring, and aralkyl group, at each occurrence, are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OH, = O, -NH ₂ 、-CN、-NO ₂ 、C _1-6 Alkyl radical, C _3-6 Cycloalkyl, 3-to 10-membered heterocyclic group, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 Aralkyl, -C (= O) R ^5’ 、-OC(＝O)R ^5’ 、-C(＝O)OR ^5’ 、-OR ^5’ 、-SR ^5’ 、-S(＝O)R ^5’ 、-S(＝O) ₂ R ^5’ 、-S(＝O) ₂ NR ^5’ R ⁶ 、-NR ^5’ R ⁶ 、-C(＝O)NR ^5’ R ⁶ 、-NR ^5’ -C(＝O)R ⁶ 、-NR ^5’ -C(＝O)OR ⁶ 、-NR ^5’ -S(＝O) ₂ -R ⁶ 、-NR ^5’ -C(＝O)-NR ^5’ R ⁶ 、-C _1-6 alkylene-OR ^5’ 、-C _1-6 alkylene-NR ^5’ R ⁶ and-O-C _1-6 alkylene-NR ^5’ R ⁶ Said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl are further optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OH, = O, -C (= O) O-tert-butyl, -NH ₂ 、-CN、-NO ₂ 、C _1-6 Alkyl radical, C _3-6 Cycloalkyl, 3-to 10-membered heterocyclic group, C _6-10 Aryl, 5-14 membered heteroaryl and C _6-12 Aralkyl group; and is

R ^5’ And R ⁶ Each occurrence is independently selected from H, C _1-6 Alkyl radical, C _3-10 Cycloalkyl, 3-to 10-membered heterocyclic group, C _6-10 Aryl, 5-14 membered heteroaryl and C _6-12 An aralkyl group.

Another aspect of the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, and one or more pharmaceutically acceptable carriers, preferably in a solid formulation, a semi-solid formulation, a liquid formulation or a gaseous formulation.

Another aspect of the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for use as an SOS1 inhibitor.

Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, for use as an SOS1 inhibitor.

Another aspect of the present invention provides a method for the prevention or treatment of a SOS 1-associated disease, which method comprises administering to a subject in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention.

Detailed Description

Definition of

Unless defined otherwise below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. Reference to the techniques used herein is intended to refer to techniques commonly understood in the art, including those variations of or alternatives to those techniques that would be apparent to one of ordinary skill in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

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

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

The term "alkyl", as used herein, is defined as a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, e.g., 1 to 6, carbon atoms. For example, as used herein, the term "C _1-6 Alkyl "refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl) optionally substituted with 1 or more (such as 1 to 3) suitable substituents such as halo (when the group is referred to as" haloalkyl ") (e.g., CF) ₃ 、C ₂ F ₅ 、CHF ₂ 、CH ₂ F、CH ₂ CF ₃ 、CH ₂ Cl or-CH ₂ CH ₂ CF ₃ Etc.). The term "C _1-4 Alkyl "refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, propyl, hexyl, heptyl) ethyl, n-propyl, ethyl, propyl, isopropyl,Isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having from 2 to 6 carbon atoms ("C) _2-6 Alkenyl "). The alkenyl group is, for example, -CH = CH ₂ 、-CH ₂ CH＝CH ₂ 、-C(CH ₃ )＝CH ₂ 、-CH ₂ -CH＝CH-CH ₃ 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compounds of the invention contain an alkenyl group, the compounds may be present in pure E (entgegen) form, in pure Z (zusammen) form or in any mixture thereof. The term "alkenylene" is a corresponding divalent radical, including, for example, "C _2-6 Alkenylene group and C _2-4 Alkenylene "and the like, specific examples of which include, but are not limited to: -CH = CH-, -CH ₂ CH＝CH-、-C(CH ₃ ) = CH-, butenylene, pentenylene, hexenylene, and the like.

As used herein, the term "alkynyl" denotes a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl, and the like. The alkynyl group is optionally substituted with one or more (such as 1 to 3) substituents which may be the same or different. The term "alkynylene" is a corresponding divalent radical, including, for example, "C _2-8 Alkynylene group and C _2-6 Alkynylene group and C _2-4 Alkynylene "and the like. Examples include, but are not limited to

Etc., said alkynylene group being optionally substituted with one or more (such as 1 to 3) same or different substituents.

As used herein, the term "fused ring" refers to a ring system formed from two or more ring structures that share two adjacent atoms with each other.

As used herein, the term "spiro" refers to a ring system formed from two or more cyclic structures that share a ring atom with each other.

As used herein, the term "bridged ring" refers to a ring system formed from two or more cyclic structures that share two atoms not directly attached to each other.

As used herein, the terms "cycloalkylene", "cycloalkyl" and "hydrocarbon ring" refer to saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings (including spiro, fused (fused) or bridged ring systems) having, for example, from 3 to 10 (suitably from 3 to 8, more suitably from 3 to 6) ring carbon atoms, including, but not limited to, (cyclo) cyclopropyl (ene), (cyclo) butyl (ene), (cyclo) cyclopentyl (ene), (cyclo) cyclohexyl (ene), (cyclo) cycloheptyl (ene), (cyclo) cyclooctyl (ene), (cyclo) cyclononyl (ene), (cyclo) cyclohexenyl (ene), and the like.

As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo [ 1.1.1.1)]Pentyl, bicyclo [2.2.1]Heptyl, bicyclo [3.2.1]Octyl or bicyclo [5.2.0]Nonyl, decalinyl, etc.), optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C _3-6 Cycloalkyl "refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) optionally substituted by 1 or more (such as 1 to 3) suitable substituents, for example, methyl-substituted cyclopropyl.

As used herein, the term "heterocyclyl" refers to a saturated or unsaturated monovalent monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms in the ring and one or more (e.g., one, two, three, or four) selected from O, S (= O) ₂ And NR ^a Wherein R is ^a Represents a hydrogen atom or C _1-6 Alkyl or halo-C _1-6 An alkyl group; the heterocyclic group may be attached to the rest of the molecule through any of the carbon atoms or the nitrogen atom (if present). In particular, a 3-10 membered heterocyclyl is a group having 3-10 carbon atoms and heteroatoms in the ring, such as, but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuryl, dioxolyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

As used herein, the term "heterocyclyl" encompasses fused ring structures, the point of attachment of which to other groups may be on any one of the fused ring structures. Thus, heterocyclyl groups of the present invention also include, but are not limited to, heterocyclo-heterocyclyl, heterocyclo-cycloalkyl, mono-heterocyclo-mono-heterocyclyl, mono-heterocyclo-mono-cycloalkyl, e.g., 3-7 membered (mono) heterocyclo-3-7 membered (mono) heterocyclyl, 3-7 membered (mono) heterocyclo- (mono) cycloalkyl, 3-7 membered (mono) heterocyclo-C _4-6 (mono) a cycloalkyl group, examples include, but are not limited to, pyrrolidinyl-cyclopropyl, cyclopentazacyclopropyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, piperidinyl-morpholinyl, pyrrolidinyl-piperidinyl, pyrrolidinyl-piperazinyl, piperidinyl-morpholinyl, and pyrrolidinyl-cyclobutyl,

As used herein, the term "heterocyclyl" encompasses bridged heterocyclyls and spiro heterocyclyls.

As used herein, the term "bridged heterocyclic ring" refers to a cyclic structure containing one or more (e.g., 1,2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, and/or sulfur atoms) formed by two saturated rings sharing two ring atoms not directly connected, including, but not limited to, 7-10 membered bridged heterocyclic rings, 8-10 membered bridged heterocyclic rings, 7-10 membered nitrogen-containing bridged heterocyclic rings, 7-10 membered oxygen-containing bridged heterocyclic rings, 7-10 membered sulfur-containing bridged heterocyclic rings, and the like, e.g.

And the like. The "nitrogen-containing bridged heterocyclic ring", "oxygen-containing bridged heterocyclic ring", "sulfur-containing bridged heterocyclic ring" optionally further contains one or more other heteroatoms selected from oxygen, nitrogen and sulfur.

As used herein, the term "spiroheterocycle" refers to a cyclic structure containing one or more (e.g., 1,2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, sulfur atoms) formed from two or more saturated rings that share a ring atom, including, but not limited to, 5-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, 6-10 membered sulfur-containing spiroheterocycles, and the like, e.g.

Said "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle", "sulfur-containing spiroheterocycle" optionally further contains one or more other heteroatoms selected from oxygen, nitrogen, sulfur. The term "6-to 10-membered nitrogen-containing spiroheterocyclyl" refers to spiroheterocyclyl groups containing a total of 6 to 10 ring atoms and in which at least one ring atom is a nitrogen atom.

As used herein, the terms "(arylene) and" aromatic ring "refer to an all-carbon monocyclic or fused ring polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, the term "C _6-10 (arylene) and C _6-10 Aromatic ring "means an aromatic group containing 6 to 10 carbon atoms, such as (phenylene) phenyl (benzene ring) or (phenylene) naphthyl (naphthalene ring). The aryl (ene) and aromatic rings are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g. halogen, -OH, -CN, -NO) ₂ 、C _1-6 Alkyl, etc.).

The term "aralkyl" preferably denotes an aryl substituted alkyl group, wherein said aryl and said alkyl are as defined herein. Typically, the aryl group can have 6 to 14 carbon atoms and the alkyl group can have 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.

As used herein, the terms "(arylene) heteroaryl" and "heteroaryl ring" refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be the same or different (said heteroatom being, for example, oxygen, nitrogen or sulfur), and which, in addition, may be benzo-fused in each case. In particular, "(arylene) heteroaryl" or "heteroaromatic ring" is selected from the group consisting of (arylene) thienyl (ring), (arylene) furyl (ring), (arylene) pyrrolyl (ring), (arylene) oxazolyl (ring), (arylene) thiazolyl (ring), (arylene) imidazolyl (ring), (arylene) pyrazolyl (ring), (arylene) isoxazolyl (ring), (arylene) isothiazolyl (ring), (arylene) oxadiazolyl (ring), (arylene) triazolyl (ring), (arylene) thiadiazolyl (ring), and the like, and benzo derivatives thereof; or pyridyl (cyclo), (pyridizinyl (cyclo), (pyrimidinylidene) (cyclo), (pyrazinylidene) (cyclo), (triazinylidene) (cyclo), etc., and benzo derivatives thereof.

As used herein, the term "halo" or "halogen" group is defined to include F, cl, br or I.

The term "alkylthio," as used herein, means an alkyl group, as defined above, appended to the parent molecular moiety through a sulfur atom. C _1-6 Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.

As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and at least one nitrogen atom in the ring, which may also optionally comprise one or more (e.g., one, two, three, or four) selected from N, O, C = O, S = O, and S (= O) ₂ A ring member of (a); the nitrogen-containing heterocyclic ring being attached to the remainder of the molecule via a nitrogen atomAnd (6) connecting. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocyclic ring. Specifically, the 3 to 14-membered nitrogen-containing heterocyclic ring is a group having 3 to 14 carbon atoms and hetero atoms (at least one of which is a nitrogen atom) in the ring, and includes, but is not limited to, a ternary nitrogen-containing heterocyclic ring (e.g., aziridinyl), a quaternary nitrogen-containing heterocyclic ring (e.g., azetidinyl), a five-membered nitrogen-containing heterocyclic ring (e.g., pyrrolyl, pyrrolidinyl (pyrrolidine ring), pyrrolinyl, pyrrolidonyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), a six-membered nitrogen-containing heterocyclic ring (e.g., piperidyl (piperidine ring), morpholinyl, thiomorpholinyl, piperazinyl), a seven-membered nitrogen-containing heterocyclic ring, and the like.

The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the current circumstances is not exceeded and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

If a substituent is described as "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced individually and/or together with an independently selected optional substituent. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogen is present) may each be replaced with an independently selected optional substituent.

If a substituent is described as being "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.

Unless indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

When a bond of a substituent is shown through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

The invention also includes all pharmaceutically acceptable isotopically-labeled compounds, which are identical to those of the present invention, except that one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion into compounds of the invention include, but are not limited to, isotopes of hydrogen (such as deuterium (D, ² h) Tritium (T, ³ h) ); isotopes of carbon (e.g. of ¹¹ C、 ¹³ C and ¹⁴ c) (ii) a Isotopes of chlorine (e.g. of ³⁶ Cl); isotopes of fluorine (e.g. of fluorine) ¹⁸ F) (ii) a Isotopes of iodine (e.g. of iodine) ¹²³ I and ¹²⁵ i) (ii) a Isotopes of nitrogen (e.g. of ¹³ N and ¹⁵ n); isotopes of oxygen (e.g. of ¹⁵ O、 ¹⁷ O and ¹⁸ o); isotopes of phosphorus (e.g. of phosphorus) ³² P); and isotopes of sulfur (e.g. of ³⁵ S). Certain isotopically-labeled compounds of the present invention (e.g., those into which a radioisotope is incorporated) are useful in drug and/or substrate tissue distribution studies (e.g., assays). Radioisotope tritium (i.e. tritium ³ H) And carbon-14 (i.e. ¹⁴ C) Are particularly useful for this purpose because of their ease of incorporation and ease of detection. Using positron-emitting isotopes (e.g. of the type ¹¹ C、 ¹⁸ F、 ¹⁵ O and ¹³ n) can be used to examine substrate receptor occupancy in Positron Emission Tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by processes analogous to those described in the accompanying schemes and/or in the examples and preparations by using an appropriate isotopically labeled reagent in place of the non-labeled reagent employed previously. Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g., D ₂ O, acetone-d ₆ Or DMSO-d ₆ 。

It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, where appropriate, in the form of a pharmaceutically acceptable derivative thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which upon administration to a patient in need thereof are capable of providing, directly or indirectly, a compound of the present invention or a metabolite or residue thereof. Thus, when reference is made herein to "a compound of the invention," it is also intended to encompass the various derivative forms of the compounds described above.

Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate/carbonate, bisulfate/sulfate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrobromide/bromide, hydroiodide, maleate, malonate, methylsulfate, naphthoate, nicotinate, nitrate, orotate, oxalate, palmitate and other similar salts.

Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, diethylamine, lysine, magnesium, meglumine, potassium and other similar salts.

For a review of suitable Salts see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: properties, selection, and Use "(Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

As used herein, the term "ester" means an ester derived from a compound of the respective general formula in the present application, including physiologically hydrolysable esters (which can be hydrolysed under physiological conditions to release the compound of the invention in free acid or alcohol form). The compounds of the invention may themselves also be esters.

The compounds of the invention may be present in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise as structural element of the crystal lattice of the compound a polar solvent, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.

Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by the process of contacting the compounds of the present invention with a mammal for a time sufficient to produce a metabolite thereof.

The present invention further includes within its scope prodrugs of the compounds of the invention which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity which, when administered into or onto the body, are converted to compounds of the invention having the desired activity, for example by hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", volume 14, ACS Symposium Series (T.Higuchi and V.Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press,1987 (E.B.Roche editions, american Pharmaceutical Association). Prodrugs of the invention may be prepared, for example, by substituting certain moieties known to those skilled in the art as "pro-moieties" (e.g., "Design of Prodrugs", described in h. Bundgaard (Elsevier, 1985)) for appropriate functional groups present in compounds of the invention.

The invention also encompasses compounds of the invention containing a protecting group. In any process for the preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting Groups, for example, as described in Protective Groups in Organic Chemistry, ed.j.f.w.mcomie, plenum Press,1973; and T.W.Greene & P.G.M.Wuts, protective Groups in Organic Synthesis, john Wiley & Sons,1991, which are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.

As used herein, the term "about" means within ± 10%, preferably within ± 5%, more preferably within ± 2% of the stated numerical value.

