CN118715210A - Androgen receptor activity modulators and their applications - Google Patents

Abstract

Provided are modulators of androgen receptor activity and uses thereof, the modulators of androgen receptor activity having the structure of formula 1-I or formula 2-I, wherein R ₁-R₇, X, ring A, ring B, ring C, n, m, p, Z ₁ and Z ₂ are as described herein, and pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substituents, polymorphs, prodrugs or metabolites of the compounds of formula 1-I or formula 2-I, and pharmaceutical compositions and uses thereof.

Description

Androgen receptor activity modulators and their applications Technical Field

The present invention relates to androgen receptor activity regulator and application thereof.

Background Art

Prostate cancer refers to an epithelial malignant tumor that occurs in the prostate gland. It is one of the most common malignant tumors in the male urogenital system. The incidence of prostate cancer varies greatly worldwide, and the incidence in Asians is much lower than that in Europeans and Americans. In the United States, the incidence of prostate cancer ranks first among all male malignant tumors, and the mortality rate ranks second only to lung cancer. Among them, metastatic prostate cancer is particularly malignant, with a 5-year survival rate of only 30%.

Androgen deprivation therapy (ADT) alone or in combination with chemotherapy is often used as the initial treatment for metastatic prostate cancer. The standard approach to ADT includes bilateral orchiectomy or medical castration with a gonadotropin-releasing hormone agonist alone or in combination with an anti-androgen drug. Although the initial remission rate is 80%-90%, almost all patients will eventually progress after ADT, which is called castration-resistant prostate cancer (CRPC).

Androgen receptor (AR) plays a very important role in maintaining prostate function and promoting prostate cancer formation, and is also an important target for drug treatment of prostate cancer. The functional domains of AR include the carboxyl-terminal ligand binding domain (LBD), DNA binding domain (DBD) and N-terminal domain (NTD), which can regulate the expression of multiple genes. After androgen binds to LBD, AR undergoes conformational changes, separates from heat shock proteins and moves into the nucleus, recognizes and binds to androgen response elements on DNA through DBD, and then regulates the transcription of target genes such as prostate-specific antigen (PSA). Currently available clinical AR inhibitors include non-steroidal anti-androgens targeting the AR LBD domain, such as bicalutamide, nilutamide, flutamide and enzalutamide, and steroidal anti-androgens such as cyproterone acetate and spironolactone.

A large number of research results show that there are many factors that lead to resistance of CRPC patients to new endocrine therapy drugs, including abnormal AR amplification, AR splice variants (AR-Vs), and LBD domain activation mutations. AR-Vs lack the LBD domain at the carboxyl terminal, but retain the NTD and DBD domains, which can enter the nucleus independently of androgen stimulation and activate the transcription of downstream target genes. There are more than 20 types of AR-Vs discovered so far, among which AR-V7 is the most common in clinical samples. The expression level of AR-V7 shows a significant upward trend with the progression of CRPC disease, and CRPC patients expressing AR-V7 are not sensitive to new endocrine therapy drugs (such as abiraterone or enzalutamide).

AR-Vs have been shown to be closely related to the occurrence and development of CRPC in more and more studies, but no drugs targeting AR-Vs have been approved for marketing. All AR-Vs retain the NTD domain, which contains the transcriptional activation domain (activation function-1, AF-1) that can interact with a variety of transcriptional co-regulatory factors (cofactors) and is essential for the transcriptional activity of AR. Therefore, inhibitors targeting the AR NTD domain can simultaneously inhibit the transcriptional activity of AR full-length and splice variants, and are expected to become a new therapeutic strategy for conquering CRPC.

Summary of the invention

In one aspect, the present invention provides a compound represented by the following formula 1-I:

or a pharmaceutically acceptable salt thereof,

in:

Ring A and Ring B are each independently cycloalkyl, heterocyclyl, aryl or heteroaryl;

Ring C is a bond, cycloalkyl, heterocyclyl, aryl or heteroaryl;

X is C, N, O or S;

R ₁ and R ₂ are each independently absent, H, halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, or -NR _a R _a ;

Provided that when X is C, _R1 and _R2 are each independently absent, H, halogen, cyano, hydroxy, optionally substituted alkyl, _optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, or _-NRaRa , or _R1 and _R2 together with X form an optionally substituted

R ₃ and R ₄ are each independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -(CH ₂ ) _r NR _a R _a or -OR _b ;

Z ₁ is a bond, -O-, -S-, -CO-, -S(O)-, -SO ₂ -, -NR _a - or -(CH ₂ ) _r -NR _a -CO-;

R ₅ is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

Z ₂ is **-Y ₁ -Y ₂ -*, wherein Y ₁ is a bond, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, Y ₂ is a bond, O, NH or S, "*" represents the point of attachment of Z ₂ to ring A, and "**" represents the point of attachment of Z ₂ to ring C;

_R6 is -N=S(O) _RcRd or -( _CH2 ) _sS (O)(= _{NRe ) Rf} ;

R ₇ is each independently halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR _a , -S(O)R _f , -SO ₂ R _f or -NR _g R _g ;

Each _Ra is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or _-CORb ;

R _b is H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

R _c and R _d are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl or -NR _a R _a ; or R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl;

R _e is H, cyano, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

_Rf is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

R _g is each independently H, -SO ₂ R _f , optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; or two R _g together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group;

r is 0, 1, 2, or 3;

s is 0, 1, 2, or 3; and

m, n and p are each independently 0, 1, 2 or 3.

In another aspect, the present invention provides a compound shown in the following formula 2-1:

or a pharmaceutically acceptable salt thereof,

in:

Ring A and Ring B are each independently cycloalkyl, heterocyclyl, aryl or heteroaryl;

Ring C is a bond, cycloalkyl, heterocyclyl, aryl or heteroaryl;

X is C, N, O or S;

R ₁ and R ₂ are each independently absent, H, halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, or -NR _a R _a ;

R ₃ and R ₄ are each independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -(CH ₂ ) _r NR _a R _a or -OR _b ;

Z ₁ is a bond, -O-, -S-, -CO-, -S(O)-, -SO ₂ -, -NR _a - or -(CH ₂ ) _r -NR _a -CO-;

_R5 is H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

R ₆ is -N=S(O)R _c R _d , -(CH ₂ ) _s S(O)(=NR _e )R _f or -NR _a -SO ₂ R _g ;

R ₇ is each independently halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR _a , -S(O)R _f , -SO ₂ R _f or -NR _h R _h ;

Each _Ra is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or _-CORb ;

R _b is H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

R _c and R _d are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR _a or -NR _a R _a ; or R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl;

R _e is H, cyano, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

_Rf is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

_Rg is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted 4-10 membered _heterocyclyl or _-NRhRh ;

R _h is each independently H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; or two R _h together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl;

r is 0, 1, 2, or 3;

s is 0, 1, 2, or 3; and

m, n and p are each independently 0, 1, 2 or 3.

In another aspect, the present invention provides a pharmaceutical composition containing a therapeutically or prophylactically effective amount of a compound of Formula 1-I or 2-I of the present invention or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition may further contain a pharmaceutically acceptable carrier.

In another aspect, the present invention provides the use of a compound of formula 1-I or 2-I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for treating androgen receptor-mediated diseases, and also provides a compound of formula 1-I or 2-I of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention for treating androgen receptor-mediated diseases.

In another aspect, the present invention provides a method for treating or preventing androgen receptor-mediated diseases, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1-I or 2-I of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof.

In another aspect, the present invention provides a method for treating or preventing a disease mediated by an androgen receptor variant, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1-I or 2-I of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof.

On the other hand, the present invention provides a method for treating or preventing diseases mediated by androgen receptor splice variants (AR-Vs), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1-I or 2-I of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof.

In another aspect, the present invention provides a method for treating or preventing an AR-V7-mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1-I or 2-I of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof.

On the other hand, the present invention provides a method for treating or preventing diseases mediated by androgen receptor and androgen receptor variants, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1-I or 2-I of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof.

On the other hand, the present invention provides a method for treating or preventing diseases mediated by androgen receptor and androgen receptor splice variants (AR-Vs), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1-I or 2-I of the present invention, a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, solvate, isotope substitution, polymorph, prodrug or metabolite, or a pharmaceutical composition thereof.

In another aspect, the present invention provides a method for treating or preventing androgen receptor and AR-V7 mediated diseases, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1-I or 2-I of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substitution, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof.

In another aspect, the present invention provides a method for treating or preventing a disease mediated by an androgen receptor variant, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1-I or 2-I of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof.

On the other hand, the present invention provides a method for treating or preventing diseases mediated by androgen receptor splice variants (AR-Vs), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1-I or 2-I of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof.

In another aspect, the present invention provides a method for treating or preventing an AR-V7-mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1-I or 2-I of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof.

A more detailed technical solution and description of the present invention are as follows.

DETAILED DESCRIPTION

In the following description, certain specific details are set forth in order to provide a comprehensive understanding of multiple embodiments. However, it will be appreciated by those skilled in the art that the present invention may be implemented without these details. In other cases, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout the specification and the following claims, the wording "comprising" and its variations, such as "including" and "containing" will be interpreted in an open, inclusive sense, that is, interpreted as "including but not limited to". In addition, the titles provided herein are only for convenience purposes and do not explain the scope or meaning of the claimed invention.

Reference to "one embodiment" in this specification means that a particular feature, structure or characteristic described with respect to the embodiment is included in at least one embodiment. Therefore, the phrase "in one embodiment" appearing in multiple places in this specification does not necessarily all refer to the same embodiment. In addition, the particular features, structures or characteristics may be combined in one or more embodiments in any suitable manner. In addition, unless the context clearly dictates otherwise, as used in this specification and claims, the singular forms "one", "an" and "the" include multiple references. It should also be noted that the term "or" is generally used in its sense including "and/or" unless the context clearly dictates otherwise.

r.Terminology

Definitions of specific functional groups and chemical terms are described in more detail below.For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover), and specific functional groups are generally defined as described herein.

Linking substituents are described in various places throughout this application. If the structure clearly requires a linking group, the Markush variations listed for that group should be understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl," it should be understood that "alkyl" represents a linking alkylene group.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then the substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which the substituent is bonded to the rest of the compound of a given formula, then the substituent may be bonded via any atom in the formula. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

"Cyano" refers to a -CN group.

"Halogen" refers to a fluoro, chloro, bromo or iodo radical.

"Hydroxy" refers to an -OH group.

"Oxo" refers to =0.

"-CO-" means -C(=O)-

In the present application, the term " _Ci - _Cj " refers to a range of carbon atoms, wherein i and j are integers, and the range of carbon atoms includes the endpoints (i.e., i and j) and each integer point in between, wherein j is greater than i. For example, _Ci - _C6 refers to a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. In some embodiments, the term " _Ci - _C12 " refers to 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3, or particularly 1 to 2 carbon atoms.

In the present application, as a group or part of other groups, "alkyl" refers to a fully saturated straight or branched hydrocarbon chain group connected to the rest of the molecule by a single bond. The term " _Ci - _Cj alkyl" refers to an alkyl with i to j carbon atoms. In some embodiments, the alkyl contains 1 to 12 carbon atoms. In some embodiments, the alkyl contains 1 to 11 carbon atoms. In some embodiments, the alkyl contains 1 to 10 carbon atoms, 1 to 9 carbon atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms or 1 to 2 carbon atoms. The non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted.

In the present application, "alkenyl" as a group or part of other groups refers to a straight or branched hydrocarbon chain group having one or more carbon-carbon double bonds (-C=C-). In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms. In some embodiments, the alkenyl group contains 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkenyl group contains 2 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl substituted alkenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl and 11-dodecenyl. Unless otherwise specifically provided in the specification, alkenyl may be optionally substituted.

In the present application, as a group or part of other groups, "alkynyl" refers to a straight or branched hydrocarbon chain group having one or more carbon-carbon triple bonds (-C≡C-). In some embodiments, the alkynyl contains 2 to 12 carbon atoms. In some embodiments, the alkynyl contains 2 to 11 carbon atoms. In some embodiments, the alkynyl contains 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkynyl contains 2 carbon atoms. Non-limiting examples of alkynyl include ethynyl, propynyl, butynyl, pentynyl, etc. Unless otherwise specifically provided in this specification, the alkynyl may be optionally substituted.

In the present application, as a group or part of other groups, the term "cycloalkyl" means a stable non-aromatic monocyclic or polycyclic hydrocarbon group (such as alkyl, alkenyl or alkynyl) consisting only of carbon atoms and hydrogen atoms, which can be connected to the rest of the molecule by a single bond via any suitable carbon atom. Unless otherwise specifically indicated in the present specification, the carbon atoms in the cycloalkyl group can be optionally oxidized, and the cycloalkyl group can be optionally substituted.

In some embodiments, the cycloalkyl group can contain 3 to 12 ring carbon atoms, 3 to 10 ring carbon atoms, 3 to 9 ring carbon atoms, 3 to 8 ring carbon atoms, 3 to 7 ring carbon atoms, 3 to 6 ring carbon atoms, 3 to 5 ring carbon atoms, 4 to 12 ring carbon atoms, 4 to 10 ring carbon atoms, 4 to 9 ring carbon atoms, 4 to 8 ring carbon atoms, 4 to 7 ring carbon atoms, 4 to 6 ring carbon atoms, 4 to 5 ring carbon atoms.

In some embodiments, the cycloalkyl group can be a non-aromatic monocyclic hydrocarbon group, examples of which include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl.

In some embodiments, the cycloalkyl group may be a non-aromatic polycyclic (e.g., bicyclic and tricyclic) hydrocarbon group, which may be a fused ring system, a spirocyclic system, or a bridged ring system. The term "fused ring" refers to a ring system having two rings sharing two adjacent atoms, the term "spirocyclic ring" refers to a ring system having two rings connected by a single common atom, and the term "bridged ring" refers to a ring system having two rings sharing three or more atoms. Examples of fused cycloalkyl groups include, but are not limited to, H-indenyl, 2,3-dihydroindanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzocycloheptene-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptene, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octahydro-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-pentalenoyl, etc. Examples of spirocyclic radicals include, but are not limited to, spiro[5.5]undecyl, spiro-pentadienyl, spiro[3.6]-decyl, etc. Examples of bridged ring groups include, but are not limited to, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.3]undecane, and the like.

In the present application, the term "heterocyclyl" as a group or part of another group means a stable non-aromatic cyclic group consisting of carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms) and heteroatoms (e.g., 1 to 6 heteroatoms) selected from nitrogen, phosphorus, oxygen and sulfur. In some embodiments, the heterocyclyl group may contain 3 to 20 ring-forming atoms, 3 to 19 ring-forming atoms, 3 to 18 ring-forming atoms, 3 to 17 ring-forming atoms, 3 to 16 ring-forming atoms, 3 to 15 ring-forming atoms, 4 to 12 ring-forming atoms, 4 to 10 ring-forming carbon atoms, 4 to 9 ring-forming atoms, 4 to 8 ring-forming atoms, 4 to 7 ring-forming atoms, 4 to 6 ring-forming atoms, 4 to 5 ring-forming atoms. Unless otherwise specifically indicated in this specification, the heterocyclic radical can be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system, a bridged ring system or a spirocyclic system. The nitrogen, carbon or sulfur atom in the heterocyclic radical may be optionally oxidized, and the nitrogen atom may be optionally quaternized. The heterocyclic radical may be connected to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. In some cases, the heterocyclic radical may be carbon-connected, nitrogen-connected or sulfur-connected. In some embodiments, the heterocyclic radical is carbon-connected. In some embodiments, the heterocyclic radical is nitrogen-connected. In some embodiments, the heterocyclic radical is sulfur-connected.

Heterocyclyl also includes groups in which the heterocyclyl group is fused to a saturated, partially unsaturated or fully unsaturated (ie, aromatic) carbocyclic or heterocyclic ring. In heterocyclyl groups containing fused rings, one or more rings may be aryl or heteroaryl as defined below. Examples of fused heterocyclic groups include, but are not limited to, phenyl fused rings or pyridyl fused rings, such as quinolyl, isoquinolyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[4,3-a]pyridinyl, etc.

In some embodiments, the heterocyclic group is a stable 4- to 12-membered, 5- to 12-membered, or 4- to 10-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, such as a stable 5- to 10-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonane-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane-2-yl, azetidinyl, oxetanyl, thietanyl, thiolanyl, pyrrolidyl, morpholin ... 1,4-oxathiolanyl, ...

In the present application, as a group or part of other groups, "aryl" refers to a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms (e.g., 6 to 14 carbon atoms or 6 to 10 carbon atoms, such as 6, 7, 8, 9 or 10 carbon atoms). The aryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused with a cycloalkyl or heterocyclic group as defined above. In the case of a polycyclic system, although all rings can be aromatic, only one ring needs to be aromatic. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazolinone-3(4H)-one-7-yl, etc. Unless otherwise specifically provided in this specification, the term "aryl" includes optionally substituted aryl groups.

In the present application, the term "heteroaryl", as a group or part of other groups, means a conjugated ring system group having carbon atoms (e.g., 1 to 15 carbon atoms, 1 to 14 carbon atoms, 1 to 13 carbon atoms, 1 to 12 carbon atoms, 1 to 11 carbon atoms, 1 to 10 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms) and heteroatoms (e.g., 1 to 6 heteroatoms) selected from nitrogen, oxygen and sulfur in the ring. In some embodiments, the heteroaryl group may contain 5 to 20 ring-forming atoms, 5 to 19 ring-forming atoms, 5 to 18 ring-forming atoms, 5 to 17 ring-forming atoms, 5 to 16 ring-forming atoms, 5 to 15 ring-forming atoms, 5 to 14 ring-forming atoms, 5 to 13 ring-forming atoms, 5 to 12 ring-forming atoms, 5 to 10 ring-forming carbon atoms, 5 to 9 ring-forming atoms, 5 to 8 ring-forming atoms, 5 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms. Unless otherwise specifically indicated in the specification, the heteroaryl group may be a monocyclic, bicyclic, tricyclic or higher ring system, and may also be fused with a cycloalkyl or heterocyclic group as defined above. The nitrogen, carbon or sulfur atoms in the heteroaryl group may be optionally oxidized, and the nitrogen atom may be optionally quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5- to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.

Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzomorpholinyl, benzisodiazolyl, benzotriazolyl, imidazopyridinyl, pyridomorpholinyl, pyrazolopyridinyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, naphthazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl , oxatriazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizinyl, o-phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridinyl, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine, tetrahydroisoquinolinyl, decahydroisoquinolinyl, dihydroindolyl, octahydroindolyl and octahydroisoindolyl, etc.

In the present application, "optional" or "optionally" means that the subsequently described event or situation may or may not occur, and the description includes both the case where the event or situation occurs and the case where it does not occur.

In this application, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. It will be understood that "substituted" or "substituted by..." includes the implicit proviso that such substitution is made according to the allowed valence of the substituted atom and that the substitution produces a stable or chemically feasible compound, such as a compound that will not spontaneously transform, such as by rearrangement, cyclization, elimination, etc. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted by more than one substituent selected from a specified group, the substituent may be the same or different at each position. It will be understood by those skilled in the art that the substituent itself may be substituted if appropriate. Unless specifically indicated as "unsubstituted", references to chemical moieties herein should be understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes substituted and unsubstituted variants.

The "optional" substituents described in the present application include, but are not limited to, the alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, cyano, hydroxyl, amino, monoalkylamino, dialkylamino, nitro, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclic, etc. described herein; these groups as substituents include alkyl, alkenyl, alkynyl, alkyl in haloalkyl, alkenyl in haloalkenyl, alkynyl in haloalkynyl, alkoxy, alkyl in monoalkylamino, alkyl in dialkylamino, aryl, heteroaryl, cycloalkyl and heterocyclic, and may also be optionally substituted by one or more groups selected from alkyl, halogen, haloalkyl, alkoxy, hydroxyl, amino, monoalkylamino, dialkylamino, nitro, aryl, heteroaryl, cycloalkyl and heterocyclic. Herein, the number of substituents may be one or more, i.e., 1, 2, 3, 4, 5 or 6 or more, depending on the nature of the substituted group and the substituent. For example, when the substituent is a halogen, the group may be substituted with 1 to 6 substituents, such as trifluoromethyl, pentafluoroethyl, etc., depending on the structure of the substituted group.

As used herein, the terms "part", "moiety", "chemical moiety", "group", "chemical group" refer to a specific fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

It will also be appreciated by those skilled in the art that in the methods described below, the functional groups of the intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, sulfhydryl and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino and guanidino include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable sulfhydryl protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, etc. Suitable carboxyl protecting groups include alkyl esters, aryl esters or aralkyl esters.

Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, TW and PGM Wuts, Protective Groups in Organi Synthesis, (1999), ^4th Ed., Wiley. The protecting group can also be a polymer resin.

As used herein, a "subject" can be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc. The subject can be suspected of having or at risk of having a cancer such as prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioblastoma, melanoma, renal cell carcinoma, mantle cell lymphoma, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, or suspected of having or at risk of having alopecia, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, age-related macular degeneration. Those skilled in the art know diagnostic methods for various cancers such as prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioblastoma, melanoma, renal cell carcinoma, mantle cell lymphoma, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, and the like, as well as diagnostic methods for alopecia, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy or age-related macular degeneration, and clinical delineation of cancers such as prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioblastoma, melanoma, renal cell carcinoma, mantle cell lymphoma, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, and the diagnosis and clinical delineation of alopecia, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy or age-related macular degeneration.

"Mammal" includes: humans; domestic animals, such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals, such as wild animals, etc.

"Pharmaceutically acceptable carriers, diluents or excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by, for example, the U.S. Food and Drug Administration (FDA) as acceptable for use in humans or farmed animals.

The compounds disclosed in the present application may exist in a variety of different forms or derivatives, all of which are within the scope of the present disclosure. These include, for example, tautomers, stereoisomers, racemic mixtures, geometric isomers, salts, prodrugs, solvates, different crystal forms or polymorphs, and active metabolites.

In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, etc.; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetates, trifluoroacetates, propionates, caproates, caprylates, decanoates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamate, pyroglutamate, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginate, ascorbate, salicylates, 4-aminosalicylates, naphthalene disulfonates, etc. These salts can be prepared by methods known in the art.

"Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and magnesium salts. The salt derived from organic base includes but is not limited to the following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the profession.

Examples of prodrugs of the compounds of the present application may include simple esters of carboxylic acid-containing compounds (e.g., esters obtained by condensation with C _1-4 alcohols according to methods known in the art); esters of hydroxyl-containing compounds (e.g., esters obtained by condensation with C _1-4 carboxylic acids, C _3-6 diacids or their anhydrides such as succinic anhydride and fumaric anhydride according to methods known in the art); imines of amino-containing compounds (e.g., imines obtained by condensation with C _1-4 aldehydes or ketones according to methods known in the art); carbamates of amino-containing compounds, such as those described by Leu et al. (J. Med. Chem., 42: 3623-3628 (1999)) and Greenwald et al. (J. Med. Chem., 42: 3657-3667 (1999)); acetals or ketal of alcohol-containing compounds (e.g., those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compound of the present invention may exist as a hydrate, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., as well as as corresponding solvated forms. The compound of the present invention may be a true solvate, while in other cases, the compound of the present invention may only retain adventitious water or a mixture of water plus some adventitious solvent.

As used herein, "stereoisomer" refers to a compound composed of the same atoms, bonded by the same bonds, but having different three-dimensional structures. This application will cover various stereoisomers and mixtures thereof.

When the compounds herein contain olefinic double bonds, and unless specified otherwise, it is intended that the compounds herein include both E- and Z- geometric isomers.

"Tautomer" refers to an isomer formed when a proton is transferred from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present application are also included within the scope of the present application.

The compounds of the present application or their pharmaceutically acceptable salts may contain one or more chiral carbon atoms, and thus may produce enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom can be defined as I- or (S)- based on stereochemistry. The present application is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The preparation of the compounds of the present application may select racemates, diastereomers or enantiomers as raw materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or can be separated using conventional techniques, such as by methods such as crystallization and chiral chromatography.

Conventional techniques for preparing/isolating individual isomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography, see, for example, GeRald Gübitz and Martin G. Schmid (Eds.), ChiRal SepaRations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; A. M. Stalcup, ChiRal SepaRations, Annu. Rev. Anal. Chem. 3: 341-63, 2010; Fumiss et al. (eds.), VOGEL’S ENCYCLOPEDIA OF PRaCTICAL ORGANIC CHEMISTRY. sup. TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.

The present invention also includes all suitable isotopic variants of the compound of the present invention or its pharmaceutically acceptable salt. Isotopic variants of the compound of the present invention or its pharmaceutically acceptable salt are defined as those in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass often found in nature. Isotopes that can be incorporated into the compound of the present invention and its pharmaceutically acceptable salt include but are not limited to isotopes of H, C, N and O, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³⁵ S, ¹⁸ F, ³⁶ Cl and ¹²⁵ I. Isotopic variants of the compound of the present invention or its pharmaceutically acceptable salt can be prepared by conventional techniques, using appropriate isotopic variants of suitable reagents.

Herein, unless otherwise specified, the wavy line on each structural formula or group generally indicates the position where the structural formula or group is connected to other parts in the compound.

As used herein, the terms "crystalline form" and "polymorph" are used interchangeably and refer to a crystal structure in which a compound (or its salt or solvate) can be crystallized in different crystal packing arrangements (all with the same elemental composition). Different crystal forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvents, crystallization rates, storage temperatures and other factors may lead to one crystal form being dominant. Polymorphs of a compound can be prepared by crystallization under different conditions.

As used herein, the term "active metabolite" is a pharmacologically active compound or a compound that is further metabolized into a pharmacologically active compound that is a derivative produced by a metabolic process in the subject. For example, such a metabolite can be produced by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound or salt or prodrug. Among them, the active metabolite is such a pharmacologically active derivative compound.

"Pharmaceutical composition" refers to a preparation of a compound of the present invention and a medium recognized in the art for delivering biologically active compounds to mammals (eg, humans). Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients thereof.

"Effective amount" refers to a therapeutically effective amount or a preventive effective amount. "Therapeutically effective amount" refers to an amount that effectively achieves the desired therapeutic outcome (such as reduced tumor size, increased life span, or increased life expectancy) at the required dose and for the required period of time. The therapeutically effective amount of a compound may vary according to factors such as the subject's disease state, age, sex, and weight, and the ability of the compound to cause the desired response in the subject. The dosing regimen may be adjusted to provide the best therapeutic response. A therapeutically effective amount is also an amount in which any toxic or deleterious effects of the compound are exceeded by the therapeutic beneficial effects. "Preventive effective amount" refers to an amount that effectively achieves the desired preventive outcome (such as smaller tumors, increased life span, increased life expectancy, or prevention of prostate cancer from progressing to a castration-resistant form) at the required dose and for the required period of time. Typically, a preventive dose is used in a subject before or in the early stages of the disease so that the preventive effective amount may be less than the therapeutically effective amount.

As used herein, "treatment" encompasses the treatment of a disease or condition of interest in a mammal, preferably a human, suffering from the disease or condition of interest, and includes:

(r) preventing the disease or condition from occurring in a mammal, particularly where the mammal is susceptible to the condition but has not yet been diagnosed with the condition;

(ii) inhibiting the disease or condition, i.e., arresting its development;

(iii) alleviate the disease or condition, i.e., cause regression of the disease or condition; or

(iv) Alleviation of symptoms caused by the disease or condition, i.e., relief of pain without addressing the underlying disease or condition.

The terms "taking", "administering", "administering", etc. as used herein refer to methods that can deliver a compound or composition to a desired site for biological action. Methods of administration known in the art can be used in the present invention. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intrapulmonary, intranasal, intrathecal, intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with the administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compound of formula I of the present invention, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted, polymorph, prodrug or metabolite, or a pharmaceutical composition thereof, is administered orally.

As used herein, "combination", "drug combination", "combination drug", or "combination therapy" and the like refer to a drug therapy obtained by mixing or combining more than one active ingredient, including fixed and non-fixed combinations of active ingredients, or to a combination of two or more different therapeutic approaches. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form. The term "non-fixed combination" refers to the simultaneous administration, combined administration, or sequential administration at variable intervals of at least one compound described herein and at least one synergistic agent to a patient in the form of separate entities. These also apply to cocktail therapy, for example, the administration of three or more active ingredients.

II. Compounds

In one aspect, the present application provides a compound shown in the following formula 1-I:

or a pharmaceutically acceptable salt thereof,

in:

Ring A and Ring B are each independently cycloalkyl, heterocyclyl, aryl or heteroaryl;

Ring C is a bond, cycloalkyl, heterocyclyl, aryl or heteroaryl;

X is C, N, O or S;

R ₁ and R ₂ are each independently absent, H, halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, or -NR _a R _a ;

Provided that when X is C, _R1 and _R2 are each independently absent, H, halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl _, optionally substituted alkynyl, optionally substituted alkoxy, or _-NRaRa , or _R1 and _R2 together with X form an optionally substituted

R ₃ and R ₄ are each independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -(CH ₂ ) _r NR _a R _a or -OR _b ;

Z ₁ is a bond, -O-, -S-, -CO-, -S(O)-, -SO ₂ -, -NR _a -, or -(CH ₂ ) _r -NR _a -CO-;

_R5 is H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

Z ₂ is **-Y ₁ -Y ₂ -*, wherein Y ₁ is a bond, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, Y ₂ is a bond, O, NH or S, "*" represents the point of attachment of Z ₂ to ring A, and "**" represents the point of attachment of Z ₂ to ring C;

_R6 is -N=S(O) _RcRd or -( _CH2 ) _sS (O)(= _{NRe ) Rf} ;

R ₇ is each independently halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR _a , -S(O)R _f , -SO ₂ R _f or -NR _g R _g ;

Each _Ra is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or _-CORb ;

R _b is H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

R _c and R _d are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl or -NR _a R _a ; or R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl;

R _e is H, cyano, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

_Rf is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

R _g is each independently H, -SO ₂ R _f , optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; or two R _g together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group;

r is 0, 1, 2, or 3;

s is 0, 1, 2, or 3; and

m, n and p are each independently 0, 1, 2 or 3.

In some embodiments, Ring A is aryl. In some embodiments, Ring A is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In some embodiments, Ring A is phenyl or naphthyl. In some embodiments, Ring A is phenyl.

In some embodiments, ring A is a heteroaryl. In some embodiments, ring A is a 5-14 membered heteroaryl, a 5-12 membered heteroaryl, a 5-10 membered heteroaryl, a 5-8 membered heteroaryl, a 5-6 membered heteroaryl. In some embodiments, ring A is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, pyrrolyl, triazolyl, triazinyl, imidazolyl, pyrazolyl, pyrrolyl, pyridinyl, pyrimidinyl or pyrazinyl.

In certain embodiments, Ring A is pyridinyl, pyrimidinyl, or thienyl. In certain embodiments, Ring A is pyridinyl.

In certain embodiments, Ring A is

In some embodiments, ring B is aryl. In some embodiments, ring B is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In some embodiments, ring B is phenyl or naphthyl.

In some embodiments, Ring B is heteroaryl. In certain embodiments, Ring B is 5-14 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl. In certain embodiments, Ring B is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, pyrrolyl, triazolyl, triazinyl, pyridonyl, benzomorpholinyl, pyridomorpholinyl, indazolyl, dihydrobenzoxazinyl, pyrazolopyridinyl, benzotriazolyl, benzimidazolyl, tetrahydroisoquinolinyl, imidazopyridinyl, pyridomorpholinyl, benzisodiazolyl, indolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, decahydroisoquinolyl, dihydroindolyl, octahydroindolyl, or octahydroisoindolyl.

In certain embodiments, Ring B is selected from pyridinyl, pyridonyl, indazolyl, dihydrobenzoxazinyl, pyrazolopyridinyl, benzomorpholinyl, pyridomorpholinyl, benzotriazolyl, benzimidazolyl, tetrahydroisoquinolinyl, imidazopyridinyl, or pyridomorpholinyl.

In certain embodiments, Select from the following group:

In some embodiments, Ring C is a bond.

In some embodiments, Ring C is cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, Ring C is aryl or heteroaryl.

In some embodiments, ring C is aryl. In some embodiments, ring C is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In some embodiments, ring C is phenyl or naphthyl. In some embodiments, ring C is phenyl.

In some embodiments, ring C is a heteroaryl. In some embodiments, ring C is a 5-14 membered heteroaryl, a 5-12 membered heteroaryl, a 5-10 membered heteroaryl, a 5-8 membered heteroaryl, a 5-6 membered heteroaryl. In some embodiments, ring C is selected from pyrimidinyl, pyrazinyl, pyridinyl, piperidinyl, piperazinyl, morpholinyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, furanyl, pyrrolyl, triazolyl or triazinyl.

In certain embodiments, Ring C is pyrimidinyl, pyrazinyl, pyridinyl, thiazolyl, or oxazolyl.

In certain embodiments, Select from the following group:

In some embodiments, X is N, O or S, and R ₁ and R ₂ are absent.

In some embodiments, X is C, and R ₁ and R ₂ are each independently H, hydroxy, or optionally substituted alkyl.

In certain embodiments, X is C, _R1 and _R2 are each optionally substituted alkyl, the optionally substituted alkyl being optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano and -NR _a R _a . In certain embodiments, X is C, _R1 and _R2 are each independently optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, X is C, and R ₁ and R ₂ are both methyl.

In certain embodiments, X is C, one of R ₁ and R ₂ is optionally substituted alkyl, and the other is H or hydroxy, wherein the optionally substituted alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and -NR _{a Ra} .

In certain embodiments, X is C, one of _R1 and _R2 is optionally substituted _C1 - _C4 alkyl, and the other is H or hydroxy, wherein the optionally substituted _C1 - _C4 alkyl is optionally substituted with one or more _substituents independently selected from halogen, hydroxy, cyano and _-NRaRa .

In certain embodiments, X is C, one of R ₁ and R ₂ is methyl and the other is hydroxy.

In certain embodiments, X is C, R ₁ and R ₂ together with X form an optionally substituted

In certain embodiments, X is C, _R1 and _R2 together with X form

In some embodiments, R ₃ and R ₄ are each independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -(CH ₂ ) _r NR _a R _a, or -OR _b .

In some embodiments, each R ₃ is independently H, halogen, optionally substituted alkyl, optionally substituted alkoxy, or -OR _b .

In some embodiments, each R ₃ is independently H, halogen, optionally substituted alkyl, or -OR _b .

In some embodiments, each R ₃ is independently optionally substituted C ₁ -C ₄ alkyl or optionally substituted C ₁ -C ₄ alkoxy.

In certain embodiments, each R ₃ is independently optionally substituted C ₁ -C ₄ alkyl or optionally substituted C ₁ -C ₄ alkoxy, wherein the optionally substituted C ₁ -C ₄ alkyl and the optionally substituted C ₁ -C ₄ alkoxy are optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano and -NR _a R _a .

In some embodiments, each R ₃ is independently H, halogen, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkoxy.

In some embodiments, each R ₃ is independently selected from halogen, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkoxy.

In some embodiments, each R ₃ is independently fluoro, chloro, methyl, methoxy.

In some embodiments, R ₃ is fluoro.

In some embodiments, R ₃ is chloro.

In some embodiments, R ₃ is methyl.

In some embodiments, R ₃ is methoxy.

In certain embodiments, _R3 is H.

In some embodiments, each _R is independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -( _CH2 ) _rNRaRa , or _-ORb , wherein _{each Ra is} independently _H , optionally substituted alkyl, or _-CORb , and _Rb is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, wherein said optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted cycloalkyl are optionally substituted with one or more _substituents independently selected from halogen, hydroxy, cyano, and _-NRaRa .

In certain embodiments, each R ₄ is independently H, halogen, cyano, oxo, cyclopropyl, -(CH ₂ ) _r NR _a R _a , or -OR _b , wherein each R _a is independently H, optionally substituted C ₂ -C ₄ alkenyl, or -COR _b , and R _b is H, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl, or optionally substituted C ₂ -C ₄ alkynyl.