Compound (I)

In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein the compound has the structure of formula (I):

wherein:

ring A is C _6-10 An aromatic or 5-14 membered heteroaromatic ring;

R ¹ Independently at each occurrence is selected from halogen, -OH, -NH ₂ 、-CN、-NO ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-to 10-membered heterocyclic group, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 Aralkyl, -C (= O) R ^a 、-OC(＝O)R ^a 、-C(＝O)OR ^a 、-OR ^a 、-SR ^a 、-S(＝O)R ^a 、-S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^a R ^b 、-NR ^a R ^b 、-C(＝O)NR ^a R ^b 、-NR ^a -C(＝O)R ^b 、-NR ^a -C(＝O)OR ^b 、-NR ^a -S(＝O) ₂ -R ^b 、-NR ^a -C(＝O)-NR ^a R ^b 、-C _1-6 alkylene-OR ^a 、-C _1-6 alkylene-NR ^a R ^b and-O-C _1-6 alkylene-NR ^a R ^b ；

R ³ 、R ⁴ 、R ^4’ and R ⁵ Each independently selected from H, halogen, -OH, -NH ₂ 、-CN、-NO ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-to 10-membered heterocyclic group, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 Aralkyl, -C (= O) R ^a 、-OC(＝O)R ^a 、-C(＝O)OR ^a 、-OR ^a 、-SR ^a 、-S(＝O)R ^a 、-S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^a R ^b 、-NR ^a R ^b 、-C(＝O)NR ^a R ^b 、-NR ^a -C(＝O)R ^b 、-NR ^a -C(＝O)OR ^b 、-NR ^a -S(＝O) ₂ -R ^b 、-NR ^a -C(＝O)-NR ^a R ^b 、-C _1-6 alkylene-OR ^a 、-C _1-6 alkylene-NR ^a R ^b and-O-C _1-6 alkylene-NR ^a R ^b ：

Or R ⁴ And R ^4’ Together with the carbon atom to which they are attached

The condition is that at this time point,

represents a single bond;

m is an integer of 0, 1,2 or 3;

n is an integer of 0, 1,2, 3 or 4;

the above alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, hydrocarbon ring, heterocyclyl, heterocycle, aryl ring, heteroaryl ring, and aralkyl group, at each occurrence, are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OH, = O, -NH ₂ 、-CN、-NO ₂ 、C _1-6 Alkyl radical, C _3-6 Cycloalkyl, 3-to 10-membered heterocyclic group, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 Aralkyl, -C (= O) R ^5’ 、-OC(＝O)R ^5’ 、-C(＝O)OR ^5’ 、-OR ^5’ 、-SR ^5’ 、-S(＝O)R ^5’ 、-S(＝O) ₂ R ^5’ 、-S(＝O) ₂ NR ^5’ R ⁶ 、-NR ^5’ R ⁶ 、-C(＝O)NR ^5’ R ⁶ 、-NR ^5’ -C(＝O)R ⁶ 、-NR ^5’ -C(＝O)OR ⁶ 、-NR ^5’ -S(＝O) ₂ -R ⁶ 、-NR ^5’ -C(＝O)-NR ^5’ R ⁶ 、-C _1-6 alkylene-OR ^5’ 、-C _1-6 alkylene-NR ^5’ R ⁶ and-O-C _1-6 alkylene-NR ^5’ R ⁶ Said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl are further optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OH, = O, -C (= O) O-tert-butyl, -NH ₂ 、-CN、-NO ₂ 、C _1-6 Alkyl radical, C _3-6 Cycloalkyl, 3-to 10-membered heterocyclic group, C _6-10 Aryl, 5-14 membered heteroaryl and C _6-12 Aralkyl group; and is

In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein the compound has the structure of formula (II), (III), or (IV):

in some embodiments, the present invention provides a compound having the structure of formula (I), formula (II), (III), or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein ring a is a benzene ring or a pyridine ring, preferably a benzene ring.

In some embodiments, the present invention provides compounds having the structure of formula (I), formula (II), (III), or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein L is-O- (CH) ₂ ) _m -, preferably-O-or-O-CH ₂ -。

In some embodiments, the present invention provides compounds having the structure of formula (I), formula (II), (III), or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R is a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R is a pharmaceutically acceptable salt of a pharmaceutically acceptable acid ¹ Each occurrence is independently selected from halogen, -OH, -NH ₂ 、-CN、-NO ₂ 、C _1-6 Alkyl radical, C _3-6 Cycloalkyl group, 3-10-membered heterocyclyl, -C (= O) R ^a 、-C(＝O)OR ^a 、-OR ^a 、-S(＝O) ₂ R ^a 、-NR ^a R ^b 、-C(＝O)NR ^a R ^b and-C _1-6 alkylene-OR ^a (ii) a The above alkyl, alkylene, cycloalkyl and heterocyclyl groups are each optionally substituted at each occurrence with one or more substituents independently selected from the group consisting of: halogen, -OH, = O, -NH ₂ 、-CN、C _1-6 Alkyl radical, C _3-6 Cycloalkyl and 3-10 membered heterocyclyl;

preferably, R ¹ Selected from-F, -Cl, -Br, -I, -OH, -NH ₂ 、-CN、-NO ₂ 、-CH ₃ 、-CH ₂ F、-CHF ₂ 、-CF ₃ 、-CH ₂ CH ₃ 、-CH ₂ CF ₃ 、-CF ₂ CH ₃ 、-CF ₂ CN、-CF ₂ CH ₂ NH ₂ 、-CH(CH ₃ )OH、-C(CH ₃ ) ₂ OH、-CF ₂ CH ₂ OH、-CF ₂ C(CH ₃ ) ₂ OH、-CF ₂ OCH ₃ 、-CF ₂ CH ₂ OCH ₃ 、-CF ₂ O- (cyclopropyl), cyclopropyl,

-C(＝O)CH ₃ 、-C(＝O)OCH ₃ 、-OCH ₃ 、-S(＝O) ₂ CH ₃ and-C (= O) NH ₂ 。

In some embodiments, the present invention provides a compound having the structure of formula (I), formula (II), (III), or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein:

when n > 1, two adjacent R ¹ Together with the group to which they are attached optionally together form C _3-6 A hydrocarbon ring, a 3-10 membered heterocyclic ring or a 5-14 membered heteroaromatic ring; the hydrocarbon ring, heterocyclic ring and heteroaromatic ring eachOptionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OH, = O, C _1-6 Alkyl and-C _1-6 alkylene-OR ⁵ ；

Preferably, when n > 1, two adjacent R are ¹ Optionally together with the group to which they are attached to form

In some embodiments, the present invention provides compounds having the structure of formula (I), formula (II), (III), or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein

In some embodiments, the present invention provides compounds having the structure of formula (I), formula (II), (III), or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R is a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof ² Is selected from

In some embodiments, the present invention provides compounds having the structure of formula (I), formula (II), (III), or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein-L-R ² Is selected from

In some embodiments, the present invention provides compounds having the structure of formula (I), formula (II), (III), or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R is a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R is a pharmaceutically acceptable salt of a pharmaceutically acceptable acid ³ Selected from H, halogen, C _1-6 Alkyl radical, C _3-6 Cycloalkyl, -OR ^a and-C _1-6 alkylene-OR ^a (ii) a The alkyl, alkylene and cycloalkyl groups are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OH and-CN;

preferably, R ³ Selected from H, F, cl, br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl,

More preferably, R ³ Selected from H, methyl, ethyl and

in some embodiments, the present invention provides a structure having formula (I), formula (II), (III), or (IV)Or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein R is ⁴ And R ^4’ Each independently selected from H, halogen, C _1-6 Alkyl radical, C _3-6 Cycloalkyl, -OR ^a and-C _1-6 alkylene-OR ^a (ii) a Each of said alkyl and cycloalkyl groups being optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OH and-CN;

R ⁴ and R ^4’ Each independently selected from H, F, cl, br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl,

Preferably, R ⁴ And R ^4’ Each independently selected from H an isopropyl group,

In some embodiments, the present invention provides compounds having the structure of formula (I), formula (II), (III), or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R is a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R is a pharmaceutically acceptable salt of a pharmaceutically acceptable acid ⁵ Is H or C _1-6 Alkyl, preferably H or methyl, more preferably methyl.

The present invention encompasses compounds resulting from any combination of the various embodiments.

In some embodiments, the present invention provides a compound having the structure of formula (I), formula (II), (III), or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein the compound is selected from the group consisting of:

pharmaceutical compositions and methods of treatment

In some embodiments, the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, and one or more pharmaceutically acceptable carriers, preferably the pharmaceutical composition is a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation. In some embodiments, the pharmaceutical composition may further comprise one or more additional therapeutic agents.

In some embodiments, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for use as an SOS1 inhibitor.

In some embodiments, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, for use as an SOS1 inhibitor.

In some embodiments, the present invention provides a method of preventing or treating a SOS 1-associated disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the invention.

In some embodiments, the SOS 1-associated disease comprises a cancer (e.g., pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma), a RAS disease (e.g., neurofibromatosis type 1 (NF 1), noonan Syndrome (NS), noonan syndrome with erythema (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), costello Syndrome (CS), cardiac-facial-skin syndrome (CFC), louses syndrome, and hereditary gingival fibromatosis).

By "pharmaceutically acceptable carrier" herein is meant a diluent, adjuvant, excipient, or vehicle that is administered with the therapeutic agent and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

Unless otherwise indicated, the term "treating," as used herein, means reversing, alleviating, inhibiting the progression of, or preventing such a disorder or condition, or one or more symptoms of such a disorder or condition, to which such term applies.

As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include human individuals (referred to as patients) having a disease (e.g., a disease described herein) or normal individuals. "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

In another embodiment, the pharmaceutical composition of the invention may further comprise one or more additional therapeutic or prophylactic agents.

Examples

The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.

The abbreviations in the present invention have the following meanings:

intermediate example a-1:

step 1

A-1a (25g, 123mmol) was dissolved in DAST (65 mL) and the reaction was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was slowly poured into a cooled aqueous sodium bicarbonate solution, and extracted with ethyl acetate (500ml. Multidot.3). The ethyl acetate phase was dried, concentrated, and purified by column chromatography to give intermediate A-1b (10g, 37%) as a colorless oily substance.

¹ H NMR(400MHz，DMSO-d ₆ )δ7.93(dd，J＝7.9，7.0Hz，1H)，7.68(t，J＝7.1Hz，1H)，7.44-7.06(m，2H).

Step 2

A-1b (9g, 40mmol), tributyl (1-ethoxyethylene) tin (17.34g, 48mmol), pd (PPh) ₃ ) ₂ Cl ₂ (2.81g, 4mmol) and triethylamine (10.11g, 100mmol) were dissolved in anhydrous 1, 4-dioxane (150 mL). After nitrogen substitution, the mixture was stirred at 100 ℃ overnight. After completion of the reaction, filtration was carried out, the filtrate was concentrated, extracted with ethyl acetate (200 mL) and saturated brine (200 mL), the ethyl acetate phase was dried and concentrated, and then the residue was dissolved in tetrahydrofuran (50 mL), and 3M aqueous hydrochloric acid (20 mL) was added and stirred at room temperature overnight. After completion of the reaction, ethyl acetate (300ml × 3) was added for extraction, and the ethyl acetate phase was dried, concentrated, and purified by column chromatography to obtain A-1c (5.6 g, 74%).

¹ H NMR(400MHz，DMSO-d ₆ )δ8.06-7.94(m，1H)，7.89(t，J＝6.9Hz，1H)，7.53-7.44(m，1H)，7.29(m，J＝54.1Hz，1H)，2.62(d，J＝4.1Hz，3H).

Step 3

A-1c (6.17g, 33mmol), (S) -tert-butylsulfinamide (6.0 g,49.5 mmol) and tetraethyltitanate (22.6 g, 99mmol) were added to tetrahydrofuran (100 ml) in this order to reflux overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, and water (500 ml) was added to the reaction mixture, followed by extraction with ethyl acetate (500 ml), drying of the ethyl acetate phase, concentration and purification by column chromatography to give intermediate A-1d (9.2g, 97%) as a yellow oily intermediate.

¹ H NMR(400MHz，DMSO-d ₆ )δ7.91-7.81(m，1H)，7.78(t，J＝6.7Hz，1H)，7.45(t，J＝7.7Hz，1H)，7.27(t，J＝54.2Hz，1H)，2.71(s，3H)，1.21(d，J＝11.9Hz，9H).MS(ESI)m/z 292.1[M+H] ⁺ .

Step 4

A-1d (9.42g, 32mmol) was dissolved in anhydrous tetrahydrofuran (150 mL), and lithium tri-sec-butylborohydride (64mL, 64mmol) was added slowly at 78 ℃. The reaction mixture was stirred at-78 ℃ for 1 hour, quenched by addition of aqueous ammonium chloride after completion of the reaction, and extracted with dichloromethane (300ml × 3). The dichloromethane phase was dried, concentrated, and purified by column chromatography to give intermediate A-1e (7.2g, 84%) as a colorless oil.

¹ H NMR(400MHz，DMSO-d ₆ )δ7.68(t，J＝7.3Hz，1H)，7.53(t，J＝7.0Hz，1H)，7.34(t，J＝7.7Hz，1H)，7.32-6.98(m，1H)，5.54(d，J＝5.7Hz，1H)，4.73(p，J＝6.6Hz，1H)，1.50(d，J＝6.8Hz，3H)，1.09(s，9H).MS(ESI)m/z 294.1[M+H] ⁺ .

Step 5

A-1e (8.0 g,27.3 mmol) was dissolved in hydrogen chloride/dioxane solution (4M, 20ml), and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was spin-dried, and petroleum ether (50 ml) was added thereto, followed by stirring and suction filtration to obtain intermediate A-1 (5.6 g, 91%) as a white solid.

¹ H NMR(400MHz，DMSO-d ₆ )δ8.78(s，3H)，7.93(d，J＝5.1Hz，1H)，7.67(t，J＝7.1Hz，1H)，7.45(t，J＝7.8Hz，1H)，7.26(t，J＝54.1Hz，1H)，4.71-4.58(m，1H)，1.55(d，J＝6.8Hz，3H).MS(ESI)m/z 190.2[M+H] ⁺ .

Intermediate example a-2:

step 1

A-2a (4.5g, 21.6mmol), N, O-dimethylhydroxylamine hydrochloride (2.53g, 26mmol), EDCI (6.2g, 32.4mmol), HOBt (4.38g, 32.4mmol) and triethylamine (10.9g, 108mmol) were added to DMF (50 ml). After completion of the reaction, water (200 ml) was added to the reaction mixture, followed by extraction with ethyl acetate (200 ml), washing with ethyl acetate phase saturated brine, drying over anhydrous sodium sulfate, concentration and purification by column chromatography to give intermediate A-2b (4.0 g, 74%).

¹ H NMR(400MHz，DMSO-d ₆ )δ7.93-7.83(m，2H)，7.51(t，J＝7.8Hz，1H)，3.48(s，3H)，3.30(s，3H).

MS(ESI)m/z[M+H] ⁺ ：252.2.

Step 2

A-2b (4 g, 15.9mmol) was dissolved in anhydrous tetrahydrofuran (8 ml), and after stirring at 0 ℃ for 5 minutes, methyl magnesium bromide (11 ml) was added dropwise. The reaction was stirred at 0 ℃ for 2 hours, after completion of the reaction, saturated aqueous ammonium chloride was added, extracted with ethyl acetate (300 ml), the ethyl acetate phase was dried, concentrated and purified by column chromatography to give intermediate A-2c (2.5g, 76%).

¹ H NMR(400MHz，DMSO-d ₆ )δ8.08(dd，J＝10.6，4.0Hz，1H)，7.80(t，J＝7.2Hz，1H)，7.34(t，J＝7.8Hz，1H)，2.69(d，J＝5.2Hz，3H).

Step 3

A-2c (2.5g, 12.1mmol), (R) - (+) -tert-butylsulfinamide (2.2g, 18.1mmol) and tetraethyltitanate (8.3g, 36.3mmol) were dissolved in tetrahydrofuran (25 ml). The reaction was stirred at reflux overnight. The reaction was cooled to-15 ℃ and methanol (2 ml) and lithium borohydride (400mg, 18.1mmol) were added. The reaction was continued for 1 hour with stirring, and after completion of the reaction, water (100 ml) and ethyl acetate (100 ml) were added, followed by suction filtration, liquid separation, and drying and concentration of ethyl acetate. The residue was purified by column chromatography to give intermediate A-2d (2.4g, 64%) as a white solid.

¹ H NMR(400MHz，DMSO-d ₆ )δ7.89(t，J＝7.0Hz，1H)，7.67(t，J＝7.0Hz，1H)，7.42(t，J＝7.8Hz，1H)，5.91(d，J＝7.8Hz，1H)，4.72(p，J＝7.0Hz，1H)，1.43(d，J＝6.8Hz，3H)，1.10(s，9H).

MS(ESI)m/z[M+H] ⁺ ：312.3.

Step 4

A-2d (2.3g, 7.4 mmol) was dissolved in hydrogen chloride/dioxane solution (16 ml) and stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was spin-dried, ethyl acetate (50 ml) was added, stirred, and suction-filtered to obtain a white solid intermediate A-2 (1.5g, 80%).

¹ H NMR(400MHz，DMSO-d ₆ )δ8.80(s，3H)，8.08(t，J＝7.2Hz，1H)，7.82(t，J＝7.2Hz，1H)，7.52(t，J＝7.8Hz，1H)，4.70(q，J＝6.8Hz，1H)，1.56(d，J＝6.8Hz，3H).

MS(ESI)m/z[M+H] ⁺ ：208.4.

Intermediate example a-3:

step 1

A-3a (4.4g, 0.02mol), trimethylsilylacetylene (4.0g, 0.04mol), triethylamine (6.15g, 0.06mol), cuprous iodide (0.38g, 0.002mol), and bis (triphenylphosphine) palladium dichloride (1.42g, 0.002mol) were sequentially added to tetrahydrofuran (60 mL) under a nitrogen blanket. The resulting solution was stirred at 80 ℃ for 16 hours. The solvent was spun dry and purified by column chromatography to give product A-3b as a yellow oil (4.5 g, yield: 95%).