In certain embodiments, each R ₄ is independently H, chloro, cyano, oxo, cyclopropyl, -OCH ₃ , -OC≡CH, or -CH ₂ NH (CH=CH ₂ ).

In certain embodiments, each R ₄ is independently H, chloro, cyano, oxo, or -OCH ₃ .

In some embodiments, Z ₁ is a bond, -O-, -CO-, -NR _a -, or -(CH ₂ ) _r -NR _a -CO-, wherein _Ra is H or optionally substituted alkyl.

In certain embodiments, Z ₁ is a bond, -O-, -CO-, -NR _a -, or -(CH ₂ ) _r -NR _a -CO-, wherein _Ra is H or optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, Z ₁ is a bond, -O-, -CO-, or -NR _a -, wherein _Ra is H or optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, Z ₁ is a bond, -O-, -CO-, -NH-, -NHCO-, or -CH ₂ NHCO-.

In certain embodiments, Z ₁ is a bond, -O-, -S-, -CO-, -S(O)-, -SO ₂ -, or -NR _a -.

In certain embodiments, Z ₁ is a bond, —O—, —S—, —CO—, —S(O)—, —SO ₂ —, or —NR _a —, wherein each _Ra is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or —COR _b .

In certain embodiments, Z ₁ is a bond, -O- or -CO-, R ₅ is H, optionally substituted C ₁ -C ₄ alkyl, said optionally substituted C ₁ -C ₄ alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano or -NR _a R _a .

In certain embodiments, Z ₁ is a bond, -O-, -CO-, or -NR _a -, wherein _Ra is H or optionally substituted alkyl.

In certain embodiments, Z ₁ is a bond, -O-, -CO-, -NH-, or -NHCO-.

In certain embodiments, Z ₁ is a bond, -O-, or -CO-.

In some embodiments, _{R 5} is H, optionally substituted C ₁ -C ₄ alkyl _, optionally _substituted C _{2 -C 4} alkenyl, or optionally substituted C _{2 -C 4} alkynyl, which is optionally substituted with one or more substituents independently selected from halogen, hydroxy, _cyano , and -NR _a R _a .

In certain embodiments, R ₅ is H, optionally substituted C ₁ -C ₄ alkyl, or optionally substituted C ₂ -C ₄ alkenyl, wherein the optionally substituted C ₁ -C ₄ alkyl and the optionally substituted C ₂ -C ₄ alkenyl are optionally substituted with one or more substituents independently selected from halogen, hydroxyl, or cyano.

In certain embodiments, R ₅ is H, methyl, ethyl, propyl, or vinyl, wherein the methyl, ethyl, propyl, and vinyl are optionally substituted with one or more substituents independently selected from chloro, hydroxy, or cyano.

In some embodiments, Z ₁ is a bond or —O—, R ₅ is H, optionally substituted C ₁ -C ₄ alkyl, the optionally substituted C ₁ -C ₄ alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or —NR _a R _a .

In certain embodiments, Z ₁ is a bond or -O-, and R ₅ is H, methyl, ethyl, or propyl, wherein the methyl, ethyl, and propyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, or cyano.

In certain embodiments, Z ₁ is a bond or -O-, and R ₅ is H, methyl, ethyl, or propyl, wherein the methyl, ethyl, and propyl groups are optionally substituted with one or more substituents independently selected from fluoro, chloro, or hydroxy.

In some embodiments, Z ₁ is -CO- or -(CH ₂ ) _r -NR _a -C(═O)-, and R ₅ is optionally substituted C _{2 -C 4 alkenyl} , which is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR _a R _a .

In some embodiments, Z ₁ is -CO-, R ₅ is optionally substituted C ₂ -C ₄ alkenyl, said optionally substituted C ₂ -C ₄ alkenyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano or -NR _a R _a .

In certain embodiments, Z ₁ is -C(O)- and R ₅ is vinyl.

In certain embodiments, Z ₁ is -C(O)- or -(CH ₂ ) _r -NR _a -C(=O)-, and R ₅ is vinyl.

In some embodiments, -Z ₁ -R ₅ is selected from -(CH ₂ ) _r Cl, -O(CH ₂ ) _r F, -O(CH ₂ ) _r Cl, or -O(CH ₂ ) _r OH, wherein r is 1, 2, or 3.

In some embodiments, Z ₁ is a bond, -O- or -CO-, R ₅ is H, optionally substituted C ₁ -C ₄ alkyl, the optionally substituted C ₁ -C ₄ alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR _a R _a .

In some embodiments, Y ₁ is a bond and Y ₂ is O, NH or S.

In some embodiments, Y ₁ is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, and Y ₂ is a bond or O, wherein the optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, alkyl, or oxo.

In some embodiments, Y ₁ is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, and Y ₂ is a bond or O, wherein the optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or oxo.

In certain embodiments, Y ₁ is optionally substituted alkyl or optionally substituted alkynyl, and Y ₂ is a bond or O, wherein optionally substituted alkyl and optionally substituted alkynyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, alkyl, or oxo.

In certain embodiments, Y ₁ is optionally substituted alkyl or optionally substituted alkynyl, and Y ₂ is a bond or O, wherein optionally substituted alkyl and optionally substituted alkynyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or oxo.

In certain embodiments, _Y1 is optionally substituted _C1 - _C4 alkyl or optionally substituted _C2 - _C4 alkynyl, and _Y2 is a bond or O, wherein optionally substituted _C1 - _C4 alkyl and optionally substituted _C2 - _C4 alkynyl are optionally substituted with one or more substituents independently selected from hydroxy or oxo.

In certain embodiments, Y ₁ is C ₁ -C ₄ alkyl optionally substituted with one or more substituents independently selected from hydroxy or oxo, and Y ₂ is O.

In certain embodiments, Y ₁ is C ₂ -C ₄ alkynyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or oxo, and Y ₂ is a bond.

In some embodiments, Z ₂ is selected from -O-, **-(C _1-3 alkyl)-O-*, ethynyl or propynyl, wherein the C _1-3 alkyl in -(C _1-3 alkyl)-O- is optionally substituted with one or more hydroxyl or oxo.

In certain embodiments, Z ₂ is **-CH ₂ O-* or ethynyl.

In some embodiments, _R6 is -N=S(O) _{RcRd , Rc} and _Rd are each independently selected from optionally substituted alkyl or _{-NRaRa ,} wherein each _Ra is independently H or optionally substituted alkyl.

In certain embodiments, R ₆ is —N═S(O)R _c R _d , R _c and R _d are each independently selected from optionally substituted C ₁ -C ₄ alkyl or —NR _{a Ra} , wherein each _Ra is independently H or optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, R ₆ is -N=S(O)R _c R _d , and R _c and R _d are each independently optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, R ₆ is -N=S(O)R _c R _d , and R _c and R _d are each independently optionally substituted methyl.

In certain embodiments, R ₆ is -N=S(O)R _c R _d , and R _c and R _d are each independently methyl.

In certain embodiments, _R6 is

In certain embodiments, R ₆ is -N=S(O)R _c R _d , one of R _c and R _d is optionally substituted C ₁ -C ₄ alkyl and the other is -NR _a R _a , wherein each R _a is independently H or optionally substituted C ₁ -C ₄ alkyl.

In some embodiments, R ₆ is —N═S(O)(CH ₃ ) ₂ or —N═S(O)(CH ₃ )(NHCH ₃ ).

In some embodiments, _R is -N=S(O) _{RcRd , Rc} , _Rd together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl, which is optionally substituted with one or more _Rh , wherein _Rh is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, _-NRaRa , -C(O) _Rg , -C(O) _{NRaRa , -S} (O) _Rf , or _{-SO2Rf ,} wherein each Ra is independently H or optionally substituted alkyl, which optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and _-ORb , wherein _Rb is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, _{and Rg} is optionally substituted alkyl or optionally substituted cycloalkyl.

In certain embodiments, _R6 is -N=S(O) _{RcRd , Rc} , _Rd together with the S atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl, which is optionally substituted by one or more _Rh , wherein _Rh is selected from optionally substituted _C1 - _C4 alkyl, optionally substituted _C2 - _C4 alkynyl, optionally substituted _C3 - _C6 cycloalkyl _, optionally substituted 4-9 membered heterocyclyl, _-NRaRa , -C(O) _Rg , -C(O) _{NRaRa ,} -S(O) _Rf or _-SO2Rf , wherein each _Ra is independently H or optionally substituted _C1 - _{C4 alkyl} , the above optionally substituted _C1 - _C4 alkyl, optionally substituted _C2 - _C4 alkynyl and optionally substituted C3- _C6 cycloalkyl are optionally substituted by _one or more substituents independently selected from halogen, hydroxyl, cyano and _-ORb , wherein R _Rb is an optionally substituted C ₁ -C ₄ alkyl group, an optionally substituted C ₂ -C ₄ alkenyl group or an optionally substituted C ₂ -C ₄ alkynyl group, and _Rg is an optionally substituted C ₁ -C ₄ alkyl group or an optionally substituted C ₂ -C ₄ cycloalkyl group.

In certain embodiments, _R6 is selected from the group consisting of:

wherein each of them is optionally substituted by one or more R _h , wherein R _h is selected from optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkynyl, optionally substituted C ₃ -C ₆ cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -NR _a R _a , -C(O)R _g , -C(O)NR _a R _a , -S(O)R _f or -SO ₂ R _f , wherein each R _a is independently H or optionally substituted C ₁ -C ₄ alkyl, the above optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkynyl and optionally substituted C ₃ -C ₆ cycloalkyl are optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano and -OR _b , wherein R _b is optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl, and R _g is optionally substituted C ₁ -C ₄ alkyl or an optionally substituted C ₂ -C ₄ cycloalkyl.

In certain embodiments, R _h is selected from the group consisting of C ₁ -C ₄ alkyl optionally substituted with one or more substituents independently selected from hydroxy, halogen, cyano or -O(C ₂ -C ₄ alkynyl), C 2 -C ₄ alkynyl, C _{3 -C 6} cycloalkyl, 4-9 membered heterocyclyl optionally substituted with one or more C ₁ -C ₄ alkyl, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -C(O)-(C ₁ -C ₄ alkyl), -C(O)-(C ₂ -C ₄ cycloalkyl), -C(O)NH ₂ , and -SO ₂ (C ₁ -C ₄ alkyl), wherein the C ₁ -C ₄ alkyl in -NH(C ₁ -C ₄ alkyl) and -C(O)-(C ₁ -C ₄ alkyl) is optionally substituted with one or more halogen or hydroxy.

In some embodiments, _R6 is selected from the group consisting of:

In some embodiments, _R6 is -N=S(O) _RcRd , _and Ring C is a bond or heteroaryl.

In some embodiments, _R6 is -( _CH2 ) _sS (O)(= _NRe ) _Rf , _Re is H, cyano or optionally substituted alkyl, _Rf is optionally substituted alkyl, wherein the optionally substituted alkyl is optionally substituted with one or more _substituents independently selected from halogen, hydroxy, cyano or _-NRaRa .

In certain embodiments, R ₆ is -(CH ₂ ) _s S(O)(=NR _e )R _f , _Re is H, cyano or optionally substituted C ₁ -C ₄ alkyl, and R _f is optionally substituted C ₁ -C ₄ alkyl, wherein the optionally substituted C ₁ -C ₄ alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano or -NR _{a Ra} .

In certain embodiments, R ₆ is —(CH ₂ ) _s S(O)(═NR _e )R _f , _Re is H, cyano or methyl, R _f is methyl, and s is 0 or 1.

In some embodiments, R ₆ is -(CH ₂ ) _s S(O)(=NR _e )R _f , and Ring C is aryl or heteroaryl.

In some embodiments, each R ₇ is independently halogen, cyano, optionally substituted alkyl, -OR _a , -S(O)R _f , -SO ₂ R _f , or -NR _g R _g .

In certain embodiments, _R7 is each independently halogen, cyano, optionally substituted C1 _{- C4} alkyl, -O( _C1 - _C4 alkyl), -O( _C2 - _C4 alkynyl), -S(O)( _C1 - _C4 alkyl), _-SO2 ( _C1 - _C4 alkyl), or _-NRgRg , wherein _Rg is each independently H, _-SO2 ( _C1 - _C4 alkyl), or hydroxy-substituted _C1 - _C4 alkyl; or two _Rgs together with the N atom to which they are attached form an optionally substituted 4-10 membered _heterocyclyl .

In some embodiments, the present application provides a compound having the following formula:

or a pharmaceutically acceptable salt thereof,

in

_V1 and _V2 are each independently N or CH;

Ring C is a bond, aryl or heteroaryl;

Z ₁ is a bond, -O-, -CO-, -NR _a - or -(CH ₂ ) _r -NR _a -CO-;

Z ₂ is **-Y ₁ -Y ₂ -*, wherein Y ₁ is a bond, optionally substituted alkyl or optionally substituted alkynyl, and Y ₂ is a bond or O;

_R1 and _R2 are each independently hydroxy or optionally substituted alkyl; or

_R1 and _R2 together with the carbon atom to which they are attached form an optionally substituted

_R3 is H, halogen or optionally substituted alkyl;

R ₄ is each independently halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -(CH ₂ ) _r NR _a R _a or -OR _b ;

_R5 is optionally substituted alkyl or optionally substituted alkenyl;

R ₇ is each independently halogen, cyano, optionally substituted alkyl, -OR _a , -S(O)R _f , -SO ₂ R _f or -NR _g R _g ; _Ra is each independently H, optionally substituted alkyl or -COR _b ;

R _b is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

R _c and R _d are each independently selected from optionally substituted alkyl or -NR _a R _a ; or R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group;

_Rf is an optionally substituted alkyl group;

_Rg is each independently H, _-SO2Rf or an optionally substituted _alkyl group; or two _Rg together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group; and

r, s, m, n and p are each independently 0, 1 or 2.

In some embodiments, It is phenyl, pyridyl or pyridonyl.

In some embodiments, Ring C is a bond.

In some embodiments, ring C is aryl. In some embodiments, ring C is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In some embodiments, ring C is phenyl or naphthyl. In some embodiments, ring C is phenyl.

In some embodiments, ring C is a heteroaryl. In some embodiments, ring C is a 5-14 membered heteroaryl, a 5-12 membered heteroaryl, a 5-10 membered heteroaryl, a 5-8 membered heteroaryl, a 5-6 membered heteroaryl. In some embodiments, ring C is selected from pyrimidinyl, pyrazinyl, pyridinyl, piperidinyl, piperazinyl, morpholinyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, furanyl, pyrrolyl, triazolyl or triazinyl.

In certain embodiments, Ring C is pyrimidinyl, pyrazinyl, pyridinyl, thiazolyl, or oxazolyl.

In certain embodiments, Select from the following group:

In some embodiments, R ₁ and R ₂ are each independently H, hydroxyl, or optionally substituted alkyl.

In certain embodiments, R ₁ and R ₂ are both optionally substituted alkyl, which are optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, and -NR _a R _a . In certain embodiments, R ₁ and R ₂ are each independently optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, R ₁ and R ₂ are both methyl.

In certain embodiments, one of R ₁ and R ₂ is optionally substituted alkyl and the other is H or hydroxy, wherein the optionally substituted alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and -NR _{a Ra} .

In certain embodiments, one of _R and _R is optionally substituted C ₁ -C ₄ alkyl and the other is H or hydroxy, wherein the optionally substituted C ₁ -C ₄ alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano and -NR _{a Ra} .

In certain embodiments, one of R ₁ and R ₂ is methyl and the other is hydroxy.

In certain embodiments, R ₁ and R ₂ together with the carbon atoms to which they are attached form an optionally substituted

In certain embodiments, R ₁ and R ₂ together with the carbon atoms to which they are attached form

In some embodiments, each R ₃ is independently H, halogen, optionally substituted alkyl, or -OR _b .

In some embodiments, each R ₃ is independently H, or optionally substituted alkyl.

In some embodiments, each R ₃ is independently H, fluoro, chloro, or optionally substituted C ₁ -C ₄ alkyl.

In some embodiments, each R ₃ is independently optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, each R ₃ is independently optionally substituted C _{1 -C 4} alkyl, which is optionally substituted with one _or more substituents independently selected from halogen, hydroxy, cyano, and -NR _a R _a .

In some embodiments, each R ₃ is independently selected from halogen.

In some embodiments, R ₃ is fluoro.

In some embodiments, R ₃ is chloro.

In certain embodiments, _R3 is H.

In some embodiments, each _R is independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -( _CH2 ) _rNRaRa , or _-ORb , wherein _{each Ra is} independently _H , optionally substituted alkyl, or _-CORb , and _Rb is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, wherein said optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted cycloalkyl are optionally substituted with one or more _substituents independently selected from halogen, hydroxy, cyano, and _-NRaRa .

In certain embodiments, each R ₄ is independently H, halogen, cyano, oxo, cyclopropyl, -(CH ₂ ) _r NR _a R _a , or -OR _b , wherein each R _a is independently H, optionally substituted C ₂ -C ₄ alkenyl, or -COR _b , and R _b is H, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl, or optionally substituted C ₂ -C ₄ alkynyl.

In certain embodiments, each R ₄ is independently H, chloro, cyano, oxo, cyclopropyl, -OCH ₃ , -OC≡CH, or -CH ₂ NH (CH=CH ₂ ).

In certain embodiments, each R ₄ is independently H, chloro, cyano, oxo, cyclopropyl, or -OCH ₃ .

In some embodiments, Z ₁ is a bond, -O-, -CO-, -NR _a -, or -(CH ₂ ) _r -NR _a -CO-, wherein _Ra is H or optionally substituted alkyl.

In certain embodiments, Z ₁ is a bond, -O-, -CO-, -NR _a -, or -(CH ₂ ) _r -NR _a -CO-, wherein _Ra is H or optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, Z ₁ is a bond, -O-, -CO-, -NH-, -NHCO-, or -CH ₂ NHCO-.

In some embodiments, _{R 5} is H, optionally substituted C ₁ -C ₄ alkyl _, optionally _substituted C _{2 -C 4} alkenyl, or optionally substituted C _{2 -C 4} alkynyl, which is optionally substituted with one or more substituents independently selected from halogen, hydroxy, _cyano , and -NR _a R _a .

In certain embodiments, R ₅ is H, optionally substituted C ₁ -C ₄ alkyl, or optionally substituted C ₂ -C ₄ alkenyl, wherein the optionally substituted C ₁ -C ₄ alkyl and the optionally substituted C ₂ -C ₄ alkenyl are optionally substituted with one or more substituents independently selected from halogen, hydroxyl, or cyano.

In certain embodiments, R ₅ is H, methyl, ethyl, propyl, or vinyl, wherein the methyl, ethyl, propyl, and vinyl are optionally substituted with one or more substituents independently selected from chloro, hydroxy, or cyano.

In some embodiments, Z ₁ is a bond or —O—, R ₅ is H, optionally substituted C ₁ -C ₄ alkyl, the optionally substituted C ₁ -C ₄ alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or —NR _a R _a .

In certain embodiments, Z ₁ is a bond or -O-, and R ₅ is H, methyl, ethyl, or propyl, wherein the methyl, ethyl, and propyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, or cyano.

In certain embodiments, Z ₁ is a bond or -O-, and R ₅ is H, methyl, ethyl, or propyl, wherein the methyl, ethyl, and propyl are optionally substituted with one or more substituents independently selected from fluoro, chloro, or hydroxy.

In some embodiments, Z ₁ is -CO- or -(CH ₂ ) _r -NR _a -CO-, and R ₅ is optionally substituted C _{2 -C 4 alkenyl} , which is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR _a R _a .

In certain embodiments, Z ₁ is -CO- or -(CH ₂ ) _r -NR _a -CO-, and R ₅ is vinyl.

In some embodiments, -Z ₁ -R ₅ is selected from -(CH ₂ ) _r Cl, -O(CH ₂ ) _r F, -O(CH ₂ ) _r Cl, or -O(CH ₂ ) _r OH, wherein r is 1, 2, or 3.

In some embodiments, Y ₁ is a bond and Y ₂ is O, NH or S.

In some embodiments, Y ₁ is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, and Y ₂ is a bond or O, wherein the optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, alkyl, or oxo.

In some embodiments, Y ₁ is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, and Y ₂ is a bond or O, wherein the optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or oxo.

In certain embodiments, Y ₁ is optionally substituted alkyl or optionally substituted alkynyl, and Y ₂ is a bond or O, wherein optionally substituted alkyl and optionally substituted alkynyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, alkyl, or oxo.

In certain embodiments, Y ₁ is optionally substituted alkyl or optionally substituted alkynyl, and Y ₂ is a bond or O, wherein optionally substituted alkyl and optionally substituted alkynyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or oxo.

In certain embodiments, _Y1 is optionally substituted _C1 - _C4 alkyl or optionally substituted _C2 - _C4 alkynyl, and _Y2 is a bond or O, wherein optionally substituted _C1 - _C4 alkyl and optionally substituted _C2 - _C4 alkynyl are optionally substituted with one or more substituents independently selected from hydroxy or oxo.

In certain embodiments, Y ₁ is C ₁ -C ₄ alkyl optionally substituted with one or more substituents independently selected from hydroxy or oxo, and Y ₂ is O.

In certain embodiments, Y ₁ is C ₂ -C ₄ alkynyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or oxo, and Y ₂ is a bond.

In some embodiments, Z ₂ is selected from -O-, **-(C _1-3 alkyl)-O-*, ethynyl or propynyl, wherein the C _1-3 alkyl in -(C _1-3 alkyl)-O- is optionally substituted with one or more hydroxyl or oxo.

In certain embodiments, Z ₂ is **-CH ₂ O-* or ethynyl.

In some embodiments, _Rc and _Rd are each independently selected from optionally substituted alkyl or _{-NRaRa ,} wherein each _Ra is independently H or optionally substituted alkyl.

In certain embodiments, R _c and R _d are each independently selected from optionally substituted C ₁ -C ₄ alkyl or -NR _a R _a , wherein each R _a is independently H or optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, R _c and R _d are each independently optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, one of R _c and R _d is optionally substituted C ₁ -C ₄ alkyl and the other is -NR _a R _a , wherein each R _a is independently H or optionally substituted C ₁ -C ₄ alkyl.

In some embodiments, R _c and R _d are both -CH ₃ -, or one of R _c and R _d is -CH ₃ and the other is -NHCH ₃ .

In some embodiments, _Rc , _Rd, and the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl, which is optionally substituted with one or more _Rh , wherein _Rh is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted _alkynyl , optionally substituted cycloalkyl, optionally substituted heterocyclyl, _-NRaRa , -C(O) _Rg , -C(O) _NRaRa , -S(O) _Rf, or _-SO2Rf , wherein each _Ra is independently H or optionally substituted alkyl, which optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted cycloalkyl are optionally substituted _{with one} or more substituents independently selected from halogen, hydroxy, cyano, and _-ORb , wherein _Rb is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, and _Rg is optionally substituted alkyl or optionally substituted cycloalkyl.

In certain embodiments, R _c , R _d and the S atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl, which is optionally substituted by one or more R _h , wherein R _h is selected from optionally substituted C ₁ -C ₄ alkyl, optionally substituted C _{2 -C 4 alkynyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -NR a Ra , -C(O)R g , -C(O)NR a Ra , -S(O)R f or -SO 2 R f , wherein each Ra is independently H or optionally substituted C 1 -C 4 alkyl , the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl are optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano and -OR b, wherein R b is optionally substituted C 1} -C ₄ alkyl, optionally substituted C ₂ -C 4 alkynyl, optionally substituted C ₃ -C ₆ cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -NR _a Ra , -C(O)R g , -C(O)NR a Ra , -S(O ₎ R f or -SO ₂ R _f , wherein each Ra is independently H or optionally substituted C _{1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2} -C ₄ alkynyl and optionally substituted C 3 -C 6 cycloalkyl Rg is an optionally substituted C ₂ -C ₄ alkenyl group or an optionally substituted C ₂ -C ₄ alkynyl group, _{and Rg} is an optionally substituted C ₁ -C ₄ alkyl group or an optionally substituted C ₂ -C ₄ cycloalkyl group.

In certain embodiments, R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl selected from the group consisting of:

wherein each of them is optionally substituted by one or more R _h , wherein R _h is selected from optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkynyl, optionally substituted C ₃ -C ₆ cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -NR _a R _a , -C(O)R _g , -C(O)NR _a R _a , -S(O)R _f or -SO ₂ R _f , wherein each R _a is independently H or optionally substituted C ₁ -C ₄ alkyl, the above optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkynyl and optionally substituted C ₃ -C ₆ cycloalkyl are optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano and -OR _b , wherein R _b is optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl, and R _g is optionally substituted C ₁ -C ₄ alkyl or an optionally substituted C ₂ -C ₄ cycloalkyl.

In certain embodiments, R _h is selected from the group consisting of C ₁ -C ₄ alkyl optionally substituted with one or more substituents independently selected from hydroxy, halogen, cyano or -O(C ₂ -C ₄ alkynyl), C 2 -C ₄ alkynyl, C _{3 -C 6} cycloalkyl, 4-9 membered heterocyclyl optionally substituted with one or more C ₁ -C ₄ alkyl, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -C(O)-(C ₁ -C ₄ alkyl), -C(O)-(C ₂ -C ₄ cycloalkyl), -C(O)NH ₂ , and -SO ₂ (C ₁ -C ₄ alkyl), wherein the C ₁ -C ₄ alkyl in -NH(C ₁ -C ₄ alkyl) and -C(O)-(C ₁ -C ₄ alkyl) is optionally substituted with one or more halogen or hydroxy.

In some embodiments, R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl selected from the group consisting of:

In some embodiments, Ring C is a bond or heteroaryl.

In some embodiments, each R ₇ is independently halogen, cyano, optionally substituted alkyl, -OR _a , -S(O)R _f , -SO ₂ R _f , or -NR _g R _g .

In certain embodiments, _R7 is each independently halogen, cyano, optionally substituted C1 _{- C4} alkyl, -O( _C1 - _C4 alkyl), -O( _C2 - _C4 alkynyl), -S(O)( _C1 - _C4 alkyl), _-SO2 ( _C1 - _C4 alkyl), or _-NRgRg , wherein _Rg is each independently H, _-SO2 ( _C1 - _C4 alkyl), or hydroxy-substituted _C1 - _C4 alkyl; or two _Rgs together with the N atom to which they are attached form an optionally substituted 4-10 membered _heterocyclyl .

In some embodiments, the present application provides a compound having the following formula:

or a pharmaceutically acceptable salt thereof,

in

_V3 is N or CH;

Ring C is a bond, aryl or heteroaryl;

Ring D is a heterocyclic group or a heteroaryl group;

Z ₁ is a bond, -O-, -CO-, -NR _a - or -(CH ₂ ) _r -NR _a -CO-;

Z ₂ is **-Y ₁ -Y ₂ -*, wherein Y ₁ is a bond, optionally substituted alkyl or optionally substituted alkynyl, and Y ₂ is a bond or O;

_R1 and _R2 are each independently hydroxy or optionally substituted alkyl; or

_R1 and _R2 together with the carbon atom to which they are attached form an optionally substituted

_R3 is H, halogen, optionally substituted alkyl or optionally substituted alkoxy;

R ₄ is each independently halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -(CH ₂ ) _r NR _a R _a or -OR _b ;

_R5 is H, optionally substituted alkyl or optionally substituted alkenyl;

R ₇ is each independently halogen, cyano, optionally substituted alkyl, -OR _a , -S(O)R _f , -SO ₂ R _f or -NR _g R _g ;

R _a is each independently H, optionally substituted alkyl or -COR _b ;

R _b is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

R _c and R _d are each independently selected from optionally substituted alkyl or -NR _a R _a ; or R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group;

_Rf is an optionally substituted alkyl group;

_Rg is each independently H, _-SO2Rf or an optionally substituted _alkyl group; or two _Rg together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group; and

r, s, m, n and p are each independently 0, 1 or 2.

In some embodiments, wherein Selected from:

In some embodiments, Ring D is substituted with 1, 2, or 3 R ₉ , _which is H, halogen, or optionally substituted alkyl.

In some embodiments, Ring D is substituted with 1, 2, or 3 R ₉ selected from H, F, Cl, _{CH 3} , and CF ₃ .

In some embodiments, The saturated nitrogen atom on the ring D is connected to -Z ₁ R ₅ .

In some embodiments, Ring C is a bond.

In some embodiments, Ring C is aryl or heteroaryl.

In some embodiments, ring C is aryl. In some embodiments, ring C is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In some embodiments, ring C is phenyl or naphthyl. In some embodiments, ring C is phenyl.

In some embodiments, ring C is a heteroaryl. In some embodiments, ring C is a 5-14 membered heteroaryl, a 5-12 membered heteroaryl, a 5-10 membered heteroaryl, a 5-8 membered heteroaryl, a 5-6 membered heteroaryl. In some embodiments, ring C is selected from pyrimidinyl, pyrazinyl, pyridinyl, piperidinyl, piperazinyl, morpholinyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, furanyl, pyrrolyl, triazolyl or triazinyl.

In certain embodiments, Ring C is pyrimidinyl, pyrazinyl, pyridinyl, thiazolyl, or oxazolyl.

In certain embodiments, Select from the following group:

In some embodiments, R ₁ and R ₂ are each independently H, hydroxyl, or optionally substituted alkyl.

In certain embodiments, _R and _R are both optionally substituted alkyl, which are optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and -NR _a R _a . In certain embodiments, _R and _R are each independently optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, R ₁ and R ₂ are both methyl.

In certain embodiments, one of R ₁ and R ₂ is optionally substituted alkyl and the other is H or hydroxy, wherein the optionally substituted alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and -NR _{a Ra} .

In certain embodiments, one of R ₁ and R ₂ is optionally substituted C ₁ -C ₄ alkyl and the other is H or hydroxy, wherein the optionally substituted C ₁ -C ₄ alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano and -NR _a R _a .

In certain embodiments, one of R ₁ and R ₂ is methyl and the other is hydroxy.

In certain embodiments, R ₁ and R ₂ together with the carbon atoms to which they are attached form an optionally substituted

In certain embodiments, _R1 and _R2 together with the carbon atoms to which they are attached form

In some embodiments, each R ₃ is independently H or optionally substituted alkyl.

In some embodiments, each R ₃ is independently H, halogen, or optionally substituted alkyl.

In some embodiments, each R ₃ is independently H, halogen, optionally substituted alkyl, or -OR _b .

In some embodiments, each R ₃ is independently H, halogen, optionally substituted alkyl, optionally substituted alkoxy, or -OR _b .

In some embodiments, each R ₃ is independently H, fluoro, chloro, optionally substituted C ₁ -C ₄ alkyl, or optionally substituted C ₁ -C ₄ alkoxy.

In some embodiments, each R ₃ is independently optionally substituted C ₁ -C ₄ alkyl.

In some embodiments, each R ₃ is independently optionally substituted C ₁ -C ₄ alkoxy.

In certain embodiments, each R ₃ is independently optionally substituted C _{1 -C 4} alkyl, which is optionally substituted with one _or more substituents independently selected from halogen, hydroxy, cyano, and -NR _a R _a .

In certain embodiments, each R ₃ is independently optionally substituted C ₁ -C ₄ alkoxy, said optionally substituted C ₁ -C ₄ alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and -NR _a R _a .

In some embodiments, each R ₃ is independently C ₁ -C ₄ alkyl.

In some embodiments, each R ₃ is independently C ₁ -C ₄ alkoxy.

In some embodiments, each R ₃ is independently methyl.

In some embodiments, each R ₃ is independently methoxy.

In some embodiments, each R ₃ is independently selected from halogen.

In some embodiments, R ₃ is fluoro.

In some embodiments, R ₃ is chloro.

In certain embodiments, _R3 is H.

In some embodiments, each _R is independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -( _CH2 ) _rNRaRa , or _-ORb , wherein _{each Ra is} independently _H , optionally substituted alkyl, or _-CORb , and _Rb is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, wherein said optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted cycloalkyl are optionally substituted with one or more _substituents independently selected from halogen, hydroxy, cyano, and _-NRaRa .

In certain embodiments, each R ₄ is independently H, halogen, cyano, oxo, cyclopropyl, -(CH ₂ ) _r NR _a R _a , or -OR _b , wherein each R _a is independently H, optionally substituted C ₂ -C ₄ alkenyl, or -COR _b , and R _b is H, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl, or optionally substituted C ₂ -C ₄ alkynyl.

In certain embodiments, each R ₄ is independently H, chloro, cyano, oxo, cyclopropyl, -OCH ₃ , -OC≡CH, or -CH ₂ NH (CH=CH ₂ ).

In certain embodiments, each R ₄ is independently H, chloro, cyano, oxo, cyclopropyl, or -OCH ₃ .

In some embodiments, Z ₁ is a bond, -O-, -CO-, or -NR _a -, wherein _Ra is H, optionally substituted alkyl, or -COR _b .

In some embodiments, Z ₁ is a bond, -O-, or -CO-.

In some embodiments, Z ₁ is a bond, -O-, -CO-, -NR _a -, or -(CH ₂ ) _r -NR _a -CO-, wherein _Ra is H or optionally substituted alkyl.

In certain embodiments, Z ₁ is a bond, -O-, -CO-, -NR _a -, or -(CH ₂ ) _r -NR _a -CO-, wherein _Ra is H or optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, Z ₁ is a bond, -O-, -CO-, -NH-, -NHCO-, or -CH ₂ NHCO-.

In some embodiments, _R is H, optionally substituted _C1 - _C4 alkyl _, optionally substituted _C2 - _C4 alkenyl _, or optionally substituted _{C2 - C4 alkynyl} , which is optionally substituted with one or more _substituents independently selected from halogen, _hydroxy , _cyano , and _-NRaRa .

In certain embodiments, R ₅ is H, optionally substituted C ₁ -C ₄ alkyl, or optionally substituted C ₂ -C ₄ alkenyl, wherein the optionally substituted C ₁ -C ₄ alkyl and the optionally substituted C ₂ -C ₄ alkenyl are optionally substituted with one or more substituents independently selected from halogen, hydroxyl, or cyano.

In certain embodiments, R ₅ is optionally substituted C _{1 -C 4} alkyl, which is optionally substituted _with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR _a R _a .

In certain embodiments, R ₅ is optionally substituted C _{1 -C 4} alkyl, which is optionally substituted _with one or more substituents independently selected from fluoro, chloro, bromo, hydroxy, cyano, or -NR _a R _a .

In certain embodiments, R ₅ is optionally substituted C _{1 -C 4} alkyl, which is optionally substituted with one _or more substituents independently selected from fluoro, chloro, hydroxy, or cyano.

In certain embodiments, R ₅ is -(CH ₂ )Cl, -CH ₂ CH ₂ (OH)CH ₃ .

In certain embodiments, R ₅ is optionally substituted C _{2 -C 4 alkenyl} , which is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR _a R _a .

In certain embodiments, R ₅ is methyl, ethyl, propyl, or vinyl, optionally substituted with one or more substituents independently selected from chloro, hydroxy, or cyano.

In certain embodiments, R ₅ is vinyl.

In some embodiments, Z ₁ is a bond or —O—, R ₅ is H, optionally substituted C ₁ -C ₄ alkyl, the optionally substituted C ₁ -C ₄ alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or —NR _a R _a .

In certain embodiments, Z ₁ is a bond or -O-, and R ₅ is H, methyl, ethyl, or propyl, wherein the methyl, ethyl, and propyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, or cyano.

In certain embodiments, Z ₁ is a bond or -O-, and R ₅ is H, methyl, ethyl, or propyl, wherein the methyl, ethyl, and propyl groups are optionally substituted with one or more substituents independently selected from fluoro, chloro, or hydroxy.

In some embodiments, Z ₁ is -CO- or -(CH ₂ ) _r -NR _a -CO-, and R ₅ is optionally substituted C _{2 -C 4 alkenyl} , which is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR _a R _a .

In certain embodiments, Z ₁ is -CO- or -(CH ₂ ) _r -NR _a -CO-, and R ₅ is vinyl.

In some embodiments, -Z ₁ -R ₅ is selected from -(CH ₂ ) _r Cl, -O(CH ₂ ) _r F, -O(CH ₂ ) _r Cl, or -O(CH ₂ ) _r OH, wherein r is 1, 2, or 3.