¹ H NMR(400MHz，CDCl ₃ )δ7.84-7.78(m，1H)，7.64-7.60(m，1H)，7.16(t，J＝7.8Hz，1H)，2.65(d，J＝5.2Hz，3H)，0.28(s，9H).

MS(ESI)m/z[M+H] ⁺ ：235.2.

Step 2

A-3b (4.5g, 19.2mmol) was dissolved in methylene chloride (6 ml) and methanol (6 ml), and potassium carbonate (26.5g, 0.19mol) was added. Stirring was carried out at room temperature for 2 hours, the solvent was spin-dried, and purification was carried out by column chromatography to obtain the product A-3c (2.9 g, yield: 93%) as a yellow solid.

¹ H NMR(400MHz，CDCl ₃ )δ7.88-7.83(m，1H)，7.68-7.63(m，1H)，7.20(t，J＝7.8Hz，1H)，3.36(s，1H)，2.66(d，J＝5.2Hz，3H).

Step 3

To a solution of A-3c (2.4 g,14.8 mmol) in hexafluoroisopropanol (20 ml) was added hydrogen fluoride pyridine (70%, 6.3 ml). Stir at room temperature for three days. The reaction solution was diluted with dichloromethane and poured into an ice solution of sodium bicarbonate, extracted with dichloromethane, dried, concentrated, and purified by column chromatography to obtain product A-3d (1.68 g, yield: 56%).

¹ H NMR(400MHz，DMSO-d ₆ )δ7.96-7.90(m，1H)，7.75-7.70(m，1H)，7.29(t，J＝7.8Hz，1H)，2.67(d，J＝5.2Hz，3H)，2.03(t，J＝18.6Hz，3H).

Step 4

A-3d (1.88g, 9.3 mmol), (R) -tert-butylsulfinamide (1.69g, 13.95mmol) and tetraethyltitanate (6.36g, 27.9 mmol) were added to tetrahydrofuran (25 ml) in this order and refluxed overnight. After cooling to-15 deg.C, methanol (2 ml) and lithium borohydride (307mg, 13.95mmol) were added. After a reaction for one hour, water (500 ml) and ethyl acetate (500 ml) were added, followed by suction filtration, separation, and drying and concentration of the organic phase. Purification by column chromatography gave the product A-3e as a white solid (1.8 g, yield: 63%).

¹ H NMR(400MHz，DMSO-d ₆ )δ7.70(t，J＝7.0Hz，1H)，7.46(dd，J＝10.6，4.4Hz，1H)，7.30(t，J＝7.8Hz，1H)，5.87(d，J＝7.8Hz，1H)，4.73-4.66(m，1H)，2.00(t，J＝19.2Hz，3H)，1.41(d，J＝6.8Hz，3H)，1.10(s，9H).

MS(ESI)m/z[M+H] ⁺ ：308.2.

Step 5

A-3e (1.7g, 5.5 mmol) was added to a solution of hydrogen chloride in dioxane (16 mL) and the reaction stirred at 50 ℃ for 2 hours. After completion of the reaction, concentration was carried out, and ethyl acetate (50 mL) was added to the residue, followed by stirring and suction filtration to obtain A-3 (1.1 g, yield: 83%) as a white solid.

¹ H NMR(400MHz，DMSO-d ₆ )δ8.72(s，3H)，7.86(t，J＝7.2Hz，1H)，7.60(t，J＝7.4Hz，1H)，7.41(t，J＝7.8Hz，1H)，4.66(d，J＝6.4Hz，1H)，2.02(t，J＝19.2Hz，3H)，1.54(d，J＝6.8Hz，3H).MS(ESI)m/z[M+H] ⁺ ：204.3.

Intermediate example A-4&A-5:

step 1

A-4a (5g, 18.6mmol), tributyl (1-ethoxyethylene) tin (8g, 22.3mmol), pd (PPh) ₃ ) ₂ Cl ₂ (1.3g, 1.85mmol) and triethylamine (5.6 g,55.7 mmol) were dissolved in anhydrous tetrahydrofuran (30 mL). After nitrogen substitution, the mixture was stirred at 80 ℃ overnight. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated, extracted with ethyl acetate (200 mL) and saturated brine (200 mL), the ethyl acetate phase was dried and concentrated, and then the residue was dissolved in tetrahydrofuran (50 mL), and 3M aqueous hydrochloric acid (10 mL) was added and stirred at ordinary temperature overnight. After completion of the reaction, ethyl acetate (200 mL) and saturated brine (200 mL) were added for extraction, and the ethyl acetate phase was dried, concentrated, and purified by column chromatography to give A-4b (3.8g, 88%).

¹ H NMR(400MHz，CDCl ₃ )δ8.95(s，1H)，8.69(s，1H)，8.53(s，1H)，2.75(s，3H).

Step 2

Dissolving A-4b (2g, 8.6 mmol) in tetrahydrofuran (20 mL), adding (R) - (+) -tert-butylsulfinamide (1.56g, 12.9 mmol) and tetraethyl titanate (5.9 g,25.7 mmol), stirring at 70 ℃ for 1 hour, cooling to room temperature after the reaction is completed, adding methanol (2 mL), slowly adding lithium borohydride (2451 mg,11.2 mmol) at-15 ℃, continuing to stir for 1 hour, adding water (100 mL) after the reaction is completed, quenching, adding ethyl acetate (200 mL), extracting, drying an ethyl acetate phase, concentrating, and purifying by column chromatography to obtain A-4c (1.7 g, 58%).

¹ H NMR(400MHz，CDCl ₃ )δ8.44(s，2H)，7.96(s，1H)，4.77-4.68(m，1H)，3.54(d，J＝4.1Hz，1H)，1.62(d，J＝6.7Hz，3H)，1.26(s，9H).

Step 3

A-4c (1.7g, 5mmol) was dissolved in methanol (20 mL), and 4M hydrogen chloride dioxane solution (5 mL) was added thereto at room temperature, and the reaction was continued overnight with stirring at room temperature, after completion of the reaction, the mixture was concentrated to obtain A-4 (1.4g, 100%).

¹ H NMR(400MHz，DMSOd ₆ )δ8.89(s，2H)，8.82(s，1H)，8.54(s，1H)，8.52(s，1H)，4.82-4.74(m，1H)，1.61(d，J＝6.8Hz，3H).

Step 4

A-4 (200mg, 0.74mmol) was dissolved in methanol (5 mL), 10% wet palladium on carbon (20mg, 10% by weight) was added, hydrogen gas was replaced, and the reaction was stirred at ordinary temperature overnight. After completion of the reaction, filtration was carried out, and the filtrate was concentrated and purified by column chromatography to obtain A-5 (70mg, 46%).

¹ H NMR(400MHz，DMSO-d ₆ )δ6.82(d，J＝8.0Hz，2H)，6.69(s，1H)，5.49(s，2H)，3.91(q，J＝6.6Hz，1H)，1.22(d，J＝6.6Hz，3H).

Intermediate examples a-6:

step 1

A-6a (10g, 46mol) was heated and stirred at 45 ℃ in DAST (22 ml) for 48 hours, and the reaction solution was poured into a saturated solution of sodium hydrogencarbonate at zero ℃ and then extracted with ethyl acetate, dried, spun-dried, and purified by column chromatography to give product A-6b (6.6g, 60%) as a colorless oil.

¹ H NMR(400MHz，CDCl ₃ )δ7.67(dd，J＝6.6，2.4Hz，1H)，7.54-7.50(m，1H)，7.06-6.99(m，1H)，1.98(t，J＝18.6Hz，3H).

Step 2

To a solution of A-6b (4.4g, 18.4mmol) in tetrahydrofuran (50 ml) was added LDA (14mL, 2M in THF) dropwise at-78 ℃ and stirred for 1h. A solution of N-methoxy-N-methylacetamide (2.5g, 24.2mmol) in tetrahydrofuran (4 ml) was slowly dropped into the solution through a syringe, and the solution was allowed to return to room temperature and stirred overnight. Saturated ammonium chloride solution was added, extracted with ethyl acetate, dried, spun-dried, and purified by column chromatography to give product A-6c (2.3g, 45%).

¹ H NMR(400MHz，CDCl ₃ )δ8.04(dd，J＝6.0，2.6Hz，1H)，7.82(dd，J＝6.2，2.6Hz，1H)，2.65(d，J＝5.2Hz，3H)，2.02(td，J＝18.6，1.0Hz，3H).

Step 3

A-6c (2g, 7.1mmol), (R) -tert-butylsulfinamide (1.29g, 10.65mmol) and tetraethyltitanate (4.86g, 21.3mmol) were added to tetrahydrofuran (20 ml) in this order and refluxed overnight. Then cooled to-15 ℃ and methanol (2 ml) and lithium borohydride (200mg, 9.23mmol) were added. After a reaction for one hour, water (500 ml) and ethyl acetate (500 ml) were added, followed by suction filtration, separation, and drying and concentration of the organic phase. Purification by column chromatography gave the product A-6d as a white solid (1.3 g, 47%).

¹ H NMR(400MHz，DMSO-d ₆ )δ7.91(dd，J＝6.0，2.4Hz，1H)，7.59(dd，J＝6.2，2.4Hz，1H)，5.94(d，J＝8.6Hz，1H)，4.69-4.62(m，1H)，2.01(t，J＝19.2Hz，3H)，1.40(d，J＝6.8Hz，3H)，1.11(s，9H).

MS(ESI)m/z[M+H] ⁺ ：388.1

Step 4

Mixing A-6d (1.2g, 3.1mmol), p-methoxybenzylamine (427mg, 3.1mmol), and Pd ₂ (dba) ₃ (285mg, 0.31mmol), xantphos (360mg, 0.62mmol) and cesium carbonate (2g, 6.2mmol) were added to dioxane (15 ml) and heated under reflux overnight under nitrogen. Water (100 ml) and ethyl acetate (100 ml) were added for extraction, the organic phase was taken out, dried, concentrated and purified by column chromatography to give product A-6e (500mg, 36%).

¹ H NMR(400MHz，DMSO-d ₆ )δ7.27(d，J＝8.6Hz，2H)，6.88(d，J＝8.6Hz，2H)，6.81(dd，J＝5.4，2.8Hz，1H)，6.60(dd，J＝5.8，2.8Hz，1H)，6.30(t，J＝5.8Hz，1H)，5.64(d，J＝6.8Hz，1H)，4.57(t，J＝6.8Hz，1H)，4.16(d，J＝5.8Hz，2H)，3.72(s，3H)，1.91(t，J＝18.8Hz，3H)，1.34(d，J＝6.8Hz，3H)，1.07(s，9H).

MS(ESI)m/z[M+H] ⁺ ：443.3.

Step 5

A-6e (500mg, 1.1mmol) was dissolved in methanol (10 mL), and 4M hydrogen chloride dioxane solution (5 mL) was added thereto at room temperature, and the reaction was continued overnight with stirring at room temperature, after completion of the reaction, the solution was concentrated to obtain A-6f (420mg, 100%).

Step 6

A-6f (400mg, 1mmol) was dissolved in trifluoroacetic acid (10 mL), and the reaction mixture was stirred at 50 ℃ for 16 hours. After completion of the reaction, the reaction mixture was concentrated, and the residue was diluted with ethyl acetate (50 mL), washed with a saturated aqueous sodium bicarbonate solution and a saturated brine. The ethyl acetate phase was dried, concentrated, and purified by column chromatography to give product A-6 (156mg, 67%).

¹ H NMR(400MHz，DMSO-d ₆ )δ6.87-6.78(m，1H)，6.55(dd，J＝6.0，2.9Hz，1H)，5.10(s，2H)，4.17(q，J＝6.6Hz，1H)，1.92(dd，J＝19.3，18.7Hz，3H)，1.21(t，J＝8.1Hz，3H).

Intermediate examples a-7:

step 1

A mixture of A-7a (25g, 115.19mmol) and DAST (10 mL) was stirred at 45 deg.C for 48h. Adding ethyl acetate for dilution, slowly adding saturated sodium bicarbonate aqueous solution dropwise until no bubbles are generated, and separating the liquid. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to give colorless oil A-7b (25g, 90%).

¹ H NMR(400MHz，Chloroform-d ₁ )δ7.77-7.69(m，1H)，7.62-7.54(m，1H)，7.07(t，J＝9.5Hz，1H)，2.03(t，J＝18.5Hz，3H).

Step 2

LDA (2M in THF, 54mL) was added dropwise to a solution of A-7b (20g, 83.67mmol) in THF (200 mL) at-78 ℃ under nitrogen protection, and after reaction at-78 ℃ for 1 hour, N-methyl-N-methoxyacetamide (8.63g, 83.67mmol) was slowly added dropwise. The reaction was continued at-78 ℃ for 1 hour. After the reaction, the mixture was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by column chromatography to give a yellow oil A-7c (7.5g, 31.9%).

¹ H NMR(400MHz，DMSO-d ₆ )δ8.07(dd，J＝5.9，2.7Hz，1H)，7.86(dd，J＝6.1，2.7Hz，1H)，2.69(d，J＝5.2Hz，3H)，2.05(t，J＝18.2Hz，3H).

Step 3

A-7c (7.5g, 28.68mmol), (R) -tert-butylsulfinamide (4.85g, 40.05mmol), THF (80 mL), and tetraethyltitanate (18.26g, 80.1mmol) were reacted at 80 ℃ for 1 hour. The temperature was reduced to-10 ℃ and methanol (5 mL) and lithium borohydride (760mg, 34.68mmol) were added to react at room temperature overnight. Diluting with ethyl acetate, quenching with small amount of water, stirring for 1 hr, adding diatomite, filtering, spin drying the filtrate, and separating by column chromatography to obtain light yellow solid A-7d (7.8g, 76%).

¹ H NMR(400MHz，DMSO-d ₆ )δ7.86(dd，J＝6.0，2.5Hz，1H)，7.63(dd，J＝6.2，2.5Hz，1H)，5.79(s，1H)，5.67(d，J＝6.2Hz，1H)，2.03(t，J＝19.2Hz，3H)，1.52(d，J＝6.8Hz，3H)，1.13(s，9H).

MS(ESI)m/z[M+H] ⁺ ：388.1

Step 4

A-7d (1.3g, 3.37mmol), zinc cyanide (0.59g, 5.05mmol), dppf (0.38g, 0.27mmol) and Pd ₂ (dba) ₃ (0.31g, 0.34mmol) and DIPEA (1.31g, 10.11mmol) were dissolved in DMF (20 mL), replaced with nitrogen 3 times, and the temperature was raised to 120 ℃ to react for 12 hours. Diluting with ethyl acetate, washing with saturated saline for 5 times, drying over anhydrous sodium sulfate, and separating by column chromatography to obtain gray solid A-7e (400mg, 35.7%).

Step 5

A-7e (1g, 2.6 mmol) in TFA (10 mL) was stirred at 50 ℃ for 16 h. Concentrate to dryness, treat with saturated aqueous sodium bicarbonate, and extract with ethyl acetate. The obtained ethyl acetate solution was washed with saturated brine, concentrated, and subjected to column chromatography to obtain yellow oil A-7 (380mg, 67%).

Intermediate examples a-8:

step 1

A-7d (1.8g, 4.7mmol), potassium ferrocyanide (1.97g, 4.7mmol), tetrakis (triphenylphosphine) palladium (560mg, 0.47mmol) and DBU (0.86g, 5.6mmol) were added to dioxane (20 ml) and water (20 ml), stirred under nitrogen at 100 ℃ for 16 h. The reaction mixture was poured into water (200 ml), extracted with ethyl acetate, dried, spin-dried, purified by column chromatography to give product A-8a (700mg, 43%).

¹ H NMR(400MHz，DMSO-d ₆ )δ8.24(d，J＝6.4Hz，1H)，8.13(s，1H)，7.97(d，J＝6.6Hz，1H)，7.52(s，1H)，5.89(d，J＝7.4Hz，1H)，4.74-4.67(m，1H)，2.03(t，J＝18.0Hz，3H)，1.44(d，J＝6.7Hz，3H)，1.09(s，9H).

MS(ESI)m/z[M+H] ⁺ ：351.2.

Step 2

A-8a (700mg, 2.0 mmol) was added to a hydrogen chloride dioxane solution (5 ml), and stirred at 50 ℃ for 16 hours. The solvent was spin-dried, ethyl acetate (20 ml) was added, stirred and suction-filtered to give the product A-8 (500 mg, yield: 89%) as a white solid.

¹ H NMR(400MHz，DMSO-d ₆ )δ8.68(s，3H)，8.47(d，J＝5.8Hz，1H)，8.24(s，1H)，8.10(d，J＝5.6Hz，1H)，7.64(s，1H)，4.75-4.63(m，1H)，2.05(t，J＝19.2Hz，3H)，1.56(d，J＝6.8Hz，3H).

MS(ESI)m/z[M+H] ⁺ ：246.9.

Intermediate examples a-9:

step 1

A-9a (42g, 0.2mol) and 1, 2-ethanedithiol (18.8g, 0.2mol) were dissolved in toluene (450 mL). P-toluenesulfonic acid (7.6 g, 0.04mol) was added at normal temperature, and the reaction solution was heated to reflux and stirred for 12 hours. After completion of the reaction, 10% aqueous sodium hydroxide solution was added and extracted with ethyl acetate (400ml × 3). The ethyl acetate phase was dried, concentrated and the residue was purified by column chromatography to give intermediate A-9b (48g, 84%) as a white solid.

¹ H NMR(400MHz，CDCl ₃ )δ7.48(d，J＝7.6Hz，1H)，7.37(d，J＝7.9Hz，1H)，7.12(t，J＝7.8Hz，1H)，3.61-3.48(m，2H)，3.49-3.38(m，2H)，2.98(t，J＝6.7Hz，2H)，2.70(dd，J＝8.5，5.0Hz，2H).

Step 2

Dibromohydantoin (190.4g, 0.67mol) was dissolved in dichloromethane (400 mL), pyridine hydrofluoride salt (600mL, 6.7 mol) was added slowly at 60 ℃. A solution of A-9b (48g, 0.17mol) in methylene chloride (100 mL) was slowly added to the reaction. The reaction solution is heated to room temperature after reacting for 4 hours at-60 ℃ and then is stirred to react for 16 hours. After the reaction was completed, a 2N aqueous solution of sodium hydroxide and a 30% aqueous solution of sodium hydrogen sulfite were added. The fractions were separated, dried over the dichloromethane phase, concentrated and the residue purified by column chromatography to give intermediate A-9c (33g, 63%).

¹ H NMR(400MHz，DMSO-d ₆ )δ7.95-7.78(m，1H)，7.72(dd，J＝17.1，5.5Hz，1H)，7.50-7.34(m，1H)，5.11(ddt，J＝13.3，10.9，7.4Hz，1H)，3.62(ddd，J＝16.5，7.7，2.7Hz，1H)，3.25-3.03(m，1H).

Step 3

A-9c (33g, 0.11mol) was dissolved in dichloromethane (300 mL) and DBU (24.1g, 0.11mol) was added under ice bath. The reaction solution was stirred at room temperature for 12 hours. After completion of the reaction, dichloromethane was added for dilution, and the organic phase was washed with a 0.5N aqueous hydrochloric acid solution and a saturated brine. The organic phase was dried, concentrated, and the residue was purified by column chromatography to give intermediate A-9d (19.8g, 79%).

¹ H NMR(400MHz，DMSO-d ₆ )δ7.71-7.61(m，1H)，7.61-7.49(m，1H)，7.34-7.21(m，1H)，7.06(t，J＝10.2Hz，1H)，6.61(d，J＝6.1Hz，1H).

Step 4

A-9d (19g, 82.3mmol) and A-9e (23.7g, 106.9mmol) were dissolved in acetonitrile (500 mL), and potassium phosphate (3.5g, 16.5mmol) and hydrazine hydrate (16.6g, 33mol) were slowly added under ice bath. The reaction solution was stirred at room temperature for 40 hours. After completion of the reaction, water (300 mL), dichloromethane (500ml × 3) was added for extraction, the organic phase was dried, concentrated, and the residue was purified by column chromatography to obtain intermediate a-9f (17.2g, 90%).

¹ H NMR(400MHz，DMSO-d ₆ )δ7.77(dd，J＝7.9，0.8Hz，1H)，7.61(dd，J＝13.5，6.6Hz，1H)，7.44-7.24(m，1H)，3.00(tt，J＝6.9，3.3Hz，2H)，2.71-2.57(m，2H).

Step 5

A-9f (15.2g, 65.2mmol) was dissolved in anhydrous dioxane (320 mL) and triethylamine (16.5g, 163mmol), tributyl (1-ethoxyethylene) tin (28.3g, 78.3mmol) and bis (triphenylphosphine) palladium dichloride (4.6g, 6.5mmol) were added. After the nitrogen gas was replaced, the reaction mixture was heated to 100 ℃ and stirred for reaction for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 1N aqueous hydrochloric acid (260 mL) was added to the reaction mixture, followed by stirring at room temperature for another 16 hours. Dichloromethane (200ml × 3) was added for extraction, the dichloromethane phase was dried and concentrated, and the residue was purified by column chromatography to obtain intermediate a-9g (8.8g, 68%).

¹ H NMR(400MHz，DMSO-d ₆ )δ8.17(d，J＝7.7Hz，1H)，7.81(d，J＝7.6Hz，1H)，7.58(dd，J＝20.4，12.8Hz，1H)，3.31(ddd，J＝10.5，6.9，3.5Hz，2H)，2.70-2.53(m，5H).

Step 6

A-9g (5g, 25.4 mmol) and (S) -tert-butylsulfinamide (4.6g, 38.2mmol) were dissolved in anhydrous tetrahydrofuran (135 mL), and tetraethyl titanate (17.4 g, 76.2mmol) was added after replacement of nitrogen. The reaction solution was heated to 70 ℃ and stirred to react for 16 hours. After the reaction was completed, it was cooled to room temperature, and then water (200 mL) and ethyl acetate (200 mL) were added for extraction, the organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain intermediate A-9h (5.7g, 75%).

¹ H NMR(400MHz，DMSO-d ₆ )δ7.95(d，J＝7.7Hz，1H)，7.72(d，J＝7.5Hz，1H)，7.59-7.44(m，1H)，3.24(t，J＝14.0Hz，2H)，2.73(d，J＝7.1Hz，3H)，2.67-2.54(m，2H)，1.21(d，J＝10.8Hz，9H).MS(ESI)m/z＝300.1[M+H] ⁺ .

Step 7

Dissolve A-9h (5.7g, 19mmol) in anhydrous tetrahydrofuran (95 mL), and slowly add lithium tri-sec-butylborohydride (38mL, 38mmol) dropwise at 78 deg.C. The reaction mixture was stirred at-78 ℃ for 2 hours. After completion of the reaction, it was quenched by addition of aqueous ammonium chloride solution and extracted with dichloromethane (200ml × 3). The organic phase was dried, concentrated and the residue was purified by column chromatography to give intermediate A-9i (5g, 88%).

¹ H NMR(400MHz，DMSO-d ₆ )δ7.56(d，J＝6.8Hz，1H)，7.47-7.31(m，2H)，5.39(d，J＝5.0Hz，1H)，4.57-4.46(m，1H)，3.06(d，J＝3.1Hz，2H)，2.65-2.54(m，2H)，1.47(d，J＝6.7Hz，3H)，1.09(s，9H).

Step 8

A-9i (5.5g, 27.3 mmol) was dissolved in dioxane (10 mL), and dioxane hydrochloride solution (4M, 50mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, concentration was carried out, and petroleum ether was added to the residue, followed by stirring and filtration to obtain intermediate A-9 (4.1g, 99%) as a white solid.

¹ H NMR(400MHz，DMSO-d ₆ )δ8.70(s，2H)，7.83(d，J＝7.4Hz，1H)，7.64-7.41(m，2H)，4.45(s，1H)，3.14(dd，J＝38.4，16.6Hz，2H)，2.69-2.52(m，2H)，1.56(t，J＝13.3Hz，3H).

Intermediate examples a-10:

step 1

Diisopropylamine (2.96g, 29.3 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and n-butyllithium (8.1mL, 20.3 mmol) was slowly added dropwise at 78 ℃. After the reaction solution was stirred at-78 ℃ for 2 hours, a solution of A-10a (5 g,22.5 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise to the reaction solution at-78 ℃. After the reaction mixture was further stirred for 2 hours, TMSCl (2.7g, 24.8mmol) was added. The reaction mixture was stirred for 2 hours and then warmed to room temperature, and the reaction was stirred for 16 hours. After completion of the reaction, it was quenched by addition of aqueous ammonium chloride solution and extracted with ethyl acetate (50ml × 3). The ethyl acetate phase was dried, concentrated, and the residue was purified by column chromatography to give A-10b (6.1g, 92%).

¹ H NMR(400MHz，DMSO-d ₆ )δ7.90-7.84(m，1H)，7.41(ddd，J＝7.0，5.2，1.6Hz，1H)，7.05-6.93(m，1H)，0.35-0.25(m，9H).

Step 2

Aluminum trichloride (544mg, 4.1mmol) was dissolved in dichloromethane (10 mL) and acetyl chloride (320mg, 4.1mmol) was added under ice bath. After the reaction mixture was stirred for 30 minutes, a solution of A-10b (1g, 3.4 mmol) in methylene chloride (5 mL) was slowly added dropwise to the reaction mixture. The reaction solution was warmed to room temperature and stirred for 2 hours. After completion of the reaction, aqueous sodium bicarbonate (10%, 25 mL) was added slowly. The aqueous phase was extracted with ethyl acetate (30ml × 3). The ethyl acetate phase was dried, concentrated, and the residue was purified by column chromatography to give A-10c (370mg, 41%).

¹ H NMR(400MHz，DMSO-d ₆ )δ8.08(ddd，J＝7.6，5.9，1.7Hz，1H)，7.81-7.73(m，1H)，7.13(t，J＝7.8Hz，1H)，2.58(d，J＝4.2Hz，3H).

Step 3

A-10c (5 g, 19mmol) was dissolved in DMSO (50 mL), and ethyl difluorobromoacetate (11.5 g, 56.8mmol) and copper (3.6 g, 56.8mmol) were added at ordinary temperature. The reaction solution was heated to 80 ℃ and stirred to react for 16 hours. After completion of the reaction, water and ether were added, a solid was precipitated, filtered, and the aqueous phase was extracted with ethyl acetate (300 mL). The ethyl acetate phase was dried, concentrated, and the residue was purified by column chromatography to give A-10d (3.3 g, 66%).

¹ H NMR(400MHz，DMSO-d ₆ )δ8.06(t，J＝7.3Hz，1H)，7.96(t，J＝7.3Hz，1H)，7.53(t，J＝7.8Hz，1H)，4.45-4.30(dd，2H)，2.60(d，J＝4.0Hz，3H)，1.24(t，J＝2.9Hz，3H).

Step 4

A-10d (3.3g, 12.7mmol) was dissolved in tetrahydrofuran (40 mL) and (R) -tert-butylsulfinamide and tetraethyl titanate (8.7g, 38mmol) were added at ambient temperature. The reaction solution was heated to 70 ℃ and stirred to react for 16 hours. After the reaction was completed, water and ether were added, a solid was precipitated, filtered, and the aqueous phase was extracted with ethyl acetate (100 mL). The ethyl acetate phase was dried, concentrated, and the residue was purified by column chromatography to give A-10e (2.9g, 63%).

¹ H NMR(400MHz，DMSO-d ₆ )δ7.92(t，J＝7.0Hz，1H)，7.85(t，J＝6.9Hz，1H)，7.50(t，J＝7.7Hz，1H)，4.39-4.28(m，2H)，2.69(s，3H)，1.23(t，J＝1.9Hz，3H)，1.22-1.15(m，9H).

Step 5

A-10e (5g, 13.8mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and DIBAI-H (62.2mL, 96.3mmol) was slowly added dropwise at-78 ℃ after replacement of nitrogen. The reaction solution was warmed to room temperature and stirred for further 16 hours. After completion of the reaction, methanol (20 mL) was added, filtered, and the filtrate was diluted with ethyl acetate (300 mL). The ethyl acetate phase was washed with saturated aqueous citric acid (100 mL). The organic phase is dried, concentrated and the residue is purified by column chromatography to give A-10f (2.3 g, 51%).

¹ H NMR(400MHz，DMSO-d ₆ )δ7.70(t，J＝7.5Hz，1H)，7.44(dd，J＝10.4，4.4Hz，1H)，7.30(t，J＝7.7Hz，1H)，5.85(d，J＝7.7Hz，1H)，5.69(t，J＝5.8Hz，1H)，4.68(dd，J＝14.2，7.1Hz，1H)，3.94-3.87(m，2H)，1.41(d，J＝6.8Hz，3H)，1.10(s，9H).

Step 6

A-10f (1.3g, 4mmol) was dissolved in tetrahydrofuran (20 mL), and cesium carbonate (3.93g, 12mmol) and 18-crown-6 (531mg, 2mmol) were added. The reaction solution was heated to 80 ℃ and stirred to react for 16 hours. After completion of the reaction, ethyl acetate (80ml × 3) and water (80 mL) were added for extraction. The organic phase was dried, concentrated, and the residue was purified by column chromatography to give A-10g (950 mg, 78%).

¹ H NMR(400MHz，DMSO-d ₆ )δ7.64(d，J＝7.6Hz，1H)，7.53-7.49(m，1H)，7.12(t，J＝7.6Hz，1H)，5.72(d，J＝7.5Hz，1H)，4.82(td，J＝16.6，1.7Hz，2H)，4.57(dd，J＝14.0，6.9Hz，1H)，1.40(d，J＝6.8Hz，3H)，1.10(d，J＝2.7Hz，9H).MS(ESI)m/z 304.2[M+H] ⁺

Step 7

A-10g (1.3g, 4.3mmol) was dissolved in hydrogen chloride dioxane solution (4M, 30mL). The reaction was stirred at room temperature for 1 hour. After completion of the reaction, concentration was carried out to obtain white solid A-10 (900mg, 89%).

¹ H NMR(400MHz，DMSO-d ₆ )δ7.63(d，J＝7.5Hz，1H)，7.45(dd，J＝7.6，1.4Hz，1H)，7.09(t，J＝7.6Hz，1H)，4.79(td，J＝16.7，3.1Hz，2H)，4.17(q，J＝6.6Hz，1H)，2.06-1.88(m，2H)，1.26(d，J＝6.6Hz，3H).

Intermediate examples a-12:

step 1:

a-12a (6.6 g,27.6 mmol), tributyl (1-ethoxyvinyl) tin (9.97g, 27.6 mmol), triethylamine (8.4 g,82.8 mmol) and bis (triphenylphosphine) palladium dichloride (1.94g, 2.76mmol) were dissolved in tetrahydrofuran (50 mL). After nitrogen gas was replaced, the reaction was stirred at 80 ℃ for 6 hours. After completion of the reaction, it was cooled to room temperature, filtered, and the filtrate was diluted with ethyl acetate (100 mL), and washed with saturated aqueous sodium bicarbonate solution and brine. The ethyl acetate phase was dried and concentrated, and the residue was dissolved in ethanol (50 mL), and 3N hydrochloric acid solution (20 mL) was added to stir the reaction at room temperature for 4 hours. After completion of the reaction, concentration was carried out, and the residue was diluted with ethyl acetate (200 mL), washed with a saturated aqueous sodium bicarbonate solution, washed with a saturated saline solution, dried over ethyl acetate phase, filtered and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 20: 1) to give A-12b (4.4g, 79%).

¹ H NMR(400MHz，CDCl ₃ )δ7.77(d，J＝7.9Hz，1H)，7.68(d，J＝7.8Hz，1H)，7.39(t，J＝7.8Hz，1H)，2.62(s，3H)，2.57(d，J＝1.8Hz，3H).

And 2, step:

a-12b (4.4g, 21.8mmol) was dissolved in tetrahydrofuran (50 mL) and (R) -tert-butylsulfenamide (3.96g, 32.6mmol) and tetraethyltitanate (14.9g, 65.3mmol) were added. The reaction mixture was stirred at 80 ℃ for 1 hour. After completion of the reaction, the reaction mixture was cooled to-15 ℃ and methanol (5 mL) and lithium borohydride (620mg, 28.3mmol) were added. The reaction mixture was stirred at-15 ℃ for 1 hour. After completion of the reaction, diluted with ethyl acetate (100 mL), quenched with a small amount of water, followed by stirring for 1 hour, filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain a-12c (2.1g, 31%).

¹ H NMR(400MHz，CDCl ₃ )δ7.63(dd，J＝15.7，7.9Hz，2H)，7.35(t，J＝7.9Hz，1H)，5.00-4.91(m，1H)，2.52(d，J＝1.9Hz，3H)，1.54(d，J＝6.5Hz，3H)，1.28(s，9H).

And 3, step 3:

a-12c (2.1g, 6.8mmol) was dissolved in a 4N hydrogen chloride/dioxane solution (20 mL), and the reaction was stirred at room temperature for 1 hour. After the reaction, the mixture was concentrated, and petroleum ether/ethyl acetate was added to the resulting mixture to obtain a mixed solution, which was then stirred at room temperature for 1 hour. Filtration afforded A-12 as a white solid (1.28g, 79%).

¹ H NMR(400MHz，DMSO-d ₆ )δ8.63(s，3H)，7.96(d，J＝7.9Hz，1H)，7.73(d，J＝7.8Hz，1H)，7.54(t，J＝7.9Hz，1H)，4.74(s，1H)，2.47(s，3H)，1.54(d，J＝6.7Hz，3H).