In some embodiments, Y ₁ is a bond and Y ₂ is O, NH or S.

In some embodiments, Y ₁ is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, and Y ₂ is a bond or O, wherein the optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or oxo.

In certain embodiments, Y ₁ is optionally substituted alkyl or optionally substituted alkynyl, and Y ₂ is a bond or O, wherein optionally substituted alkyl and optionally substituted alkynyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or oxo.

In certain embodiments, _Y1 is optionally substituted _C1 - _C4 alkyl or optionally substituted _C2 - _C4 alkynyl, and _Y2 is a bond or O, wherein optionally substituted _C1 - _C4 alkyl and optionally substituted _C2 - _C4 alkynyl are optionally substituted with one or more substituents independently selected from hydroxy or oxo.

In certain embodiments, Y ₁ is C ₁ -C ₄ alkyl optionally substituted with one or more substituents independently selected from hydroxy or oxo, and Y ₂ is O.

In certain embodiments, Y ₁ is C ₂ -C ₄ alkynyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or oxo, and Y ₂ is a bond.

In some embodiments, Z ₂ is -O-, C ₂ -C ₄ alkynyl, or **-(optionally substituted C _{1 -C 4} alkyl)-O-*, wherein the optionally substituted C _{1 -C 4} alkyl is optionally substituted with one or more substituents selected from hydroxy, C 1 -C 4 alkyl, or oxo.

In some embodiments, Z ₂ is -O-, C ₂ -C ₄ alkynyl, or **-(optionally substituted C ₁ -C ₄ alkyl)-O-*, wherein the optionally substituted C _{1 -C 4} alkyl is optionally substituted with one or more substituents selected from hydroxy, or oxo.

In some embodiments, Z ₂ is selected from -O-, **-(C _1-3 alkyl)-O-*, ethynyl or propynyl, wherein the C _1-3 alkyl in -(C _1-3 alkyl)-O- is optionally substituted with one or more hydroxyl or oxo.

In certain embodiments, Z ₂ is **-CH ₂ O-* or ethynyl.

In some embodiments, _Rc and _Rd are each independently selected from optionally substituted alkyl or _{-NRaRa ,} wherein each _Ra is independently H or optionally substituted alkyl.

In certain embodiments, one of R _c and R _d is optionally substituted C ₁ -C ₄ alkyl and the other is -NR _a R _a , wherein each R _a is independently H or optionally substituted C ₁ -C ₄ alkyl.

In some embodiments, one of R _c and R _d is -CH ₃ and the other is -NHCH ₃ .

In certain embodiments, R _c and R _d are each independently selected from optionally substituted C ₁ -C ₄ alkyl or -NR _a R _a , wherein each R _a is independently H or optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, R _c and R _d are each independently optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, R _c and R _d are each independently optionally substituted methyl.

In certain embodiments, R _c and R _d are both methyl.

In certain embodiments, one of R _c and R _d is optionally substituted C ₁ -C ₄ alkyl and the other is -NR _a R _a , wherein each R _a is independently H or optionally substituted C ₁ -C ₄ alkyl.

In some embodiments, R _c and R _d are both -CH ₃ -, or one of R _c and R _d is -CH ₃ and the other is -NHCH ₃ .

In some embodiments, _Rc , _Rd, and the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl, which is optionally substituted with one or more _Rh , wherein _Rh is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted _alkynyl , optionally substituted cycloalkyl, optionally substituted heterocyclyl, _-NRaRa , -C(O) _Rg , -C(O) _NRaRa , -S(O) _Rf, or _-SO2Rf , wherein each _Ra is independently H or optionally substituted alkyl, which optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted cycloalkyl are optionally substituted _{with one} or more substituents independently selected from halogen, hydroxy, cyano, and _-ORb , wherein _Rb is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, and _Rg is optionally substituted alkyl or optionally substituted cycloalkyl.

In certain embodiments, R _c , R _d and the S atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl, which is optionally substituted by one or more R _h , wherein R _h is selected from optionally substituted C ₁ -C ₄ alkyl, optionally substituted C _{2 -C 4 alkynyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -NR a Ra , -C(O)R g , -C(O)NR a Ra , -S(O)R f or -SO 2 R f , wherein each Ra is independently H or optionally substituted C 1 -C 4 alkyl , the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkynyl and optionally substituted C 3 -C 6 cycloalkyl are optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano and -OR b, wherein R b is optionally substituted C 1} -C ₄ alkyl, optionally substituted C ₂ -C 4 alkynyl, optionally substituted C ₃ -C ₆ cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -NR _a Ra , -C(O)R g , -C(O)NR a Ra , -S(O ₎ R f or -SO ₂ R _f , wherein each Ra is independently H or optionally substituted C _{1 -C 4 alkyl, the above optionally substituted C 1 -C 4 alkyl, optionally substituted C 2} -C ₄ alkynyl and optionally substituted C 3 -C 6 cycloalkyl Rg is an optionally substituted C ₂ -C ₄ alkenyl group or an optionally substituted C ₂ -C ₄ alkynyl group, _{and Rg} is an optionally substituted C ₁ -C ₄ alkyl group or an optionally substituted C ₂ -C ₄ cycloalkyl group.

In certain embodiments, R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl selected from the group consisting of:

wherein each of them is optionally substituted by one or more R _h , wherein R _h is selected from optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkynyl, optionally substituted C ₃ -C ₆ cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -NR _a R _a , -C(O)R _g , -C(O)NR _a R _a , -S(O)R _f or -SO ₂ R _f , wherein each R _a is independently H or optionally substituted C ₁ -C ₄ alkyl, the above optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkynyl and optionally substituted C ₃ -C ₆ cycloalkyl are optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano and -OR _b , wherein R _b is optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl, and R _g is optionally substituted C ₁ -C ₄ alkyl or an optionally substituted C ₂ -C ₄ cycloalkyl.

In certain embodiments, R _h is selected from the group consisting of C ₁ -C ₄ alkyl optionally substituted with one or more substituents independently selected from hydroxy, halogen, cyano or -O(C ₂ -C ₄ alkynyl), C 2 -C ₄ alkynyl, C _{3 -C 6} cycloalkyl, 4-9 membered heterocyclyl optionally substituted with one or more C ₁ -C ₄ alkyl, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -C(O)-(C ₁ -C ₄ alkyl), -C(O)-(C ₂ -C ₄ cycloalkyl), -C(O)NH ₂ , and -SO ₂ (C ₁ -C ₄ alkyl), wherein the C ₁ -C ₄ alkyl in -NH(C ₁ -C ₄ alkyl) and -C(O)-(C ₁ -C ₄ alkyl) is optionally substituted with one or more halogen or hydroxy.

In some embodiments, R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl selected from the group consisting of:

In some embodiments, Ring C is a bond or heteroaryl.

In some embodiments, each R ₇ is independently halogen, cyano, optionally substituted alkyl, -OR _a , -S(O)R _f , -SO ₂ R _f , or -NR _g R _g .

In certain embodiments, _R7 is each independently halogen, cyano, optionally substituted C1 _{- C4} alkyl, -O( _C1 - _C4 alkyl), -O( _C2 - _C4 alkynyl), -S(O)( _C1 - _C4 alkyl), _-SO2 ( _C1 - _C4 alkyl), or _-NRgRg , wherein _Rg is each independently H, _-SO2 ( _C1 - _C4 alkyl), or hydroxy-substituted _C1 - _C4 alkyl; or two _Rgs together with the N atom to which they are attached form an optionally substituted 4-10 membered _heterocyclyl .

In some embodiments, R _c and R _d in the compounds of Formula 1-IIa and Formula 1-IIb are each independently C ₁ -C ₄ alkyl or —NH—(C ₁ -C ₄ alkyl).

In some embodiments, R _c and R _d in the compounds of Formula 1-IIa and Formula 1-IIb, together with the S atom to which they are attached, form a 4-10 membered heterocyclyl optionally substituted with one or more R _h .

In some embodiments, _Z2 in the compounds of Formula 1-IIa and Formula 1-IIb is -O-, _C2 - _C4 alkynyl or **-(optionally substituted C1 _{- C4} alkyl)-O-*, wherein the optionally substituted C1 _{- C4} alkyl is optionally substituted with one or more substituents selected from hydroxy or oxo.

In some embodiments, Ring C in the compounds of Formula 1-IIa and Formula 1-IIb is a bond, phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, or oxazolyl.

In one aspect, the present application provides a compound shown in the following formula 2-1:

or a pharmaceutically acceptable salt thereof,

in:

Ring A and Ring B are each independently cycloalkyl, heterocyclyl, aryl or heteroaryl;

Ring C is a bond, cycloalkyl, heterocyclyl, aryl or heteroaryl;

X is C, N, O or S;

R ₁ and R ₂ are each independently absent, H, halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, or -NR _a R _a ;

R ₃ and R ₄ are each independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -(CH ₂ ) _r NR _a R _a or -OR _b ;

Z ₁ is a bond, -O-, -S-, -CO-, -S(O)-, -SO ₂ -, -NR _a - or -(CH ₂ ) _r -NR _a -CO-;

R ₅ is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

R ₆ is -N=S(O)R _c R _d , -(CH ₂ ) _s S(O)(=NR _e )R _f or -NR _a -SO ₂ R _g ;

R ₇ is each independently halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR _a , -S(O)R _f , -SO ₂ R _f or -NR _h R _h ;

Each _Ra is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or _-CORb ;

R _b is H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

R _c and R _d are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR _a or -NR _a R _a ; or R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl;

R _e is H, cyano, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

_Rf is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

_Rg is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted 4-10 membered _heterocyclyl or _-NRhRh ;

R _h is each independently H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; or two R _h together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl;

r is 0, 1, 2, or 3;

s is 0, 1, 2, or 3; and

m, n and p are each independently 0, 1, 2 or 3.

In some embodiments, Ring A is aryl. In some embodiments, Ring A is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In some embodiments, Ring A is phenyl or naphthyl. In some embodiments, Ring A is phenyl.

In some embodiments, ring A is a heteroaryl. In some embodiments, ring A is a 5-14 membered heteroaryl, a 5-12 membered heteroaryl, a 5-10 membered heteroaryl, a 5-8 membered heteroaryl, a 5-6 membered heteroaryl. In some embodiments, ring A is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, pyrrolyl, triazolyl, triazinyl, imidazolyl, pyrazolyl, pyrrolyl, pyridinyl, pyrimidinyl or pyrazinyl.

In certain embodiments, Ring A is pyridinyl, pyrimidinyl, or thienyl. In certain embodiments, Ring A is pyridinyl.

In certain embodiments, Ring A is

In some embodiments, ring B is a heterocyclyl. In some embodiments, ring B is a 5-14 membered heterocyclyl, a 5-12 membered heterocyclyl, a 5-10 membered heterocyclyl, a 5-8 membered heterocyclyl. In some embodiments, ring B is a pyridonyl.

In some embodiments, ring B is aryl. In some embodiments, ring B is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In some embodiments, ring B is phenyl or naphthyl. In some embodiments, ring B is phenyl.

In some embodiments, ring B is a heteroaryl. In certain embodiments, ring B is a 5-14 membered heteroaryl, a 5-12 membered heteroaryl, a 5-10 membered heteroaryl, a 5-8 membered heteroaryl, a 5-6 membered heteroaryl. In certain embodiments, ring B is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, pyrrolyl, triazolyl, triazinyl, pyridonyl, benzomorpholinyl, indazolyl, dihydrobenzoxazinyl, pyrazolopyridinyl, benzotriazolyl, benzimidazolyl, tetrahydroisoquinolinyl, indazolyl, imidazopyridinyl, pyridomorpholinyl, benzisodiazolyl, indolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, decahydroisoquinolyl, dihydroindolyl, octahydroindolyl or octahydroisoindolyl.

In certain embodiments, ring B is selected from pyridinyl, pyridonyl, indazolyl, dihydrobenzoxazinyl, pyrazolopyridinyl, benzotriazolyl, benzimidazolyl, tetrahydroisoquinolinyl, indazolyl, imidazopyridinyl or pyridomorpholinyl. In certain embodiments, ring B is selected from indazolyl, dihydrobenzoxazinyl, benzimidazolyl, benzomorpholinyl, pyridomorpholinyl, pyrazolopyridinyl or benzotriazolyl.

In certain embodiments, Select from the following group:

In some embodiments, Ring C is a bond.

In some embodiments, ring C is aryl. In some embodiments, ring C is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In some embodiments, ring C is phenyl or naphthyl. In some embodiments, ring C is phenyl.

In some embodiments, ring C is a heteroaryl. In certain embodiments, ring C is a 5-14 membered heteroaryl, a 5-12 membered heteroaryl, a 5-10 membered heteroaryl, a 5-8 membered heteroaryl, a 5-6 membered heteroaryl. In certain embodiments, ring C is selected from pyrimidinyl, pyrazinyl, pyridinyl, piperidinyl, piperazinyl, morpholinyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, furanyl, pyrrolyl, triazolyl or triazinyl. In certain embodiments, ring C is a pyrimidinyl, pyrazinyl, pyridinyl, thiazolyl or oxazolyl. In certain embodiments, ring C is a pyrimidinyl, pyrazinyl or pyridinyl.

In certain embodiments, Select from the following group:

In some embodiments, X is N, O or S, and R ₁ and R ₂ are absent.

In some embodiments, X is C, and R ₁ and R ₂ are each independently H, hydroxy, or optionally substituted alkyl.

In certain embodiments, X is C, _R1 and _R2 are each optionally substituted alkyl, the optionally substituted alkyl being optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano and -NR _a R _a . In certain embodiments, X is C, _R1 and _R2 are each independently optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, X is C, and R ₁ and R ₂ are both methyl.

In certain embodiments, X is C, one of R ₁ and R ₂ is optionally substituted alkyl, and the other is H or hydroxy, wherein the optionally substituted alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and -NR _{a Ra} .

In certain embodiments, X is C, one of _R1 and _R2 is optionally substituted _C1 - _C4 alkyl, and the other is H or hydroxy, wherein the optionally substituted _C1 - _C4 alkyl is optionally substituted with one or more _substituents independently selected from halogen, hydroxy, cyano and _-NRaRa .

In certain embodiments, X is C, one of R ₁ and R ₂ is methyl and the other is hydroxy.

In some embodiments, each R ₃ is independently H, halogen, OR _b , or optionally substituted alkyl.

In some embodiments, each R ₃ is independently optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, each R ₃ is independently optionally substituted C _{1 -C 4} alkyl, which is optionally substituted with one _or more substituents independently selected from halogen, hydroxy, cyano, and -NR _a R _a .

In some embodiments, each R ₃ is independently H or halogen.

In some embodiments, each R ₃ is independently selected from halogen.

In some embodiments, each R ₃ is independently fluoro or chloro.

In some embodiments, R ₃ is fluoro.

In some embodiments, R ₃ is chloro.

In certain embodiments, _R3 is H.

In some embodiments, each _R is independently H, halo, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -( _CH2 ) _{rNRaRa ,} or _-ORb , wherein each _Ra is independently _H , optionally substituted alkyl, or _-CORb , and _Rb is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, wherein said optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl are optionally substituted with one or more substituents independently selected from halo, _hydroxy , cyano, and _-NRaRa .

In certain embodiments, each R ₄ is independently H, halogen, cyano, oxo, -(CH ₂ ) _r NR _a R _a, or -OR _b , wherein each R _a is independently H, optionally substituted C ₂ -C ₄ alkenyl, or -COR _b , and R _b is H, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl, or optionally substituted C ₂ -C ₄ alkynyl.

In certain embodiments, each R ₄ is independently H, chloro, cyano, oxo, -OCH ₃ , -OC≡CH, or -CH ₂ NH (CH=CH ₂ ).

In certain embodiments, each R ₄ is independently H, chloro, cyano, oxo, or -OCH ₃ .

In some embodiments, Z ₁ is a bond, -O-, -CO-, or -NR _a -, wherein _Ra is H or optionally substituted alkyl.

In some embodiments, Z ₁ is a bond, -O-, -S-, -CO-, -S(O)-, -SO ₂ -, or -NR _a -.

In some embodiments, Z ₁ is a bond, -O-, -S-, -CO-, -S(O)-, -SO ₂ -, or -NR _a -, wherein Ra is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or -COR _b , wherein R _{b is} H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl.

In some embodiments, Z ₁ is a bond, -O-, -CO-, or -(CH ₂ ) _r -NR _a -CO-, wherein _Ra is H or optionally substituted alkyl.

In certain embodiments, Z ₁ is a bond, -O-, -CO-, -NR _a -, or -(CH ₂ ) _r -NR _a -CO-, wherein _Ra is H or optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, Z ₁ is a bond, -O-, -CO-, -NH-, -NHCO-, or -CH ₂ NHCO-.

In some embodiments, R ₅ is optionally substituted C ₁ -C ₄ alkyl, optionally substituted C _{2 -C 4} alkenyl, or optionally substituted C _{2 -C 4 alkynyl ,} which is optionally substituted with one or more _substituents independently selected from halogen, hydroxy _, cyano, and -NR _a R _a .

In certain embodiments, R ₅ is optionally substituted C ₁ -C ₄ alkyl or optionally substituted C ₂ -C ₄ alkenyl, wherein the optionally substituted C ₁ -C ₄ alkyl and the optionally substituted C ₂ -C ₄ alkenyl are optionally substituted with one or more substituents independently selected from halogen, hydroxyl or cyano.

In certain embodiments, R ₅ is methyl, ethyl, propyl, or vinyl, optionally substituted with one or more substituents independently selected from chloro, hydroxy, or cyano.

In some embodiments, Z ₁ is a bond or —O—, and R ₅ is optionally substituted C _{1 -C 4} alkyl _, which is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or —NR _a R _a .

In certain embodiments, Z ₁ is a bond or -O-, and R ₅ is methyl, ethyl, or propyl, wherein the methyl, ethyl, and propyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, or cyano.

In certain embodiments, Z ₁ is a bond or -O-, and R ₅ is methyl, ethyl, or propyl, wherein the methyl, ethyl, and propyl groups are optionally substituted with one or more substituents independently selected from fluoro, chloro, or hydroxy.

In some embodiments, Z ₁ is -CO- or -(CH ₂ ) _r -NR _a -CO-, and R ₅ is optionally substituted C _{2 -C 4 alkenyl} , which is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR _a R _a .

In certain embodiments, Z ₁ is -CO- or -(CH ₂ ) _r -NR _a -CO-, and R ₅ is vinyl.

In some embodiments, -Z ₁ -R ₅ is selected from -(CH ₂ ) _r Cl, -O(CH ₂ ) _r F, -O(CH ₂ ) _r Cl, or -O(CH ₂ ) _r OH, wherein r is 1, 2, or 3.

In some embodiments _{, R6} is -N=S(O) _RcRd or _{-NRa - SO2Rg} .

In some embodiments, _R6 is -N=S(O) _{RcRd , Rc} and _Rd are each independently selected from optionally substituted alkyl, _-ORa , or _-NRaRa , wherein each _Ra is independently H, optionally substituted alkyl, or optionally substituted _alkynyl .

In certain embodiments, R ₆ is -N=S(O)R _c R _d , R _c and R _d are each independently selected from optionally substituted C ₁ -C ₄ alkyl, -OR _a or -NR _{a Ra} , wherein each _Ra is independently H, optionally substituted C ₁ -C ₄ alkyl or optionally substituted C ₂ -C ₄ alkynyl.

In certain embodiments, R ₆ is -N=S(O)R _c R _d , and R _c and R _d are each independently optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, R ₆ is -N=S(O)R _c R _d , one of R _c and R _d is optionally substituted C ₁ -C ₄ alkyl and the other is -OR _a or -NR _{a Ra} , wherein each _Ra is independently H, optionally substituted C ₁ -C ₄ alkyl or optionally substituted C ₂ -C ₄ alkynyl.

In certain embodiments, R ₆ is -N=S(O)R _c R _d , one of R _c and R _d is optionally substituted C ₁ -C ₄ alkyl and the other is -NR _a R _a , wherein each R _a is independently H or optionally substituted C ₁ -C ₄ alkyl.

In some embodiments, R ₆ is —N═S(O)(CH ₃ ) ₂ or —N═S(O)(CH ₃ )(NHCH ₃ ).

In some embodiments, _R is -N=S(O) _{RcRd , Rc} , _Rd together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl, which is optionally substituted with one or more _R , wherein _R is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -C(O) _Rj- , _-NRaRa , -C(O) _{NRaRa ,} -S(O) _Rf , or _-SO2Rf , wherein each _Ra is independently H or optionally substituted alkyl, _which is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted cycloalkyl, which is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and _-ORb , wherein _{Rb is} optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, and _Rj is optionally substituted alkyl or cycloalkyl.

In certain embodiments, _R6 is -N=S(O) _{RcRd , Rc} , _Rd together with the S atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl, the optionally substituted 4-6 membered heterocyclyl is optionally substituted by one or more _R , wherein _R1 is selected from optionally substituted _C1 - _{C4 alkyl} , optionally substituted _C2 - _C4 alkynyl _, optionally substituted C3 _{- C6} cycloalkyl, _-NRaRa , -C(O) _NRaRa , -S(O) _Rf or _-SO2Rf , wherein each _Ra is independently H or optionally substituted _C1 - _C4 alkyl, the above optionally substituted _C1 - _C4 alkyl _, optionally substituted C2- _C4 alkynyl and optionally substituted _C3 - _C6 cycloalkyl are optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano and _-ORb , wherein _Rb is optionally substituted _C1 - _C4 alkyl, optionally substituted _C2 - _C4 alkynyl, -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl.

In certain embodiments, _R6 is selected from the group consisting of:

Each of which is optionally substituted by one or more R _i , wherein R _i is selected from optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkynyl, optionally substituted C ₃ -C ₆ cycloalkyl, -NR _a R _a , -C(O)NR _a R _a , -S(O)R _f or -SO ₂ R _f , wherein R _a is each independently H or optionally substituted C ₁ -C ₄ alkyl, the above optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkynyl and optionally substituted C ₃ -C ₆ cycloalkyl are optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano and -OR _b , wherein R _b is optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl.

In certain embodiments, R _i is selected from the group consisting of C ₁ -C ₄ alkyl optionally substituted with one or more hydroxyl, cyano, -O(C ₁ -C ₄ alkyl), or -O(C ₂ -C ₄ alkynyl), C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -C(O)NH ₂ , and -SO ₂ (C ₁ -C ₄ alkyl), wherein the C ₁ -C ₄ alkyl in -NH(C ₁ -C ₄ alkyl) is optionally substituted with one or more halogen or hydroxyl.

In some embodiments, _R6 is selected from the group consisting of:

In some embodiments, _R6 is -N=S(O) _RcRd , and Ring C is a bond or _{heteroaryl. In certain embodiments, R6 is -N=S(O)RcRd , and} Ring C is a bond, pyrimidinyl _, or pyrazinyl.

In some embodiments, _R6 is -( _CH2 ) _sS (O)(= _NRe ) _Rf , _Re is H, cyano or optionally substituted alkyl, _Rf is optionally substituted alkyl, wherein the optionally substituted alkyl is optionally substituted with one or more _substituents independently selected from halogen, hydroxy, cyano or _-NRaRa .

In certain embodiments, R ₆ is -(CH ₂ ) _s S(O)(=NR _e )R _f , _Re is H, cyano or optionally substituted C ₁ -C ₄ alkyl, and R _f is optionally substituted C ₁ -C ₄ alkyl, wherein the optionally substituted C ₁ -C ₄ alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano or -NR _{a Ra} .

In certain embodiments, R ₆ is —(CH ₂ ) _s S(O)(═NR _e )R _f , _Re is H, cyano or methyl, R _f is methyl, and s is 0 or 1.

In some embodiments, _R6 is -( _CH2 ) _sS (O)(= _NRe ) _Rf , and Ring C is aryl or heteroaryl. In certain embodiments, _R6 is -( _CH2 ) _sS (O)(= _NRe ) _Rf , and Ring C is phenyl, pyridinyl, or pyrimidinyl.

In some embodiments, R ₆ is —NR _a —SO ₂ R _g , _Ra is H or optionally substituted alkyl, and R _g is optionally substituted alkyl, optionally substituted 4-10 membered heterocyclyl, or —NR _h R _h .

In certain embodiments, _R6 is _{-NRa- SO2Rg} , _Ra is H or alkyl optionally substituted with one or more _substituents independently selected from halogen, hydroxyl, or _cyano . In certain embodiments, _R6 is _{-NRa- SO2Rg} , _Ra is H or -( _CH2 ) _2OH .

In certain embodiments, _R is -NR _a -SO ₂ R _g , R _g is alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano or -NR _{a Ra} . In certain embodiments, _R is -NR _a -SO ₂ R _g , R _g is C ₁ -C ₄ alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano or -NR _{a Ra} . In certain embodiments, _R is -NR _a -SO ₂ R _g , R _g is methyl, -(CH ₂ ) ₂ NH ₂ or -(CH ₂ ) ₂ N(CH ₃ ) ₂ .

In certain embodiments, _R6 is _{-NRa- SO2Rg , Rg} is a 4-10 membered heterocyclyl optionally substituted with one or more substituents independently selected from halogen, hydroxyl, _cyano or _-NRaRa , wherein _Ra is independently selected from hydrogen or _alkyl . In certain embodiments, _R6 is _{-NRa- SO2Rg} , _Rg is piperidinyl or tetrahydropyranyl.

In certain embodiments, R ₆ is -NR _a -SO ₂ R _g , R _g is -NR _h R _h , wherein each R _h is independently hydrogen or alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl or cyano, or two R _h together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl. In certain embodiments, R ₆ is -NR _a -SO ₂ R _g , R _g is -NR _h R _h , wherein each R _h is independently hydrogen, methyl or -(CH ₂ ) ₂ OH, or two R _h together with the N atom to which they are attached form a piperazinyl.

In some embodiments, each R ₇ is independently halogen, cyano, optionally substituted alkyl, -OR _a , -S(O)R _f , -SO ₂ R _f , or -NR _g R _g .

In certain embodiments, _R7 is each independently halogen, cyano, optionally substituted C1 _{- C4} alkyl, -O( _C1 - _C4 alkyl), -O( _C2 - _C4 alkynyl), -S(O)( _C1 - _C4 alkyl), _-SO2 ( _C1 - _C4 alkyl), or _-NRgRg , wherein _Rg is each independently H, _-SO2 ( _C1 - _C4 alkyl), or hydroxy-substituted _C1 - _C4 alkyl; or two _Rgs together with the N atom to which they are attached form an optionally substituted 4-10 membered _heterocyclyl .

In some embodiments, the present application provides a compound having the following formula:

or a pharmaceutically acceptable salt thereof,

in

_V1 and _V2 are each independently N or CH;

Ring C is a bond, aryl or heteroaryl;

Z ₁ is a bond, -O-, -CO-, -NR _a - or -(CH ₂ ) _r -NR _a -CO-;

_R1 and _R2 are each independently hydroxy or optionally substituted alkyl;

_R3 is H, _ORb or optionally substituted alkyl;

R ₄ is each independently halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -(CH ₂ ) _r NR _a R _a or -OR _b ;

_R5 is optionally substituted alkyl or optionally substituted alkenyl;

R ₇ is each independently halogen, cyano, optionally substituted alkyl, -OR _a , -S(O)R _f , -SO ₂ R _f or -NR _h R _h ; _{Ra is} each independently H, optionally substituted alkyl or -COR _b ;

R _b is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

R _c and R _d are each independently selected from optionally substituted alkyl or -NR _a R _a ; or R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group;

_Rf is an optionally substituted alkyl group;

R _h is each independently H, -SO ₂ R _f or an optionally substituted alkyl group; or two R _h together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl group; and

r, s, m, n and p are each independently 0, 1 or 2.

In some embodiments, It is phenyl, pyridyl or pyridonyl.

In certain embodiments, Select from the following group:

In some embodiments, Ring C is a bond.

In some embodiments, Ring C is aryl or heteroaryl.

In some embodiments, ring C is aryl. In some embodiments, ring C is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In some embodiments, ring C is phenyl or naphthyl. In some embodiments, ring C is phenyl.

In some embodiments, ring C is a heteroaryl. In certain embodiments, ring C is a 5-14 membered heteroaryl, a 5-12 membered heteroaryl, a 5-10 membered heteroaryl, a 5-8 membered heteroaryl, a 5-6 membered heteroaryl. In certain embodiments, ring C is selected from pyrimidinyl, pyrazinyl, pyridinyl, piperidinyl, piperazinyl, morpholinyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, furanyl, pyrrolyl, triazolyl or triazinyl. In certain embodiments, ring C is a pyrimidinyl, pyrazinyl, pyridinyl, thiazolyl or oxazolyl. In certain embodiments, ring C is a pyrimidinyl, pyrazinyl or pyridinyl.

In certain embodiments, Select from the following group:

In some embodiments, each R ₃ is independently H, halogen, OR _b , or optionally substituted alkyl.

In some embodiments, each R ₃ is independently optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, each R ₃ is independently optionally substituted C _{1 -C 4} alkyl, which is optionally substituted with one _or more substituents independently selected from halogen, hydroxy, cyano, and -NR _a R _a .

In some embodiments, each R ₃ is independently H or halogen.

In some embodiments, each R ₃ is independently selected from halogen.

In some embodiments, each R ₃ is independently fluoro or chloro.

In some embodiments, R ₃ is fluoro.

In some embodiments, R ₃ is chloro.

In certain embodiments, _R3 is H.

In some embodiments, each _R is independently H, halo, _cyano , oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -( _CH2 ) _{rNRaRa ,} or _-ORb , wherein each _Ra is independently H, optionally substituted alkyl, or _-CORb , and _Rb is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, wherein said optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl are optionally substituted with one or more substituents independently selected from halo, _hydroxy , cyano, and _-NRaRa .

In certain embodiments, each R ₄ is independently H, halogen, cyano, oxo, -(CH ₂ ) _r NR _a R _a, or -OR _b , wherein each R _a is independently H, optionally substituted C ₂ -C ₄ alkenyl, or -COR _b , and R _b is H, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl, or optionally substituted C ₂ -C ₄ alkynyl.

In certain embodiments, each R ₄ is independently H, chloro, cyano, oxo, -OCH ₃ , -OC≡CH, or -CH ₂ NH (CH=CH ₂ ).

In certain embodiments, each R ₄ is independently H, chloro, cyano, oxo, or -OCH ₃ .

In some embodiments, Z ₁ is a bond, -O-, -CO-, -NR _a -, or -(CH ₂ ) _r -NR _a -CO-, wherein _Ra is H or optionally substituted alkyl.

In certain embodiments, Z ₁ is a bond, -O-, -CO-, -NR _a -, or -(CH ₂ ) _r -NR _a -CO-, wherein _Ra is H or optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, Z ₁ is a bond, -O-, -CO-, -NH-, -NHCO-, or -CH ₂ NHCO-.

In certain embodiments, Z ₁ is a bond, -O-, or -CO-.

In some embodiments, R ₅ is optionally substituted C ₁ -C ₄ alkyl, optionally substituted C _{2 -C 4} alkenyl, or optionally substituted C _{2 -C 4 alkynyl ,} which is optionally substituted with one or more _substituents independently selected from halogen, hydroxy _, cyano, and -NR _a R _a .

In certain embodiments, R ₅ is optionally substituted C ₁ -C ₄ alkyl or optionally substituted C ₂ -C ₄ alkenyl, wherein the optionally substituted C ₁ -C ₄ alkyl and the optionally substituted C ₂ -C ₄ alkenyl are optionally substituted with one or more substituents independently selected from halogen, hydroxyl or cyano.

In certain embodiments, R ₅ is methyl, ethyl, propyl, or vinyl, optionally substituted with one or more substituents independently selected from chloro, hydroxy, or cyano.

In some embodiments, Z ₁ is a bond or —O—, and R ₅ is optionally substituted C _{1 -C 4} alkyl _, which is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or —NR _a R _a .

In certain embodiments, Z ₁ is a bond or -O-, and R ₅ is methyl, ethyl, or propyl, wherein the methyl, ethyl, and propyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, or cyano.

In certain embodiments, Z ₁ is a bond or -O-, and R ₅ is methyl, ethyl, or propyl, wherein the methyl, ethyl, and propyl groups are optionally substituted with one or more substituents independently selected from fluoro, chloro, or hydroxy.

In some embodiments, Z ₁ is -CO- or -(CH ₂ ) _r -NR _a -CO-, and R ₅ is optionally substituted C _{2 -C 4 alkenyl} , which is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR _a R _a .

In certain embodiments, Z ₁ is -CO- or -(CH ₂ ) _r -NR _a -CO-, and R ₅ is vinyl.

In some embodiments, -Z ₁ -R ₅ is selected from -(CH ₂ ) _r Cl, -O(CH ₂ ) _r F, -O(CH ₂ ) _r Cl, or -O(CH ₂ ) _r OH, wherein r is 1, 2, or 3.

In some embodiments, _Rc and _Rd are each independently selected from optionally substituted alkyl or _{-NRaRa ,} wherein each _Ra is independently H or optionally substituted alkyl.

In certain embodiments, R _c and R _d are each independently selected from optionally substituted C ₁ -C ₄ alkyl or -NR _a R _a , wherein each R _a is independently H or optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, R _c and R _d are each independently optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, one of R _c and R _d is optionally substituted C ₁ -C ₄ alkyl and the other is -NR _a R _a , wherein each R _a is independently H or optionally substituted C ₁ -C ₄ alkyl.

In some embodiments, R _c and R _d are both -CH ₃ -, or one of R _c and R _d is -CH ₃ and the other is -NHCH ₃ .

In some embodiments, R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl, which optionally substituted 4-10 membered heterocyclyl is optionally substituted with one or more R _i , wherein R _i is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -C(O)R _j -, -NR _{a Ra} , -C(O)NR _{a Ra} , -S(O)R _f or -SO ₂ R _f , wherein each _Ra is independently H or optionally substituted alkyl, which optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano and -OR _b , wherein R _b is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, and R _j is optionally substituted alkyl or cycloalkyl.

In certain embodiments, R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl, which is optionally substituted by one or more R _i , wherein R _i is selected from optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkynyl, optionally substituted C ₃ -C ₆ cycloalkyl, -NR _{a Ra} , -C(O)NR _{a Ra} , -S(O)R _f or -SO ₂ R _f , wherein each _Ra is independently H or optionally substituted C ₁ -C ₄ alkyl, the above optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkynyl and optionally substituted C ₃ -C ₆ cycloalkyl are optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano and -OR _b , wherein R _b is optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ Alkynyl.

In certain embodiments, R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl selected from the group consisting of:

Each of which is optionally substituted by one or more R _i , wherein R _i is selected from optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkynyl, optionally substituted C ₃ -C ₆ cycloalkyl, -NR _a R _a , -C(O)NR _a R _a , -S(O)R _f or -SO ₂ R _f , wherein R _a is each independently H or optionally substituted C ₁ -C ₄ alkyl, the above optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkynyl and optionally substituted C ₃ -C ₆ cycloalkyl are optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano and -OR _b , wherein R _b is optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl.

In certain embodiments, R _i is selected from the group consisting of C ₁ -C ₄ alkyl optionally substituted with one or more hydroxyl, cyano, -O(C ₁ -C ₄ alkyl), or -O(C ₂ -C ₄ alkynyl), C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -C(O)NH ₂ , and -SO ₂ (C ₁ -C ₄ alkyl), wherein the C ₁ -C ₄ alkyl in -NH(C ₁ -C ₄ alkyl) is optionally substituted with one or more halogen or hydroxyl.

In some embodiments, R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl selected from the group consisting of:

In some embodiments, ring C is a bond or a heteroaryl. In certain embodiments, ring C is a bond, a pyrimidinyl group, or a pyrazinyl group.

In some embodiments, each R ₇ is independently halogen, cyano, optionally substituted alkyl, -OR _a , -S(O)R _f , -SO ₂ R _f , or -NR _g R _g .