Intermediate examples a-13:

step 1:

ethyl difluorobromoacetate (16.9g, 83mmol) and copper powder (5.3g, 83mmol) were dissolved in dimethyl sulfoxide (70 mL), the reaction was stirred at room temperature under nitrogen for 45 minutes, and A-13a (10g, 33mmol) was added. The reaction solution was heated to 70 ℃ and reacted for 3 hours. After completion of the reaction, it was cooled to room temperature, quenched with water (50 mL), filtered, and the filtrate was extracted with ethyl acetate (100ml × 3). The ethyl acetate phase was dried, filtered, concentrated, and the residue was purified by column chromatography to give A-13b (5.95g, 60%).

¹ H NMR(400MHz，CDCl ₃ )δ7.71(t，J＝7.3Hz，1H)，7.59(t，J＝7.2Hz，1H)，7.15(t，J＝7.9Hz，1H)，4.37(q，J＝7.2Hz，2H)，1.34(td，J＝7.1，0.9Hz，3H).

Step 2:

a-13b (5.95g, 20mmol) was dissolved in tetrahydrofuran (70 mL), and methylmagnesium bromide (3M, 20mL, 60mmol) was added under ice bath. The reaction solution was stirred at room temperature for 2 hours, after completion of the reaction, an aqueous ammonium chloride solution (50 mL) was added to quench, and extraction was performed with ethyl acetate (100ml × 2). The ethyl acetate phase was dried, filtered, concentrated, and the residue was purified by column chromatography to give A-13c (5.1g, 90%).

¹ H NMR(400MHz，DMSO-d ₆ )δ7.86(ddd，J＝8.0，6.2，1.6Hz，1H)，7.46(ddd，J＝8.2，6.6，1.7Hz，1H)，7.30-7.21(m，1H)，5.40(s，1H)，1.20(d，J＝1.4Hz，6H).

And step 3:

a-13c (5.1g, 18mmol), tributyl (1-ethoxyvinyl) tin (7.8g, 21.6mmol), triethylamine (5.46g, 54mmol), and bis (triphenylphosphine) palladium dichloride (1.26g, 1.8mmol) were dissolved in 1, 4-dioxane (50 mL). After nitrogen gas was replaced, the reaction was stirred at 100 ℃ for 16 hours. After completion of the reaction, it was cooled to room temperature, filtered, and the filtrate was diluted with ethyl acetate (100 mL), and washed with saturated aqueous sodium bicarbonate solution and brine. The ethyl acetate phase was dried and concentrated, and the residue was dissolved in ethanol (50 mL), and 3N hydrochloric acid solution (20 mL) was added to stir the reaction at room temperature for 1 hour. After completion of the reaction, concentration was carried out, and the residue was diluted with ethyl acetate (200 mL), washed with a saturated aqueous sodium bicarbonate solution, washed with a saturated brine, dried over ethyl acetate phase, filtered and concentrated. The residue was purified by column chromatography to give A-13d (3.77g, 85%).

¹ H NMR(400MHz，CDCl ₃ )δ7.94(td，J＝7.3，6.5，1.9Hz，1H)，7.69-7.59(m，1H)，7.29(d，J＝7.7Hz，1H)，2.65(dd，J＝5.4，1.7Hz，3H)，1.36(d，J＝1.8Hz，6H).

And 4, step 4:

a-13d (3.77g, 15.3 mmol) was dissolved in tetrahydrofuran (40 mL) and (R) -tert-butylsulfinamide (2.78g, 23mmol) and tetraethyl titanate (10.5g, 46mmol) were added. The reaction mixture was stirred at 80 ℃ for 12 hours. After completion of the reaction, the reaction mixture was cooled to-15 ℃ and methanol (3.5 mL) and lithium borohydride (404mg, 18.4 mmol) were added. The reaction mixture was stirred at-15 ℃ for 1 hour. After completion of the reaction, ethyl acetate was added to dilute (100 mL), and a small amount of water was added to quench, followed by stirring for 1 hour, filtration, concentration of the filtrate, and purification of the residue by column chromatography to give A-13e (3.5g, 65%).

And 5:

a-13e (3.5g, 10mmol) was dissolved in a 4N hydrogen chloride/dioxane solution (20 mL), and the reaction was stirred at room temperature for 2 hours. After the reaction, the mixture was concentrated, and petroleum ether/ethyl acetate was added to the resulting mixture to obtain a mixed solution, which was then stirred at room temperature for 1 hour. Filtration afforded white solid A-13 (2.67g, 95%).

¹ H NMR(400MHz，DMSO-d6)δ8.68(s，3H)，7.87-7.77(m，1H)，7.47(td，J＝7.5，1.7Hz，1H)，7.37(t，J＝7.8Hz，1H)，4.64(p，J＝6.2Hz，1H)，1.53(d，J＝6.8Hz，3H)，1.21(s，6H).LCMS m/z[M+H] ⁺ ：248.4.

Intermediate example B-1:

step 1

B-1a (5g, 26mmol) was dissolved in a dioxane solution of ammonia (4M, 100mL), and the reaction was stirred at room temperature with a sealed tube for 1 hour. After the reaction was completed, the solution was spin-dried, and the residue was purified by column chromatography to give intermediate B-1B (4.28g, 98%) as a white solid.

¹ H NMR(400MHz，DMSO-d ₆ )δ10.20(s，1H)，8.55(d，J＝42.5Hz，2H)，2.40(s，3H).

MS(ESI)m/z172.2[M+H] ⁺ .

Step 2

B-1c (30g, 0.34mol) was dissolved in anhydrous tetrahydrofuran (750 mL), sodium hydride (20.4 g, 051mol) was added slowly in portions under ice bath, and ethyl bromoacetate (113.6 g, 0.68mol) was added after stirring for 6 hours. The reaction was stirred at ambient temperature for an additional 40 hours. After completion of the reaction, the reaction was quenched by addition of ice water (200 mL) and extracted with ethyl acetate (200ml × 3). Ethyl acetate was dried, concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give intermediate B-1d (25g, 21%) as a colorless oil.

¹ H NMR(400MHz，CDCl ₃ )δ4.31-4.13(m，3H)，4.15-4.04(m，2H)，3.92-3.78(m，4H)，2.15-1.83(m，2H)，1.33-1.26(m，3H).

Step 3

B-1d (18.5g, 106mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and after replacement of nitrogen gas, liHMDS (122mL, 122mmol) was slowly added at-78 ℃. After stirring for an additional 1 hour, B-1B (9 g, 53mmol) was dissolved in dry tetrahydrofuran (100 mL) and added dropwise slowly to the reaction. The reaction solution was slowly warmed to room temperature and stirred for further reaction for 18 hours. After completion of the reaction, 6N hydrochloric acid (19 mL) was added for quenching. Ethyl acetate (200ml × 3) was added for extraction. The ethyl acetate phase was dried, concentrated and purified by column chromatography (dichloromethane: methanol = 20: 1) to yield intermediate B-1 as a white solid (4.6g, 30%).

¹ H NMR(400MHz，DMSO-d ₆ )δ12.89(s，1H)，7.02(s，1H)，5.20(d，J＝1.9Hz，1H)，3.90(d，J＝3.9Hz，2H)，3.87-3.81(m，1H)，3.77(td，J＝8.3，4.8Hz，1H)，2.57(S，3H)，2.28(td，J＝14.2，8.0Hz，1H)，2.08-1.98(m，1H).

MS(ESI)m/z 282.1[M+H] ⁺ .

Intermediate example B-2:

step 1

B-1a (4 g, 21mmol) was dissolved in tetrahydrofuran (150 mL), methylamine (2M in THF, 21mL, 42mmol) was added, and the reaction was stirred at room temperature with a tube sealed for 1 hour. After the reaction was completed, the solution was spin-dried, and the residue was purified by column chromatography to give bright yellow intermediate B-2a (3.85g, 99%).

¹ H NMR(400MHz，DMSO-d ₆ )δ10.21(s，1H)，9.12(s，1H)，3.01(d，J＝4.9Hz，3H)，2.44(s，3H).

MS(ESI)m/z186.2[M+H] ⁺ .

Step 2

B-1d (3.8g, 21.6mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and after replacement of nitrogen gas, liHMDS (32.4mL, 122mmol) was slowly added at-78 ℃. After stirring for 1 hour, B-2a (2g, 10.8 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) and slowly added dropwise to the reaction mixture. The reaction solution was slowly warmed to room temperature and stirred for further reaction for 18 hours. After completion of the reaction, 6N hydrochloric acid (4 mL) was added for quenching. Ethyl acetate (200ml × 3) was added for extraction. The ethyl acetate phase was dried, concentrated, and purified by column chromatography (dichloromethane: methanol = 20: 1) to give intermediate B-2 (1.2g, 38%) as a white solid.

¹ H NMR(400MHz，DMSO-d ₆ )δ7.09(s，1H)，5.28-5.19(m，1H)，3.95-3.89(m，2H)，3.88-3.82(m，1H)，3.77(td，J＝8.4，4.8Hz，1H)，3.65(s，3H)，2.64(s，3H)，2.35-2.23(m，1H)，2.03(dt，J＝18.9，6.1Hz，1H).

MS(ESI)m/z 296.1[M+H] ⁺ .

Intermediate example B-3:

step 1

B-1a (4 g, 21mmol) was dissolved in tetrahydrofuran (150 mL), ethylamine (10.5mL, 21mmol) was added, and the reaction mixture was stirred at room temperature with a sealed tube for 1 hour. After the reaction was complete, the solution was spun dry and the residue was purified by column chromatography to give bright yellow intermediate B-3a (2.9g, 69%).

¹ H NMR(400MHz，DMSO-d ₆ )δ10.20(s，1H)，9.18(s，1H)，3.59-3.48(m，2H)，2.43(s，3H)，1.16(t，J＝7.2Hz，3H).

LCMS(ESI)：200.1[M+H] ⁺ .

Step 2

B-1d (3.6g, 21mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and after replacement of nitrogen gas, liHMDS (31.5mL, 31.5mmol) was slowly added at-78 ℃. After stirring for 1 hour, B-3a (2.1g, 10.5mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) and slowly added dropwise to the reaction mixture. The reaction solution was slowly warmed to room temperature and stirred for further reaction for 18 hours. After completion of the reaction, 6N hydrochloric acid (4 mL) was added for quenching. Ethyl acetate (200ml × 3) was added for extraction. The ethyl acetate phase was dried, concentrated and purified by column chromatography (dichloromethane: methanol = 20: 1) to give intermediate B-3 (2.6 g, 80%) as a white solid.

¹ H NMR(400MHz，DMSO-d ₆ )δ7.08(s，1H)，5.26-5.18(m，1H)，4.43-4.31(m，2H)，3.90(t，J＝4.2Hz，2H)，3.89-3.82(m，1H)，3.77(td，J＝8.3，4.8Hz，1H)，2.65(s，3H)，2.37-2.20(m，1H)，2.11-1.97(m，1H)，1.20(q，J＝6.9Hz，3H).

MS(ESI)m/z 310.1[M+H] ⁺ .

Intermediate example B-4:

step 1

To a solution of B-4a (4 g, 21mmol) in tetrahydrofuran (150 mL) was added 2, 2-trifluoroethylamine (2.08g, 21mmol). Stirring was carried out at 25 ℃ for 1h. Filtration, concentration of the filtrate, and purification by reverse phase preparative chromatography gave B-4B (2.7g, 52%) as a yellow solid.

¹ H NMR(400MHz，DMSO-d ₆ )δ8.68(s，1H)，4.61-4.42(m，2H)，2.65(d，J＝5.3Hz，3H).

Step 2

B-1d (3.14g, 11.8mmol) was added to a stirred solution of LiHMDS (1M, 27mL,27mmol in THF) in tetrahydrofuran (50 mL) at-78 ℃. After one hour, a solution of B-4B (2.32g, 9mmol) in tetrahydrofuran (50 mL) was slowly added dropwise. The temperature was gradually increased to 25 ℃. After 18 hours, quench with hydrochloric acid (6N, 3.3mL) to give a suspension. Filtration and purification of the filter cake by column chromatography gave B-4 as a yellow solid (300mg, 9%).

¹ H NMR(400MHz，DMSO-d ₆ )δ7.15(s，1H)，5.30-5.24(m，1H)，5.24-5.12(m，2H)，3.96-3.89(m，2H)，3.86(t，J＝7.8Hz，1H)，3.78(td，J＝8.3，4.8Hz，1H)，2.65(s，3H)，2.31(td，J＝14.1，7.9Hz，1H)，2.15-1.96(m，1H).

Intermediate example B-5&B-6&B-7:

step 1

B-5a (7.1g, 26mmol) was added to a stirred solution of LiHMDS (1M in THF, 39mL, 39mmol) in tetrahydrofuran (50 mL) at-78 ℃. After 1 hour, a solution of B-1B (2.2 g, 13mmol) in tetrahydrofuran (50 mL) was added dropwise at this temperature. After gradually warming to 25 ℃ for 18 hours, the reaction was directly concentrated and purified by column chromatography to give B-5 (1.65g, 33%) as a yellow oil.

MS(ESI)m/z 381.1[M+H] ⁺ .

Step 2

To a solution of B-5 (1.3g, 3.4 mmol) in dichloromethane (9 mL) was added TFA (3 mL). Stirred for 2 hours at 25 ℃. The reaction mixture was directly concentrated and purified by column chromatography to give B-6 (700mg, 73%) as a yellow solid.

MS(ESI)m/z 281.1[M+H] ⁺ .

Step 3

To a solution of B-6 (210mg, 0.75mmol) in DCM (5 mL) was added pyridine (118mg, 1.5mmol) and acetyl chloride (88mg, 1.13mmol). Stirring at 25 deg.C for 16 hr, concentrating, treating with saturated saline solution, and extracting with ethyl acetate. The extract was concentrated and purified by thin layer chromatography to give B-7 (24mg, 9%) as a white solid.

MS(ESI)m/z 323.1[M+H] ⁺ .

Intermediate example B-8:

lithium bis (trimethylsilyl) amide (1M/THF, 87.4mL,87.4 mmol) was dissolved in tetrahydrofuran (100 mL), and methyl phenoxyacetate (9.68g, 58mmol) was added slowly at-78 ℃. After stirring for 1 hour, B-1B (5g, 29mmol) was dissolved in tetrahydrofuran (50 mL) and slowly added dropwise to the reaction mixture at-78 ℃. The reaction solution was slowly warmed to room temperature, and the reaction was continued with stirring for 18 hours. After the reaction was completed, it was concentrated. The residue was purified by preparative chromatography to give B-8 as a white solid (4.2g, 50%).

¹ H NMR(400MHz，DMSO-d ₆ )δ7.43(dt，J＝24.5，12.3Hz，2H)，7.26-7.11(m，4H)，6.95(t，J＝8.1Hz，1H)，2.59(d，J＝4.5Hz，3H).MS(ESI)m/z 288[M+H] ⁺ .

Intermediate example B-9:

lithium bis (trimethylsilyl) amide (1M/THF, 81mL, 81mmol) was dissolved in tetrahydrofuran (100 mL) and methyl phenoxyacetate (8.97g, 54mmol) was added slowly at-78 ℃. After stirring for 1 hour, B-2a (5g, 27mmol) was dissolved in tetrahydrofuran (50 mL) and slowly added dropwise to the reaction mixture at-78 ℃. The reaction solution was slowly warmed to room temperature and stirred for further reaction for 18 hours. After the reaction was completed, the reaction mixture was concentrated. The residue was purified by preparative chromatography to give B-9 (1.9g, 23%) as a white solid.

Intermediate example B-10:

step 1

B-10a (1g, 8.2mmol) and ethyl diazoacetate (1.87g, 16.4 mmol) were dissolved in dichloromethane (8 mL) and rhodium acetate (72mg, 0.16mmol) was added in portions under ice bath. The reaction mixture was stirred at room temperature for 12 hours, and after completion of the reaction, water (15 mL) was added thereto for quenching. Dichloromethane (10 ml × 2) was extracted, and the dichloromethane phase was washed with saturated brine, dried, filtered, and concentrated. The residue was purified by column chromatography to give B-10B (426mg, 25%).

¹ H NMR(400MHz，CDCl ₃ )δ4.22(q，J＝7.1Hz，2H)，4.08(s，2H)，3.58(d，J＝5.6Hz，2H)，2.74-2.56(m，2H)，2.44(dt，J＝14.3，8.9Hz，3H)，1.29(t，J＝7.1Hz，3H).

Step 2

Lithium bis (trimethylsilyl) amide (1M/THF, 2.3mL,2.3 mmol) was dissolved in tetrahydrofuran (3 mL) and B-10B (312mg, 1.5 mmol) was added slowly at 78 ℃. After stirring for 1 hour, B-1B (129mg, 0.75mmol) was dissolved in tetrahydrofuran (3 mL) and slowly added dropwise to the reaction solution at-78 ℃. The reaction solution was slowly warmed to room temperature, and the reaction was continued with stirring for 18 hours. After completion of the reaction, concentration was carried out, and the residue was purified by preparative chromatography to give B-10 (50mg, 21%) as a white solid.MS(ESI)m/z 316.1[M+H] ⁺ .