In certain embodiments, _R7 is each independently halogen, cyano, optionally substituted C1 _{- C4} alkyl, -O( _C1 - _C4 alkyl), -O( _C2 - _C4 alkynyl), -S(O)( _C1 - _C4 alkyl), _-SO2 ( _C1 - _C4 alkyl), or _-NRgRg , wherein _Rg is each independently H, _-SO2 ( _C1 - _C4 alkyl), or hydroxy-substituted _C1 - _C4 alkyl; or two _Rgs together with the N atom to which they are attached form an optionally substituted 4-10 membered _heterocyclyl .

In some embodiments, the present application provides a compound having the following formula:

or a pharmaceutically acceptable salt thereof,

in

_V3 is N or CH;

Ring C is a bond, aryl or heteroaryl;

Ring D is a heterocyclic group or a heteroaryl group;

Z ₁ is a bond, -O-, -CO-, -NR _a - or -(CH ₂ ) _r -NR _a -CO-;

_R1 and _R2 are each independently hydroxy or optionally substituted alkyl;

_R3 is H, _ORb or optionally substituted alkyl;

R ₄ is each independently halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -(CH ₂ ) _r NR _a R _a or -OR _b ;

_R5 is optionally substituted alkyl or optionally substituted alkenyl;

R ₇ is each independently halogen, cyano, optionally substituted alkyl, -OR _a , -S(O)R _f , -SO ₂ R _f or -NR _h R _h ;

R _a is each independently H, optionally substituted alkyl or -COR _b ;

R _b is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

R _c and R _d are each independently selected from optionally substituted alkyl or -NR _a R _a ; or R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group;

_Rf is an optionally substituted alkyl group;

R _h is each independently H, -SO ₂ R _f or an optionally substituted alkyl group; or two R _h together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl group; and

r, s, m, n and p are each independently 0, 1 or 2.

In some embodiments, wherein Selected from:

In some embodiments, Ring D is substituted with 1, 2, or 3 R ₉ , said R ₉ being H, halogen, or optionally substituted alkyl.

In some embodiments, The saturated nitrogen atom on the ring D is connected to -Z ₁ R ₅ .

In some embodiments, ring C is a bond.

In some embodiments, Ring C is aryl or heteroaryl.

In some embodiments, ring C is aryl. In some embodiments, ring C is 6-14 membered aryl, 6-12 membered aryl, 6-10 membered aryl, 6-8 membered aryl. In some embodiments, ring C is phenyl or naphthyl. In some embodiments, ring C is phenyl.

In some embodiments, ring C is a heteroaryl. In certain embodiments, ring C is a 5-14 membered heteroaryl, a 5-12 membered heteroaryl, a 5-10 membered heteroaryl, a 5-8 membered heteroaryl, a 5-6 membered heteroaryl. In certain embodiments, ring C is selected from pyrimidinyl, pyrazinyl, pyridinyl, piperidinyl, piperazinyl, morpholinyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, furanyl, pyrrolyl, triazolyl or triazinyl. In certain embodiments, ring C is a pyrimidinyl, pyrazinyl, pyridinyl, thiazolyl or oxazolyl. In certain embodiments, ring C is a pyrimidinyl, pyrazinyl or pyridinyl.

In certain embodiments, Select from the following group:

In some embodiments, each R ₃ is independently H, halogen, OR _b , or optionally substituted alkyl.

In some embodiments, each R ₃ is independently optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, each R ₃ is independently optionally substituted C _{1 -C 4} alkyl, which is optionally substituted with one _or more substituents independently selected from halogen, hydroxy, cyano, and -NR _a R _a .

In some embodiments, each R ₃ is independently H or halogen.

In some embodiments, each R ₃ is independently selected from halogen.

In some embodiments, each R ₃ is independently fluoro or chloro.

In some embodiments, R ₃ is fluoro.

In some embodiments, R ₃ is chloro.

In certain embodiments, _R3 is H.

In some embodiments, each _R is independently H, halo, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -( _CH2 ) _{rNRaRa ,} or _-ORb , wherein each _Ra is independently _H , optionally substituted alkyl, or _-CORb , and _Rb is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, wherein said optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl are optionally substituted with one or more substituents independently selected from halo, _hydroxy , cyano, and _-NRaRa .

In certain embodiments, each R ₄ is independently H, halogen, cyano, oxo, -(CH ₂ ) _r NR _a R _a, or -OR _b , wherein each R _a is independently H, optionally substituted C ₂ -C ₄ alkenyl, or -COR _b , and R _b is H, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl, or optionally substituted C ₂ -C ₄ alkynyl.

In certain embodiments, each R ₄ is independently H, chloro, cyano, oxo, -OCH ₃ , -OC≡CH, or -CH ₂ NH (CH=CH ₂ ).

In certain embodiments, each R ₄ is independently H, chloro, cyano, oxo, or -OCH ₃ .

In some embodiments, Z ₁ is a bond, -O-, -CO-, -NR _a -, or -(CH ₂ ) _r -NR _a -CO-, wherein _Ra is H or optionally substituted alkyl.

In certain embodiments, Z ₁ is a bond, -O-, -CO-, -NR _a -, or -(CH ₂ ) _r -NR _a -CO-, wherein _Ra is H or optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, Z ₁ is a bond, -O-, -CO-, -NH-, -NHCO-, or -CH ₂ NHCO-.

In certain embodiments, Z ₁ is a bond, -O-, or -CO-.

In some embodiments, R ₅ is optionally substituted C ₁ -C ₄ alkyl, optionally substituted C _{2 -C 4} alkenyl, or optionally substituted C _{2 -C 4 alkynyl ,} which is optionally substituted with one or more _substituents independently selected from halogen, hydroxy _, cyano, and -NR _a R _a .

In certain embodiments, R ₅ is optionally substituted C ₁ -C ₄ alkyl or optionally substituted C ₂ -C ₄ alkenyl, wherein the optionally substituted C ₁ -C ₄ alkyl and the optionally substituted C ₂ -C ₄ alkenyl are optionally substituted with one or more substituents independently selected from halogen, hydroxyl or cyano.

In certain embodiments, R ₅ is methyl, ethyl, propyl, or vinyl, optionally substituted with one or more substituents independently selected from chloro, hydroxy, or cyano.

In some embodiments, Z ₁ is a bond or —O—, and R ₅ is optionally substituted C _{1 -C 4} alkyl _, which is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or —NR _a R _a .

In certain embodiments, Z ₁ is a bond or -O-, and R ₅ is methyl, ethyl, or propyl, wherein the methyl, ethyl, and propyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, or cyano.

In certain embodiments, Z ₁ is a bond or -O-, and R ₅ is methyl, ethyl, or propyl, wherein the methyl, ethyl, and propyl groups are optionally substituted with one or more substituents independently selected from fluoro, chloro, or hydroxy.

In some embodiments, Z ₁ is -CO- or -(CH ₂ ) _r -NR _a -CO-, and R ₅ is optionally substituted C _{2 -C 4 alkenyl} , which is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, or -NR _a R _a .

In certain embodiments, Z ₁ is -CO- or -(CH ₂ ) _r -NR _a -CO-, and R ₅ is vinyl.

In some embodiments, -Z ₁ -R ₅ is selected from -(CH ₂ ) _r Cl, -O(CH ₂ ) _r F, -O(CH ₂ ) _r Cl, or -O(CH ₂ ) _r OH, wherein r is 1, 2, or 3.

In some embodiments, _Rc and _Rd are each independently selected from optionally substituted alkyl or _{-NRaRa ,} wherein each _Ra is independently H or optionally substituted alkyl.

In certain embodiments, R _c and R _d are each independently selected from optionally substituted C ₁ -C ₄ alkyl or -NR _a R _a , wherein each R _a is independently H or optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, R _c and R _d are each independently optionally substituted C ₁ -C ₄ alkyl.

In certain embodiments, one of R _c and R _d is optionally substituted C ₁ -C ₄ alkyl and the other is -NR _a R _a , wherein each R _a is independently H or optionally substituted C ₁ -C ₄ alkyl.

In some embodiments, R _c and R _d are both -CH ₃ -, or one of R _c and R _d is -CH ₃ and the other is -NHCH ₃ .

In some embodiments, R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl, which optionally substituted 4-10 membered heterocyclyl is optionally substituted with one or more R _i , wherein R _i is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -C(O)R _j -, -NR _{a Ra} , -C(O)NR _{a Ra} , -S(O)R _f or -SO ₂ R _f , wherein each _Ra is independently H or optionally substituted alkyl, which optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano and -OR _b , wherein R _b is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, and R _j is optionally substituted alkyl or cycloalkyl.

In certain embodiments, R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl, which is optionally substituted by one or more R _i , wherein R _i is selected from optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkynyl, optionally substituted C ₃ -C ₆ cycloalkyl, -NR _{a Ra} , -C(O)NR _{a Ra} , -S(O)R _f or -SO ₂ R _f , wherein each _Ra is independently H or optionally substituted C ₁ -C ₄ alkyl, the above optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkynyl and optionally substituted C ₃ -C ₆ cycloalkyl are optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano and -OR _b , wherein R _b is optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ Alkynyl.

In certain embodiments, R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl selected from the group consisting of:

Each of which is optionally substituted by one or more R _i , wherein R _i is selected from optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkynyl, optionally substituted C ₃ -C ₆ cycloalkyl, -NR _a R _a , -C(O)NR _a R _a , -S(O)R _f or -SO ₂ R _f , wherein R _a is each independently H or optionally substituted C ₁ -C ₄ alkyl, the above optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkynyl and optionally substituted C ₃ -C ₆ cycloalkyl are optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano and -OR _b , wherein R _b is optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl.

In certain embodiments, R _i is selected from the group consisting of C ₁ -C ₄ alkyl optionally substituted with one or more hydroxyl, cyano, -O(C ₁ -C ₄ alkyl) or -O(C ₂ -C ₄ alkynyl), C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -C(O)NH ₂ , and -SO ₂ (C ₁ -C ₄ alkyl), wherein the C ₁ -C ₄ alkyl in -NH(C ₁ -C ₄ alkyl) is optionally substituted with one or more halogen or hydroxyl.

In some embodiments, R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl selected from the group consisting of:

In some embodiments, ring C is a bond or a heteroaryl. In certain embodiments, ring C is a bond, a pyrimidinyl group, or a pyrazinyl group.

In some embodiments, each R ₇ is independently halogen, cyano, optionally substituted alkyl, -OR _a , -S(O)R _f , -SO ₂ R _f , or -NR _g R _g .

In certain embodiments, _R7 is each independently halogen, cyano, optionally substituted C1 _{- C4} alkyl, -O( _C1 - _C4 alkyl), -O( _C2 - _C4 alkynyl), -S(O)( _C1 - _C4 alkyl), _-SO2 ( _C1 - _C4 alkyl), or _-NRgRg , wherein _Rg is each independently H, _-SO2 ( _C1 - _C4 alkyl), or hydroxy-substituted _C1 - _C4 alkyl; or two _Rgs together with the N atom to which they are attached form an optionally substituted 4-10 membered _heterocyclyl .

In some embodiments, R _c and R _d in the compounds of Formula 2-Ia and Formula 2-Ib are each independently C ₁ -C ₄ alkyl or —NH—(C ₁ -C ₄ alkyl).

In some embodiments, R _c and R _d in the compounds of Formula 2-Ia and Formula 2-Ib, together with the S atom to which they are attached, form a 4-10 membered heterocyclyl optionally substituted with one or more R _i .

In some embodiments, Ring C in the compounds of Formula 2-Ia and Formula 2-Ib is a bond, phenyl, pyridinyl, pyrimidinyl, or pyrazinyl.

In another aspect, the present application provides a compound shown in the following formula III:

or a pharmaceutically acceptable salt thereof,

in:

Ring A' and Ring B' are each independently a cycloalkyl group, an aryl group, a heteroaryl group or a heterocyclic group;

X' is O, S, N or C;

R ₁₁ is absent or is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, halogen, hydroxy, -NH ₂ , -NHR _1a or -NR _1a R _1a ;

R ₁₂ is absent or is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, halogen, hydroxy, -NH ₂ , -NHR _1a or -NR _1a R _1a ;

each R ₁₃ is independently H, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, halogen, -NH ₂ , -NHR _1a or -NR _1a R _1a ;

each R ₁₄ is independently H, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, halogen, oxo, -NH ₂ , -NHR _1a or -NR _1a R _1a ;

Z ₁₁ is absent or is -O-, -NR'-, -NR'-CO- or -S-;

Z ₁₂ is alkylene, alkenylene, alkynylene or -R"-Y ₁₁ -R"'-; wherein R" and R"' are each a bond, alkylene, alkenylene or alkynylene, and R" and R"' are not bonds at the same time, and Y ₁₁ is O, NH or S; wherein Z ₁₂ is optionally substituted;

R ₁₅ is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

R ₁₆ is -N=S(O)R ₁₇ R ₁₈ , -N(R')-S(O) ₂ -R ₁₉ , substituted aryl, substituted heteroaryl, substituted heterocyclic group or substituted cycloalkyl; wherein at least one of the substituents on the substituted aryl, substituted heteroaryl, substituted heterocyclic group and substituted cycloalkyl is -N=S(O)R ₁₇ R ₁₈ or -N(R')-S(O) ₂ -R ₁₉ ; provided that when the substituted aryl, substituted heteroaryl, substituted heterocyclic group and substituted cycloalkyl is substituted with only one substituent and the substituent is -N(R')-S(O) ₂ -R ₁₉ , Z ₁₂ is a group containing a carbon-carbon triple bond;

each R' is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted alkoxy;

R ₁₇ and R ₁₈ are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -NH ₂ , -NHR _1a or -NR _1a R _1a ; or R ₁₇ , R ₁₈ together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl;

R ₁₉ is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, -NH ₂ , -NHR _1a or -NR _1a R _1a ;

R _1a is each independently optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

n' and m' are each independently an integer of 0, 1, 2 or 3.

In some embodiments, ring A' is an aryl or heteroaryl group, preferably a 6-14-membered aryl group or a 5-10-membered heteroaryl group, and the 5-10-membered heteroaryl group is preferably a 5-10-membered monocyclic or bicyclic heteroaryl group; more preferably, the ring A' is selected from: phenyl, naphthyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, pyrrolyl, triazolyl and triazinyl, more preferably phenyl or pyridinyl.

In some embodiments, ring B' is aryl, heteroaryl or heterocyclyl, preferably 6-14 membered aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, and the 5-10 membered heteroaryl is preferably 5-10 membered monocyclic or bicyclic heteroaryl; More preferably, the ring B' is selected from: phenyl, naphthyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, pyrrolyl, triazolyl, triazinyl, benzomorpholinyl, pyridomorpholinyl, benzimidazolyl, benzisodiazolyl, indolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, tetrahydroisoquinolyl, decahydroisoquinolyl, dihydroindolyl, octahydroindolyl and octahydroisoindolyl, more preferably phenyl, pyridinyl, indazolyl, dihydroindolyl or benzomorpholinyl.

In some embodiments, X' is O or S, R ₁₁ and R ₁₂ are absent; or X' is N, one of R ₁₁ and R ₁₂ is absent, and the other is H or optionally substituted C ₁ -C ₆ alkyl; or X' is C, R ₁₁ and R ₁₂ are each independently H, hydroxyl or optionally substituted C ₁ -C ₆ alkyl; preferably, the optionally substituted alkyl is optionally substituted with 1-3 substituents selected from halogen, hydroxyl, cyano, -NH ₂ , -NHR _1a and -NR _1a R _1a , wherein each R _1a is each independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl substituted with hydroxyl or halogenated C ₁ -C ₄ alkyl; preferably, X' is C, R ₁₁ is C ₁ -C ₄ alkyl, R ₁₂ is C ₁ -C ₄ alkyl or hydroxyl; more preferably, X' is C, R ₁₁ and R ₁₂ are each independently C ₁ -C ₄ Alkyl.

In some embodiments, each R ₁₃ is independently H, halogen or optionally substituted C1-C6 alkyl; preferably, the optionally substituted alkyl is optionally substituted with 1-3 substituents selected from halogen, hydroxyl, cyano, -NH ₂ , -NHR _1a and -NR _1a R _1a , wherein each R _1a is independently C ₁ -C ₄ alkyl, hydroxyl substituted C ₁ -C ₄ alkyl or halo C ₁ -C ₄ alkyl; wherein, when R ₁₃ is a non-hydrogen substituent, n' is preferably 1 or 2; preferably, R ₁₃ is H.

In some embodiments, each R ₁₄ is independently H, cyano, halogen, optionally substituted C ₁ -C ₄ alkoxy, optionally substituted alkyl C ₁ -C ₄ or oxo; preferably, the optionally substituted C 1 -C ₄ alkyl and the optionally substituted C ₁ -C ₄ alkoxy are each optionally substituted by 1-3 substituents selected from halogen, hydroxy, cyano, C ₂ -C ₄ alkynyl, -NH ₂ , -NHR _1a and -NR _1a R _1a , wherein R _1a is each independently C ₁ -C ₄ alkyl, hydroxy-substituted C ₁ -C ₄ alkyl or halogenated C _{1 -C 4} alkyl; preferably, R ₁₄ is a non-hydrogen substituent, and m' is 1 or 2; more preferably, m is 2, and the two R ₁₄ are cyano and halogen, respectively, or both are cyano, or are C ₁ -C ₄ alkyl and oxo, respectively, or are cyano and C ₁ -C 4 alkyl and oxo, respectively. Preferably _{, m} ' is ₂ , and two R _{14 are cyano} and halogen, respectively.

In some embodiments, Z ₁₁ is absent, or is -O- or -NR'-CO-; preferably, the R' is H or C ₁ -C ₄ alkyl.

In some embodiments, R ₁₅ is optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl, more preferably optionally substituted C ₁ -C ₄ alkyl; preferably, the substituents of R ₁₅ are selected from halogen, hydroxy, -NH ₂ , -NHR _1a , -NR _1a R _1a and -CH ₂ NR _1b R _1b , wherein R _1a is preferably each independently C ₁ -C ₄ alkyl, C _{1 -C 4 alkyl substituted with hydroxy or halogenated C 1 -C 4 alkyl} , R _1b is preferably each independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl substituted with hydroxy or halogenated C ₁ -C ₄ alkyl, or two R wherein _{R 15} is a C 1 -C _{4 alkyl radical optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, -NHR 1a , -NR 1a R 1a , a C 1 -C 4 alkoxy radical , a} halo-substituted C ₁ -C ₄ alkoxy radical, and a C ₂ -C ₄ alkynyl-substituted C ₁ -C ₄ alkoxy radical; and R ₁₆ is a C ₁ -C ₄ alkyl radical optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, -NHR _1a , and -NR _1a R _1a , more preferably a C ₁ -C ₄ alkyl radical optionally substituted with 1 to ₃ substituents selected _from the group consisting of halogen _{and hydroxyl, and more preferably a C 1 -C 4} alkyl radical optionally substituted with 1 to 3 substituents selected from the group consisting of halogen and hydroxyl. ₁ -C ₄ alkyl, wherein the last carbon of the alkyl is substituted with at least one substituent selected from halogen and hydroxy.

In some embodiments, -Z ₁₁ -R ₁₅ is optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₁ -C ₄ alkoxy, -NR'-CO-(optionally substituted C ₂ -C ₄ alkenyl) or -NR'-CO-(optionally substituted C ₁ -C ₄ alkyl), wherein the C ₁ -C ₄ alkyl and the alkyl moiety in the C _{1 -C 4 alkoxy and the C 2 -C 4 alkenyl are} optionally substituted with 1, 2 or 3 substituents selected from halogen and hydroxy, and preferably the terminal C of the C ₁ -C ₄ alkyl, the alkyl moiety or the alkenyl is substituted with at least one substituent selected from halogen and hydroxy; preferably, -Z ₁₁ -R ₁₅ is optionally substituted C ₁ -C ₄ alkyl or optionally substituted C ₁ -C ₄ alkoxy, wherein the C ₁ -C ₄ alkyl and the C ₁ -C The alkyl portion in the _{C 1} -C 4 alkoxy group is optionally substituted with 1, 2 or 3 substituents selected from halogen and hydroxy, and preferably the C ₁ -C ₄ alkyl group or the terminal carbon of the alkyl portion is substituted with at least one substituent selected from the halogen and hydroxy.

In some embodiments, Z ₁₂ is C ₂ -C ₄ alkenylene, C ₂ -C ₄ alkynylene or -R"-Y ₁₁ -R"'-, more preferably C ₂ -C ₄ alkynylene or -R"-Y ₁₁ -R"'-; preferably, R" and R"' are each a bond, C ₁ -C ₄ alkylene, C ₂ -C ₄ alkenylene or C ₂ -C ₄ alkynylene, and R" and R"' are not simultaneously a bond; preferably, Z ₁₂ is (C ₁ -C ₄ alkylene)-O-, (C ₂ -C ₄ alkenylene)-O-, (C ₂ -C ₄ alkynylene)-O-, (C ₁ -C ₄ alkylene)-NH-, (C ₂ -C ₄ alkenylene)-NH-, (C ₂ -C ₄ alkynylene)-NH-, (C ₁ -C ₄ alkylene)-S-, (C Preferably, Z ₂ is _{C 2} -C ₄ alkynylene)-S- and (C ₂ -C ₄ alkynylene)-S-; preferably, Z 2 is C ₂ -C ₄ alkynylene or (C ₁ -C ₄ alkylene)-O-; preferably, Z ₂ is optionally substituted with 1-3 substituents selected from halogen, hydroxy, amino, oxo (═O) and C ₁ -C ₄ alkoxy.

In some embodiments, R ₁₆ is a substituted 6-14 membered aryl, a substituted 5-10 membered heteroaryl, a substituted 4-10 membered heterocyclyl or a substituted C ₃ -C ₈ cycloalkyl; preferably, the 6-14 membered aryl includes phenyl and naphthyl, the 4-10 membered heterocyclyl includes azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, and the 5-10 membered heteroaryl includes thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, pyrrolyl, triazolyl and triazinyl; more preferably, R ₁₆ is a substituted pyrazinyl, substituted pyrimidinyl, substituted pyridazinyl, substituted pyrazolyl or substituted imidazolyl.

In certain embodiments, R ₁₆ is substituted 6-14 membered aryl, substituted 5-10 membered heteroaryl, substituted 4-10 membered heterocyclyl, or substituted C ₃ -C ₈ cycloalkyl, and in the substituent -N=S(O)R ₁₇ R ₁₈ on the substituted 6-14 membered aryl, substituted 5-10 membered heteroaryl, substituted 4-10 membered heterocyclyl, or substituted C ₃ -C ₈ cycloalkyl:

(i) R ₁₇ and R ₁₈ are each independently optionally substituted alkyl, preferably optionally substituted C ₁ -C ₄ alkyl; preferably, the alkyl is optionally substituted by 1 to 3 substituents selected from the group consisting of hydroxy, -NH ₂ , -NHR _1a , -NR _1a R _1a , halogen, C 1 -C ₄ alkyl optionally substituted by 1 or 2 substituents selected from the group consisting of halogen, cyano, hydroxy, -NH ₂ , -NHR _1a and -NR _1a R _1a , and C ₁ -C 4 alkoxy optionally substituted by 1 _{or 2} substituents selected from the group consisting of halogen, cyano, C ₂ -C ₄ alkynyl, hydroxy, -NH ₂ , -NHR _1a and -NR _1a R _1a ; or

(ii) R ₁₇ and R ₁₈ together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group containing S and optionally containing 1 or 2 heteroatoms selected from O and N, preferably including thietanyl, thiolanyl, thiohexanyl, thiomorpholinyl and 1,4-oxathianyl; preferably, the heterocyclic group is optionally substituted by 1 or 2 substituents selected from halogen, C 1 -C 4 alkyl optionally substituted by 1 or 2 substituents selected from halogen, cyano, hydroxyl, -NH ₂ , -NHR _1a and -NR _1a R _1a , C ₂ -C ₄ alkynyl, C _{1 -C 4} alkoxy optionally substituted by 1 or 2 substituents selected from halogen, cyano, hydroxyl _, -NH ₂ , -NHR _1a and -NR _1a R _1a , (C ₂ -C ₄ alkynyl)-O-(C ₁ -C ₄ alkylene), -NH ₂ , -NHR _1a and -NR _1a R _1a , wherein _Ra is preferably independently C ₁ -C ₄ alkyl, hydroxy-substituted C ₁ -C ₄ alkyl or halogenated C ₁ -C ₄ alkyl.

In some embodiments, the substituents on R' are 1-3 substituents selected from halogen, hydroxyl, _-NH2 , -NHR _1a and -NR _1a R _1a , wherein R _1a is preferably each independently _C1 - _C4 alkyl, _C1 - _{C4 alkyl substituted with hydroxyl or halogenated C1-C4 alkyl ;} preferably, R' is H or _C1 - _C4 alkyl optionally substituted with hydroxyl.

In some embodiments, R ₁₉ is optionally substituted C ₁ -C ₄ alkyl, optionally substituted 4-10 membered heterocyclyl, -NHR _1a or -NR _1a R _1a , wherein each R _1a is independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl substituted with hydroxyl or halogenated C ₁ -C ₄ alkyl; preferably, the heterocyclyl is a 4-10 membered nitrogen and/or oxygen-containing heterocyclyl, preferably selected from piperidinyl, piperazinyl, tetrahydropyranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl and morpholinyl; preferably, when R ₁₉ is substituted, the substituent is 1, 2 or 3 selected from halogen, C ₁ -C ₄ alkyl, halogenated C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogenated C ₁ -C ₄ alkoxy, hydroxyl, -NH ₂ , -NHR _1a or -NR _1a R The substituents of _{R 1a} , wherein each R _1a is independently C ₁ -C ₄ alkyl, hydroxy-substituted C ₁ -C ₄ alkyl or halogenated C ₁ -C ₄ alkyl; preferably, the heterocyclic group is unsubstituted or substituted by a group selected from C ₁ -C ₄ alkyl and halogen.

In some embodiments, the substituents on R ₁₆ , in addition to the -N=S(O)R ₁₇ R ₁₈ or -N(R')-S(O) ₂ -R ₁₉ , optionally include 1, 2 or 3 substituents selected from cyano, optionally substituted C ₁ -C ₄ alkyl, hydroxy, -NH ₂ , -NHR _1a , -NR _1a R _1a , halogen, optionally substituted C ₁ -C ₄ alkoxy, 4-10 membered heterocyclyl, -NR ₁₁₀ -S(O) ₂ -R _19' and -S(O) ₂ -R _19' , wherein R ₁₁₀ is H or C ₁ -C ₄ alkyl, R _19' is C ₁ -C ₄ alkyl, and R _1a are each independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl substituted with hydroxy or halogenated C ₁ -C ₄ alkyl; the optionally substituted C ₁ -C The optionally substituted C ₁ -C ₄ alkyl is preferably optionally substituted by 1 or 2 substituents selected from the group consisting of halogen, cyano, hydroxyl, -NH ₂ , -NHR _1a and -NR _1a R _1a , and the optionally substituted C 1 _{-C 4} alkoxy is preferably optionally substituted by 1 or 2 substituents selected from the group consisting of halogen, cyano, C ₂ -C ₄ alkynyl, hydroxyl, _{-NH 2 , -NHR 1a and -NR 1a R 1a, wherein Ra is each independently C 1 -C 4 alkyl , C 1 -C 4 alkyl substituted by} hydroxyl or halogenated C ₁ -C ₄ alkyl; preferably, the 4-10 heterocyclic group in the substituent is a nitrogen-containing heterocyclic group, more preferably an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

In some embodiments, R ₁₆ is -N=S(O)R ₁₇ R ₁₈ ; preferably, R ₁₇ , R ₁₈ together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group containing S and optionally containing 1 or 2 heteroatoms selected from O and N, preferably including thietanyl, thiolanyl, thiohexane, thiomorpholinyl and 1,4-oxathiinyl; preferably, the heterocyclic group is optionally substituted by 1 or 2 substituents selected from halogen, C ₁ -C 4 alkyl optionally substituted by 1 or 2 substituents selected from halogen, cyano, hydroxyl, -NH ₂ , -NHR _1a and -NR _1a R _1a , C 2 -C ₄ alkynyl, C ₁ -C ₄ alkoxy optionally substituted by 1 or 2 substituents selected from halogen, cyano, hydroxyl, -NH _{2 ,} -NHR _{1a and} -NR _1a R _1a , (C ₂ -C ₄ alkynyl)-O-(C ₁ -C ₄ alkylene), -NH ₂ , -NHR _1a and -NR _1a R _1a , wherein R _1a is preferably each independently C ₁ -C ₄ alkyl, hydroxy-substituted C ₁ -C ₄ alkyl or halogenated C ₁ -C ₄ alkyl; or

R ₁₆ is -N(R')-S(O) ₂ -R ₁₉ ; wherein R' is H, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl, optionally substituted C ₂ -C ₄ alkynyl or optionally substituted C ₁ -C ₄ alkoxy; when R' is substituted, the substituents are preferably 1-3 substituents selected from halogen, hydroxy, -NH ₂ , -NHR _1a and -NR _1a R _1a , wherein R _1a is preferably independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl substituted with hydroxy or halogenated C ₁ -C ₄ alkyl; preferably, R' is H or C ₁ -C ₄ alkyl optionally substituted with hydroxy; R ₁₉ is optionally substituted C ₁ -C ₄ alkyl, optionally substituted 4-10 membered heterocyclyl, -NHR _1a or -NR _1a R _1a , wherein R wherein _{R 1a} is independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl substituted with hydroxyl or halogenated C ₁ -C ₄ alkyl; when R ₁₉ is substituted, the substituents are 1, 2 or 3 substituents selected from halogen, C ₁ -C ₄ alkyl, halogenated C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogenated C ₁ -C ₄ alkoxy, hydroxyl, -NH ₂ , -NHR _1a and -NR _1a R _1a , wherein R _1a is independently C ₁ -C ₄ alkyl, C ₁ -C 4 alkyl substituted with hydroxyl or halogenated C ₁ -C ₄ alkyl. Preferably, the _4-10 membered heterocyclic group is a 4-10 membered nitrogen and/or oxygen-containing heterocyclic group, preferably selected from piperidinyl, piperazinyl, tetrahydropyranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl and morpholinyl; preferably, the heterocyclic group is unsubstituted or substituted by a group selected from C ₁ -C ₄ alkyl and halogen.

In some embodiments, R ₁₆ is -N=S(O)R ₁₇ R ₁₈ having the following structure:

wherein the ring containing S and X ₁₁ is a 4-6 membered heterocycle, X ₁₁ is CH ₂ or NH or O, R ₁₁₁ is selected from: H, C ₁ -C ₄ alkyl optionally substituted by hydroxyl or halogen, C ₂ -C ₄ alkynyl, (C ₂ -C ₄ alkynyl)-O-(C ₁ -C ₄ alkylene), -NH ₂ , -NHR _1a and -NR _1a R _1a , wherein R _1a is preferably each independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl substituted by hydroxyl or halogenated C ₁ -C ₄ alkyl; when X ₁₁ is substituted by R ₁₁₁ , X ₁₁ is CH or N.

In certain embodiments, R ₁₆ is -N=S(O)R ₇ R ₈ having the following structure:

In some embodiments,

Ring A' is phenyl or pyridyl;

Ring B' is phenyl, pyridyl, indazolyl, indolinyl or benzomorpholinyl;

X’ is C;

R ₁₁ is C ₁ -C ₄ alkyl or hydroxyl;

R ₁₂ is C ₁ -C ₄ alkyl or hydroxyl;

n is 1;

R ₁₃ is H or C ₁ -C ₄ alkyl, preferably H;

m is 1 or 2;

R ₁₄ is selected from cyano, halogen, C ₁ -C ₄ alkyl, oxo, and C ₁ -C ₄ alkoxy optionally substituted by C ₂ -C ₄ alkynyl;

Z ₁₁ is absent, or is -O- or -NR'-CO-;

Z ₁₂ is C ₂ -C ₄ alkynylene or -R"-Y ₁₁ -R"'-, wherein R" and R"' are each a bond or an optionally substituted C ₁ -C ₄ alkylene, and R" and R"' are not simultaneously a bond, Y ₁₁ is O, and the C ₁ -C ₄ alkylene is optionally substituted with one substituent selected from oxo and hydroxy;

R ₁₅ is C ₁ -C ₄ alkyl or C ₂ -C ₄ alkenyl optionally substituted with 1-3 substituents selected from halogen, hydroxy, -NHR _1a and -NR _1a R _1a , more preferably C ₁ -C 4 alkyl optionally substituted with 1-3 substituents selected from halogen and hydroxy, more preferably C ₁ -C ₄ alkyl substituted with 1-3 substituents selected from halogen and hydroxy, and the last carbon of the _alkyl is substituted with at least one substituent selected from halogen and hydroxy;

R ₁₆ is -N=S(O)R ₁₇ R ₁₈ , -N(R')-S(O) ₂ -R ₁₉ or a substituted heteroaryl; wherein the heteroaryl is thiazolyl, isothiazolyl, pyrimidinyl, pyrazinyl or pyridazinyl, preferably thiazolyl, pyrazinyl or pyrimidinyl; wherein the substituent on the heteroaryl includes at least -N=S(O)R ₁₇ R ₁₈ or -N(R')-S(O) ₂ -R ₁₉ , and in addition to the -N=S(O)R ₁₇ R ₁₈ or -N(R')-S(O) ₂ -R ₁₉ , optionally includes one selected from C ₁ -C ₄ alkoxy optionally substituted by C ₂ -C ₄ alkynyl, -S(O) ₂ -R _19' , cyano, -NR ₁₁₀ -S(O) ₂ -R _19' , -NH ₂ , -NHR _1a , -NR _1a R _1a and a substituent of a 4-10 membered heterocyclic group, wherein R ₁₁₀ is H or a C ₁ -C ₄ alkyl group, and R _19' is a C ₁ -C ₄ alkyl group; wherein, when the heteroaryl group is substituted by only one substituent and the substituent is -N(R')-S(O) ₂ -R ₁₉ , Z ₁₂ is a group containing a carbon-carbon triple bond, and wherein, when R ₁₆ is the -N(R')-S(O) ₂ -R ₁₉ , Z ₁₂ is a group containing a carbon-carbon triple bond, preferably a C ₂ -C ₄ alkynylene group;

R' is H or C ₁ -C ₄ alkyl optionally substituted by hydroxy;

R ₁₇ and R ₁₈ are each independently an unsubstituted C ₁ -C ₄ alkyl group, or R ₁₇ , R ₁₈ together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group contains, in addition to S, 1 or 2 heteroatoms selected from O and N, and the 4-10 membered heterocyclic group is preferably a thietanyl group, a thiolanyl group, a thiohexane group, a thiomorpholinyl group and a 1,4-oxathiinyl group; preferably, the 4-10 membered heterocyclic group is optionally substituted with 1 to 3 substituents selected from the group consisting of a C ₁ -C ₄ alkyl group optionally substituted with 1 or 2 substituents selected from a cyano group and a hydroxyl group, a C ₂ -C ₄ alkynyl group, a (C ₂ -C ₄ alkynyl group)-O-(C ₁ -C ₄ alkylene group), -NH ₂ , -NHR _1a and -NR _1a R _1a ;

R ₁₉ is: C ₁ -C ₄ alkyl optionally substituted by a substituent selected from -NH ₂ , -NHR _1a and -NR _1a R _1a , -NH ₂ , -NHR _1a , -NR _1a R _1a or a 4-10 membered heterocyclic group; and

R _1a is each independently C ₁ -C ₄ alkyl, hydroxy-substituted C ₁ -C ₄ alkyl or halogenated C ₁ -C ₄ alkyl.

In some embodiments,

Ring A' is phenyl or pyridyl;

Ring B' is phenyl, pyridyl, indazolyl, indolinyl or benzomorpholinyl;

X’ is C;

R ₁₁ is C ₁ -C ₄ alkyl or hydroxyl;

R ₁₂ is C ₁ -C ₄ alkyl or hydroxyl;

n is 1;

R ₁₃ is H or C ₁ -C ₄ alkyl, preferably H;

m is 1 or 2;

R ₁₄ is selected from cyano, halogen, C ₁ -C ₄ alkyl, oxo, and C ₁ -C ₄ alkoxy optionally substituted by C ₂ -C ₄ alkynyl;

Z ₁₁ is absent, or is -O- or -NR'-CO-;

Z ₁₂ is C ₂ -C ₄ alkynylene or -C ₁ -C ₄ alkylene-O-, wherein the C ₁ -C ₄ alkylene is optionally substituted by one substituent selected from oxo and hydroxyl;

R ₁₅ is C ₁ -C ₄ alkyl or C ₂ -C ₄ alkenyl optionally substituted with 1-3 substituents selected from halogen, hydroxy, -NHR _1a and -NR _1a R _1a , more preferably C ₁ -C 4 alkyl optionally substituted with 1-3 substituents selected from halogen and hydroxy, more preferably C ₁ -C ₄ alkyl substituted with 1-3 substituents selected from halogen and hydroxy, and the last C of the _alkyl is substituted with at least one substituent selected from halogen and hydroxy;

R ₁₆ is a heteroaryl substituted with -N=S(O)R ₁₇ R ₁₈ ; wherein the heteroaryl is thiazolyl, isothiazolyl, pyrimidinyl, pyrazinyl or pyridazinyl, preferably thiazolyl, pyrazinyl or pyrimidinyl; wherein the substituent on the heteroaryl includes at least -N=S(O)R ₁₇ R ₁₈ , and in addition to the -N=S(O)R ₁₇ R ₁₈ , optionally includes one substituent selected from C ₁ -C ₄ alkoxy, -S(O) ₂ -R _19' , cyano, -NR ₁₁₀ -S(O) ₂ -R _19' , -NH ₂ , -NHR _1a , -NR _1a R _1a and 4-10 membered heterocyclic group, wherein R ₁₁₀ is H or C ₁ -C ₄ alkyl, and R _19' is C ₁ -C ₄ alkyl;

R ₁₇ and R ₁₈ are each independently an unsubstituted C ₁ -C ₄ alkyl group, or R ₁₇ , R ₁₈ together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group contains, in addition to S, 1 or 2 heteroatoms selected from O and N, and the 4-10 membered heterocyclic group is preferably a thietanyl group, a thiolanyl group, a thiohexane group, a thiomorpholinyl group and a 1,4-oxathiinyl group; preferably, the 4-10 membered heterocyclic group is optionally substituted with 1 to 3 substituents selected from the group consisting of a C ₁ -C ₄ alkyl group optionally substituted with 1 or 2 substituents selected from a cyano group and a hydroxyl group, a C ₂ -C ₄ alkynyl group, a (C ₂ -C ₄ alkynyl group)-O-(C ₁ -C ₄ alkylene group), -NH ₂ , -NHR _1a and -NR _1a R _1a ;

R' is H or C ₁ -C ₄ alkyl; and

R _1a is each independently C ₁ -C ₄ alkyl, hydroxy-substituted C ₁ -C ₄ alkyl or halogenated C ₁ -C ₄ alkyl.

In some embodiments,

Ring A' is phenyl or pyridyl;

Ring B' is phenyl, pyridyl, indazolyl, indolinyl or benzomorpholinyl, preferably phenyl;

X’ is C;

R ₁₁ is C ₁ -C ₄ alkyl or hydroxyl;

R ₁₂ is C ₁ -C ₄ alkyl or hydroxyl;

n is 1;

R ₁₃ is H or C ₁ -C ₄ alkyl, preferably H;

m is 1 or 2;

R ₁₄ is selected from cyano, halogen, C ₁ -C ₄ alkyl, oxo and C ₁ -C ₄ alkoxy;

Z ₁₁ does not exist or is -O-;

Z ₁₂ is C ₂ -C ₄ alkynylene;

R ₁₅ is C ₁ -C ₄ alkyl optionally substituted by 1-3 substituents selected from halogen, hydroxy, -NHR _1a and -NR _1a R _1a , more preferably C ₁ -C ₄ alkyl optionally substituted by 1-3 substituents selected from halogen and hydroxy, more preferably C ₁ -C ₄ alkyl substituted by 1-3 substituents selected from halogen and hydroxy, and the last C of the alkyl is substituted by at least one substituent selected from halogen and hydroxy;

R ₁₆ is -N=S(O)R ₁₇ R ₁₈ , -N(R')-S(O) ₂ -R ₁₉ or a substituted heteroaryl; wherein the heteroaryl is thiazolyl, isothiazolyl, pyrimidinyl, pyrazinyl or pyridazinyl, preferably thiazolyl, pyrazinyl or pyrimidinyl; wherein the substituent on the heteroaryl includes at least -N=S(O)R ₁₇ R ₁₈ or -N(R')-S(O) ₂ -R ₁₉ ;

R ₁₇ and R ₁₈ are each independently an unsubstituted C ₁ -C ₄ alkyl group, or R ₁₇ , R ₁₈ together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group contains, in addition to S, 1 or 2 heteroatoms selected from O and N, and the 4-10 membered heterocyclic group is preferably thietanyl, thiolanyl, thiohexane, thiomorpholinyl and 1,4-oxathiinyl; preferably, the 4-10 membered heterocyclic group is optionally substituted with 1 to 3 substituents selected from the following group: C ₁ -C ₄ alkyl group optionally substituted with 1 or 2 substituents selected from cyano and hydroxyl, C ₂ -C ₄ alkynyl, (C ₂ -C ₄ alkynyl)-O-(C ₁ -C ₄ alkylene), -NH ₂ , -NHR _1a and -NR _1a R _1a ;

R' is H or C ₁ -C ₄ alkyl optionally substituted by hydroxy;

R ₁₉ is: C ₁ -C ₄ alkyl optionally substituted by a substituent selected from -NH ₂ , -NHR _1a and -NR _1a R _1a , -NH ₂ , -NHR _1a , -NR _1a R _1a or a 4-10 membered heterocyclic group;

R _1a is each independently C ₁ -C ₄ alkyl, hydroxy-substituted C ₁ -C ₄ alkyl or halogenated C ₁ -C ₄ alkyl.

In another aspect, the present application provides a compound having a structure shown in the following formula IV:

or a pharmaceutically acceptable salt thereof,

in:

R ₁₁ is C ₁ -C ₄ alkyl or hydroxyl;

R ₁₂ is C ₁ -C ₄ alkyl or hydroxyl;

R ₁₄ 'is H, halogen or cyano;

R ₁₄ ″ is H, halogen, cyano or optionally substituted C ₁ -C ₄ alkoxy, such as C 1 -C ₄ alkoxy optionally substituted by 1 _to 3 substituents selected from halogen, hydroxy, cyano, C ₂ -C ₄ alkynyl, -NH ₂ , -NHR _1a and -NR _1a R _1a ;

Z ₁₁ is O or -NR'-CO-;

R ₁₅ is C ₁ -C ₄ alkyl or C ₂ -C ₄ alkenyl optionally substituted with 1-3 substituents selected from halogen, hydroxy, -NHR _1a and -NR _1a R _1a , more preferably C ₁ -C 4 alkyl optionally substituted with 1-3 substituents selected from halogen and hydroxy, more preferably C ₁ -C ₄ alkyl substituted with 1-3 substituents selected from halogen and hydroxy, and the last C of the _alkyl is substituted with at least one substituent selected from halogen and hydroxy;

Z ₁₂ is C ₁ -C ₄ alkylene-O- or C ₂ -C ₄ alkynyl;

The -N=S(O)R ₁₇ R ₁₈ has the following structure:

In the formula, the ring containing S and X ₁₁ is a 4-6 membered heterocyclic ring, X ₁₁ is CH ₂ or NH or O, R ₁₁₁ is selected from: H, C ₁ -C ₄ alkyl optionally substituted by hydroxy, C ₂ -C ₄ alkynyl, (C ₂ -C ₄ alkynyl)-O-(C ₁ -C ₄ alkylene), -NH ₂ , -NHR _1a and -NR _1a R _1a , wherein R _1a is preferably each independently C1-C4 alkyl, C ₁ -C ₄ alkyl substituted by hydroxy or halogenated C ₁ -C ₄ alkyl; wherein, when R ₁₁₁ is located on X ₁₁ , X ₁₁ is CH or N;

R ₁₁₂ is H or C ₁ -C ₄ alkyl;

R ₁₁₃ is selected from the group consisting of: optionally substituted C ₁ -C ₄ alkoxy, -S(O) ₂ -R _19' , cyano, -NR ₁₁₀ -S(O) ₂ -R _19' , -NH ₂ , -NHR _1a , -NR _1a R _1a and 4-10 membered heterocyclyl, wherein R ₁₁₀ is H or C ₁ -C ₄ alkyl, and R _19' is C 1 -C ₄ alkyl; preferably, the optionally substituted C ₁ -C ₄ alkoxy is preferably a C ₁ -C 4 alkoxy optionally substituted by ₁ or 2 substituents selected from the group consisting of halogen, cyano, C ₂ -C ₄ alkynyl, hydroxyl, -NH ₂ , -NHR _1a and -NR _1a R _1a , such as _{a C 1 -C 4 alkynyl optionally substituted} by ₄ -alkoxy; preferably, the 4-10 membered heterocyclic group is a nitrogen-containing heterocyclic group, more preferably azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl; and

R _1a is each independently C ₁ -C ₄ alkyl, hydroxy-substituted C ₁ -C ₄ alkyl or halogenated C ₁ -C ₄ alkyl.

In another aspect, the present application provides a compound having a structure shown in the following formula V:

or a pharmaceutically acceptable salt thereof,

in:

R ₁₁ is C ₁ -C ₄ alkyl or hydroxyl;

R ₁₂ is C ₁ -C ₄ alkyl or hydroxyl;

R ₁₄ 'is H, halogen or cyano;

R ₁₄ ″ is H, halogen, cyano or C ₁ -C ₄ alkoxy optionally substituted by C ₂ -C ₄ alkynyl;

Z ₁₁ is O;

R ₁₅ is C ₁ -C ₄ alkyl optionally substituted by 1-3 substituents selected from halogen, hydroxy, -NHR _1a and -NR _1a R _1a , more preferably C ₁ -C ₄ alkyl optionally substituted by 1-3 substituents selected from halogen and hydroxy, more preferably C ₁ -C ₄ alkyl substituted by 1-3 substituents selected from halogen and hydroxy, and the last C of the alkyl is substituted by at least one substituent selected from halogen and hydroxy;

Z ₁₂ is C ₂ -C ₄ alkynyl;

One of _X12 and _X13 is CH, and the other is N;

R ₁₁₄ is -N(R')-S(O) ₂ -R ₁₉ ; wherein R' is H or C ₁ -C ₄ alkyl optionally substituted by hydroxy; R ₁₉ is C ₁ -C ₄ alkyl optionally substituted by a substituent selected from -NH ₂ , -NHR _1a and -NR _1a R _1a , -NH ₂ , -NHR _1a , -NR _1a R _1a or a 4-10 membered heterocyclyl; preferably, the 4-10 membered heterocyclyl is selected from piperidinyl, piperazinyl, tetrahydropyranyl, oxetanyl, tetrahydrofuranyl, azetidinyl and pyrrolidinyl; and

R _1a is each independently C ₁ -C ₄ alkyl, hydroxy-substituted C ₁ -C ₄ alkyl or halogenated C ₁ -C ₄ alkyl.

In some embodiments, the present application provides a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of the present application is not the following compound:

III. Preparation of Compounds

The preparation process of some compounds of the present invention is described by taking the following formula II-6 as an example. The preparation method thereof at least includes the steps of alkylation substitution reaction, catalytic coupling, Grignard reaction, etc. described below. The exemplary reaction process can be shown in the following process I. It should be understood that other compounds of the present invention can be synthesized by similar methods or improved methods.

Process I

In process I, intermediate II-1 is subjected to alkylation reaction to obtain intermediate II-2; II-2 reacts with a Grignard reagent to obtain intermediate II-3; II-3 is subjected to Friedel-Crafts alkylation under Lewis acid catalysis to obtain intermediate II-4; II-4 is subjected to alkylation reaction to obtain compound II-5; compound II-5 is subjected to coupling reaction with a sulfenimine intermediate R _c R _d S(O)=NH to obtain compound II-6. The reaction conditions of each step are shown in the reaction flow.

In the formulae of reaction scheme I, the definitions of the groups are as described above, and W is halogen, preferably chlorine or bromine.

In the preparation method of the present invention, intermediate II-1 reacts with different halogenated alkanes to obtain II-2 with different substituents. The reaction is carried out in an organic solvent (preferably DMF or acetonitrile) under the action of a base (preferably cesium carbonate). The Friedel-Crafts alkylation reaction of intermediate II-3 to intermediate II-4 constructs a diphenyl subunit structure.

II-5 is coupled with different sulfenimine intermediates R _c R _d S(O)=NH to construct the left fragment with different substituents. The reaction is catalyzed by a base (preferably cesium carbonate) in an organic solvent (preferably toluene or dioxane) using a palladium reagent (preferably palladium acetate) and heated to obtain II-6.

The preparation process of some compounds of the present invention is illustrated by taking the compound of formula III-3 as an example. The preparation method thereof includes at least the steps of catalytic coupling and esterification reaction described below. The exemplary reaction process can be shown in the following process II. It should be understood that other compounds of the present invention can be obtained by similar synthesis through similar methods or improved methods.

Process II

In process II, intermediate II-4 undergoes a one-step esterification reaction to generate III-1; III-1 is catalytically coupled with an acetylene compound to obtain intermediate III-2; III-2 is catalytically coupled with a halide again to obtain compound III-3. The reaction conditions of each step are shown in the reaction process.

In the formulae of Reaction Scheme II, the definitions of the groups are as described above, and W is halogen, preferably chlorine, bromine and iodine.

In the preparation method of the present invention, the intermediate III-1 is coupled with an acetylene compound to introduce an alkynyl group. The intermediate III-2 and different halides, preferably aromatic halides, undergo coupling reactions to obtain compounds III-3 containing different substituents. The reaction is carried out under the action of a base (preferably diisopropylethylamine) and the catalysis of a metal catalyst (preferably Pd(PPh ₃ ) ₄ and cuprous iodide); and is carried out in an organic solvent (preferably tetrahydrofuran) under heating conditions.

If the above scheme includes a step of removing the Boc protecting group, the deprotection reaction can be carried out in a conventional manner.

In the above scheme, if the final product has a chiral center and chiral separation is required, conventional methods in the art, such as SFC or chiral HPLC, can be used for chiral separation.

In the above scheme, when purification is required, it can be purified by conventional methods in the art, for example, extraction can be performed first, and then column chromatography can be performed.

IV. Pharmaceutical compositions, uses and methods of treatment

The compounds provided in the present application are modulators of androgen receptor (AR) and can be used to modulate the activity of AR. Modulating AR activity can be used to treat and/or prevent androgen receptor-mediated diseases.

In one aspect, the present application provides a pharmaceutical composition containing a therapeutically or prophylactically effective amount of a compound of the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition of the present application may further contain other therapeutic agents, especially therapeutic agents for treating androgen receptor-mediated diseases described herein.

In certain embodiments, the additional therapeutic agent may be used to treat prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration.

In certain embodiments, examples of additional therapeutic agents include, but are not limited to, enzalutamide, galactron, ODN-201 abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, bevacizumab (avastatin), OSU-HDAC42, VITAXIN, sunitinib, ZD-4054, cabazitaxel (XRP-6258), MDX-010 (ipilimumab), OGX 427, OGX 011, finasteride, dutasteride, torosterone, beclosterol, azosterol, FCE 28260, SKF105,111, ODM-201 ODM-204, niclosamide, apalutamide, ARV-330, VPC-14449, TAS3681, 3E10-AR441 bsAb, sintokamide, or a related compound thereof.

Suitable pharmaceutical compositions can be formulated by methods known in the art and by its mode of administration and dosage determined by skilled practitioners. For parenteral administration, the compound can be dissolved in sterile water or saline or in a pharmaceutically acceptable vehicle (such as those for vitamin K) for the administration of non-water-soluble compounds. For enteral administration, the compound can be administered in tablets, capsules or dissolved in liquid form. Tablets or capsules can be enteric coated, or in the form of a formulation for sustained release. A variety of suitable formulations are known, including polymers or protein microparticles, ointments, pastes, gels, hydrogels or solutions encapsulating the compound to be released, which can be used for compounds through the surface or topically. Sustained release patches or implants can be used to provide release over an extended period of time. Preparations for parenteral administration can, for example, contain excipients polyalkylene glycols (such as polyethylene glycol), oils of plant origin or hydrogenated naphthalene. Biocompatible, biodegradable lactide polymers, lactide/glycolide copolymers or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of the compound. Other potentially useful parenteral delivery systems for modulating compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems and liposomes. Formulations for inhalation may contain excipients such as lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration as nasal drops, or in the form of a gel.

It should be noted that dosage values may vary with the exact imaging protocol. With respect to any particular subject, a specific dosage regimen may be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition. The dosage ranges described herein are exemplary only and do not limit the dosage ranges that a medical practitioner may select. The amount of active compound in the composition may vary according to factors such as the subject's disease state, age, sex, and weight. The dosage regimen may be adjusted to provide optimal imaging results. For example, a single bolus may be administered, several divided doses may be administered over time, or the dosage may be proportionally reduced or increased as indicated by the imaging results. It may be advantageous to prepare parenteral compositions in a unit dosage form that is easy to administer and achieves uniformity of dosage.

In another aspect, the present application provides use of the compound of the present application or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing androgen receptor-mediated diseases.

In another aspect, the present application provides a compound of the present application or a pharmaceutically acceptable salt thereof for use in treating or preventing androgen receptor-mediated diseases.

In another aspect, the present application provides a compound of the present application or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease mediated by an androgen receptor variant.

In another aspect, the present application provides a compound of the present application or a pharmaceutically acceptable salt thereof for use in treating or preventing diseases mediated by androgen receptor splice variants (AR-Vs).

In another aspect, the present application provides a compound of the present application or a pharmaceutically acceptable salt thereof for use in treating or preventing an AR-V7-mediated disease.

In another aspect, the present application provides a method for treating or preventing an androgen receptor-mediated disease in a subject, the method comprising administering to the subject a therapeutically effective amount or a preventively effective amount of a compound of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a therapeutically effective amount or a preventively effective amount of a compound of the present application or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method for treating or preventing a disease mediated by an androgen receptor variant, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1-I or 2-I of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof.

On the other hand, the present invention provides a method for treating or preventing diseases mediated by androgen receptor splice variants (AR-Vs), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1-I or 2-I of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof.

In another aspect, the present invention provides a method for treating or preventing an AR-V7-mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1-I or 2-I of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof.

On the other hand, the present invention provides a method for treating or preventing diseases mediated by androgen receptor and androgen receptor variants, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1-I or 2-I of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof.

On the other hand, the present invention provides a method for treating or preventing diseases mediated by androgen receptor and androgen receptor splice variants (AR-Vs), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1-I or 2-I of the present invention, a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, solvate, isotope substitution, polymorph, prodrug or metabolite, or a pharmaceutical composition thereof.

In another aspect, the present invention provides a method for treating or preventing androgen receptor and AR-V7 mediated diseases, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1-I or 2-I of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substitution, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition thereof.

Drugs can be administered orally, intraduodenally, parenterally (including intrapulmonary, intranasal, intrathecal, intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topically, and rectally. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compounds of the present application or their pharmaceutically acceptable salts or the pharmaceutical compositions of the present application are administered orally.

In the treatment methods, prevention methods and uses described herein, the compounds of the present application or their pharmaceutically acceptable salts or the pharmaceutical compositions of the present application can be used in combination with other pharmacologically active compounds to treat or prevent various diseases mediated by androgen receptors described herein. For example, the compounds of the present application or their pharmaceutically acceptable salts or the pharmaceutical compositions of the present application can be administered simultaneously, sequentially or separately in combination with one or more drugs selected from the following: enzalutamide, galactron, ODN-201 abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, bevacizumab (avastatin), OSU-HDAC42, VITAXIN, sunitinib, ZD-4054, cabazitaxel (XRP-6258), MDX-010 (ipilimumab), OGX 427, OGX011, finasteride, dutasteride, torosterone, beclosterol, azosternol, FCE 28260, SKF105,111, ODM-201ODM-204, niclosamide, apalutamide, ARV-330, VPC-14449, TAS3681, 3E10-AR441bsAb, sintokamide and related compounds thereof. Alternatively, the compound of the present application or its pharmaceutically acceptable salt or the pharmaceutical composition of the present application can be used in combination with conventional radiotherapy.

In some embodiments, androgen receptor-mediated diseases may include prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioblastoma, melanoma, renal cell carcinoma, mantle cell lymphoma, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, alopecia, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, age-related macular degeneration, and combinations thereof.

In some embodiments, androgen receptor mediated diseases are prostate cancer. In some embodiments, the prostate cancer is primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer or metastatic castration-resistant prostate cancer (CRPC) or hormone-sensitive prostate cancer. In other embodiments, the prostate cancer is androgen-dependent prostate cancer. In some embodiments, the spinal cord and bulbar muscular atrophy is Kennedy's disease.

Example

The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

The starting materials used in the following examples can be purchased from chemical dealers such as Aldrich, TCI, Alfa Aesar, Bidrich, Anergy, etc., or can be synthesized by known methods.

Intermediate synthesis

Synthesis of Intermediate I-A1: 3-Chloro-2-(2-chloroethoxy)-5-(2-(4-hydroxyphenyl)propan-2-yl)benzonitrile

Step 1: Dissolve the raw material I-A1-1 (80g, 429mmol) in dichloromethane (1000mL), stir at 0℃ for 5 minutes, and then add NIS (116g, 515mmol) at 0℃. The above mixture is reacted at room temperature for 16 hours, and LC-MS detection shows that the reaction is complete. The reaction mixture is put into water (1000ml), extracted with dichloromethane (1000mL*2), the organic phases are combined, washed with saturated brine (1000mL*2), and the organic phases are dried over anhydrous sodium sulfate and concentrated. The concentrated mixture is recrystallized using acetonitrile to obtain the product I-A1-2 (117g, yield: 87.3%), which is a white solid.

LC-MS[M-1] ^- =310.7

Step 2: At room temperature, I-A1-2 (100 g, 320 mmol) and I-A1-3 (91 g, 640 mmol) were dissolved in N, N-dimethylformamide (1200 mL), and then cesium carbonate (208 g, 640 mmol) was added. The mixture was stirred at 70 ° C for 16 hours, and the reaction was complete when detected by TLC. The reaction mixture was put into water (1500 ml) and extracted with ethyl acetate (1000 mL * 3). The organic phase was washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain the desired product I-A1-4 (103.4 g, yield: 86.1%) as a colorless oily liquid.

LC-MS [M+1] ⁺ = 374.7

Step 3: Dissolve the intermediate I-A1-4 (53g, 141.3mmol) in N-methylpyrrolidone (600mL), add CuCN (19g, 200mmol), and stir the reaction at 160°C under nitrogen protection for 3 hours. TLC detection shows that the reaction is complete. The reaction mixture is quenched with ammonia (2000mL, 23%) and extracted with ethyl acetate (1000mL*3). The organic phase is washed with saturated brine (1000mL) and dried over anhydrous sodium sulfate. The filtrate is concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain the desired product I-A1-5 (21g, yield: 54.3%) as a white solid.

LC-MS [M+1] ⁺ = 274.0

Step 4: Dissolve I-A1-5 (21g, 76.6mmol) in tetrahydrofuran (100mL) and add dropwise to methylmagnesium bromide (613ml, 1M tetrahydrofuran solution) protected by nitrogen at room temperature. After the addition is complete, react at room temperature for 2 hours. TLC detection shows that the reaction is complete. The reaction mixture is slowly added to a saturated aqueous ammonium chloride solution at 0°C and extracted with ethyl acetate (300mL*3). The organic phase is washed with saturated brine (500mL), dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the desired product I-A1-6 (17g, yield: 80.9%) as a yellow oily liquid.

LC-MS[M+17] ⁺ ＝290.9

Step 5: Dissolve I-A1-6 (17g, 62mmol) and I-A1-7 (19.2g, 310mmol) in dichloromethane (200mL) at -78°C, add boron trifluoride ether solution (34ml, 47%) under nitrogen protection, and naturally warm to room temperature for 2 hours after the addition. TLC detection shows that the reaction is complete, the reaction mixture is added to water (200ml) and extracted with dichloromethane (100mL*3). The organic phase is washed with saturated brine (300mL), dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the desired product intermediate I-A1 (18g, yield: 83%) as a yellow oily liquid.

¹ H NMR (400MHz, Chloroform-d) δ7.44 (d, J＝2.4Hz, 1H), 7.33 (dd, J＝4.9, 2.4Hz, 1H), 7.06–7.02 (m, 2H), 6.80–6.76 (m,2H),4.41(t,J＝6.2Hz,2H),3.87(t,J＝6.2Hz,2H),1.63(s,6H).

LC-MS[M-1] ^- =347.9

Synthesis of Intermediate I-A2: 3-Chloro-2-(2-chloroethoxy)-5-(2-(4-ethynylphenyl)propan-2-yl)benzonitrile

Step 1: Dissolve I-A1 (5.8 g, 16 mmol) and triethylamine (4.87 g, 48 mmol) in dichloromethane (100 mL), stir at 0°C for 5 minutes, and then add Tf ₂ O (6.78 g, 24 mmol). The above mixture is reacted at 25°C for 2 hours, and the reaction is complete after TLC detection. The reaction mixture is concentrated and column chromatography (petroleum ether/ethyl acetate = 30/1) is used to obtain the product I-A2-1 (6 g, yield: 78%) as an orange oil.

Step 2: I-A2-1 (6 g, 12.5 mmol) and trimethylsilyl acetylene (12 g, 122.2 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (1.6 g, 2.3 mmol), cuprous iodide (1.3 g, 6.8 mmol) and triethylamine (23.31 g, 230.4 mmol) were dissolved in acetonitrile (133 ml) at room temperature. The mixture was stirred at 80°C under nitrogen protection for 16 hours. TLC detected that the reaction was complete. The reaction mixture was concentrated and purified by column chromatography to obtain the desired product I-A2-2 (4.2 g, yield: 69%) as an orange oily liquid.

Step 3: Dissolve the intermediate I-A2-2 (4.2 g, 9.79 mmol) in methanol (650 mL), add potassium fluoride (4.2 g, 72.3 mmol), and stir the reaction at 25 ° C under nitrogen protection for 12 hours. TLC detection shows that the reaction is complete. After the reaction mixture is concentrated, column chromatography (petroleum ether/ethyl acetate = 10/1) is performed to obtain the desired product intermediate I-A2 (2.8 g, yield: 80%) as an orange oily liquid.

¹ H NMR (400MHz, Chloroform-d) δ7.48–7.42(m,2H),7.41(d,J＝2.4Hz,1H),7.33(d,J＝2.4Hz,1H),7.16–7.11(m ,2H),4.42(t,J＝6.2Hz,2H),3.88(t,J＝6.2Hz,2H),3.07(s,1H),1.65(s,6H).

Synthesis of Intermediate I-A3: 4-(2-(7-chloro-1-(2-chloroethoxy)-1H-indazol-5-yl)propan-2-yl)phenol

Step 1: Dissolve the intermediate I-A3-1 (30.0 g, 182 mmol) in acetonitrile (240 mL), add NCS (29.1 g, 218 mmol) in batches at 75 ° C. After stirring at 75 ° C. for 2 hours, concentrate the reaction mixture and separate it by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the product I-A3-2 (35 g, yield: 97%) as a yellow solid.

LCMS [M+1] ⁺ = 199.9

Step 2: Dissolve the intermediate I-A3-2 (4.00 g, 6.55 mmol) in acetic acid (100 mL) and deionized water (5 mL), slowly add a solution of sodium nitrite (6.2 g, 90.2 mmol) in water (5 mL) at 0 ° C, stir at room temperature for 4 hours, concentrate the mixture, adjust the pH to 8 with saturated sodium bicarbonate solution, and then extract with ethyl acetate (500 mL * 2). After the organic phase is concentrated, column chromatography separation (dichloromethane / methanol = 100 / 4) is performed to obtain the product I-A3-3 (14 g, yield: 88%) as a yellow solid.

LCMS [M+1] ⁺ = 210.9

Step 3: Dissolve the intermediate I-A3-3 (10.8 g, 51.3 mmol) and potassium carbonate (17.7 g, 128 mmol) in DMF (160 mL), then add 1-bromo-2-chloroethane (29.4 g, 205 mmol), and stir the mixture at 75°C for 4 hours. Concentrate the reaction solution and perform HPLC separation (ACN/H ₂ O=40/60) to obtain the desired product I-A3-4 (4.7 g, yield: 34%) as a yellow solid.

¹ H NMR (400MHz, Chloroform-d) δ8.40 (s, 1H), 8.16 (s, 1H), 8.07 (s, 1H), 5.12 (t, J = 8.0Hz, 2H), 3.96-3.94 (m ,5H).

LCMS [M+1] ⁺ = 273.0.

Step 4: Dissolve methylmagnesium bromide (33mL, 99.0mmol) in anhydrous tetrahydrofuran (80mL), cool it to 0°C, add intermediate I-A3-4 (4.5g, 16.5mmol) in batches, and then stir at room temperature for 2 hours. TLC detection shows that the reaction is complete. The reaction system is quenched by adding saturated aqueous ammonium chloride solution (40mL) and extracted with ethyl acetate (50mL*3). The organic phase is washed with saturated brine (70mL) and dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated to obtain the desired product I-A3-5 (4.5g, yield: 99%) as a yellow oil.

LCMS [M+1] ⁺ = 273.0

Step 5: Dissolve the intermediate I-A3-5 (4.5 g, 16.5 mmol) and phenol (7.8 g, 82.4 mmol) in dichloromethane (130 mL), lower the temperature to -78 ° C, slowly drip boron trifluoride ether (7.0 g, 49.4 mmol), then naturally warm to room temperature and stir overnight. The reaction system was quenched by adding distilled water (100 mL) and extracted with dichloromethane (200 mL * 2). The organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate and filtered. The mixture was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 6/1) to obtain the product intermediate I-A3 (3.9 g, yield: 68%) as a yellow oil.

LCMS [M+1] ⁺ = 349.0

Synthesis of Intermediate I-A4: 7-Chloro-1-(2-chloroethoxy)-5-(2-(4-ethynylphenyl)propan-2-yl)-1H-indazole

Refer to the synthetic route of intermediate I-A2. Replace I-A1 with I-A3 and synthesize I-A4 through three steps.

LCMS [M+1] ⁺ = 357.1

Synthesis of Intermediate I-A5: 4-(2-(7-chloro-2-(2-chloroethyl)-2H-indazol-5-yl)propan-2-yl)phenol

Refer to the synthetic route of intermediate I-A3. Intermediate I-A5 is synthesized from raw material I-A3-1 through five steps.

LCMS [M+1] ⁺ = 349.0

Synthesis of intermediate I-A6: 2-(2-chloroethoxy)-5-(2-(4-hydroxyphenyl)propan-2-yl)-3-methoxybenzene toluenenitrile

Step 1: Dissolve the raw material I-A6-1 (23g, 126.25mmol) in dichloromethane (300mL), stir at 20℃ for 5 minutes, and then add NIS (32.76g, 189.38mmol) at 20℃. The above mixture is reacted at room temperature (20℃) for 4 hours. Pour the reaction mixture into water (200mL), extract with dichloromethane (200mL*2), combine the organic phases, wash with saturated brine (200mL*2), and dry the organic phase with anhydrous sodium sulfate and concentrate. The concentrated mixture is recrystallized using acetonitrile to obtain the product I-A6-2 (24g, yield: 62%), which is a white solid.

LC-MS [M+1] ⁺ = 308.9

Step 2: Dissolve I-A6-2 (24 g, 77.9 mmol) and 1-bromo-2-chloroethane (22.34 g, 155.81 mmol) in N,N-dimethylformamide (250 mL) at room temperature, and then add cesium carbonate (50.7 g, 155.81 mmol). The mixture was stirred at 70 ° C for 16 hours. The reaction mixture was put into water (200 ml) and extracted with ethyl acetate (200 mL * 3). The organic phase was washed with saturated brine (200 mL) and dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the desired product I-A6-3 (19.5 g, yield: 68%) as a colorless solid.

Step 3: Dissolve the intermediate I-A6-3 (19.5 g, 52.62 mmol) in N-methylpyrrolidone (200 mL), add CuCN (5.662 g, 63.15 mmol), and stir the reaction at 160 ° C under nitrogen protection for 3 hours. TLC detection reaction is complete. The reaction mixture is quenched with ammonia (200 mL, 23%) and extracted with ethyl acetate (200 mL*3). The organic phase is washed with saturated brine (200 mL) and dried over anhydrous sodium sulfate. The filtrate is concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the desired product I-A6-4 (12.5 g, yield: 88%) as a white solid.

LC-MS [M+1] ⁺ = 269.90

Step 4: Dissolve I-A6-4 (12.5 g, 46.5 mmol) in tetrahydrofuran (200 mL), add dropwise to methylmagnesium bromide (124 mL, 3 M tetrahydrofuran solution) protected by nitrogen at room temperature, and react at room temperature for 3 hours after the addition. Slowly add the reaction mixture to a saturated ammonium chloride solution at 0°C and extract with ethyl acetate (100 mL*3). Wash the organic phase with saturated brine (200 mL), dry with anhydrous sodium sulfate and filter. Concentrate the filtrate to obtain the desired crude product I-A6-5 (12.5 g, yield: 100%) as a yellow solid, which is directly used in the next step.

Step 5: Dissolve I-A6-5 (12.5 g, 46.34 mmol) and phenol (17.45 g, 185.37 mmol) in dichloromethane (120 mL). Add boron trifluoride ether solution (17.5 ml, 47%) dropwise at -78 °C under nitrogen protection. After the addition is complete, naturally warm to room temperature and react for 2 hours. TLC detection shows that the reaction is complete. Add the reaction mixture to water (200 ml) and extract with dichloromethane (100 mL*3). Wash the organic phase with saturated brine (200 mL), dry with anhydrous sodium sulfate and filter. Concentrate the filtrate and separate by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the desired product intermediate I-A6 (14 g, yield: 87%) as a colorless oily liquid.

LC-MS [M+1] ⁺ = 346.10.

Synthesis of Intermediate I-A7: 2-(2-chloroethoxy)-5-(2-(4-hydroxyphenyl)propan-2-yl)isophthalonitrile

Step 1: Dissolve the raw material I-A7-1 (19.5g, 128mmol) in 50% acetic acid aqueous solution (1400mL), add potassium iodide (53g, 320mmol) at room temperature, and then slowly add sodium peroxide carbonate (80.4g, 512mmol). The above mixture is reacted at 60°C for 3 hours, and TLC detection shows that the reaction is complete. The reaction mixture is put into a mixed solution of dichloromethane and saturated sodium sulfite that is stirred vigorously, extracted with dichloromethane (500mL*3), the organic phases are combined, washed with saturated brine (1000mL*2), and the organic phases are dried over anhydrous sodium sulfate and concentrated. After concentration, the product I-A7-2 (50g, yield: 96.5%) is obtained as a white solid.

LC-MS [M+1] ⁺ = 404.6

Step 2: Dissolve I-A7-2 (50 g, 124 mmol) and 1-chloro-2-bromoethane (35.5 g, 248 mmol) in N,N-dimethylformamide (500 mL) at room temperature, and then add cesium carbonate (80.8 g, 248 mmol). The mixture was stirred at 70 ° C for 16 hours, and the reaction was complete after TLC detection. The reaction mixture was put into water (500 ml) and extracted with ethyl acetate (300 mL * 2). The organic phase was washed with saturated brine (1000 mL) and dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the desired product I-A7-3 (41.3 g, yield: 71.6%) as a white solid.

¹ H-NMR (400MHz, Chloroform-d) δ8.42 (s, 2H), 4.25 (d, J = 6.2Hz, 2H), 3.98–3.93 (m, 2H), 3.89 (s, 3H).