Intermediate example B-11:

step 1

B-11a (10g, 135mmol) was dissolved in tetrahydrofuran (200 mL), and sodium hydride (8.1g, 203mmol) was added in portions under ice bath. The reaction mixture was stirred for 2 hours, and ethyl bromoacetate (45g, 269mmol) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours. After completion of the reaction, quench with water (100 mL), add ethyl acetate (200ml x 3), dry the ethyl acetate phase, filter, and concentrate. The residue was purified by column chromatography to give B-11B (10g, 45%).

¹ H NMR(400MHz，DMSO-d ₆ )δ4.67-4.57(m，3H)，4.48-4.44(m，2H)，4.15-4.08(m，4H)，1.20(t，J＝7.2Hz，3H).

Step 2

Lithium bis (trimethylsilyl) amide (1M/THF, 8.7mL, 8.7mmol) was dissolved in tetrahydrofuran (8 mL) and B-11B (929mg, 5.8mmol) was added slowly at 78 ℃. After stirring for 1 hour, B-1B (500mg, 2.9mmol) was dissolved in tetrahydrofuran (5 mL) and slowly added dropwise to the reaction solution at-78 ℃. The reaction solution was slowly warmed to room temperature and stirred for further reaction for 18 hours. After completion of the reaction, the reaction was quenched by addition of 6M hydrochloric acid (3 mL), extracted with dichloromethane (50ml × 3), the dichloromethane phase was dried, filtered and concentrated. The residue was purified by preparative chromatography to give B-11 as a white solid (35mg, 5%). MS (ESI) m/z =268.1[ 2 ] M + H] ⁺ .

Intermediate example B-12:

step 1

B-12a (9g, 90mmol) was dissolved in tetrahydrofuran (200 mL) and sodium hydride (5.3g, 135mmol) was added slowly in portions under ice. After stirring for 2 hours, ethyl bromoacetate (29.4 g, 176mmol) was added slowly. The reaction solution was warmed to room temperatureThe reaction was stirred for an additional 12 hours. After completion of the reaction, water (250 mL) was added for quenching, and ethyl acetate (150ml × 2) was added for extraction. The ethyl acetate phase was dried, filtered and concentrated. The residue was purified by preparative chromatography to give B-12B (5.9g, 37%). ¹ H NMR(400MHz，CDCl ₃ )δ4.58(d，J＝5.8Hz，2H)，4.38(d，J＝5.8Hz，2H)，4.22(d，J＝7.0Hz，2H)，4.13(s，2H)，3.62(s，2H)，1.35(s，3H)，1.30(t，J＝8.1，6.2Hz，3H).

Step 2

Lithium bis (trimethylsilyl) amide (1M/THF, 3.9mL,3.9 mmol) was dissolved in tetrahydrofuran (4 mL) and B-12B (500mg, 2.6 mmol) was added slowly at 78 ℃. After stirring for 1 hour, B-1B (227mg, 1.3mmol) was dissolved in tetrahydrofuran (3 mL) and added dropwise slowly to the reaction mixture at-78 ℃. The reaction solution was slowly warmed to room temperature and stirred for further reaction for 18 hours. After completion of the reaction, concentration was carried out, and the residue was purified by preparative chromatography to give B-12 (30mg, 8%) as a white solid. MS (ESI) M/z296.1[ M + H ]] ⁺ .

Intermediate example B-13:

step 1

Ethylmercaptoacetate (3.78g, 31.5mmol) and potassium carbonate (4.55g, 33mmol) were dissolved in DMF (80 mL) and B-13a (5g, 33mmol) was added at room temperature. The reaction was stirred at room temperature for 2 hours. After completion of the reaction, water (30 mL) and ethyl acetate (25ml × 2) were added for extraction. The ethyl acetate phase was dried, filtered and concentrated. The residue was purified by preparative chromatography to give B-13B (3g, 57%).

¹ H NMR(400MHz，DMSO-d ₆ )δ4.16-4.05(m，2H)，3.98-3.87(m，1H)，3.80-3.64(m，2H)，3.55-3.43(m，2H)，3.41(s，2H)，2.31-2.13(m，1H)，1.71(dq，J＝7.5，5.9Hz，1H)，1.19(dt，J＝11.0，7.1Hz，3H).

Step 2

Lithium bis (trimethylsilyl) amide (1M/THF, 1.7mL, 1.7mmol) was dissolved in tetrahydrofuran (2 mL) and B-13B (220mg, 1.2mmol) was added slowly at 78 ℃. After stirring for 1 hour, B-1B (101mg, 0.59mmol) was dissolved in tetrahydrofuran (1 mL) and slowly added dropwise to the reaction at-78 ℃. The reaction solution was slowly warmed to room temperature and stirred for further reaction for 18 hours. After completion of the reaction, the reaction was quenched by addition of 6M hydrochloric acid (1 mL), extracted with dichloromethane (30ml × 2), and the dichloromethane phase was dried, filtered and concentrated. The residue was purified by preparative chromatography to give B-13 as a white solid (100mg, 57%).

¹ H NMR(400MHz，DMSO-d ₆ )δ13.02(s，1H)，7.55(s，1H)，4.24-4.02(m，2H)，3.89-3.74(m，2H)，3.65(dd，J＝8.7，3.6Hz，1H)，2.59(s，3H)，2.49-2.35(m，1H)，1.87(dt，J＝17.1，6.5Hz，1H).

Synthesis of intermediate B-14:

lithium bis (trimethylsilyl) amide (1M/THF, 8.1mL, 8.1mmol) was dissolved in tetrahydrofuran (6 mL), and B-13B (1g, 5.4 mmol) was added slowly at 78 ℃. After stirring for 1 hour, B-2a (500mg, 2.7 mmol) was dissolved in tetrahydrofuran (10 mL) and slowly added dropwise to the reaction mixture at-78 ℃. The reaction solution was slowly warmed to room temperature, and the reaction was continued with stirring for 18 hours. After completion of the reaction, it was quenched by addition of 6M hydrochloric acid (2 mL), extracted with dichloromethane (50ml × 2), and the dichloromethane phase was dried, filtered and concentrated. The residue was purified by preparative chromatography to give B-14 as a white solid (176mg, 11%). MS (ESI) m/z 312.1[ 2 ] M + H] ⁺ .

Intermediate examples B-15:

step 1

B-15a (10g, 116mmol) was dissolved in tetrahydrofuran (200 mL), and methylmagnesium bromide (46.5mL, 3mol/L) was added at 0 ℃. The reaction was stirred at this temperature for 1 hour. The reaction was quenched by addition of saturated ammonium chloride and extracted with ethyl acetate. The ethyl acetate phase was dried, filtered and concentrated. Column chromatography of the residue gave B-15B (5g, 41%) as a colorless liquid.

¹ H NMR(400MHz，CDCl ₃ )δ4.13-4.01(m，1H)，3.94-3.90(m，1H)，3.73(d，J＝9.2Hz，1H)，3.55(d，J＝9.2Hz，1H)，2.31-2.18(m，1H)，2.10-1.88(m，2H)，1.45(s，3H).

Step 2

Rhodium acetate (20mg, 0.045mmol) was added to a stirred solution of B-15B (3.2g, 31.3mmol) in methylene chloride (32 mL), and ethyl diazoacetate (3.57g, 31.3mmol) was slowly added dropwise and stirred at room temperature for 1 hour. Rhodium acetate (20mg, 0.045mmol) was added thereto, ethyl diazoacetate (1.8g, 169mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with brine, the organic phase was dried, filtered, concentrated, and the residue was subjected to column chromatography to give yellow liquid B-15c (2.3 g, 39%).

¹ H NMR(400MHz，CDCl ₃ )δ4.26(q，J＝7.1Hz，2H)，4.09(s，2H)，4.08-4.01(m，1H)，3.98-3.86(m，2H)，3.55(d，J＝9.6Hz，1H)，2.29-2.15(m，1H)，1.96-1.77(m，1H)，1.43(s，3H)，1.32(t，J＝7.2Hz，3H).

Step 3

To a solution of B-15c (504mg, 2.68mmol) in tetrahydrofuran (10 mL) was slowly added lithium bis (trimethylsilyl) amide (1M/THF, 4mL, 4mmol) dropwise with stirring at-78 ℃. The reaction was stirred for 2 hours. B-1B (230mg, 1.34mmol) was added at-78 ℃. The reaction was allowed to return to room temperature and continued for 16 hours. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate phase was washed with saturated brine, dried, filtered, concentrated, and the residue was subjected to column chromatography to give B-15 (120mg, 31%) as a white solid.

¹ H NMR(400MHz，CDCl ₃ )δ7.24(s，1H)，4.28(d，J＝10.0Hz，1H)，4.10(d，J＝8.6Hz，1H)，4.01-3.84(m，2H)，3.79(d，J＝10.0Hz，1H)，2.71(s，3H)，2.66-2.57(m，1H)，2.12(dt，J＝13.3，7.5Hz，1H)，1.72(s，3H).MS(ESI)m/z 296.2[M+H] ⁺ .

Intermediate examples B-16:

b15 (50mg, 0.15mmol) was dissolved in acetonitrile (5 mL), and cesium carbonate (150mg, 0.45mmol) and iodomethane (49mg, 0.35mmol) were added. The reaction was heated to 80 ℃ for 6 hours. Water (50 mL) was added, extracted with ethyl acetate (50ml × 2), the ethyl acetate phase was dried and concentrated to give crude B-16 (50mg, 96%). MS (ESI) m/z 310.3[ 2 ] M + H] ⁺ .

Intermediate examples B-17:

step 1

To a stirred solution of B-17a (5.5 g, 62.42mmol) in tetrahydrofuran (120 mL) at 0 deg.C was added sodium hydride (3 g,74.9mmol, 60%) and the mixture was allowed to return to room temperature and stirred for 2 hours. Ethyl bromoacetate (12.5g, 74.9 mmol) was added thereto at 0 ℃ and stirred at room temperature for 16 hours. Water (100 mL) was added and extraction was performed with ethyl acetate (100mL. Multidot.2). The ethyl acetate phase was dried, filtered and concentrated. Column chromatography of the residue gave B-17B (5.2g, 47%) as a yellow liquid.

¹ H NMR(400MHz，CDCl ₃ )δ4.70(d，J＝6.6Hz，2H)，4.39-4.30(m，2H)，4.19(d，J＝7.1Hz，2H)，4.03(s，2H)，1.54(s，3H)，1.26(t，J＝7.2Hz，3H).

Step 2

To a solution of B-17B (501mg, 2.82mmol) in tetrahydrofuran (10 mL) at-78 deg.C was added LiHMDS (4.3 mL, 1mol/L). The mixture was allowed to return to room temperature and stirred for 2 hours. Compound B-1B (242mg, 1.41mmol) was added at-78 deg.C. The reaction was slowly returned to room temperature for 16 hours. The reaction was quenched by addition of saturated ammonium chloride and extracted with ethyl acetate. The ethyl acetate phase was dried, filtered, concentrated, and the residue was isolated by column chromatography to give B-17 (200mg, 45%) as a white solid.

¹ H NMR(400MHz，CDCl ₃ )δ10.30(s，1H)，6.75(s，1H)，5.03(d，J＝6.8Hz，2H)，4.62(d，J＝7.0Hz，2H)，2.72(s，3H)，1.83(s，3H).MS(ESI)m/z 282.2[M+H] ⁺ .

Intermediate examples B-18:

LiHMDS (11.7mL, 1mol/L) was added to a solution of B-17B (1.34g, 7.8mmol) in tetrahydrofuran (10 mL) at-78 ℃ and stirred for 2 h. Compound B-2a (737mg, 3.9 mmol) was added at-78 deg.C. The reaction was slowly returned to room temperature for 16 hours. The reaction was quenched by addition of saturated ammonium chloride and extracted with ethyl acetate. The ethyl acetate phase was dried, filtered, concentrated, and the residue was isolated by column chromatography to give B-18 (295mg, 26%) as a white solid.

¹ H NMR(400MHz，DMSO-d ₆ )δ6.73(s，1H)，4.82(d，J＝7.0Hz，2H)，4.61(d，J＝7.3Hz，2H)，3.65(s，3H)，2.65(s，3H)，1.71(s，3H).MS(ESI)m/z 296.0[M+H] ⁺ .

Synthesis of intermediate B-19:

step 1

B-19a (900mg, 8.5 mmol) was dissolved in tetrahydrofuran (20 mL), and sodium hydride (510mg, 12.7 mmol) was added slowly in portions under ice bath. After stirring the reaction for 2 hours, ethyl bromoacetate (2.8g, 17mmol) was slowly added. The reaction solution was warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction mixture was quenched by addition of water (30 mL) and extracted by addition of ethyl acetate (20mL. Multidot.2). The ethyl acetate phase was dried, filtered and concentrated. The residue was purified by preparative chromatography to give B-19B (902mg, 55%).

¹ H NMR(400MHz，CDCl ₃ )δ4.93-4.72(m，2H)，4.72-4.58(m，2H)，4.23(q，J＝7.1Hz，2H)，4.18(s，2H)，3.95(d，J＝21.0Hz，2H)，1.29(t，J＝7.0Hz，3H).

Step 2

Lithium bis (trimethylsilyl) amide (1M/THF, 5.5mL,5.5 mmol) was dissolved in tetrahydrofuran (3 mL) and B-19B (700mg, 3.6 mmol) was added slowly at-78 ℃. Stirring for 1 hourThen, a solution of B-1B (312mg, 1.8mmol) in tetrahydrofuran (3 mL) was slowly added dropwise to the reaction solution at-78 ℃. The reaction solution was slowly warmed to room temperature and stirred for further reaction for 18 hours. After completion of the reaction, concentration was carried out, and the residue was purified by preparative chromatography to give B-19 (100mg, 18%) as a white solid. MS (ESI) m/z 300.0[ 2 ], [ M + H ]] ⁺ .

Example I-1:

dissolve A-1 (1 eq) and B-1 (1.1 eq) in N-butanol (2 mL) and add N, N-diisopropylethylamine (10 eq). The reaction solution was heated to 120 ℃ and stirred for reaction for 16 hours. After completion of the reaction, the solvent was spun dry and the residue was purified by column chromatography (dichloromethane: methanol = 100: 1 to 10: 1) to give I-1 (50mg, 64%) as a white solid.

¹ H NMR(400MHz，DMSO-d ₆ )δ12.09(s，1H)，7.95(d，J＝7.2Hz，1H)，7.66-7.59(m，2H)，7.50(t，J＝7.0Hz，1H)，7.38-7.09(m，2H)，5.77-5.68(m，1H)，5.09(s，1H)，3.97-3.76(m，4H)，2.34-2.26(m，1H)，2.26-2.23(m，3H)，2.06-1.95(m，1H)，1.57(d，J＝7.1Hz，3H).

MS(ESI)m/z 435.2[M+H] ⁺ .

Example I-2:

referring to the preparation method of example I-1, starting from A-2 and B-1, I-2 (5mg, 9%) was obtained.

¹ H NMR(400MHz，DMSO-d ₆ )δ12.12(s，1H)，8.05(d，J＝7.0Hz，1H)，7.79(t，J＝7.1Hz，1H)，7.70-7.62(m，2H)，7.40(t，J＝7.7Hz，1H)，5.75-5.66(m，1H)，5.13(s，1H)，3.97(dd，J＝10.2，4.4Hz，1H)，3.92-3.78(m，3H)，2.38-2.28(m，1H)，2.25(s，3H)，2.09-2.00(m，1H)，1.62(d，J＝7.1Hz，3H).

MS(ESI)m/z 453.3[M+H] ⁺ .

Example I-3:

by the preparation method of reference example I-1, using A-3 and B-1 as starting materials, I-3 (5mg, 10%) was obtained.

¹ H NMR(400MHz，DMSO-d ₆ )δ12.09(s，1H)，7.96(d，J＝7.2Hz，1H)，7.62-7.56(m，2H)，7.43(t，J＝7.4Hz，1H)，7.26(t，J＝7.6Hz，1H)，5.75-5.67(m，1H)，5.10(s，1H)，3.94(dd，J＝10.1，4.3Hz，1H)，3.90-3.76(m，3H)，2.30(dd，J＝13.6，7.0Hz，1H)，2.24(s，3H)，2.08-1.96(m，4H)，1.56(d，J＝7.0Hz，3H).

MS(ESI)m/z 449.2[M+H] ⁺ .

Example I-4:

referring to the preparation method of example I-1, I-4 (320mg, 94%) was obtained using A-4 and B-1 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ12.15(s，1H)，8.59(s，1H)，8.38(s，1H)，8.32(s，1H)，8.06(d，J＝7.3Hz，1H)，7.57(s，1H)，5.70-5.63(m，1H)，5.13(t，J＝5.5Hz，1H)，3.99-3.80(m，4H)，2.37-2.31(m，1H)，2.30(s，3H)，2.09-2.02(m，1H)，1.67(d，J＝7.1Hz，3H).