Step 3: Dissolve the intermediate I-A7-3 (30 g, 64.4 mmol) in N-methylpyrrolidone (500 mL), add CuCN (17.3 g, 193.2 mmol), and stir the reaction at 160 ° C under nitrogen protection for 3 hours. TLC detection shows that the reaction is complete. The reaction mixture is quenched with ammonia (1000 mL, 23%) and extracted with ethyl acetate (500 mL*3). The organic phase is washed with saturated brine (1500 mL) and dried over anhydrous sodium sulfate. The filtrate is concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the desired product I-A7-4 (5.6 g, yield: 32.9%) as a brown solid.

¹ H-NMR(400MHz,Chloroform-d)δ8.44(s,2H),4.86(s,2H),3.96(s,3H),3.90(s,2H).

Step 4: Dissolve I-A7-4 (1.7 g, 6.4 mmol) in tetrahydrofuran (15 mL) at -10 ° C, add methyl magnesium bromide (6.4 ml, 3M tetrahydrofuran solution) dropwise in a nitrogen atmosphere, and react at -10 ° C for 4 hours after the addition. The reaction mixture is slowly added to a saturated ammonium chloride solution at 0 ° C and extracted with ethyl acetate (50 mL * 3). The organic phase is washed with saturated brine (60 mL), dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the desired product I-A7-5 (1.14 g, yield: 67%) as a yellow oily solid.

¹ H-NMR (400MHz, Chloroform-d) δ7.92 (s, 2H), 4.68 (s, 2H), 3.89 (s, 2H), 1.55 (s, 6H).

Step 5: Dissolve I-A7-5 (1.14 g, 4.3 mmol) and phenol (2.0 g, 21.5 mmol) in dichloromethane (12 mL), add boron trifluoride ether solution (1.8 g, 47%) dropwise under nitrogen protection at -78 ° C, and naturally warm to room temperature for 3 hours after the addition. TLC detection shows that the reaction is complete, the reaction mixture is added to water (20 mL) and extracted with dichloromethane (50 mL * 3). The organic phase is washed with saturated brine (60 mL), dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the desired product intermediate I-A7 (1.0 g, yield: 68%) as a yellow solid.

¹ H-NMR (400MHz, Chloroform-d) δ7.61 (s, 2H), 7.02 (d, J = 8.7Hz, 2H), 6.79 (d, J = 7.2Hz, 2H), 4.67 (d, J = 7.0Hz, 2H), 3.86 (d, J = 6.3Hz, 2H), 1.63 (s, 6H).

Synthesis of Intermediate I-A8: 3-Chloro-2-(2-chloroethoxy)-5-(1-(4-ethynylphenyl)-1-hydroxyethyl)benzonitrile

Step 1: Dissolve the raw material I-A8-1 (7.0 g, 51.4 mmol) in toluene (100 mL) and add diisopropylamine hydrochloride (358 mg, 2.6 mmol) and intermediate I-A8-2 (10.1 g, 51.4 mmol) under stirring at 0°C. The above mixture is reacted at 0°C for 4 hours. The reaction is quenched with a saturated aqueous sodium sulfite solution, extracted with dichloromethane (150 mL*2), the organic phases are combined, washed with saturated brine (100 mL*2), and the organic phases are dried over anhydrous sodium sulfate and concentrated. The concentrated mixture is subjected to column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the product I-A8-3 (2.5 g, yield: 28.5%) as a white solid.

LC-MS [M+1] ^+- = 170.9

Step 2: At room temperature, the intermediate I-A8-3 (2.5 g, 14.6 mmol) was dissolved in dichloromethane (30 mL), and NIS (3.3 g, 14.6 mmol) was added at 0 ° C. The mixture was stirred at room temperature for 16 hours. LC-MS detected that the reaction was complete. The reaction mixture was put into water (50 mL) and extracted with dichloromethane (50 mL * 3). The organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the desired product I-A8-4 (4.0 g, yield: 93%) as a brown solid.

LC-MS [M+1] ⁺ = 296.8

Step 3: Dissolve I-A8-4 (6.7 g, 22.6 mmol) in N, N-dimethylformamide (100 mL), add 1-bromo-2-chloroethane (6.5 g, 45.2 mmol), cesium carbonate (14.7 g, 45.2 mmol). The mixture was stirred at 70 ° C for 16 hours. TLC detected that the reaction was complete. The reaction mixture was put into water (100 mL) and extracted with ethyl acetate (100 mL*3). The organic phase was washed with saturated brine (300 mL) and dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated and then column chromatography (petroleum ether/ethyl acetate = 5/1) was used to obtain the desired product I-A8-5 (5.6 g, yield: 69%), which was a yellow solid.

¹ H NMR (400MHz, Chloroform-d) δ8.24(s,1H),7.94(s,1H),4.30(s,2H),3.91(s,2H),2.55(s,3H).

Step 3: Dissolve the intermediate I-A8-5 (5.6 g, 15.6 mmol) in N-methylpyrrolidone (60 mL) and add CuCN (2.1 g, 23.4 mmol). The mixture was stirred at 160 ° C for 3 hours under a nitrogen atmosphere. TLC detected that the reaction was complete, and the reaction mixture was quenched with ammonia (300 mL, 23%) and extracted with ethyl acetate (200 mL*3). The organic phase was washed with saturated brine (500 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the desired product I-A8-6 (3.0 g, yield: 75%) as a yellow solid.

Step 4: Dissolve the intermediate I-A8-7 (909 mg, 3.85 mmol) in tetrahydrofuran (5 mL) at -77 ° C, add n-butyl lithium (2.6 ml, 1.6 M n-hexane solution) dropwise under nitrogen atmosphere, react at -77 ° C for 30 minutes, then add the tetrahydrofuran (4 mL) solution of the intermediate I-A8-6 (900 mg, 3.5 mmol) dropwise to the above mixture, and keep -77 ° C for 2 hours after the addition. LC-MS detection reaction is complete. The reaction mixture is slowly added to a saturated ammonium chloride solution at 0 ° C and extracted with ethyl acetate (20 mL * 3). The organic phase is washed with saturated brine (60 mL), dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the desired product I-A8-8 (1.1 g, yield: 76.4%) as a yellow oily liquid.

LC-MS[M+23] ⁺ ＝437.9

Step 5: At room temperature, the intermediate I-A8-8 (1.1 g, 2.65 mmol) and trimethylsilyl acetylene (2.6 g, 26.5 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (190 mg, 0.27 mmol), cuprous iodide (51 mg, 0.27 mmol), N,N-diisopropylethylamine (6.8 g, 53 mmol) were dissolved in tetrahydrofuran (10 ml). The mixture was stirred at 80° C. under nitrogen protection for 16 hours. TLC detected that the reaction was complete. After the reaction mixture was concentrated, it was purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain the desired product I-A8-9 (900 mg, yield: 78.3%) as a yellow oily liquid.

¹ H NMR(400MHz,Chloroform-d)δ7.60(s,1H),7.50(s,1H),7.43(s,2H),7.32(s,2H),4.42–4.38(m,2H),3.87 –3.83(m,2H),1.90(s,3H),0.23(s,9H)

Step 6: Dissolve the intermediate I-A8-9 (900 mg, 2.1 mmol) in methanol (10 mL), add potassium fluoride (974 mg, 16.8 mmol), and stir the mixture under nitrogen protection at 25°C for 16 hours. TLC detection shows that the reaction is complete. After the reaction mixture is concentrated, column chromatography (petroleum ether/ethyl acetate = 10/1) is performed to obtain the desired product intermediate I-A8 (590 mg, yield: 78.7%), which is a yellow oily liquid.

¹ H NMR(400MHz,Chloroform-d)δ7.64(s,1H),7.52(s,1H),7.49–7.44(m,2H),7.35(s,2H),4.39(s,2H),3.87 (s,2H),3.08(s,1H),1.91(s,3H).

Synthesis of Intermediate I-A9: 3-Chloro-5-(2-(4-hydroxyphenyl)propan-2-yl)-2-methoxybenzonitrile

Referring to the synthesis method of intermediate I-A1, iodomethane was used instead of I-A1-3, and a four-step reaction was carried out to obtain intermediate I-A9.

LC-MS [M+18] ⁺ = 319.1

Synthesis of Intermediate I-A10: 1-(2-chloroethyl)-5-(2-(4-hydroxyphenyl)propan-2-yl)-1H-indazole-7-carbonitrile

Step 1: Add NBS (48 g, 272 mmol) to acetonitrile (400 mL) of the raw material I-A3-1 (30 g, 181 mmol). The above mixed solution was reacted at room temperature for 3 hours, and LCMS detected the formation of the product. The reaction mixture was cooled to room temperature, 200 mL of saturated sodium sulfite was added to the reaction solution, and the acetonitrile was concentrated under reduced pressure and extracted with ethyl acetate (100 mL*2), and the organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether: ethyl acetate = 20%) to obtain the desired product intermediate I-A10-1 (35 g, yield: 78%) as a yellow solid.

LC-MS [M+1] ⁺ = 243.8/245.8

Step 2: Dissolve the intermediate I-A10-1 (11 g, 45.07 mmol) in 100 mL of acetic acid, add a saturated sodium nitrite solution at 0°C, and stir the mixture at room temperature for 3 hours. LCMS detected that the reaction was complete. After removing the acetic acid under reduced pressure, column chromatography (petroleum ether/ethyl acetate = 5/1) was performed to obtain the desired product I-A10-2 (8.4 g, yield: 73%) as a brown solid.

LC-MS [M+1] ^+- = 254.9/356.9

Step 3: Mix the raw material I-A10-2 (1.5 g, 6 mmol) and zinc cyanide (1.60 g, 15 mmol), add NMP (2 mL), and then add tri-tert-butylphosphine palladium (1.0 g, 1.96 mmol) to the mixture. The above mixed solution is reacted at 150 ° C (microwave) for 1 hour. The reaction mixture is cooled to room temperature, 30 mL of ethyl acetate and 50 mL of water are added to the reaction solution, and then extracted with ethyl acetate (10 mL * 2), and the organic phase is dried with anhydrous sodium sulfate and filtered. The filtrate is concentrated and separated by column chromatography (pure petroleum ether) to obtain the desired product I-A10-3 (900 mg, yield: 76%) as a yellow solid.

¹ H-NMR (400MHz, Chloroform-d) δ8.75 (d, J＝1.1Hz, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 3.98-3.95 (m, 3H)

Step 4: Mix the intermediate I-A10-3 (0.8 g, 3.98 mmol) and potassium carbonate (550 mg, 3.98 mmol) in 10 mL DMF, add 1-chloro-2-bromoethane (2.0 g, 13.9 mmol), and stir the mixture at 75 ° C for 1 hour. LCMS detection reaction is complete. The reaction mixture is introduced into 50 mL of water and extracted with ethyl acetate. After the extract is concentrated, column chromatography (petroleum ether/ethyl acetate = 5/1) is performed to obtain the desired product I-A10-4 (170 mg, yield: 16%), which is a yellow oil.

LC-MS[M+1] ^- =263.8

Step 5: Add methylmagnesium bromide (2mL, 2mmol, 1M in THF) dropwise to a solution of the intermediate I-A10-4 (170mg, 0.64mmol) in tetrahydrofuran (5mL) at room temperature. The above mixture was stirred at room temperature for 2 hours. LCMS detected that the reaction was complete. The reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (10mL) at 0°C, extracted with ethyl acetate (15mL*3), the combined organic phase was washed with saturated brine (10mL) and dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 2/1), The desired product I-A10-5 (160mg, yield: 94%) was obtained as a colorless oil.

LC-MS [M+1] ⁺ = 264.1

Step 6: Add boron trifluoride ether solution (213 mg, 1.5 mmol) to a dichloromethane (6 mL) solution of intermediate I-A10-5 (160 mg, 0.6 mmol) and phenol (142 mg, 1.5 mmol) at -78°C. The above mixture was stirred at -78°C for 2 hours. TLC detected that the reaction was complete. The reaction solution was quenched with water (20 mL), extracted with dichloromethane (20 mL*3), the combined organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain the desired product intermediate I-A10 (200 mg, yield: 97%) as a colorless oil.

LC-MS [M+1] ⁺ = 339.9

Synthesis of Intermediate I-A11: 2-(2-chloroethoxy)-5-(2-(4-ethynylphenyl)propan-2-yl)-3-methoxybenzonitrile

Referring to the synthetic route of intermediate I-A2, intermediate I-A6 was used instead of intermediate I-A1 to synthesize 2-(2-chloroethoxy)-5-(2-(4-ethynylphenyl)propane-2-yl)-3-methoxybenzonitrile (intermediate I-A11) through three steps.

¹ H NMR (400MHz, Chloroform-d) δ7.42(d,J＝2.0Hz,1H),7.40(d,J＝2.0Hz,1H),7.15(d,J＝2.0Hz,1H),7.12( d,J＝2.0Hz,1H),7.04(d,J＝1.6Hz,1H),6.80(d,J＝2.4Hz,1H),4.37(t,J＝6.4Hz,2H),3.80(t, J＝6.3Hz,2H),3.73(s,3H),3.05(s,1H),1.63(s,6H).

LC-MS [M+1] ⁺ =354.10.

Synthesis of Intermediate I-A12: 2-(2-chloroethoxy)-5-(2-(4-ethynylphenyl)propan-2-yl)isophthalonitrile

Referring to the synthetic route of intermediate I-A2, intermediate I-A7 was used instead of intermediate I-A1 to synthesize 2-(2-chloroethoxy)-5-(2-(4-ethynylphenyl)propane-2-yl)isophthalonitrile (intermediate I-A12) as a yellow oily liquid through three steps of reaction.

LC-MS [M+23] ⁺ = 371.1

Synthesis of intermediate I-A13: 1-(2-chloroethyl)-5-(2-(4-ethynylphenyl)propan-2-yl)-1H-indazole-7-cyano

Step 1: Dissolve the intermediate I-A10 (200 mg, 0.59 mmol) in DCM (5 mL), add triethylamine (179 mg, 1.77 mmol). Add Tf ₂ O (250 mg, 0.88 mmol) at 0°C, and react the mixture at 25°C for 1 hour. TLC detection shows that the reaction is complete. The mixture is separated on a preparative silica gel plate to obtain the product I-A13-1 (207 mg, yield: 74.5%), which is a yellow oily liquid.

LC-MS [M+1] ⁺ = 472.0

Step 8: I-A13-1 (2.0 g, 4.24 mmol) and trimethylsilyl acetylene (1.25 g, 12.72 mmol), triethylamine (2.14 g, 21.19 mmol, 2.96 mL) were dissolved in ACN (20 mL), CuI (80.72 mg, 423.84 μmol), Pd(PPh ₃ ) ₂ Cl ₂ (297.53 mg, 423.84 μmol) were added, the mixture was replaced with nitrogen three times, and reacted at 80°C for 5 hours. After the mixture was concentrated, it was separated by column chromatography (petroleum ether/ethyl acetate = 95/5) to obtain the product I-A13-2 (1.7 g, yield: 93.3%) as a brown oily liquid.

LC-MS [M+1] ⁺ = 420.3

Step 9: I-A13-2 (1.7 g, 4.5 mmol) was added to MeOH (20 mL), and KF (1.7 g, 29.3 mmol) was added at room temperature, and the reaction solution was reacted at 30°C for 4 hours. The mixture was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain intermediate I-A13 (1.1 g, yield: 76.6%) as a yellow solid.

LC-MS [M+1] ⁺ = 348.3

Synthesis of Intermediate I-A14: 2-Chloro-3-(2-chloroethoxy)-6-(2-(4-hydroxyphenyl)propan-2-yl)isonicotinonitrile

Step 1: Dissolve the raw material I-A14-1 (5g, 19.5mmol) in N,N-dimethylformamide (50mL), add Zn(CN) ₂ (1.35g, 11.7mmol), Pd(PPh ₃ ) ₄ (1.8g, 1.56mmol) to the solution. The above mixture was stirred at 100°C for 16 hours under nitrogen protection, and TLC detection showed that the reaction was complete. The reaction mixture was put into water (100mL), extracted with ethyl acetate (100mL*2), the organic phases were combined, washed with saturated brine (150mL*2), and the organic phases were dried over anhydrous sodium sulfate and concentrated. The concentrated mixture was subjected to column chromatography to obtain the product I-A14-2 (1.6g, yield: 53.3%) as a yellow solid.

LC-MS [M+1] ⁺ = 155.0

Step 2: I-A14-2 (1.6 g, 10.3 mmol) was dissolved in a methanol solution of hydrogen chloride (4 M, 26 ml, 104 mmol) at room temperature, and the mixture was stirred at 80 ° C for 20 hours. The reaction was complete after LC-MS detection. The reaction solution was filtered using silica gel, and the filtrate was concentrated to obtain a yellow solid. The yellow solid was dissolved in hot 1,4-dioxane (100 mL, 65 ° C), and hot n-hexane (100 mL) was added to the solution. The solution was slowly cooled to room temperature and the mixture was filtered. The solid was rinsed with n-hexane, and the filtered solid was collected and vacuum dried to obtain the product I-A14-3 (1.7 g, yield: 88.1%) as a yellow solid.

LC-MS [M+1] ⁺ = 188.0

Step 3: Dissolve the raw material I-A14-3 (1.7 g, 9.1 mmol) in N,N-dimethylformamide (20 mL) and add NIS (3.07 g, 13.65 mmol). The above mixture was reacted at 100°C for 16 hours, and LC-MS detection showed that the reaction was complete. The reaction mixture was put into water (100 mL), extracted with ethyl acetate (50 mL*2), the organic phases were combined, washed with saturated brine (100 mL*2), and the organic phases were dried over anhydrous sodium sulfate and concentrated. After concentration, the crude product I-A14-4 (3.9 g) was obtained as a reddish brown solid.

LC-MS [M+1] ⁺ = 313.9

Step 4: At room temperature, I-A14-4 (3.9, 12.5 mmol) and 1-bromo-2-chloroethane (8.9 g, 62.5 mmol) were dissolved in N, N-dimethylformamide (40 mL), and then cesium carbonate (8 g, 25 mmol) was added. The mixture was stirred at 70 ° C for 16 hours, and the reaction was complete by TLC. The reaction mixture was put into water (50 mL) and extracted with ethyl acetate (50 mL * 3). The organic phase was washed with saturated brine (100 mL), dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the desired product I-A14-5 (1.6 g, yield: 47%) as a yellow solid.

Step 5: Dissolve the intermediate I-A14-5 (1.6 g, 4.3 mmol) in N-methylpyrrolidone (20 mL), add CuCN (614 mg, 6.9 mmol), and stir the reaction at 160 ° C under nitrogen protection for 3 hours. TLC detection reaction is complete. The reaction mixture is put into water (100 mL) and extracted with ethyl acetate (50 mL * 3). The organic phase is washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The filtrate is concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain the desired product I-A14-6 (270 mg, yield: 23%) as a yellow solid.

LC-MS [M+1] ⁺ = 274.9

Step 6: Dissolve I-A14-6 (200 mg, 0.7 mmol) in tetrahydrofuran (6 mL), replace with nitrogen 3 times, add methylmagnesium bromide (1.3 mL, 1 M tetrahydrofuran solution) dropwise at -77 ° C, and react at -77 ° C for 30 minutes after the addition. LC-MS detection shows that the reaction is complete. The reaction mixture is slowly added to a saturated aqueous ammonium chloride solution at 0 ° C and extracted with ethyl acetate (10 mL*3). The organic phase is washed with saturated brine (50 mL), and dried with anhydrous sodium sulfate and filtered. The filtrate is concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the desired product I-A14-7 (150 mg, yield: 75%), which is a yellow oily liquid.

¹ H NMR (400MHz, Chloroform-d) δ7.63 (s, 1H), 4.53–4.44 (m, 2H), 3.89 (t, J = 5.7Hz, 2H), 1.56 (s, 6H).

Step 7: I-A14-7 (140 mg, 0.51 mmol) and phenol (240 mg, 2.55 mmol) were dissolved in 1,2-dichloroethane (6 mL), anhydrous AlCl ₃ (136 mg, 1.02 mmol) was added to the solution, and the mixture was reacted at 100°C for 3 hours. The reaction mixture was added to water (10 mL) and extracted with dichloromethane (10 mL*3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the desired product I-A14 (55 mg, yield: 62%) as a yellow oily liquid.

¹ H NMR(400MHz,Chloroform-d)δ7.11(d,J＝10.3Hz,2H),7.07(s,1H),6.78(d,J＝8.4Hz,2H),4.46(s,2H), 3.86(s,2H),1.68(s,6H).

According to the synthesis method of the above intermediates or references, the following intermediates were synthesized respectively:

Synthesis of Intermediate I-A18: 4-(2-chloroethyl)-7-(2-(4-hydroxyphenyl)propan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbonitrile

Step 1: I-A18-1 (5.0 g, 29.91 mmol) was dissolved in DCM (100 mL) and DMF (10 mL), and NBS (6.92 g, 38.88 mmol) was added in batches at 0°C. The reaction solution was stirred at 30°C for 2 hours, and H ₂ O (50 mL) was added. The aqueous layer was extracted three times with DCM (100 mL), and the organic phases were combined, dried, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain I-A18-2 (2.50 g, yield: 27.09%) as a brown solid.

LC-MS [M+1] ⁺ = 245.9

Step 2: Dissolve I-A18-2 (2.3 g, 9.35 mmol) and K ₂ CO ₃ (6.45 g, 46.74 mmol) in DMF (140 mL), add 1,2-dibromoethane (4.39 g, 23.37 mmol). The reaction solution was stirred at 80 ^° C. for 18 hours, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain I-A18-3 (1.10 g, yield: 41.09%) as a light yellow solid.

LC-MS [M+1] ⁺ = 272.0

Step 3: I-A18-3 (1 g, 3.68 mmol) and K ₂ CO ₃ (1.01 g, 7.35 mmol) were dissolved in DMF (20 mL), and Zn(CN) ₂ (863.12 mg, 7.35 mmol) and Pd(PPh ₃ ) ₄ (849.70 mg, 735.04 μmol) were added respectively, and then microwaved at 120° C. for 4 hours. After the reaction solution was concentrated, it was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to obtain I-A18-4 (620.00 mg, yield: 68.03%) as a white solid.

LC-MS [M+1] ⁺ = 219.1

Step 4: Dissolve I-A18-4 (1 g, 4.58 mmol) and Cs ₂ CO ₃ (2.24 g, 6.87 mmol) in DMF (30 mL), add 2-chloroethyl methanesulfonate (1.45 g, 9.17 mmol), react at 50°C for 18 hours, concentrate, and purify by column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain I-A18-5 (270.00 mg, yield: 18.89%) as a colorless oil.

LC-MS [M+1] ⁺ = 281.1

Step 5: I-A18-5 (270 mg, 961.86 μmol) was dissolved in THF (2 mL), and MeMgBr (1 M, 4.81 mL, 4.81 mmol) was added at 30°C. After stirring at 40°C for 1.5 hours, the mixture was quenched with saturated NH ₄ Cl (10 mL), and then extracted three times with ethyl acetate (30 mL). The organic phases were combined and concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give I-A18-6 (30.00 mg, yield: 10.00%) as a colorless liquid.

LC-MS [M+1] ⁺ = 281.1

Step 6: I-A18-6 (60 mg, 213.71 μmol) and phenol (100.56 mg, 1.07 mmol) were dissolved in DCE (4 mL), and AlCl ₃ (56.85 mg, 427.43 μmol) was added at 0°C, and the mixture was reacted for 3 hours at 0°C. The mixture was quenched with saturated NaHCO ₃ (10 mL), and then extracted three times with ethyl acetate (30 mL), the organic phases were combined and concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain I-A18 (40.00 mg, yield: 31.47%) as a brown oil.

LCMS: m/z 357.13 [M+H] ⁺

Synthesis of intermediates I-A19 and I-A19-5:

Step 1: Add I-A19-1 (2 g, 9.71 mmol), ethylene glycol (1.21 g, 19.42 mmol) and Cs ₂ CO ₃ (9.49 g, 29.12 mmol) to DMF (25 mL) and react with microwave at 100°C for 2 hours. The reaction solution was cooled to room temperature, and MeI (1.17 g, 8.27 mmol) was added and stirred at 25°C for 2 hours. 60 mL of water was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (20 mL*5), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent, and separated by column chromatography (petroleum ether/tetrahydrofuran = 1:1) to obtain intermediate I-A19-2 (1.0 g, yield: 44.44%) as a white solid.

LC-MS [M+1] ⁺ = 232.10

Step 2: Dissolve I-A19-2 (1.0 g, 3.37 mmol) in THF (8 mL), replace with nitrogen three times, add MeMgBr (1 M, 20.20 mL) dropwise at 25 ° C, and continue to stir and react for 0.5 hours after addition. The reaction solution was quenched with saturated aqueous ammonium chloride at 0 ° C, extracted with ethyl acetate (20 mL * 2), washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated and separated by column chromatography (petroleum ether/tetrahydrofuran = 6:4) to obtain the intermediate I-A19-3 (800.00 mg, yield: 75.99%) as a light yellow solid.

LC-MS [M+1] ⁺ = 232.10

Step 3: Add intermediate I-A19-3 (0.16 g, 1.99 mmol), phenol (934.30 mg, 9.93 mmol) and AlCl ₃ (529.50 mg, 3.97 mmol) to solvent DCE (5 mL), heat to 80°C and stir for 2 hours. LC-MS detection shows that the reaction is complete, column chromatography separation (petroleum ether/tetrahydrofuran = 5/1) gives intermediate I-A19-4 (500.00 mg, crude product) as a light yellow oil.

LC-MS [M+1] ⁺ = 308.20

Step 4: SOCl ₂ (5 mL) was added dropwise to the intermediate I-A19-4 (0.5 g, 1.62 mmol) at 0°C, and the reaction was continued under stirring for 2 hours at this temperature. LC-MS detection showed that the reaction was complete, and the pH of the reaction solution was adjusted to neutral with sodium bicarbonate solution, extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to obtain the intermediate I-A19 (200.00 mg, crude product) as a white solid.

LC-MS [M+1] ⁺ = 326.30

Step 5: According to the operation steps of I-A10-2 to I-A10-3, intermediate I-A19 is reacted in one step to generate intermediate I-A19-5.

LC-MS [M+1] ⁺ = 317.20

Synthesis of Intermediate I-A20: 1-(3-chloropropane)-4-(2-(4-hydroxyphenyl)propan-2-yl)-6-methylpyridin-2(1H)-one

Step 1: Dissolve I-A20-1 (10 g, 59.82 mmol) and 1,3-chlorobromopropane (28.25 g, 179.5 mmol) in acetonitrile (120 mL), and add Cs ₂ CO ₃ (38.88 g, 119.6 mmol). The reaction solution was reacted at 80°C for 16 hours. The reaction solution was concentrated and separated by column chromatography (petroleum ether/tetrahydrofuran = 1/1) to obtain the desired product I-A20-2 (5.4 g, yield: 40%), which was a yellow oily liquid.

LC-MS [M+1] ⁺ = 226.2

Step 2: I-A20-2 (5.4 g, 23.97 mmol) was dissolved in dichloromethane (50 mL), SOCl ₂ (11.4 g, 95.9 mmol) was added at 0°C, and the reaction solution was stirred at room temperature for 3 hours. The mixture was spin-dried and then separated by column chromatography (petroleum ether/tetrahydrofuran = 1/1) to obtain the desired product I-A20-3 (3.0 g, yield: 27.5%) as a yellow solid.

LC-MS [M+1] ⁺ = 244.2

Step 3: Add methylmagnesium bromide (123mL, 123mmol, 1M in THF) dropwise to a solution of I-A20-3 (3.0g, 12.3mmol) in tetrahydrofuran (20mL) at room temperature. The above mixture was stirred at room temperature for 4 hours. The reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (100mL) at 0°C, extracted with ethyl acetate (100mL*3), the combined organic phase was washed with saturated brine (300mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated and separated by column chromatography (petroleum ether/tetrahydrofuran = 1/1), and the desired product I-A20-4 (1.1g, yield: 26.76%) was obtained as a light yellow oil.

LC-MS [M+1] ⁺ = 244.2

Step 6: Add a solution of boron trifluoride in ether (2.98 g, 9.85 mmol) to a solution of I-A20-4 (800 mg, 3.28 mmol) and phenol (1.54 g, 16.4 mmol) in 1,2-dichloroethane (10 mL) at room temperature. The mixture was stirred at 100 ° C to room temperature for 3 hours. The reaction solution was quenched with water (20 mL), extracted with dichloromethane (20 mL * 3), the combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated and separated by column chromatography (petroleum ether/tetrahydrofuran = 1/1) to obtain the desired product I-A20 (340 mg, yield: 22.1%) as a yellow oil.

LC-MS [M+1] ⁺ = 320.3

I-A33 was synthesized by referring to the synthesis method of I-A20.

Synthesis of Intermediate I-A21: 4-(2-(7-chloro-1-(2-chloroethyl)-1H-benzo[d][1,2,3]triazol-5-yl)propan-2-yl)phenol

Step 1: At 0°C, 3-chloro-4-fluorobenzoic acid (500 mg, 2.86 mmol) was dissolved in H ₂ SO ₄ (3 mL), and HNO ₃ (416.51 mg, 4.30 mmol, 297.50 μL, purity 65%) was added dropwise. After the reaction solution was reacted at 25°C for 1 hour, the reaction solution was poured into ice water, and a white solid precipitated. The white solid was then filtered, collected, and freeze-dried to obtain the product I-A21-1 (350 mg, yield: 50.09%) as a white solid.

LC-MS[M-1] ^- =218.0

Step 2: Dissolve I-A21-1 (100 mg, 455.47 μmol) in SOCl ₂ (162.56 mg, 1.37 mmol), react at 70°C for 3 hours, then drop the reaction solution into MeOH (10 mL) at 0°C, stir for 30 minutes, and concentrate to obtain the product I-A21-2 (100 mg, yield: 84.60%) as a white solid.

LC-MS [M+1] ⁺ = 234.0

Step 3: Dissolve I-A21-2 (2.1 g, 8.99 mmol) and DIEA (1.14 g, 11.69 mmol) in DMF (20 mL), and add 2-aminoethanol hydrochloride (1.14 g, 11.69 mmol) at 25°C. The reaction solution was reacted at 25°C for 18 hours. After concentration, the product I-A21-3 (130 mg, yield: 6%) was purified by column (petroleum ether/ethyl acetate = 3:1) as a yellow solid.

LC-MS [M+1] ⁺ = 275.1

Step 4: Dissolve I-A21-3 (130 mg, 473.32 μmol) and iron powder (132.16 mg, 2.37 mmol) in AcOH (2 mL). The reaction solution was reacted at 40 ° C for 2 hours. The reaction solution was adjusted to pH = 8 with saturated sodium carbonate solution, extracted with ethyl acetate (30 mL * 3), and the organic phase was concentrated to obtain I-A21-4 (110 mg, yield: 85.49%), which was a yellow oil.

LC-MS [M+1] ⁺ = 245.1

Step 5: Dissolve I-A21-4 (90 mg, 367.84 μmol) in AcOH (2 mL), cool to 0°C, add solid NaNO ₂ (30.46 mg, 441.40 μmol) in batches, heat to 25°C and react for 2 hours, adjust pH to 8 with saturated Na ₂ CO ₃ , extract three times with ethyl acetate (40 mL), combine the organic phases, concentrate and purify by column (petroleum ether/ethyl acetate = 1:1) to obtain I-A21-5 (90.00 mg, yield: 90.92%) as a brown solid.

LC-MS [M+1] ⁺ = 256.1

Step 6: After dissolving I-A21-5 (70 mg, 273.80 μmol) and PPh ₃ (86.18 mg, 328.56 μmol) in DCM (5 mL), NCS (43.87 mg, 328.56 μmol) was added at 25° C. The reaction was allowed to react at 25° C. for 3 hours, concentrated, and purified by preparative TLC (petroleum ether/ethyl acetate=4:1) to give I-A21-6 (56.00 mg, yield: 70.89%) as a white solid.

LC-MS [M+1] ⁺ = 274.0

Step 7: I-A21-6 (55 mg, 200.65 μmol) was dissolved in anhydrous THF (3 mL), and MeMgBr (1 M, 601.96 μL) was added dropwise at 0°C. The reaction solution was stirred at 25°C for 2 hours, quenched with saturated NH ₄ Cl solution (10 mL), and then extracted three times with ethyl acetate (30 mL). The organic phases were combined and concentrated, and purified by preparative TLC (petroleum ether/ethyl acetate = 3:1) to obtain I-A21-7 (50.00 mg, yield: 90%) as a white solid.

LC-MS [M+1] ⁺ = 274.0

Step 8: I-A21-7 (50 mg, 182.38 μmol) and phenol (17.16 mg, 182.38 μmol) were dissolved in anhydrous DCM (2 mL), 4A molecular sieves (50 mg) were added, the mixture was cooled to -78 °C, and BF3·Et2O (25.89 mg, 182.38 μmol) was added. Then the mixture was naturally warmed to room temperature and reacted for 2 hours, concentrated, and purified by preparative TLC (petroleum ether/ethyl acetate = 3:1) to obtain intermediate I-A21 (25.00 mg, yield: 35.22%) as a white solid.

LC-MS [M+1] ⁺ = 350.1

Synthesis of Intermediate I-A22: 4-(2-(1-(2-chloroethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)propan-2-yl)phenol

Step 1: Add I-A22-1 (2 g, 12.26 mmol) to methanol (50 mL), slowly add H ₂ SO ₄ (3 mL) at room temperature, and raise the temperature to 70°C for reflux reaction for 12 hours. Remove most of the solvent by rotary evaporation, pour the reaction solution into ice water to precipitate a light yellow solid. Filter and freeze-dry the solid to obtain intermediate I-A22-2 (1.63 g, yield: 71.29%), which is a light yellow solid.

LC-MS [M+1] ⁺ = 178.10

Step 2: Add I-A22-2 (750 mg, 4.23 mmol), 1-bromo-2-chloroethane (1.82 g, 12.7 mmol) and Cs ₂ CO ₃ (1.17 g, 5.88 mmol) to N,N-dimethylformamide solvent (15 mL), heat to 80°C, and stir to react for 3 hours. Add water to the reaction solution to quench, extract with ethyl acetate several times (20 mL*3), wash with saturated brine, dry with anhydrous sodium sulfate, remove the solvent by rotary evaporation, and separate by column chromatography (petroleum ether/tetrahydrofuran=3/1) to obtain intermediate I-A22-3 (711 mg, yield: 66.57%) as a white solid.

LC-MS[M+1] ⁺ ＝240.60

Step 3: Add I-A22-3 (580 mg, 2.24 mmol) to tetrahydrofuran (6 mL), stir overnight at room temperature, protect with nitrogen, add methylmagnesium bromide (865.72 mg, 7.26 mmol) under ice bath, remove ice bath after addition, stir and react at room temperature for 0.5 hours. Add saturated aqueous ammonium chloride at 0°C to the reaction solution to quench, extract with ethyl acetate several times (20 mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, separate by column chromatography (petroleum ether/tetrahydrofuran=1/1) to obtain intermediate I-A22-4 (430 mg, yield: 73.38%) as a yellow oil.

LC-MS[M+1] ⁺ ＝240.70

Step 4: Dissolve the intermediate I-A22-4 (280 mg, 1.17 mmol) and phenol (549.67 mg, 5.84 mmol) in 1,2-dichloroethane (4 mL), and add aluminum chloride (311.52 mg, 2.34 mmol) at room temperature. Heat the reaction to 100°C and stir for 3 hours. LC-MS detection shows that the reaction is complete, and column chromatography separation (petroleum ether/tetrahydrofuran = 7/3) is used to obtain the intermediate I-A22 (265 mg, yield: 71.84%) as a light yellow solid.

LC-MS [M+1] ⁺ = 316.30

Synthesis of intermediate I-A23: 1-(2-chloroethyl)-5-(2-(4-ethynylphenyl)propan-2-yl)-1H-pyrazolo[3,4-b]pyridine

Step 1: Add intermediate I-A22 (1 g, 3.17 mmol) and triethylamine (640.86 mg, 6.33 mmol) to dichloromethane (13 mL), add Tf ₂ O (1.07 g, 3.80 mmol) dropwise at 0°C, and continue stirring for 1 hour. LC-MS detection shows that the reaction is complete, and the solvent is evaporated and separated by column chromatography (petroleum ether/tetrahydrofuran = 3/1) to obtain intermediate I-A23-1 (900 mg, yield: 60.29%) as a light yellow oil.

¹ H NMR (400MHz, DMSO-d6) δ8.32(s,1H),8.14(s,1H),8.13(s,1H),7.39(s,4H),4.71(s,2H),4.08(s ,2H),1.73(s,6H).

LC-MS [M+1] ⁺ = 448.1

Step 2: The intermediate I-A23-1 (150 mg, 334.93 μmol) was dissolved in acetonitrile (5 mL), triethylsilyl acetylene (140.97 mg, 1.00 mmol), DIEA (216.43 mg, 1.67 mmol), t-Buxphos Pd G3 (26.61 mg, 33.49 μmol) and 100 mg 4A molecular sieve were added, and microwave reaction was performed at 80°C for 1 hour. LC-MS detection showed that the reaction was complete, the solvent was evaporated, and column chromatography (petroleum ether/ethyl acetate = 15/1) was used to obtain the intermediate I-A23-2 (110 mg, yield: 69.72%) as a yellow oil.

LC-MS [M+1] ⁺ = 438.4

Step 3: Add intermediate I-A23-2 (0.1 g, 228.27 μmol) and KF (132.62 mg, 2.28 mmol) to methanol (8 mL) and stir at 45 °C for 12 hours. LC-MS detection shows that the reaction is complete, and the solvent is removed by rotary evaporation. Column chromatography (petroleum ether/ethyl acetate = 5/1) is used to obtain intermediate I-A23 (60 mg, yield: 70.62%) as a light yellow oil.

¹ H-NMR (400MHz, DMSO-D6) δ8.34(d,J＝2.2Hz,1H),8.15(t,J＝2.5Hz,2H),7.41(dd,J＝6.5,1.8Hz,2H) ,7.27(dd,J＝6.6,2.2Hz,2H),4.75(t,J＝5.9Hz,2H),4.13-4.10(m,2H),2.21(s,1H),1.74(s,6H)

LC-MS [M+1] ⁺ = 324.30

A59 was synthesized according to the above synthesis method of intermediate I-A23.

Synthesis of Intermediate I-A24: 2-(2-chloroethoxy)-3-fluoro-5-(2-(4-hydroxyphenyl)propan-2-yl)benzonitrile

Step 1: Dissolve I-A24-1 (4 g, 23.51 mmol) in acetonitrile (60 mL), stir at 25 ° C for 5 minutes, and then add NIS (10.58 g, 47.02 mmol) at 25 ° C. The reaction solution is reacted at 25 ° C for 4 hours. The reaction solution is spin-dried, extracted with ethyl acetate (300 mL*2), the organic phases are combined, washed with saturated brine (300 mL*2), and the organic phases are dried over anhydrous sodium sulfate and concentrated. After concentration, column chromatography (petroleum ether/ethyl acetate = 10/1) is performed to obtain the desired product I-A24-2 (6.40 g, yield: 82.76%) as a light orange solid.

LC-MS[M+1] ⁺ ＝297.00

Step 2: Dissolve I-A24-2 (6.4 g, 21.62 mmol) and 1,2-dichloroethane (12.40 g, 86.48 mmol) in DMF (80 mL) at room temperature, and then add cesium carbonate (14.05 g, 43.24 mmol). The mixture was stirred at 70 ° C for 3 hours, and the reaction was complete when detected by TLC. The reaction mixture was put into water and extracted with ethyl acetate (100 mL * 3). The organic phase was washed with saturated brine (100 mL * 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain the desired product I-A24-3 (7.0 g, yield: 81.28%) as a colorless oil.

LC-MS [M+1]+＝359.00

Step 3: Dissolve I-A24-3 (1.0 g, 3.29 mmol) in NMP (10 mL), add CuCN (522.13 mg, 5.58 mmol), and stir the reaction at 160 ° C under nitrogen protection for 1 hour. LCMS detected that the reaction was complete. The reaction mixture was quenched with aqueous ammonium chloride (20 mL, 23%) and extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the desired product I-A24-4 (700 mg, yield: 97.41%) as a white solid.

LC-MS [M+1]+＝258.00

Step 4: Add methylmagnesium bromide (10mL, 10.87mmol, 1M in THF) dropwise to a solution of I-A24-4 (700mg, 2.72mmol) in tetrahydrofuran (20mL) at room temperature. The above mixture was stirred at room temperature for 15 minutes. TLC (petroleum ether/ethyl acetate = 5/1)) detected that the reaction was complete. The reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (100mL) at 0°C, extracted with ethyl acetate (30mL*3), the combined organic phase was washed with brine (50mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the desired product I-A24-5 (560mg, yield: 71.99%) as a colorless oily liquid.

Step 5: Add boron trifluoride ether solution (294.73 mg, 4.35 mmol) to a dichloromethane (10 mL) solution of I-A24-5 (560 mg, 2.17 mmol) and phenol (409.04 mg, 4.35 mmol) at -78°C. The above mixture was stirred at -78°C to room temperature for 2 hours. TLC detected that the reaction was complete. The reaction solution was quenched with water (20 mL), extracted with dichloromethane (20 mL*3), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain the desired product I-A24 (580 mg, yield: 71.96%) as a colorless oil.

LC-MS [M+1]+＝334.10

Synthesis of intermediate I-A25: 1-(2-chloroethane)-5-(2-(4-hydroxyphenyl)propan-2-yl)-1H-benzo[d][1,2,3]triazole-7-cyano

Step 1: Dissolve I-A25-1 (1 g, 5.02 mmol) in H ₂ SO ₄ (5 mL) at 0°C and add NBS

(893.78 mg, 5.02 mmol) was added and stirred at 60°C for 1.5 hours. After TLC detection, the raw material was completely converted. The reaction solution was poured into ice water (40 mL), extracted twice with ethyl acetate (40 mL), and the organic phases were combined and concentrated to give intermediate I-A25-2 (1.50 g, crude product) as a white solid.

¹ H NMR (400MHz, DMSO-d6) δ8.55-8.52 (m, 2H), 3.92 (s, 3H). LC-MS[M+1] ⁺ =278.1

Step 2: Dissolve I-A25-2 (350 mg, 1.26 mmol) in DMF (3 mL), add DIEA (488.09 mg, 3.78 mmol) and 2-aminoethanol (92.27 mg, 1.51 mmol), stir at 30 ° C for 2 hours, concentrate, and purify by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain intermediate I-A25-3 (330.00 mg, yield: 80.51%) as a yellow liquid.

¹ H NMR(400MHz,Chloroform-d)δ8.51(d,J＝2.0Hz,1H),8.29(d,J＝2.0Hz,1H),8.67(s,1H),3.90(s,3H), 3.87-3.83(m,2H),3.50-3.46(m,2H).

LC-MS [M+1] ⁺ = 319.1

Step 3: Dissolve I-A25-3 (330 mg, 1.03 mmol) and iron powder (288.76 mg, 5.17 mmol) in AcOH (5 mL), stir at 40°C for 3 hours, concentrate, adjust pH to 8 with saturated NaHCO ₃ (20 mL), extract three times with ethyl acetate (40 mL), combine the organic phases and concentrate to obtain intermediate I-A25-4 (270.00 mg, yield: 90.30%) as a colorless oil.

LC-MS [M+1] ⁺ = 289.1

Step 4: Dissolve I-A25-4 (270 mg, 933.85 μmol) in AcOH (10 mL), cool to 0°C, add solid NaNO ₂ (77.32 mg, 1.12 mmol) in batches, heat to 30°C, react for 2 hours, concentrate to remove most of the AcOH, adjust pH to 8 with saturated Na ₂ CO ₃ , extract three times with ethyl acetate (40 mL), combine the organic phases, and concentrate to obtain intermediate I-A25-5 (230.00 mg, crude product) as a black solid.

¹ H NMR (400MHz, Chloroform-d) δ9.00 (d, J = 1.6Hz, 1H), 8.56 (d, J = 1.6Hz, 1H), 5.10 (t, J = 5.2Hz, 1H), 4.27- 4.26(m,2H),4.02(s,3H),2.22(s,1H)

LC-MS [M+1] ⁺ = 300.1

Step 5: I-A25-5 (230 mg, 766.39 μmol) and K ₂ CO ₃ (211.52 mg, 1.53 mmol) were dissolved in DMF (2 mL), and Zn(CN) ₂ (179.99 mg, 1.53 mmol) and Pd(PPh ₃ ) ₄ (132.89 mg, 114.96 μmol) were added respectively, and microwave reaction was performed at 120° C. for 1 hour. After concentrating to remove DMF, the intermediate I-A25-6 (100.00 mg, yield: 47.69%) was obtained by purification by column chromatography (petroleum ether/ethyl acetate=2/1) as a light yellow solid.

LC-MS [M+1] ⁺ = 247.1

Step 6: After dissolving I-A25-6 (70 mg, 284.30 μmol) and PPh ₃ (89.48 mg, 341.16 μmol) in DCM (3 mL), NCS (45.56 mg, 341.16 μmol) was added at 0°C. The reaction was allowed to react at 30°C for 1 hour, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain intermediate I-A25-7 (70.00 mg, yield: 83.73%) as a white solid.

LC-MS [M+1] ⁺ = 265.1

Step 7: I-A25-7 (40 mg, 151.13 μmol) was dissolved in THF (0.5 mL), and MeMgBr (1 M, 453.40 μL) was added at 0°C. After stirring for 30 minutes, TLC detected that the raw material was completely converted, and the mixture was quenched with saturated NH ₄ Cl (10 mL), and then extracted three times with ethyl acetate (30 mL). The organic phases were combined and concentrated to give the intermediate I-A25-8 (40.00 mg, crude product) as a yellow solid.

LC-MS [M+1] ⁺ = 265.1

Step 8: I-A25-8 (70 mg, 264.44 μmol) and phenol (74.66 mg, 793.32 μmol) were dissolved in DCE (1 mL), and BF ₃ ·Et ₂ O (112.59 mg, 793.32 μmol) was added at -78°C. After stirring at 45°C for 1 hour, the mixture was concentrated and purified by preparative TLC (petroleum ether/ethyl acetate=3/1) to obtain the product I-A25 (25.0 mg, yield: 27.74%) as a colorless oil.

LC-MS [M+1] ⁺ = 341.1

According to the above synthesis method of intermediate I-A2, intermediate I-A26 was synthesized from intermediate I-A25 in three steps; A38 and A52 were synthesized according to the synthesis method of I-A25.

Synthesis of Intermediate I-A27: 1-(2-chloroethyl)-5-(2-(4-hydroxyphenyl)propan-2-yl)-1H-benzo[d]imidazole-7-cyano

Step 1: At 0°C, add I-A27-1 (21 g, 105.46 mmol) to H ₂ SO ₄ (100 mL) to dissolve, add NBS (26.28 g, 147.64 mmol) in batches, raise the temperature to 60°C to react for 1 hour, add the reaction solution dropwise into H ₂ O (400 mL) stirred at 0°C to quench, add ethyl acetate (400 mL) to extract, and dry and concentrate the organic phase to obtain I-A27-2 (31.63 g, crude product) as a white solid.

MS(ESI)m/z＝278.0/279.9[M+H] ⁺

Step 2: At 0°C, add I-A27-2 (31.63 g, 113.76 mmol) to DMF (31 mL), add DIPEA (44.11 g, 341.28 mmol) and 2-aminoethanol (9.03 g, 147.89 mmol) in batches while stirring, raise the temperature to 30°C and react for 2 hours, add H ₂ O (50 mL), extract the organic phase with ethyl acetate (100 mL), extract the aqueous phase twice with ethyl acetate (50 mL), combine the organic phases, dry and concentrate to obtain I-A27-3 (29.62 g, crude product) as a yellow solid.

MS(ESI)m/z＝319.1/321.1[M+H] ⁺

Step 3: Add I-A27-3 (10 g, 31.34 mmol) to AcOH (100 mL) and stir to dissolve, add iron powder (8.75 g, 156.69 mmol) in batches, raise the temperature to 40°C, and continue the reaction for 2 hours. The reaction was adjusted to pH 8 with saturated NaHCO ₃ (400 mL), extracted twice with ethyl acetate (100 mL), and the organic phases were combined, dried and concentrated. Purification by column chromatography (petroleum ether: tetrahydrofuran = 2: 1) gave I-A27-4 (5.17 g, 17.03 mmol, yield: 54.33%) as a yellow solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ7.56 (d, J = 1.9 Hz, 1H), 7.23 (d, J = 1.6 Hz, 1H), 4.08-3.98 (m, 2H), 3.80 (s, 3H ),3.70-3.66(m,2H),3.16(t,J＝4.8Hz,2H),0.02--0.08(m,2H)

MS(ESI)m/z＝289.1/291.1[M+H] ⁺

Step 4: I-A27-4 (4.7 g, 16.26 mmol) and p-toluenesulfonic acid monohydrate complex (773.04 mg, 4.06 mmol) were dissolved in CH(OMe) ₃ (80 mL), stirred at 60°C for 3 hours, 1 M HCl (100 mL) was added, and the mixture was extracted once with ethyl acetate (100 mL); the aqueous phase was adjusted to pH 8 with saturated NaHCO ₃ , and then extracted three times with ethyl acetate (100 mL), and the organic phases were combined and concentrated to obtain I-A27-5 (4.50 g, 13.54 mmol, 83.29% yield) as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ): δ7.83-7.76 (m, 3H), 4.58 (t, J = 4.7Hz, 2H), 4.09-4.02 (m, 2H), 3.89 (s, 3H)

MS(ESI)m/z＝299.0/301.0[M+H] ⁺

Step 5: I-A27-5 (1.0 g, 3.34 mmol) and K ₂ CO ₃ (922.71 mg, 6.69 mmol) were dissolved in DMF (10 mL), zinc cyanide (785.13 mg, 6.69 mmol) and Pd(PPh ₃ ) ₄ (386.47 mg, 334.31 μmol) were added respectively, and microwave reaction was performed at 120° C. for 1 hour. The reaction solution was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain I-A27-6 (650.00 mg, 2.39 mmol, yield: 71.35%) as a white solid.

MS (ESI) m/z = 246.1 [M + H] ⁺

Step 6: After dissolving I-A27-6 (100 mg, 407.77 μmol) and PPh ₃ (128.34 mg, 489.33 μmol) in DCM (3 mL), NCS (65.34 mg, 489.33 μmol) was added at 0°C. After the reaction was carried out at 30°C for 1 hour, the reaction solution was concentrated and purified by preparative TLC (petroleum ether: ethyl acetate = 1:1) to obtain I-A27-7 (150.00 mg, 227.55 μmol, yield: 55.80%) as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ): δ8.69-8.78(1H), 8.35-8.46(1H), 8.12-8.22(1H), 4.80-4.96(2H), 3.93-4.04(5H)

MS (ESI) m/z = 264.1 [M + H] ⁺

Step 7: I-A27-7 (4 g, 15.17 mmol) was dissolved in THF (40 mL), and MeMgBr (1 M, 45.51 mL) was added at 0°C. After stirring for 30 minutes, TLC detected that the raw material was completely converted, and the mixture was quenched with saturated NH ₄ Cl (50 mL), and then extracted three times with ethyl acetate (30 mL). The organic phases were combined and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain I-A27-8 (1.84 g, 6.28 mmol, yield: 41.39%) as a yellow oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ8.17 (d, J = 1.6 Hz, 1H), 8.05 (s, 1H), 7.87 (d, J = 1.6 Hz, 1H), 4.81 (t, J = 5.5 Hz,2H),3.97(t,J＝5.4Hz,2H),1.66(s,6H),-0.00(s,1H)

MS (ESI) m/z = 264.1 [M + H] ⁺

Step 8: Phenol (107.06 mg, 1.14 mmol) and I-A27-8 (100 mg, 379.19 μmol) were dissolved in DCM (3 mL), and BF _3· Et ₂ O (161.45 mg, 1.14 mmol) was added dropwise under nitrogen protection. After the addition was complete, the temperature was raised to 40°C and stirred for 5 hours. The reaction was completed by TLC detection. The mixture was cooled to room temperature and methanol (10 mL) was added to quench the reaction. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography (HPLC, acetonitrile/water = 0 to 100%) to obtain I-A27 (90.00 mg, 254.25 μmol, yield: 67.05%) as a white solid.

¹ H-NMR (400MHz, MeOD): δ8.35(s,1H),7.87(d,J＝1.6Hz,1H),7.56-7.54(m,1H),7.07(dd,J＝6.6,2.2Hz ,2H),6.71(dd,J＝6.9,2.2Hz,2H),4.86(s,-2H),4.04(t,J＝5.6Hz,2H),3.31-3.30(m,10H),1.72(s ,6H)

MS (ESI) m/z = 340.2 [M + H] ⁺

According to the synthesis method of intermediate I-A2, intermediate I-A28 was synthesized from intermediate I-A27 in three steps; intermediate I-A29 was synthesized from intermediate I-A19 in three steps; intermediate I-A30 was synthesized from intermediate I-A19-5 in three steps; intermediate I-A31 was synthesized by referring to the synthesis method of intermediate I-A11. Referring to intermediate I-A2, intermediate I-A32 was synthesized from intermediate I-A31 in three steps.

Synthesis of Intermediate A6: 3-Chloro-5-(2-(4-ethynylphenyl)propan-2-yl)-2-methoxybenzonitrile

The synthesis steps refer to the synthesis method of intermediates I-A1 and I-A2, using iodomethane instead of I-A1-3, and performing seven steps of reaction to obtain intermediate A6.

LC-MS [M+18] ⁺ = 310.1

Synthesis of Intermediate A8: 2-Chloro-3-(2-chloroethoxy)-6-(2-(4-ethynylphenyl)propan-2-yl)isonicotinonitrile

Step 1: Dissolve the raw material A8-1 (5g, 19.5mmol) in N,N-dimethylformamide (50mL), add Zn(CN) ₂ (1.35g, 11.7mmol), Pd(PPh ₃ ) ₄ (1.8g, 1.56mmol) to the solution. The above mixture was stirred at 100°C for 16 hours under nitrogen protection, and TLC detection showed that the reaction was complete. The reaction mixture was put into water (100mL), extracted with ethyl acetate (100mL*2), the organic phases were combined, washed with saturated brine (150mL*2), and the organic phases were dried over anhydrous sodium sulfate and concentrated. The concentrated mixture was subjected to column chromatography to obtain the product A8-2 (1.6g, yield: 53.3%) as a yellow solid.

LC-MS [M+1] ⁺ = 155.0

Step 2: At room temperature, A8-2 (1.6 g, 10.3 mmol) was dissolved in a methanol solution of hydrogen chloride (4 M, 26 ml, 104 mmol), and the mixture was stirred at 80 ° C for 20 hours. The reaction was complete after LC-MS detection. The reaction solution was filtered using silica gel, and the filtrate was concentrated to obtain a yellow solid. The yellow solid was dissolved in hot 1,4-dioxane (100 mL, 65 ° C), and hot n-hexane (100 mL) was added to the solution. The solution was slowly cooled to room temperature and the mixture was filtered. The solid was rinsed with n-hexane, and the filtered solid was collected and vacuum dried to obtain the product A8-3 (1.7 g, yield: 88.1%) as a yellow solid.

LC-MS [M+1] ⁺ = 188.0

Step 3: Dissolve the raw material A8-3 (1.7 g, 9.1 mmol) in N,N-dimethylformamide (20 mL) and add NIS (3.07 g, 13.65 mmol). The above mixture was reacted at 100 ° C for 16 hours, and LC-MS detection showed that the reaction was complete. The reaction mixture was put into water (100 mL), extracted with ethyl acetate (50 mL * 2), the organic phases were combined, washed with saturated brine (100 mL * 2), and the organic phases were dried over anhydrous sodium sulfate and concentrated. After concentration, the crude product A8-4 (3.9 g) was obtained as a reddish brown solid.

LC-MS [M+1] ⁺ = 313.9

Step 4: A8-4 (3.9, 12.5 mmol) and 1-bromo-2-chloroethane (8.9 g, 62.5 mmol) were dissolved in N,N-dimethylformamide (40 mL) at room temperature, and then cesium carbonate (8 g, 25 mmol) was added. The mixture was stirred at 70 ° C for 16 hours, and the reaction was complete after TLC detection. The reaction mixture was put into water (50 ml) and extracted with ethyl acetate (50 mL * 3). The organic phase was washed with saturated brine (100 mL), dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the desired product A8-5 (1.6 g, yield: 47%) as a yellow solid.

Step 5: Dissolve compound A8-5 (1.6 g, 4.3 mmol) in N-methylpyrrolidone (20 mL), add CuCN (614 mg, 6.9 mmol), stir and react for 3 hours at 160 ° C under nitrogen protection. TLC detection shows that the reaction is complete. The reaction mixture is put into water (100 mL) and extracted with ethyl acetate (50 mL*3). The organic phase is washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The filtrate is concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain the desired product A8-6 (270 mg, yield: 23%) as a yellow solid.

LC-MS [M+1] ⁺ = 274.9

Step 6: A8-6 (200 mg, 0.7 mmol) was dissolved in tetrahydrofuran (6 mL), replaced with nitrogen 3 times, and methylmagnesium bromide (1.3 ml, 1 M tetrahydrofuran solution) was added dropwise at -77 ° C. After the addition was complete, the mixture was reacted at -77 ° C for 30 minutes. LC-MS detected that the reaction was complete. The reaction mixture was slowly added to a saturated ammonium chloride solution at 0 ° C and extracted with ethyl acetate (10 mL * 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the desired product A8-7 (150 mg, yield: 75%) as a yellow oily liquid.

¹ H NMR (400MHz, Chloroform-d) δ7.63 (s, 1H), 4.53–4.44 (m, 2H), 3.89 (t, J = 5.7Hz, 2H), 1.56 (s, 6H).

Step 7: A8-7 (140 mg, 0.51 mmol) and phenol (240 mg, 2.55 mmol) were dissolved in 1,2-dichloroethane (6 mL), anhydrous AlCl ₃ (136 mg, 1.02 mmol) was added to the solution, and the mixture was reacted at 100°C for 3 hours. The reaction mixture was added to water (10 ml) and extracted with dichloromethane (10 mL* 3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the desired product A8-8 (55 mg, yield: 62%) as a yellow oily liquid.

¹ H NMR(400MHz,Chloroform-d)δ7.11(d,J＝10.3Hz,2H),7.07(s,1H),6.78(d,J＝8.4Hz,2H),4.46(s,2H), 3.86(s,2H),1.68(s,6H).

The next three steps of reaction refer to the synthesis route of intermediate I-A2, using A8-8 instead of I-A1, and the intermediate A8 is synthesized through three steps of reaction as a yellow oily liquid.

LC-MS [M+1] ⁺ = 359.1

According to the above synthesis method or references, the following intermediates were synthesized respectively:

Synthesis of Intermediate A11: 4-(2-chloroethyl)-7-(2-(4-ethynylphenyl)propan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-cyano

Referring to the synthetic route of intermediate I-A2, I-A18 was used to replace I-A1, and intermediate A11 was synthesized through three steps. LC-MS [M+1] ⁺ = 365.1

Synthesis of Intermediate A13: 1-(3-chloropropane)-4-(2-(4-alkynylphenyl)propan-2-yl)-6-methylpyridin-2(1H)-one

Step 1: A13-1 (10 g, 59.82 mmol) and 1,3-chlorobromopropane (28.25 g, 179.5 mmol) were dissolved in acetonitrile (120 mL), and Cs ₂ CO ₃ (38.88 g, 119.6 mmol) was added. The reaction solution was reacted at 80°C for 16 hours. The reaction solution was concentrated and separated by column chromatography (petroleum ether/tetrahydrofuran = 1/1) to obtain the desired product A13-2 (5.4 g, yield: 40%), which was a yellow oily liquid.

LC-MS [M+1] ⁺ = 226.2

Step 2: A13-2 (5.4 g, 23.97 mmol) was dissolved in dichloromethane (50 mL), SOCl ₂ (11.4 g, 95.9 mmol) was added at 0°C, and the reaction solution was stirred at room temperature for 3 hours. The mixture was spin-dried and then separated by column chromatography (petroleum ether/tetrahydrofuran = 1/1) to obtain the desired product A13-3 (3.0 g, yield: 27.5%) as a yellow solid.

LC-MS [M+1] ⁺ = 244.2

Step 3: Add methylmagnesium bromide (123mL, 123mmol, 1M in THF) dropwise to a solution of A13-3 (3.0g, 12.3mmol) in tetrahydrofuran (20mL) at room temperature. The above mixture was stirred at room temperature for 4 hours. The reaction solution was slowly poured into an iced aqueous solution of ammonium chloride (100mL), extracted with ethyl acetate (100mL*3), the combined organic phase was washed with saturated brine (300mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated and separated by column chromatography (petroleum ether/tetrahydrofuran = 1/1) to obtain the desired product A13-4 (1.1g, yield: 26.76%) as a light yellow oil.

LC-MS [M+1] ⁺ = 244.2

Step 6: Add a solution of boron trifluoride in ether (2.98 g, 9.85 mmol) to a solution of A13-4 (800 mg, 3.28 mmol) and phenol (1.54 g, 16.4 mmol) in 1,2-dichloroethane (10 mL) at room temperature. The mixture was stirred at 100°C to room temperature for 3 hours. The reaction solution was quenched with water (20 mL), extracted with dichloromethane (20 mL*3), the combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated and separated by column chromatography (petroleum ether/tetrahydrofuran = 1/1), and the desired product A13-5 (340 mg, yield: 22.1%) was obtained as a yellow oil. LC-MS [M+1] ⁺ = 320.3

The following three steps of reaction refer to the synthetic route of intermediate I-A2, using A13-5 instead of I-A1, and synthesizing intermediate A13 through three steps of reaction. LC-MS[M+1] ⁺ =328.1

Synthesis of intermediate A14: 7-chloro-1-(2-chloroethyl)-5-(2-(4-ethynylphenyl)propan-2-yl)-1H-benzo[d][1,2,3]triazole

Referring to the synthetic route of intermediate I-A2, intermediate A14 was synthesized by replacing I-A1 with I-A21 through three steps.

LC-MS [M+1] ⁺ = 358.1

Synthesis of Intermediate A16: 2-(2-chloroethoxy)-3-fluoro-5-(2-(4-ethynylphenyl)propan-2-yl)benzonitrile

Referring to the synthetic route of intermediate I-A2, intermediate A16 was synthesized by replacing I-A1 with I-A24 through three steps.

LC-MS [M+1] ⁺ = 342.1

Intermediate A19 was synthesized according to the above synthesis method of intermediate A13; intermediate A21 was synthesized according to the synthesis method of intermediate I-A29.

Synthesis of intermediate A23: 3-(2-chloroethyl)-6-(2-(4-ethynylphenyl)propan-2-yl)-3H-imidazo[4,5-b]pyridine

Step 1: Dissolve the raw material A23-1 (10 g, 46.17 mmol) in DMF (100 mL), add A23-2 (2.82 g, 46.17 mmol) and DIEA (11.91 g, 92.35 mmol), and react at 25°C for 2 hours. Pour the reaction mixture into saturated brine (200 mL), extract with ethyl acetate (200 mL*2), combine the organic phases, dry with anhydrous sodium sulfate, and concentrate. After concentration, the crude product A23-3 (11.7 g) is obtained as a yellow solid.

LC-MS[M-1] ^- =242.1

Step 2: A23-3 (11.7 g, 48.51 mmol), reduced iron powder (13.55 g, 242.5 mmol), NH ₄ Cl (15.57 g, 291.04 mmol) were dissolved in ethanol (150 mL) and water (50 mL) at room temperature. The mixture was stirred at 85°C for 4 hours. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL*3). The organic phase was washed with saturated brine (600 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the product A23-4 (7.7 g) as a yellow solid.

LC-MS [M+1] ⁺ = 212.2

Step 3: Dissolve compound A23-4 (4.3 g, 20.36 mmol) in triethyl orthoformate (40 mL), add TsOH (350.3 mg, 2.4 mmol) at room temperature, and heat to 130°C for 16 hours. LC-MS detection shows that the raw material reacts completely and the product is generated. After concentration, column chromatography (PE/EA=1/4) is used to obtain product A23-5 (3.8 g, yield: 67.25), a yellow oily liquid.

LC-MS [M+1] ⁺ = 222.1

Step 4: A23-5 (3.7 g, 16.7 mmol) was dissolved in tetrahydrofuran (30 mL) and added dropwise to methylmagnesium bromide (100 mL, 1 M tetrahydrofuran solution) protected by nitrogen at 0°C. After the addition, the mixture was reacted at room temperature for 2 hours. The reaction mixture was slowly added to a saturated ammonium chloride solution at 0°C and extracted with ethyl acetate (150 mL*3). The organic phase was washed with saturated brine (450 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 2/3) to obtain the desired product A23-6 (2.1 g, yield: 56.75%) as a yellow oily liquid.

¹ H NMR(400MHz,Chloroform-d)δ8.53(s,1H),8.17(s,1H),8.13(s,1H),4.46(s,2H),3.92(s,2H),1.64(s ,6H).LC-MS[M+1] ⁺ =222.2

Step 5: A23-6 (1.9 g, 8.59 mmol) and phenol (4.04 g, 42.94 mmol) were dissolved in dichloromethane (30 mL), and a boron trifluoride ether solution (6.85 mL, 47%) was added dropwise under nitrogen protection at room temperature. After the addition, the temperature was naturally raised to 90 ° C for 2 hours. The reaction was complete after TLC detection. The reaction mixture was concentrated and then column chromatography was performed to separate A23-8 (2.8 g, yield: 87.7%), which was a yellow oily liquid.

¹ H NMR (400MHz, Methanol-d ₄ ) δ9.47(s,1H),8.49(s,1H),8.17(s,1H),7.10–7.04(m,2H),6.73–6.67(m,2H ),4.63(s,2H),3.98(s,3H),1.75(s,6H).LC-MS[M+1] ⁺ =298.1

Step 6: A23-8 (800 mg, 2.69 mmol) was dissolved in DCM (10 mL) at room temperature, and SOCl ₂ (1.92 g, 16.14 mmol) was added dropwise at room temperature. After the addition was completed, the mixture was reacted at 45°C for 16 hours. LC-MS detected that the raw material reaction was complete, and the mixture was concentrated and added with DCM (10 mL), and then washed with saturated sodium bicarbonate (10 mL) and saturated laboratory (10 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate and concentrated, and column chromatography (PE/THF=1/1) was performed to obtain the product A23-9 (510 mg, yield: 34%), which was a yellow oily liquid.

LC-MS [M+1] ⁺ = 316.2

Referring to the synthetic route of intermediate I-A2, intermediate A23-9 was used to replace intermediate I-A1, and intermediate A23 was synthesized through three steps. LCMS [M+H] ⁺ = 324.1 m/z

Synthesis of Intermediate A34: 4-(2-(1-(2-chloroethane)-7-methyl-1H-indazol-5-yl)propan-2-yl)phenol

Step 1: A34-1 (2 g, 9.48 mmol) was dissolved in N, N-dimethylformamide (20 mL), 1-bromo-2-chloroethane (4.08 g, 28.43 mmol) and potassium carbonate (1.96 g, 14.21 mmol) were added, and stirred at 75°C for 3 hours. The reaction solution was extracted twice with ethyl acetate (100 mL*2), the combined organic phases were washed three times with saturated brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether/tetrahydrofuran = 6/1) to obtain intermediate A34-2 (830 mg, yield: 31.89%) as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.07 (s, 1H), 7.81 (s, 1H), 7.29 (s, 1H), 4.85 (d, J = 6.0Hz, 2H), 4.02 (d, J＝6.7Hz,2H),2.68(s,3H).

LC-MS [M+1] ⁺ = 273.10

Step 2: A34-2 (510 mg, 1.86 mmol) was dissolved in ethanol (6 mL) and N,N-dimethylformamide (2 mL), TEA (565.96 mg, 5.59 mmol) and Pd(dppf)Cl ₂ (135.16 mg, 186.43 μmol) were added, CO gas was replaced, and the reaction was carried out at 85°C overnight for 16 hours. The filtrate was filtered and concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether/tetrahydrofuran = 6/1) to obtain A34-3 (400 mg, yield: 76.42%) as a white solid.

¹ H NMR (400MHz, Acetonitrile-d ₃ ) δ8.29 (s, 1H), 8.14 (s, 1H), 7.75 (s, 1H), 5.03–4.76 (m, 2H), 4.32 (q, J＝7.3 ,6.3Hz,2H),4.11–3.93(m,2H),2.74(s,3H),1.34(d,J=11.7Hz,3H).

LC-MS [M+1] ⁺ = 267.10

Step 3: A34-3 (250 mg, 989.33 μmol) was dissolved in tetrahydrofuran (5 mL), replaced with nitrogen, preheated at 40 ° C, added MeMgBr (1M, 3.96 mL), and kept at 30 ° C for 10 minutes. The reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (50 mL) at 0 ° C, and ethyl acetate was added for extraction twice (30 mL * 2), the organic phases were combined and washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether/tetrahydrofuran = 3/1) to obtain intermediate A34-4 (310 mg, yield: 69.74%) as a colorless oil.

¹ H NMR (400MHz, Acetonitrile-d ₃ ) δ7.95 (s, 1H), 7.63 (s, 1H), 7.28 (s, 1H), 4.85 (d, J = 6.0Hz, 2H), 3.99 (d, J＝5.8Hz,2H),2.70(s,3H),1.50(s,6H).

LC-MS [M+1] ⁺ = 253.10

Step 4: A34-4 (520 mg, 2.06 mmol) was dissolved in dichloromethane (10 mL), phenol (968.15 mg, 10.29 mmol) was added, and nitrogen was replaced. Boron trifluoride-ether solution (1.86 g, 6.17 mmol, 1.64 mL, 47% purity) was added dropwise at 0°C, and the mixture was reacted at room temperature of 25°C for 4 hours. The reaction solution was slowly poured into 20 mL of water, extracted twice with ethyl acetate (20 mL*2), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The mixture was separated by column chromatography (petroleum ether/tetrahydrofuran = 3/1) to obtain intermediate A34 (510 mg, yield 53.80%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.13(s,1H),8.01(s,1H),7.44(s,1H),7.05–6.94(m,2H),6.84(s,1H), 6.72–6.55(m,2H),4.79(s,2H),4.01(s,2H),2.57(s,3H),1.59(s,6H).

Synthesis of Intermediate A35: 4-(2-(1-(2-chloroethane)-7-fluoro-1H-indazol-5-yl)propan-2-yl)phenol

Step 1: A35-1 (4 g, 18.60 mmol) was dissolved in N, N-dimethylformamide (80 mL), potassium carbonate (7.71 g, 55.81 mmol) and 1-bromo-2-chloroethane (8.00 g, 55.81 mmol) were added, and stirred at 75°C for 3 hours. The reaction solution was extracted twice with ethyl acetate (100 mL*2), the combined organic phases were washed three times with saturated brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether/tetrahydrofuran = 6/1) to obtain intermediate A35-2 (3.6 g, yield: 53.10%), which was a white solid. LC-MS [M+1] ⁺ = 279.10

Step 2: A35-2 (3.6 g, 12.97 mmol) was dissolved in methanol (40 mL), TEA (3.94 g, 38.92 mmol) and Pd(dppf)Cl ₂ (941.33 mg, 1.30 mmol) were added, CO gas was completely replaced, and the reaction was carried out at 75°C overnight for 16 hours. Filter, concentrate the filtrate to obtain a crude product, and purify it by column chromatography (petroleum ether/tetrahydrofuran = 6/1) to obtain A35-3 (3.2 g, yield: 95.15%), which was a white solid. LC-MS [M+1] ⁺ = 257.00

Step 3: A35-3 (1 g, 3.90 mmol) was dissolved in tetrahydrofuran (10 mL), replaced with nitrogen, preheated the reaction solution at 30°C, and methylmagnesium bromide (1M, 15.58 mL) was added dropwise, and the reaction was maintained at 30°C for 10 minutes. The reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (50 mL) at 0°C, and ethyl acetate was added for extraction twice (30 mL*2), the organic phases were combined and washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether/tetrahydrofuran = 3/1) to obtain intermediate A35-4 (630 mg, yield: 61.73%) as a colorless oil. ¹ H NMR (400MHz, Chloroform-d) δ7.98 (s, 1H), 7.56 (s, 1H), 7.25 (s, 1H), 4.81 (d, J = 11.0Hz, 2H), 3.93 (d, J = 10.7Hz, 2H), 1.62 (s, 6H).