MS(ESI)m/z 480.7[M+H] ⁺ .

Example I-5:

referring to the preparation method of example I-1, starting from A-5 and B-1, I-5 (5mg, 8%) was obtained.

¹ H NMR(400MHz，DMSO-d ₆ )δ12.10(s，1H)，7.88(d，J＝7.9Hz，1H)，7.61(s，1H)，6.86(d，J＝12.8Hz，2H)，6.73(s，1H)，5.35(d，J＝5.1Hz，1H)，5.12-5.08(m，1H)，3.98-3.81(m，4H)，3.60(d，J＝4.5Hz，2H)，2.35-2.24(m，5H)，1.55(d，J＝7.0Hz，3H).

MS(ESI)m/z 450.2[M+H] ⁺ .

Examples I to 6:

referring to the preparation method of example I-1, I-6 (30mg, 36%) was obtained using A-6 and B-1 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ12.02(s，1H)，7.81(s，1H)，7.61(s，1H)，6.72-6.67(m，1H)，6.57(dd，J＝5.8，2.8Hz，1H)，5.62(t，J＝7.1Hz，1H)，5.17(s，2H)，5.11(s，1H)，3.93(dd，J＝10.2，4.5Hz，1H)，3.89-3.83(m，1H)，3.83-3.75(m，2H)，2.31-2.19(m，4H)，2.07-2.00(m，1H)，1.95(t，J＝19.0Hz，3H)，1.50(d，J＝7.0Hz，3H).

MS(ESI)m/z 464.2[M+H] ⁺ .

Example I-7:

referring to the preparation method of example I-1, I-7 (12mg, 14%) was obtained using A-7 and B-1 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ12.11(s，1H)，8.12(d，J＝5.9Hz，1H)，7.98(dd，J＝18.9，5.8Hz，2H)，7.62-7.57(m，1H)，5.66(q，J＝7.0Hz，1H)，5.14(s，1H)，4.03-3.78(m，4H)，2.34-2.23(m，4H)，2.16-1.98(m，4H)，1.62(d，J＝7.1Hz，3H).

Examples I to 8:

referring to the preparation method of example I-1, I-8 (40mg, 45%) was obtained using A-8 and B-1 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ12.11(s，1H)，8.17(d，J＝8.3Hz，2H)，8.03(d，J＝7.0Hz，1H)，7.99(d，J＝6.3Hz，1H)，7.62(s，1H)，7.51(s，1H)，5.72(p，J＝6.9Hz，1H)，5.13(t，J＝5.2Hz，1H)，4.01-3.80(m，4H)，2.27(s，4H)，2.08(t，J＝19.1Hz，4H)，1.61(d，J＝7.0Hz，3H).

MS(ESI)m/z 492.3[M+H] ⁺ .

Examples I to 9:

referring to the preparation method of example I-1, I-9 (110mg, 47%) was obtained using A-9 and B-1 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ12.05(s，1H)，7.95(d，J＝7.2Hz，1H)，7.58(s，2H)，7.49-7.33(m，2H)，5.50(p，J＝7.0Hz，1H)，5.10(s，1H)，4.03-3.67(m，4H)，3.31-3.20(m，1H)，3.11(d，J＝16.8Hz，1H)，2.63(td，J＝14.4，7.1Hz，2H)，2.34-2.19(m，4H)，2.00(dd，J＝12.7，6.2Hz，1H)，1.56(d，J＝7.0Hz，3H).MS(ESI)m/z＝443.1[M+H] ⁺ .

Examples I to 10:

the method comprises the following steps:

a-10 (20mg, 0.085mmol) and B-1 (24mg, 0.085mmol) were dissolved in N-butanol (2 mL), and N, N-diisopropylethylamine (110mg, 0.85mmol) was added. The reaction solution was heated to 120 ℃ and stirred to react for 16 hours. After completion of the reaction, the solvent was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain I-10 (10mg, 26%) as a white solid.

¹ H NMR(400MHz，DMSO-d ₆ )δ12.06(s，1H)，7.85(d，J＝7.7Hz，1H)，7.61(s，1H)，7.52(dd，J＝12.4，7.7Hz，2H)，7.10(t，J＝7.6Hz，1H)，5.67(t，J＝7.2Hz，1H)，5.10(s，1H)，4.86(t，J＝16.7Hz，2H)，3.99-3.71(m，4H)，2.25(d，J＝10.7Hz，3H)，2.06-1.93(m，2H)，1.55(d，J＝7.0Hz，3H).

MS(ESI)m/z 445.2[M+H] ⁺ .

Example I-11:

the method comprises the following steps:

i-11 (21mg, 54%) was obtained by the preparation method of example I-1 using A-10 and B-2 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ7.91(d，J＝7.5Hz，1H)，7.67(s，1H)，7.52(dd，J＝10.3，7.8Hz，2H)，7.09(t，J＝7.6Hz，1H)，5.69(p，J＝6.8Hz，1H)，5.13(dd，J＝6.0，4.5Hz，1H)，4.86(t，J＝16.7Hz，2H)，3.97-3.75(m，4H)，3.57(s，3H)，2.32(d，J＝10.1Hz，3H)，2.29-2.14(m，1H)，2.08-2.01(m，1H)，1.57(d，J＝7.0Hz，3H).

MS(ESI)m/z 459.2[M+H] ⁺ .

Examples I to 12:

the procedure of example I-1 was followed, using A-11 and B-1 as starting materials, to give I-12 (10mg, 49%).

¹ H NMR(400MHz，DMSO-d ₆ )δ12.09(s，1H)，7.95(d，J＝7.3Hz，1H)，7.71-7.63(m，2H)，7.61(s，1H)，7.28(t，J＝7.7Hz，1H)，5.75(p，J＝7.1Hz，1H)，5.13-5.08(m，1H)，3.97-3.77(m，4H)，2.60(d，J＝4.0Hz，3H)，2.34-2.26(m，1H)，2.26(s，3H)，2.06-1.98(m，1H)，1.58(d，J＝7.1Hz，3H).

MS(ESI)m/z 427.3[M+H] ⁺ .

Examples I to 13:

referring to the preparation method of example I-1, I-13 (150mg, 74%) was obtained using A-6 and B-2 as starting materials. ¹ H NMR(400MHz，DMSO-d ₆ )δ7.89(d，J＝7.4Hz，1H)，7.69(s，1H)，6.66(s，1H)，6.58(d，J＝6.0Hz，1H)，5.63(t，J＝7.2Hz，1H)，5.15(s，3H)，4.00-3.75(m，4H)，3.57(s，3H)，2.34(s，3H)，2.32-2.21(m，1H)，2.03(d，J＝25.5Hz，1H)，1.95(t，J＝19.0Hz，3H)，1.52(d，J＝7.0Hz，3H).MS(ESI)m/z＝478.3[M+H] ⁺ .

Examples I to 14:

referring to the preparation method of example I-1, I-14 (140mg, 71%) was obtained using A-6 and B-3 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ7.89(d，J＝7.4Hz，1H)，7.66(s，1H)，6.65(dd，J＝5.7，2.6Hz，1H)，6.58(dd，J＝5.9，2.8Hz，1H)，5.63(p，J＝7.1Hz，1H)，5.15(s，2H)，5.13(d，J＝4.6Hz，1H)，4.38-4.28(m，2H)，3.95(dd，J＝10.2，4.5Hz，1H)，3.89(dd，J＝15.4，8.0Hz，1H)，3.85-3.76(m，2H)，2.34(s，3H)，2.28(dd，J＝14.1，7.9Hz，1H)，2.04(dd，J＝13.2，6.6Hz，1H)，1.95(t，J＝19.0Hz，3H)，1.52(d，J＝7.0Hz，3H)，1.14(t，J＝7.0Hz，3H).MS(ESI)m/z 492.3[M+H] ⁺ .

Examples I to 15:

referring to the preparation method of example I-1, starting from A-6 and B-4, I-15 (8.8mg, 16%) was obtained.

¹ H NMR(400MHz，DMSO-d ₆ )δ8.02(d，J＝7.1Hz，1H)，7.74(s，1H)，6.67(s，1H)，6.58(d，J＝3.5Hz，1H)，5.69-5.56(m，1H)，5.15(d，J＝6.5Hz，3H)，5.14(s，2H)，3.95(dt，J＝9.2，4.8Hz，1H)，3.91-3.75(m，3H)，2.36-2.27(m，4H)，2.13-2.01(m，1H)，1.95(t，J＝19.0Hz，3H)，1.53(d，J＝6.9Hz，3H).MS(ESI)m/z 546.2[M+H] ⁺ .

Examples I to 16:

referring to the preparation method of example I-1, I-16 (100mg, 44%) was obtained using A-6 and B-5 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ12.06(s，1H)，7.85(d，J＝7.4Hz，1H)，7.70(d，J＝4.4Hz，1H)，6.68-6.63(m，1H)，6.58(dd，J＝6.2，2.4Hz，1H)，5.66-5.57(m，1H)，5.15(s，2H)，5.12-5.04(m，1H)，3.61(dd，J＝12.3，4.4Hz，1H)，3.50-3.35(m，3H)，2.27(s，3H)，2.19-2.05(m，2H)，1.95(t，J＝18.9Hz，4H)，1.51(d，J＝7.0Hz，3H)，1.42(s，9H).

MS(ESI)m/z 563.3[M+H] ⁺ .

Examples I to 17:

i-16 (80mg, 0.14mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was concentrated, and aqueous sodium bicarbonate and ethyl acetate (10ml × 2) were added for extraction, and the ethyl acetate phase was dried, concentrated, and purified by column chromatography to obtain I-17 (48mg, 75%) as a white solid.

¹ H NMR(400MHz，DMSO-d ₆ )δ7.84(d，J＝7.3Hz，1H)，7.58(s，1H)，6.66(s，1H)，6.60-6.55(m，1H)，5.62(t，J＝7.1Hz，1H)，5.15(s，2H)，4.93(s，1H)，3.15(dd，J＝12.2，5.3Hz，1H)，2.94(d，J＝10.0Hz，1H)，2.85(d，J＝12.2Hz，2H)，2.26(s，3H)，2.09(dd，J＝13.3，7.1Hz，1H)，1.95(t，J＝19.0Hz，3H)，1.83(s，1H)，1.51(d，J＝7.0Hz，3H).MS(ESI)m/z 463.2[M+H] ⁺ .

Examples I to 18:

by the preparation method of example I-1, starting from A-6 and B-7, I-18 (8.5mg, 21%) was obtained.

¹ H NMR(400MHz，DMSO-d ₆ )δ7.67(s，2H)，6.69(s，1H)，6.56(d，J＝3.1Hz，1H)，5.71-5.54(m，1H)，5.13(d，J＝23.4Hz，3H)，3.56(dd，J＝14.7，7.9Hz，3H)，2.23(s，3H)，1.95(t，J＝19.2Hz，8H)，1.49(d，J＝6.6Hz，3H).MS(ESI)m/z 505.2[M+H] ⁺ .

Examples I to 19:

referring to the preparation method of example I-1, I-19 (49mg, 61%) was obtained using A-12 and B-1 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ12.06(s，1H)，8.04(d，J＝7.0Hz，1H)，7.75(d，J＝7.8Hz，1H)，7.63(s，1H)，7.56(d，J＝7.8Hz，1H)，7.40(t，J＝7.8Hz，1H)，5.69(p，J＝7.0Hz，1H)，5.18-5.09(m，1H)，4.02-3.78(m，4H)，2.62(s，3H)，2.38-2.24(m，4H)，2.10-1.99(m，1H)，1.55(d，J＝7.0Hz，3H).

Examples I to 20:

referring to the preparation of example I-1, starting from A-1 and B-10, I-20 (18mg, 24%) was obtained.

¹ H NMR(400MHz，DMSO-d ₆ )δ12.78-10.90(m，1H)，7.89(s，1H)，7.66(t，J＝7.3Hz，1H)，7.60(s，1H)，7.49(t，J＝6.8Hz，1H)，7.26(dt，J＝73.6，37.0Hz，2H)，5.73(t，J＝7.0Hz，1H)，4.07(d，J＝6.4Hz，2H)，2.87-2.68(m，2H)，2.67-2.54(m，2H)，2.47-2.39(m，1H)，2.23(s，3H)，1.57(d，J＝7.1Hz，3H).MS(ESI)m/z 469.1[M+H] ⁺ .

Examples I to 21:

referring to the preparation method of example I-1, I-21 (68mg, 49%) was obtained using A-2 and B-2 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ8.03(d，J＝6.8Hz，1H)，7.75(t，J＝7.1Hz，1H)，7.69-7.57(m，2H)，7.37(t，J＝7.8Hz，1H)，5.70(t，J＝7.1Hz，1H)，5.13(s，1H)，4.01-3.89(m，1H)，3.83(ddd，J＝12.9，11.9，5.9Hz，3H)，3.56(s，3H)，2.30(s，3H)，2.28-2.22(m，1H)，2.11-1.98(m，1H)，1.60(d，J＝7.1Hz，3H).MS(ESI)m/z 467.1[M+H] ⁺

Examples I to 22:

referring to the preparation method of example I-1, I-22 (82mg, 49%) was obtained using A-3 and B-2 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ7.99(d，J＝7.2Hz，1H)，7.66(s，1H)，7.58(t，J＝7.0Hz，1H)，7.43(t，J＝6.9Hz，1H)，7.25(t，J＝7.7Hz，1H)，5.80-5.66(m，1H)，5.14(s，1H)，3.95(dd，J＝10.2，4.5Hz，1H)，3.83(ddd，J＝12.9，12.0，6.0Hz，3H)，3.56(s，3H)，2.31(d，J＝7.0Hz，3H)，2.27(dd，J＝14.1，7.8Hz，1H)，2.03(dd，J＝23.7，14.4Hz，4H)，1.58(d，J＝7.1Hz，3H).MS(ESI)m/z 463.1[M+H] ⁺ .

Examples I to 23:

referring to the preparation method of example I-1, I-23 (86mg, 56%) was obtained using A-1 and B-2 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ7.99(d，J＝7.3Hz，1H)，7.74-7.58(m，2H)，7.50(t，J＝6.6Hz，1H)，7.27(dt，J＝73.4，37.2Hz，2H)，5.84-5.58(m，1H)，5.13(s，1H)，4.02-3.75(m，4H)，3.56(s，3H)，2.35-2.21(m，4H)，2.11-1.97(m，1H)，1.59(d，J＝7.1Hz，3H).MS(ESI)m/z＝449.1[M+H] ⁺ .

Examples I to 24:

referring to the preparation method of example I-1, I-24 (84mg, 55%) was obtained using A-9 and B-2 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ8.00(d，J＝7.3Hz，1H)，7.64(s，1H)，7.58(dd，J＝8.3，6.0Hz，1H)，7.45-7.27(m，2H)，5.52(p，J＝6.9Hz，1H)，5.12(dd，J＝6.0，4.5Hz，1H)，4.01-3.76(m，4H)，3.55(s，3H)，3.36(dd，J＝5.6，3.2Hz，1H)，3.11(d，J＝16.0Hz，1H)，2.62(ddd，J＝21.6，14.4，7.0Hz，2H)，2.31(d，J＝12.9Hz，3H)，2.30-2.14(m，1H)，2.09-1.94(m，1H)，1.57(d，J＝7.0Hz，3H).MS(ESI)m/z＝457.2[M+H] ⁺ .

Examples I to 25:

referring to the preparation method of example I-1, I-25 was obtained using A-1 and B-11 as starting materials.

MS(ESI)m/z＝421.2[M+H] ⁺ 。

Examples I to 26:

by referring to the production method of example I-1, I-26 (11mg, 24%) was obtained using A-1 and B-12 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ11.94(s，1H)，7.97(d，J＝7.2Hz，1H)，7.75-7.60(m，2H)，7.50(t，J＝6.9Hz，1H)，7.27(dt，J＝75.9，36.0Hz，2H)，5.74(dd，J＝8.7，5.6Hz，1H)，4.53(d，J＝5.8Hz，2H)，4.34(d，J＝5.8Hz，2H)，4.11(q，J＝9.7Hz，2H)，2.25(s，3H)，1.58(d，J＝7.1Hz，3H)，1.41(s，3H).MS(ESI)m/z 449.1[M+H] ⁺ .

Examples I to 27:

referring to the preparation method of example I-1, I-27 (35mg, 47%) was obtained using A-1 and B-13 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ12.13(s，1H)，8.24(d，J＝6.6Hz，1H)，8.20(s，1H)，7.65(t，J＝7.1Hz，1H)，7.50(t，J＝6.9Hz，1H)，7.27(dt，J＝76.4，35.7Hz，2H)，5.74(t，J＝7.1Hz，1H)，4.14(d，J＝8.9Hz，1H)，4.12-4.03(m，1H)，3.87-3.72(m，2H)，3.53(ddd，J＝8.8，4.6，1.8Hz，1H)，2.47-2.32(m，1H)，2.26(s，3H)，1.80(dt，J＝12.9，6.5Hz，1H)，1.57(d，J＝7.1Hz，3H).MS(ESI)m/z451.2[M+H] ⁺ .

Examples I to 28:

referring to the preparation method of example I-1, I-28 (30mg, 40%) was obtained using A-12 and B-15 as starting materials.

¹ H NMR(400MHz，Methanol-d ₄ )δ7.80(d，J＝1.2Hz，1H)，7.69(d，J＝7.9Hz，1H)，7.55(d，J＝7.7Hz，1H)，7.33(t，J＝7.9Hz，1H)，5.78(dd，J＝7.0，2.3Hz，1H)，4.29(d，J＝9.7Hz，1H)，4.11(q，J＝7.9Hz，1H)，4.00-3.96(m，1H)，3.72(d，J＝9.7Hz，1H)，2.66(s，3H)，2.59(d，J＝6.5Hz，1H)，2.36(s，3H)，2.12(dt，J＝13.3，8.4Hz，1H)，1.62(d，J＝7.2Hz，6H).MS(ESI)m/z 463.3[M+H] ⁺ .

Examples I to 29:

referring to the preparation method of example I-1, I-29 was obtained using A-12 and B-17 as starting materials.

MS(ESI)m/z 449.2[M+H] ⁺ .

Examples I to 30:

referring to the preparation method of example I-1, I-30 (10 mg, 10%) was obtained using A-1 and B-14 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ8.37-8.32(m，1H)，8.25(s，1H)，7.65(t，J＝7.4Hz，1H)，7.50(t，J＝6.9Hz，1H)，7.38-7.09(m，2H)，5.80-5.72(m，1H)，4.15(q，J＝11.5，9.0Hz，2H)，3.86-3.79(m，2H)，3.57(s，3H)，2.33(s，3H)，2.04-1.95(m，1H)，1.80(t，J＝6.7Hz，1H)，1.59(d，J＝7.1Hz，3H).

MS(ESI)m/z 465.1[M+H] ⁺ .

Examples I to 31:

by the preparation method of example I-1, starting from A-10 and B-18, I-31 (1.5mg, 1.3%) was obtained.

¹ H NMR(400MHz，DMSO-d ₆ )δ7.98(d，J＝7.6Hz，1H)，7.75(s，1H)，7.51(dd，J＝11.8，7.6Hz，2H)，7.09(t，J＝7.6Hz，1H)，5.67(p，J＝6.7Hz，1H)，4.84(dd，J＝29.5，12.1Hz，4H)，4.49(d，J＝6.9Hz，2H)，3.57(s，3H)，2.33(s，3H)，1.57(d，J＝11.0Hz，3H)，1.54(d，J＝7.0Hz，3H).MS(ESI)m/z＝459.1[M+H] ⁺

Examples I to 32:

referring to the preparation method of example I-1, I-32 (13mg, 29%) was obtained using A-1 and B-19 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ12.08(s，1H)，7.93(s，1H)，7.75(s，1H)，7.65(t，J＝7.7Hz，1H)，7.50(t，J＝6.7Hz，1H)，7.26(dt，J＝76.9，35.4Hz，2H)，5.73(t，J＝7.2Hz，1H)，4.85-4.63(m，4H)，4.46(d，J＝20.7Hz，2H)，2.25(s，3H)，1.57(d，J＝7.0Hz，3H).MS(ESI)m/z 453.1[M+H] ⁺

Examples I to 33:

referring to the preparation method of example I-1, I-33 was obtained using A-14 and B-1 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ12.05(s，1H)，8.31(d，J＝4.3Hz，1H)，7.97(d，J＝7.7Hz，1H)，7.63(s，1H)，7.56(d，J＝7.7Hz，1H)，7.42(d，J＝7.3Hz，1H)，7.32(t，J＝7.6Hz，1H)，6.01(p，J＝7.1Hz，1H)，5.13-5.08(m，1H)，3.94(dd，J＝10.2，4.5Hz，1H)，3.89-3.77(m，3H)，2.31-2.26(m，1H)，2.23(s，3H)，2.06-1.98(m，1H)，1.66(d，J＝7.1Hz，3H).MS(ESI)m/z 425.2[M+H] ⁺ .

Examples I to 34:

referring to the preparation method of example I-1, I-34 (27mg, 31%) was obtained using A-13 and B-1 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ12.05(s，1H)，7.92(d，J＝7.6Hz，1H)，7.61(s，1H)，7.54(d，J＝6.0Hz，1H)，7.31(t，J＝6.6Hz，1H)，7.23(t，J＝7.8Hz，1H)，5.72(t，J＝7.1Hz，1H)，5.10(s，1H)，4.12-3.67(m，4H)，2.38-2.17(m，5H)，2.03(s，1H)，1.55(d，J＝7.0Hz，3H)，1.19(t，J＝15.7Hz，6H).MS(ESI)m/z＝493.1[M+H] ⁺ .

Examples I to 35:

by referring to the production method of example I-1, I-35 (11mg, 16%) was obtained using A-1 and B-15 as starting materials.

¹ H NMR(400MHz，Methanol-d ₄ )δ7.81(s，1H)，7.61(t，J＝7.5Hz，1H)，7.50(t，J＝7.2Hz，1H)，7.27(t，J＝7.7Hz，1H)，7.04(t，J＝54.9Hz，1H)，5.81(d，J＝6.8Hz，1H)，4.29(d，J＝9.8Hz，1H)，4.12(q，J＝7.9Hz，1H)，3.99-3.90(m，1H)，3.73(d，J＝9.7Hz，1H)，2.65-2.54(m，1H)，2.36(s，3H)，2.16-2.04(m，1H)，1.68(d，J＝7.1Hz，3H)，1.64(s，3H).MS(ESI)m/z 449.2[M+H] ⁺ .

Examples I to 36:

referring to the preparation method of example I-1, I-36 (9 mg, 13%) was obtained using A-9 and B-15 as starting materials.

¹ H NMR(400MHz，Methanol-d ₄ )δ7.78(d，J＝1.4Hz，1H)，7.58(d，J＝7.0Hz，1H)，7.43-7.29(m，2H)，5.61(dt，J＝8.0，4.0Hz，1H)，4.28(d，J＝9.8Hz，1H)，4.15-4.07(m，1H)，3.98(dt，J＝8.4，4.2Hz，1H)，3.72(d，J＝9.8Hz，1H)，3.58-3.39(m，1H)，3.17-3.13(m，1H)，2.69-2.54(m，3H)，2.37(s，3H)，2.17-2.04(m，1H)，1.65(d，J＝7.1Hz，3H)，1.62(s，3H).MS(ESI)m/z 457.2[M+H] ⁺ .

Examples I-37:

referring to the preparation method of example I-1, I-37 was obtained using A-1 and B-16 as starting materials.

MS(ESI)m/z 463.2[M+H] ⁺ .

Examples I to 38:

referring to the preparation method of example I-1, I-38 (10mg, 20%) was obtained using A-9 and B-16 as starting materials.

¹ H NMR(400 MHz，Methanol-d ₄ )δ7.80(d，J＝1.3Hz，1H)，7.58(d，J＝7.2Hz，1H)，7.43-7.27(m，2H)，5.62(dd，J＝7.1，2.1Hz，1H)，4.28(d，J＝9.7Hz，1H)，4.15-4.05(m，1H)，3.99-3.91(m，1H)，3.74(s，3H)，3.71(d，J＝9.7Hz，1H)，3.45-3.39(m，1H)，3.19-3.10(m，1H)，2.67-2.51(m，3H)，2.42(s，3H)，2.13-2.06(m，1H)，1.65(d，J＝7.0Hz，3H)，1.61(s，3H)。MS(ESI)m/z 471.3[M+H] ⁺

Examples I to 39:

referring to the preparation method of example I-1, I-39 (1.52mg, 2%) was obtained using A-1 and B-18 as starting materials.

¹ H NMR(400MHz，DMSO-d ₆ )δ8.07(d，J＝7.2Hz，1H)，7.75(s，1H)，7.64(t，J＝7.2Hz，1H)，7.49(d，J＝6.6Hz，1H)，7.27(dt，J＝74.1，36.8Hz，2H)，5.79-5.67(m，1H)，4.81(d，J＝6.1Hz，2H)，4.49(d，J＝6.9Hz，2H)，3.56(s，3H)，2.33(s，3H)，1.63-1.53(m，6H).MS(ESI)m/z 449.1[M+H] ⁺ .

Biological assay

Experimental example 1.

The test was performed using the KRAS-G12C/SOS1 binding assay kit (Cisbio #63ADK000CB16 PEG). The initial concentration of test compound was set at 10. Mu.M (0.5% DMSO), diluted 1: 10, and 7 concentration gradients were set, 2 wells per concentration. A white 384-well plate (Comming # 3572) was used, and 2. Mu.L of the test compound, 4. Mu.L of SOS1, 4. Mu.L of KRAS-G12C protein (diluted 100-fold with dilution buffer according to the assay kit instructions) were added to each well and incubated at room temperature for 15min. mu.L of anti-Tag1-Tb (diluted 100 times with assay buffer as specified in the assay kit) and 5. Mu.L of anti-Tag2-XL665 (diluted 25 times with assay buffer as specified in the assay kit) were added, and the mixture was incubated at 4 ℃ for 3 hours to determine TRF (620nm, 665nm, delayed by 100us, integrated by 200 us). And simultaneously setting a negative control hole without adding KRAS-G12C protein and a positive control hole without adding the compound.

IC ₅₀ Data processing: statistical compound treatment group RFU665/RFU620 ratio, using GraphPad Prism 7.0 software, using nonlinear regression model to draw sigmoidal dose-inhibition curves, fitting and calculating IC ₅₀ The value is obtained.

The results are shown in the table below.

Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference (including all patents, patent applications, journal articles, books, and any other publications) cited in this application is hereby incorporated by reference in its entirety.

Claims

1. A compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein the compound has the structure of formula (I):

wherein:

ring A is C _6-10 An aromatic or 5-14 membered heteroaromatic ring;

R ¹ Each occurrence is independently selected from halogen, -OH, -NH ₂ 、-CN、-NO ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-to 10-membered heterocyclic group, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 Aralkyl, -C (= O) R ^a 、-OC(＝O)R ^a 、-C(＝O)OR ^a 、-OR ^a 、-SR ^a 、-S(＝O)R ^a 、-S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^a R ^b 、-NR ^a R ^b 、-C(＝O)NR ^a R ^b 、-NR ^a -C(＝O)R ^b 、-NR ^a -C(＝O)OR ^b 、-NRa-S(＝O) ₂ -R ^b 、-NR ^a -C(＝O)-NR ^a R ^b 、-C _1-6 alkylene-OR ^a 、-C _1-6 alkylene-NR ^a R ^b and-O-C _1-6 alkylene-NR ^a R ^b ；

Or R ⁴ And R ^4’ Together with the carbon atom to which they are attached

The condition is that at this time point,

represents a single bond;

m is an integer of 0, 1,2 or 3;

n is an integer of 0, 1,2, 3 or 4;

the above alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, hydrocarbon ring, heterocyclyl, heterocycle, aryl ring, heteroaryl ring, and aralkyl group, at each occurrence, are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OH, = O, -NH ₂ 、-CN、-NO ₂ 、C _1-6 Alkyl radical, C _3-6 Cycloalkyl, 3-to 10-membered heterocyclic group, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 Aralkyl, -C (= O) R ^5’ 、-OC(＝O)R ^5’ 、-C(＝O)OR ^5’ 、-OR ^5’ 、-SR ^5’ 、-S(＝O)R ^5’ 、-S(＝O) ₂ R ^5’ 、-S(＝O) ₂ NR ^5’ R ⁶ 、-NR ^5’ R ⁶ 、-C(＝O)NR ^5’ R ⁶ 、-NR ^5’ -C(＝O)R ⁶ 、-NR ^5’ -C(＝O)OR ⁶ 、-NR ^5’ -S(＝O) ₂ -R ⁶ 、-NR ^5’ -C(＝O)-NR ^5’ R ⁶ 、-C _1-6 alkylene-OR ^5’ 、-C _1-6 alkylene-NR ^5’ R ⁶ and-O-C _1-6 alkylene-NR ^5’ R ⁶ Said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are further optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OH, = O, -C (= O) O-tert-butyl, -NH ₂ 、-CN、-NO ₂ 、C _1-6 Alkyl radical, C _3-6 Cycloalkyl, 3-to 10-membered heterocyclic group, C _6-10 Aryl, 5-14 membered heteroaryl and C _6-12 Aralkyl group; and is provided with

R ^5’ And R ⁶ At each occurrence is independently selected fromH、C _1-6 Alkyl radical, C _3-10 Cycloalkyl, 3-to 10-membered heterocyclic group, C _6-10 Aryl, 5-14 membered heteroaryl and C _6-12 An aralkyl group.

2. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein said compound has the structure of formula (II), (III) or (IV):

3. the compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein ring a is a phenyl ring or a pyridine ring, preferably a phenyl ring.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein L is-O- (CH) ₂ ) _m -, preferably-O-or-O-CH ₂ -。

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R is ¹ Independently at each occurrence is selected from halogen, -OH, -NH ₂ 、-CN、-NO ₂ 、C _1-6 Alkyl radical, C _3-6 Cycloalkyl, 3-to 10-membered heterocyclyl, -C (= O) R ^a 、-C(＝O)OR ^a 、-OR ^a 、-S(＝O) ₂ R ^a 、-NR ^a R ^b 、-C(＝O)NR ^a R ^b and-C _1-6 alkylene-OR ^a (ii) a The above alkyl, alkylene, cycloalkyl and heterocyclyl groups are each optionally substituted at each occurrence with one or more substituents independently selected from the group consisting of: halogen, -OH, = O, -NH ₂ 、-CN、C _1-6 Alkyl radical, C _3-6 Cycloalkyl and 3-10 membered heterocyclyl;

preferably, R ¹ Selected from-F, -Cl, -Br, -I, -OH and-NH ₂ 、-CN、-NO ₂ 、-CH ₃ 、-CH ₂ F、-CHF ₂ 、-CF ₃ 、-CH ₂ CH ₃ 、-CH ₂ CF ₃ 、-CF ₂ CH ₃ 、-CF ₂ CN、-CF ₂ CH ₂ NH ₂ 、-CH(CH ₃ )OH、-C(CH ₃ ) ₂ OH、-CF ₂ CH ₂ OH、-CF ₂ C(CH ₃ ) ₂ OH、-CF ₂ OCH ₃ 、-CF ₂ CH ₂ OCH ₃ 、-CF ₂ O- (cyclopropyl), cyclopropyl,

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein:

when n > 1, two adjacent R ¹ Optionally together with the group to which they are attached form C _3-6 A hydrocarbon ring, a 3-to 10-membered heterocyclic ring, or a 5-to 14-membered heteroaromatic ring; the hydrocarbon ring, heterocyclic ring and heteroaromatic ring are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OH, = O, C _1-6 Alkyl and-C _1-6 alkylene-OR ^5’ ；

Preferably, the first and second electrodes are formed of a metal,when n > 1, two adjacent R ¹ Optionally together with the group to which they are attached form

7. The compound of any one of claims 1-6 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein

Is selected from

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R is ² Is selected from

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein-L-R ² Is selected from

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R is ³ Selected from H, halogen, C _1-6 Alkyl radical, C _3-6 Cycloalkyl, -OR ^a and-C _1-6 alkylene-OR ^a (ii) a The alkyl, alkylene and cycloalkyl groups are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OH and-CN;

More preferably, R ³ Selected from H, methyl, ethyl and

11. the process of any one of claims 1 to 10A compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein R is ⁴ And R ^4’ Each independently selected from H, halogen, C _1-6 Alkyl radical, C _3-6 Cycloalkyl, -OR ^a and-C _1-6 alkylene-OR ^a (ii) a Each of said alkyl and cycloalkyl groups being optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OH and-CN;

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R is ⁵ Is H or C _1-6 Alkyl, preferably H or methyl, more preferably methyl.

13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound or prodrug thereof, wherein said compound is selected from the group consisting of

14. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1-13, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier, preferably said pharmaceutical composition is a solid formulation, a semi-solid formulation, a liquid formulation or a gaseous formulation.

15. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition according to claim 14, for the manufacture of a medicament for the inhibition of SOS1, preferably for the prevention or treatment of cancer (e.g. pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma), RAS diseases (e.g. neurofibromatosis type 1 (NF 1), noonan Syndrome (NS), noonan syndrome with multiple plaques (NSML), angio-quiet vein syndrome (CM-AVM), costal Syndrome (CS), cardio-facies syndrome (CFC), and dyscapillosis).