LC-MS[M+1] ⁺ ＝257.00

Step 4: A35-4 (600 mg, 2.34 mmol) was dissolved in DCM (10 mL), phenol (1.10 g, 11.69 mmol) was added, and nitrogen was replaced. Boron trifluoride-ether solution (2.11 g, 7.01 mmol, 1.87 mL, 47% purity) was added dropwise at 0°C, and the reaction was carried out at 15°C for 4 hours. The reaction solution was slowly poured into 20 mL of water, extracted twice with ethyl acetate (20 mL*2), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The mixture was separated by column chromatography (petroleum ether/tetrahydrofuran = 3/1) to obtain intermediate A35 (550 mg, yield: 65.76%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.19 (s, 1H), 8.13 (s, 1H), 7.45 (s, 1H), 7.00 (t, J = 7.5Hz, 2H), 6.88 (d, J＝12.9Hz,1H),6.68–6.59(m,2H),4.72(s,2H),4.02(s,2H),1.61(s,6H).

LC-MS [M+1] ⁺ = 333.10

Intermediates A53, A54, A55 and A56 were synthesized by referring to the synthesis method of intermediate A35. A60 was synthesized by further one-step reaction referring to the synthesis method of A35.

Synthesis of Intermediate A37: 4-(2-(3-(2-chloroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)propan-2-yl)phenol

Step 1: Dissolve the raw material A37-1 (10 g, 46.17 mmol) in DMF (100 mL), add 2-hydroxyethylamine (2.82 g, 46.17 mmol) and DIEA (11.91 g, 92.35 mmol), react at 25 ° C for 2 hours, and TLC detection shows that the reaction is complete. The reaction mixture is put into saturated brine (200 mL), extracted with ethyl acetate (200 mL*2), and the organic phases are combined, dried over anhydrous sodium sulfate, and concentrated. After concentration, the crude product A37-3 (11.7 g) is obtained as a yellow solid.

LC-MS [M-1]-＝242.1

Step 2: A37-3 (11.7 g, 48.51 mmol), reduced iron powder (13.55 g, 242.5 mmol), NH4Cl (15.57 g, 291.04 mmol) were dissolved in ethanol (150 mL) and water (50 mL) at room temperature. The mixture was stirred at 85°C for 4 hours. The reaction mixture was put into water (200 mL) and extracted with ethyl acetate (200 mL*3). The organic phase was washed with saturated brine (600 mL), dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the desired product A37-4 (7.7 g) as a yellow solid.

LC-MS [M+1]+＝212.2

Step 3: Dissolve compound A37-4 (3 g, 14.20 mmol) in AcOH (30 mL), cool to 0°C, add solid NaNO2 (1.27 g, 18.46 mmol) in batches, and heat to 30°C for 2 hours. After concentrating to remove most of AcOH, adjust pH to 8 with saturated Na2CO3, extract three times with ethyl acetate (40 mL*3), combine the organic phases, and concentrate to obtain the crude product A37-5 (3 g) as a brown solid.

LC-MS [M+1]+＝223.2

Step 4: A37-5 (2g, 9mmol) was dissolved in tetrahydrofuran (20mL) and added dropwise to methylmagnesium bromide (54mL, 1M tetrahydrofuran solution) protected by nitrogen at 0°C. After the addition, the mixture was reacted at room temperature for 2 hours. TLC detected that the reaction was complete. The reaction mixture was slowly added to a saturated ammonium chloride solution at 0°C and extracted with ethyl acetate (100mL*3). The organic phase was washed with saturated brine (300mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (PE/EA=2/3) to obtain the desired product A37-6 (750mg, yield: 35.6%) as a yellow oily liquid.

1H NMR(400MHz,Chloroform-d)δ8.77(s,1H),8.34(s,1H),4.84(s,2H),4.19(s,2H),1.65(s,6H).LC-MS[ M+1]+＝223.1

Step 5: A37-6 (750 mg, 3.37 mmol) and phenol (1.59 g, 16.87 mmol) were dissolved in dichloromethane (10 mL), and a boron trifluoride ether solution (2.69 mL, 47%) was added dropwise under nitrogen protection at room temperature. After the addition was completed, the temperature was naturally raised to 90°C for 2 hours. The reaction mixture was concentrated and separated by column chromatography (PE/THF=2/1) to obtain A37-8 (1.0 g, yield: 71%) as a yellow oily liquid.

LC-MS [M+1]+＝299.2

Step 6: A37-8 (300 mg, 1.01 mmol) was dissolved in DCM (4 mL) at room temperature, and SOCl2 (718 mg, 6.06 mmol) was added dropwise at room temperature. After the addition was completed, the mixture was reacted at 45°C for 16 hours. The mixture was concentrated and DCM (5 mL) was added, and it was washed with saturated sodium bicarbonate (10 mL) and saturated laboratory (10 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the product by column chromatography (PE/THF=1/1), and A37 (100 mg, yield: 30%) was obtained as a yellow oily liquid.

1H NMR (400MHz, DMSO-d6) δ9.26 (s, 1H), 8.46 (s, 1H), 8.40 (s, 1H), 7.04 (d, J = 10.0Hz, 2H), 6.70–6.64 (m, 2H),5.00(s,2H),4.22(s,2H),1.70(s,6H).LC-MS[M+1]+＝317.2

Synthesis of Intermediate A39: 4-(2-(1-(2-chloroethane)-7-methoxy-1H-indazol-5-yl)propan-2-yl)phenol

Step 1: Add A39-1 (40 g, 291.59 mmol) and acetic acid (46 mL) to methanol (230 mL), cool to 0°C, slowly drop Br ₂ (46.60 g, 291.59 mmol), heat to 25°C and stir for 2 hours. Add ethyl acetate (200 mL), filter, wash the filter cake with ethyl acetate (30 mL), and concentrate under vacuum to dryness to obtain the acetate of A39-2 (55.00 g, crude product) as an off-white solid.

LC-MS [M+1] ⁺ = 216.08

Step 2: Add A39-2 (20 g, 92.56 mmol) to AcOH (210 mL), cool to 0°C, slowly dropwise add an aqueous solution (5 mL) of NaNO ₂ (12.77 g, 185.12 mmol), slowly raise the temperature to 25°C and stir to react for 16 hours, concentrate the reaction solution to dryness, add ethyl acetate (200 mL), wash with sodium bicarbonate solution (200 mL) and saturated brine (100 mL), separate the organic phase and concentrate to dryness, and purify the residue by column chromatography (EA/PE=0 to 40%) to obtain A39-3 (5.80 g, yield: 24.84%) as a yellow solid product.

LC-MS [M+1] ⁺ = 227.06

Step 3: A39-3 (19 g, 83.68 mmol), 1-bromo-2-chloro-ethane (24.00 g, 167.36 mmol), and Cs ₂ CO ₃ (68.16 g, 209.20 mmol) were added to DMF (10 mL) in sequence, and the reaction was stirred at 25° C. for 1 hour. The reaction solution was filtered, and the filtrate was directly concentrated to dryness. The residue was purified by column chromatography (ethyl acetate/petroleum ether = 0 to 25%) to obtain A39-4 (17.00 g, yield: 63.15%) as a white solid product.

Step 4: A39-4 (8.4 g, 29.01 mmol), Pd(dppf)Cl ₂ (2.11 g, 2.90 mmol), and triethylamine (29.30 g, 290.10 mmol) were added to methanol (200 mL) in sequence, and the carbon monoxide gas was replaced three times. The reaction solution was heated to 90° C. and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated to dryness under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether = 0 to 20%) to obtain A39-5 (5.50 g, yield: 63.50%) as a yellow solid product.

LC-MS [M+1] ⁺ = 269.10

Step 5: Add A39-5 (268.7 mg, 1.00 mmol) to THF (4 mL), replace with nitrogen 3 times, cool to 0 ° C, add MeMgBr (1M, 4.00 mL) dropwise, heat to 25 ° C and stir to react for 1 hour at 0 ° C, slowly pour the reaction solution into saturated aqueous ammonium chloride solution, add ethyl acetate (5 mL) and extract twice, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate to obtain a crude product, and the crude product is purified by column chromatography (PE: EA = 1: 0 ~ 5: 1) to obtain the product A39-6 (220 mg, yield: 90.22%) as a white solid.

Step 6: A39-6 (4.8 g, 17.86 mmol) and phenol (3.36 g, 35.72 mmol) were dissolved in DCM (80 mL), replaced with nitrogen, and BF ₃ .Et ₂ O (16.11 g, 53.58 mmol, 14.26 mL, 47% purity) was added dropwise at 0°C. After the addition was complete, the room temperature was raised to 25°C for reaction for 3 hours. The reaction solution was poured into 20 mL of water, extracted twice with ethyl acetate (300 mL*2), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The mixture was separated by column chromatography (PE/THF=1/0-5/1) to obtain the product A39 (3.90 g, yield: 56.99%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.95(s,1H),7.14(s,1H),7.00(s,2H),6.62(s,2H),6.51(s,1H),4.79( s,2H),3.97(s,2H),3.76(s,3H),1.60(s,6H). LC-MS[M+1] ⁺ =344.10

Synthesis of Intermediate A44: 4-(2-(3-chloro-1-(2-chloroethane)-7-fluoro-1H-indazol-5-yl)propan-2-yl)phenol

Step 1: A44-1 (2.5 g, 11.63 mmol) was dissolved in N, N-dimethylformamide (20 mL), and N-chlorosuccinimide (1.71 g, 12.79 mmol) was added, and the reaction was stirred at 25°C for 1 hour. The reaction solution was directly concentrated and purified by column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain A44-2 (1.90 g, 6.85 mmol, yield: 58.96%), which was a white solid.

LC-MS [M+1] ⁺ = 248.82

Step 2: A44-2 (1.9 g, 7.62 mmol), Pd(dppf)Cl ₂ (552.18 mg, 761.62 μmol) and triethylamine (15.41 g, 152.32 mmol) were added to anhydrous ethanol (50 mL) in sequence, and carbon monoxide was replaced three times. The reaction temperature was raised to 90°C and stirred for 5 hours. The reaction solution was cooled to room temperature and concentrated, and purified by column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain A44-3 (1.70 g, 6.31 mmol, 82.79% yield, 90% purity) as a yellow solid.

Step 3: A44-3 (1.7 g, 7.01 mmol), 1-bromo-2-chloroethane (2.01 g, 14.01 mmol), and cesium carbonate (6.85 g, 21.02 mmol) were added to N,N-dimethylformamide (5 mL) in sequence, and the reaction was stirred at 25 ° C for 1 hour. The reaction solution was directly concentrated and purified by column chromatography (ethyl acetate/petroleum ether = 0-10%) to obtain A44-4 (1.80 g, 5.31 mmol, 75.78% yield, 90% purity) as a yellow solid product.

LC-MS [M+1] ⁺ = 304.10

Step 4: A44-4 (1.6 g, 5.24 mmol) was dissolved in tetrahydrofuran (16 mL), replaced with nitrogen 3 times, and then the temperature was raised to 35°C and methylmagnesium bromide (1M, 20.97 mL) was added dropwise. After the addition, the mixture was stirred for 1 hour. The reaction solution was poured into glacial ammonium chloride (20 mL), extracted with ethyl acetate (20 mL*3), the organic phases were combined and concentrated, and purified by column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain A44-5 (1.40 g, 4.33 mmol, 82.53% yield, 90% purity) as a yellow solid product.

LC-MS [M+1] ⁺ = 291.10

Step 5: A44-5 (1.46 g, 5.00 mmol) and phenol (1.88 g, 20.00 mmol) were added to dichloromethane (20 mL) in sequence, replaced with nitrogen 3 times, the system was cooled to -60°C, and boron trifluoride (2.13 g, 15.00 mmol) was slowly added dropwise. After the addition, the temperature was naturally raised to 25°C, and the reaction was stirred at 25°C for 1 hour. Methanol (3 mL) was added to quench the reaction, and the reaction solution was directly concentrated and purified by column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain A44 (1.40 g, 3.62 mmol, yield: 72.42%) as a colorless oil.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.27 (d, J = 1.4 Hz, 1H), 7.10-6.92 (m, 2H), 6.75-6.56 (m, 1H), 4.69 (t, J = 5.6 Hz, 2H), 4.02 (t, J = 5.4Hz, 2H), 1.62 (s, 4H).

LC-MS [M+1] ⁺ = 368.70

Synthesis of Intermediate A51: 3-Chloro-2-(2-chloroethoxy)-5-(1-(4-ethynylphenyl)-1-hydroxyethyl)benzonitrile

Step 1: Add A51-1 (20 g, 146.90 mmol), A51-2 (1.01 g, 7.34 mmol, HCl), and A51-3 (28.94 g, 146.90 mmol) to toluene (700 mL) at 0°C, react for 4 hours at 0°C, pour the reaction solution into a saturated aqueous solution of ammonium chloride, add DCM (400 mL*3) for extraction, and combine the organic phases. The organic phase is dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product A51-4 (16.80 g, crude product) as a white solid.

LC-MS [M+1] ⁺ = 170.9

Step 2: A51-4 (16.8 g, 98.48 mmol) was dissolved in DCM (200 mL), protected by _N2 , and NIS (44.31 g, 196.96 mmol) was added at 10°C, and stirred at 10°C for 16 hours. The reaction solution was spin-dried, slurried once with DCM (60 mL), slurried once with ethyl acetate (60 mL), and slurried once with (300 mL), and filtered to obtain the target product A51-5 (17.80 g, yield: 60.96%), which was a white solid.

LC-MS [M+1] ⁺ = 296.8

Step 3: Add A51-5 (16.6 g, 55.99 mmol), A51-6 (16.06 g, 111.98 mmol, 9.32 mL), and Cs ₂ CO ₃ (36.39 g, 111.98 mmol) to DMF (159.66 mL), stir at 70°C for 16 hours, pour the reaction solution into water (500 mL), add ethyl acetate for extraction (300 mL*3), combine the organic phases, wash with saturated brine (300 mL*3), mix the sample, and purify by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the target product A51-7 (15.90 g, yield: 79.11%) as a white solid.

¹ H NMR (400MHz, Chloroform-d) δ8.24(s,1H),7.94(s,1H),4.30(s,2H),3.91(s,2H),2.55(s,3H).

Step 4: Add A51-7 (15.9 g, 44.29 mmol) and CuCN (6.22 g, 66.44 mmol) to NMP (200 mL), stir at 160 ° C for 3 hours, pour the reaction solution into water (1000 mL), add ethyl acetate for extraction (300 mL*3), combine the organic phases, wash with saturated brine (500 mL*3), stir, and column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product A51-8 (6.50 g, yield: 56.86%), which is a white solid.

Step 5: A51-9 (7.13 g, 30.22 mmol) was dissolved in THF (200 mL), and the mixture was cooled to -77 °C in a dry ice bath. Under _N2 protection, n-Butyllithium (2.5 M, 13.02 mL) was added dropwise. After the addition was completed, the mixture was stirred for 1 hour. A solution of A51-8 (6.00 g, 23.25 mmol) in THF (60 mL) was added dropwise again. After the addition was completed, the mixture was stirred for 2 hours. An aqueous solution of ammonium chloride was poured into the reaction solution, and ethyl acetate (300 mL) was added for extraction. The organic phase was separated and washed three times with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA = 6: 1) to obtain the target product A51-10 (7.40 g, yield: 76.68%) as a yellow oil.

LC-MS[M+23] ⁺ ＝437.9

Step 6: Add A51-10 (2 g, 4.82 mmol), A51-11 (4.73 g, 48.18 mmol, 6.81 mL), DIPEA (9.34 g, 72.27 mmol, 11.94 mL), CuI (91.76 mg, 481.80 μmol), Pd(pph ₃ ) ₂ Cl ₂ (352.20 mg, 481.80 μmol) to THF (15 mL), under N ₂ protection, stir at 80 ° C for 5 hours under sealed tube, mix the reaction solution, and perform column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain the target product A51-12 (1.50 g, yield: 72.00%) as a yellow oil.

¹ H NMR(400MHz,Chloroform-d)δ7.60(s,1H),7.50(s,1H),7.43(s,2H),7.32(s,2H),4.42–4.38(m,2H),3.87 –3.83(m,2H),1.90(s,3H),0.23(s,9H)

Step 7: A51-12 (1.5 g, 3.47 mmol) was dissolved in MeOH (20 mL), KF (2.02 g, 34.69 mmol) was added, and the mixture was stirred at 40°C for 2 hours. The reaction solution was concentrated and then purified by column chromatography (silica, petroleum ether: ethyl acetate = 6:1) to obtain the target product A51 (1.00 g, yield: 80.02%) as a yellow oil.

¹ H NMR(400MHz,Chloroform-d)δ7.64(s,1H),7.52(s,1H),7.49–7.44(m,2H),7.35(s,2H),4.39(s,2H),3.87 (s,2H),3.08(s,1H),1.91(s,3H).

Intermediates A36, A40, A41, A42, A46, A47, A48, A49, A50, A57 and A58 were synthesized by referring to the synthesis method of A34.

Intermediates A43 and A45 were synthesized by referring to the synthesis method of A44.

Synthesis of Intermediate A61: 4-(1-(1-(2-chloroethyl)-7-fluoro-1H-indazol-5-yl)vinyl)phenol

Step 1: Add A61-1 (5 g, 23.25 mmol), 1-bromo-2-chloro-ethane (10.00 g, 69.76 mmol, 5.81 mL), and Cs ₂ CO ₃ (11.34 g, 34.88 mmol) to DMF (47.68 mL), protect with N ₂ , stir at 20°C for 3 hours, and monitor the completion of the reaction by LCMS. Pour the reaction solution into water, extract with EA (50 mL), wash the organic phase with saturated brine 3 times (50 mL x 3), concentrate the organic phase, and purify by column chromatography to obtain the target product A61-2 (2.70 g, yield: 41.84%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.17(d,J＝2.3Hz,1H),7.83(d,J＝1.5Hz,1H),7.47(dd,J＝11.4,1.5Hz,1H) ,4.76(t,J＝5.6Hz,2H),4.03(t,J＝5.6Hz,2H).LC-MS[M+1] ⁺ ＝278.9

Step 2: A61-2 (2.5 g, 9.55 mmol), tributyl(1-ethoxyethylene)tin (6.90 g, 19.10 mmol, 6.45 mL), Pd(dppf)Cl ₂ (763.91 mg, 954.88 μmol) were added to dioxane (25 mL), N ₂ was protected, stirred at 90°C for 16 hours, cooled to room temperature, 2M HCl was added and stirred, and the reaction was monitored by TLC to be complete. The reaction solution was poured into a potassium fluoride aqueous solution (100 mL), stirred, filtered, extracted with EA (500 mL), separated, and the organic phase was washed with saturated brine 3 times (100 mL x 3). The organic phase was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the target product A61-3 (2.00 g, yield: 87.03%) as a white solid.

LC-MS [M+1] ⁺ = 241.0

Step 3: A61-3 (1.85 g, 7.69 mmol) was dissolved in THF (5 mL), and 4-(2-tetrahydro-2H-pyranyloxy)phenylmagnesium bromide solution (0.5 M, 61.50 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction was completed after monitoring by LCMS. The reaction solution was poured into water, EA was added, the layers were separated, the organic phase was concentrated, and the target product A61-4 (2.70 g, yield: 83.85%) was purified by column chromatography as a colorless oil.

LC-MS [M+1] ⁺ = 419.1

Step 4: Add A61-4 (2.6 g, 6.21 mmol) to a mixed solution of glacial acetic acid (15 mL) and H ₂ O (15 mL), stir at 40° C. for 1 hour, monitor the reaction by LC-MS, add EA to extract EA (500 mL x 2), concentrate the organic phase, and purify by column chromatography to obtain the target product A61 (1.70 g, yield: 86.47%) as a white solid.

¹ H NMR (400MHz, DMSO-d6) δ9.57 (s, 1H), 8.18 (d, J = 2.0Hz, 1H), 7.43 (s, 1H), 7.13 (dd, J = 17.8, 11.3Hz, 3H ), 6.74 (d, J = 8.5Hz, 2H), 5.34 (d, J = 9.2Hz, 2H), 4.78 (t, J = 5.5Hz, 2H), 4.05 (t, J = 5.3Hz, 2H).

LC-MS [M+1] ⁺ = 317.0

Intermediates A62, A63, A64 and A65 were synthesized by referring to the synthetic method of A61.

Refer to the synthesis method of A61 and synthesize A66 through another one-step reaction.

Synthesis of intermediate A67: 4-(1-(1-(2-chloroethyl)-7-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)vinyl)phenol

Step 1: A67-1 (10.0 g, 42 mmol) was dissolved in EtOH (150 mL), and aminopropanol (5.13 g, 84 mmol) was added in batches, and the reaction solution was stirred at room temperature for 16 hours. LC-MS detection showed that the raw material was completely reacted, and the reaction solution was poured into H ₂ O (600 mL) and stirred while adding. After the addition was complete, ethyl acetate (200 mL x 3) was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain compound A67-2 (12 g, crude product) as a brown viscous oil.

LC-MS [M+1] ⁺ = 279.0

Step 2: Add A67-2 (12 g, 43.00 mmol) to a mixed solvent of EtOH (200 mL) and saturated NH ₄ Cl solution (20 mL), then add iron powder (24.01 g, 430.01 mmol), heat to 90°C, and stir to react for 16 hours. LC-MS detected that the reaction raw materials were complete, the reaction solution was diluted with a large amount of ethyl acetate (500 mL) and filtered through diatomaceous earth, the filtrate was evaporated to remove the solvent, and column chromatography was performed (petroleum ether/ethyl acetate = 55%) to obtain compound A67-3 (10.50 g, 42.16 mmol, yield: 98.03%) as a brown-black solid.

LC-MS [M+1] ⁺ = 249.0

Step 3: Compound A67-3 (10.4 g, 41.75 mmol) was added to acetic acid (100 mL) and ACN (10 mL), stirred and cooled to -5°C. NaNO ₂ solution (3.17 g, 45.93 mmol) was added dropwise and the reaction was continued for 2 hours. LC-MS detection showed that the raw material was completely reacted. The reaction solution was poured into water (500 mL), extracted with ethyl acetate (100 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography (petroleum ether/ethyl acetate = 60%) to obtain compound A67-4 (7.00 g, crude product) as a reddish brown solid oily mixture.

LC-MS [M+1] ⁺ = 260.0

Step 4: Compound A67-4 (6 g, 23.07 mmol) was dissolved in DCM (50 mL), SOCl ₂ (8.23 g, 69.21 mmol) was added, and then DMF (2-3 drops of catalytic amount) was added, and the temperature was raised to 45°C and stirred for 12 hours. LC-MS detection showed that the reaction was complete, and the reaction solution was evaporated to remove the solvent, and column chromatography (ethyl acetate/petroleum ether = 25-40%) was used to obtain compound A67-5 (4.0 g, 14.36 mmol, yield: 62.25%) as a brown solid. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ8.04 (d, J = 1.3 Hz, 1H), 7.50 (dd, J = 10.1, 1.4 Hz, 1H), 5.22–5.05 (m, 2H), 4.10 (t, J = 5.9, 0.6 Hz, 2H).

LC-MS [M+1] ⁺ = 278.0

Step 5: A67-5 (700 mg, 2.51 mmol) was dissolved in dioxane (10 mL), tributyl (1-ethoxyethylene) tin (1.82 g, 5.03 mmol) and Pd (dppf) Cl ₂ (182.39 mg, 251.34 μmol) were added, nitrogen was protected, and the reaction was carried out at 90°C for 12 hours. LC-MS showed that an intermediate was generated. The temperature was lowered to room temperature 25°C, 2.2N HCl (10 mL) was added, and the reaction was continued for 2 hours. LC-MS showed that the raw material was basically reacted. The reaction solution was quenched with KF solution, extracted with ethyl acetate (50 mL x 3), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The target product A67-6 (500 mg, yield: 74.09%) was separated and purified by column chromatography (petroleum ether/ethyl acetate = 5/1) as a white solid.

LC-MS [M+1] ⁺ = 242.1

Step 6: Compound A67-6 (500 mg, 2.07 mmol) was dissolved in THF (10 mL) and added dropwise to 4-(2-tetrahydro-2H-pyranyloxy)phenylmagnesium bromide solution (0.5 M, 16.55 mL) at 0°C. The mixture was stirred at 0°C for 1 hour. LC-MS detection showed that the reaction was complete, and the reaction solution was poured into water (30 mL) for quenching, extracted with ethyl acetate (30 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (ethyl acetate/petroleum ether = 0-100%) gave compound A67-7 (868 mg, 2.07 mmol, yield: 99.91%) as a light yellow oil.

LC-MS [M+1] ⁺ = 420.3

Step 7: Compound A67-7 (800 mg, 1.91 mmol) was dissolved in AcOH (1 mL) and H ₂ O (0.3 mL), and stirred at 25° C. for 2 hours. LC-MS showed that the reaction was complete, and the reaction solution was concentrated under reduced pressure and column chromatography (petroleum ether/ethyl acetate = 3/1) was used to obtain compound A67 (567 mg, 1.79 mmol, yield: 93.7%) as a yellow oil.

LC-MS [M+1] ⁺ = 318.1

Synthesis of Intermediate A68: (1-(2-chloroethyl)-7-fluoro-1H-indazol-5-yl)(4-hydroxyphenyl)methanone

Step 1: Add A68-1 (2 g, 7.79 mmol) to tetrahydrofuran (16 mL) and water (4 mL), then add lithium hydroxide (373.26 mg, 15.58 mmol), and stir at 25 ° C for 16 hours. After the reaction is completed, add a small amount of ice water (20 mL) to the reaction solution, adjust the pH (pH = 3) with 4M hydrochloric acid, and filter after the solid precipitates to obtain A68-2 (1.99 g, 7.37 mmol, yield: 94.54%), which is a white solid.

LC-MS [M+1] ⁺ = 242.9

Step 2: A68-2 (1.9 g, 7.83 mmol) and methoxymethylamine (478.32 mg, 7.83 mmol) were added to N, N-dimethylformamide (30 mL), followed by triethylamine (2.38 g, 23.49 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (5.95 g, 15.66 mmol), and the system was reacted at 25 ° C for 2 hours. After the reaction, water (20 mL) and ethyl acetate (200 mL) were added, washed with saturated sodium chloride (200 mL x 3), dried over anhydrous sodium sulfate, and the organic phase was concentrated to dryness and purified by column chromatography (ethyl acetate/petroleum ether = 0 to 20%) to obtain A68-3 (2.00 g, 6.30 mmol, yield: 80.46%), which was a light yellow oil.

LC-MS [M+1] ⁺ = 286.10

Step 3: A68-3 (2.2 g, 7.70 mmol) was dissolved in tetrahydrofuran (20 mL), the temperature was raised to 35 ° C, 4-(2-tetrahydro-2H-pyranyloxy)phenylmagnesium bromide solution (0.5 M, 9.24 mmol) was slowly added dropwise, and the system was stirred for 1 hour. After the reaction, the mixture was cooled to room temperature, poured into a saturated ammonium chloride solution, and extracted with ethyl acetate (300 mL x 3), and the organic phase was concentrated to dryness. Purification by column chromatography (ethyl acetate/petroleum ether = 0 to 30%) gave A68-4 (2.84 g, 6.34 mmol, yield: 82.34%), which was a light yellow oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.39(d,J＝2.2Hz,1H),8.05–7.96(m,1H),7.74(d,J＝8.9Hz,2H),7.57(dd,J＝12.7,1.2Hz,1H),7.15(d,J＝8.9Hz,2H),5.61(d,J＝ 3.4Hz,1H),4.84(t,J＝5.6Hz,2H),4.08(t,J＝5.4Hz,2H),2.09–0.58(m,8H).LC-MS[M+1] ⁺ ＝403.2

Step 4: A68-4 (1 g, 2.48 mmol) was dissolved in 1,4-dioxane (1 mL), replaced with nitrogen 3 times, and hydrochloric acid (181.02 mg, 4.96 mmol) was added dropwise at 25°C, and stirred for 1 hour. After the reaction was completed, the reaction solution was concentrated, ethyl acetate (50 mL) was added, and washed with saturated sodium bicarbonate (50 mL x 2) and saturated sodium chloride (50 mL x 2), dried over anhydrous sodium sulfate, and the organic phase was concentrated to dryness and purified by column chromatography (ethyl acetate/petroleum ether = 0 to 40%) to obtain A68 (769.00 mg, 2.17 mmol, yield: 87.48%) as a white solid.

LC-MS [M+1] ⁺ = 319.2

Synthesis of Intermediate A69: 4-((1-(2-chloroethyl)-7-fluoro-1H-indazol-5-yl)thio)phenol

Step 1: Add A69-1 (5 g, 23.25 mmol), 1-bromo-2-chloro-ethane (10.00 g, 69.76 mmol, 5.81 mL), and Cs ₂ CO ₃ (11.34 g, 34.88 mmol) to DMF (47.68 mL), and stir at 20°C for 3 hours under N ₂ protection. The reaction was completed by LCMS monitoring. The reaction solution was poured into water, extracted with EA (200 mL), and the organic phase was washed with saturated brine (300 mL*3). The organic phase was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the target product A69-2 (2.70 g, yield: 41.84%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.17(d,J＝2.3Hz,1H),7.83(d,J＝1.5Hz,1H),7.47(dd,J＝11.4,1.5Hz,1H) ,4.76(t,J＝5.6Hz,2H),4.03(t,J＝5.6Hz,2H).

LC-MS [M+1] ⁺ = 279.0

Step 2: Add A69-2 (1 g, 3.60 mmol), p-methoxythiophenol (757.80 mg, 5.41 mmol), DIPEA (931.39 mg, 7.21 mmol), Pd ₂ (dba) ₃ (329.96 mg, 360.33 μmol), Xantphos (208.50 mg, 360.33 μmol) to dioxane (15 mL), N ₂ protection, and stir at 100° C. for 8 hours. LCMS monitoring reaction completion. The organic phase was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the target product A69-3 (700.00 mg, yield: 57.68%) as a yellow solid.

LC-MS [M+1] ⁺ = 337.0

Step 3: A69-3 (480 mg, 1.43 mmol) was dissolved in DCM (6 mL), and BBr ₃ (1.79 g, 7.13 mmol) was added dropwise. The mixture was protected by N ₂ and stirred at 0°C for 1 hour. The reaction was completed by LCMS monitoring. The reaction solution was poured into water, extracted with DCM (20 mL), and the organic phase was washed with saturated brine (30 mL*3). The organic phase was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the target product A69 (330.00 mg, yield: 71.74%) as a yellow oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.83 (s, 1H), 8.11 (d, J = 2.3Hz, 1H), 7.35 (d, J = 1.4Hz, 1H), 7.32–7.27 (m, 2H), 7.06 (dd, J = 12.3, 1.4Hz, 1H), 6.82–6.76 (m, 2H) ,4.73(t,J＝5.7Hz,2H), 4.01(t,J＝5.4Hz,2H).

LC-MS [M+1] ⁺ = 323.0

Synthesis of intermediate I-B1: Thiophene, 1,1,2,3,4,5-hexahydro-1-imino-1-oxide

Step 1: Methanol (5 mL), tetrahydrothiophene (0.20 mL, 2.27 mmol), ammonium carbamate (177.1 mg, 2.27 mmol) and iodobenzene acetate (1826.6 mg, 5.67 mmol) were added to the reaction flask in sequence, and stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under pressure and purified by column chromatography (0-7% methanol/dichloromethane) to obtain a yellow liquid I-B1 (200 mg, 1.68 mmol, 73.98%).

¹ H NMR (400MHz, Chloroform-d) δ3.22-3.12 (m, 4H), 2.36-2.22 (m 4H).

Synthesis of Intermediate I-B2: 1λ ⁴ -thiophene-1-imine-1-oxide

Referring to the synthesis method of intermediate I-B1, trimethylol sulfide was used instead of tetrahydrothiophene to carry out a one-step reaction to obtain intermediate I-B2.

¹ H NMR (400MHz, Chloroform-d) δ4.21-4.03 (m, 4H), 2.29-2.06 (m, 2H).

Synthesis of Intermediate I-B3: 1λ ⁴ -thiopyran-1-imine-hexahydro-1-oxide

Referring to the synthesis method of intermediate I-B1, cyclopentane sulfide is used instead of tetrahydrothiophene to carry out a one-step reaction to obtain intermediate I-B3.

¹ H NMR (400MHz, Chloroform-d) δ3.12-2.88(m,4H), 2.17-1.99(m,4H), 1.69-1.49(m,2H).

Synthesis of intermediate I-B4: 2H-4λ ⁴ -1,4-oxathiocin-4-imine-4-oxide

Referring to the synthesis method of intermediate I-B1, 1,4-thioxane is used instead of tetrahydrothiophene to carry out a one-step reaction to obtain intermediate I-B4.

¹ H NMR (400MHz, Chloroform-d) δ4.31 (brs, 1H), 4.17-3.86 (m, 4H), 3.12 (t, J = 5.2Hz, 4H).

Synthesis of Intermediate I-B5: 1λ ⁴ -thiomorpholine-4-carboxylic acid-1-imino-1,1-dimethylethyl ester-1-oxide

Step 1: Add dichloromethane (10 mL), thiomorpholine (0.18 mL, 1.94 mmol), triethylamine (0.81 mL, 5.82 mmol) and Boc ₂ O (634.5 mg, 2.91 mmol) to the reaction bottle in sequence, stir at 25°C for 12 hours. After the reaction is complete, the reaction solution is concentrated under pressure and purified by column chromatography (0-8% ethyl acetate/petroleum ether) to obtain a white solid I-B5-1 (370 mg, 1.82 mmol, 93.90%).

¹ H NMR (400MHz, Chloroform-d) δ3.80-3.60 (m, 4H), 2.72-2.49 (m, 4H), 1.49 (s, 9H).

Step 2: Referring to the synthesis method of intermediate I-B1, use intermediate I-B5-1 instead of tetrahydrothiophene to carry out a one-step reaction to obtain intermediate I-B5.

¹ H NMR(400MHz,Chloroform-d)δ5.18(s,1H),4.09-3.92(m,2H),3.91-3.78(m,2H),3.15-2.98(m,4H),1.49(s, 9H).

Synthesis of Intermediate I-B6: (S)-N-(1-Imino-1-oxytrihydro-1H-1λ ⁶ -thiophen-3-yl)-2-methylpropane-2-sulfinamide

Step 1: Add thiophene-3-one (2g, 19.58mmol), (R)-tert-butylsulfenamide (2.61g, 21.54mmol) and anhydrous tetrahydrofuran (40mL) to the reaction bottle in sequence, and finally add tetraethyl titanate (8.21mL, 39.15mmol). The yellow reaction solution was stirred at 65°C for 2 hours, then cooled to 0°C and added dropwise to the prepared sodium borohydride/tetrahydrofuran (1.48g n dissolved in 40mL), and continued to stir for 2 hours. After slowly adding methanol (20mL) to quench the reaction solution, it was concentrated under reduced pressure, and the residue was diluted and filtered with ethyl acetate (60mL). The filtrate was washed with saturated brine (40mL), dried, concentrated under reduced pressure, and purified by column chromatography (0-40% ethyl acetate/petroleum ether) to obtain a yellow solid I-B6-1 (2.75g, 13.26mmol, 67.75%).

Step 2: Referring to the synthesis method of intermediate I-B1, use intermediate I-B6-1 instead of tetrahydrothiophene to carry out a one-step reaction to obtain intermediate I-B6.

Synthesis of Intermediate I-B7: (S)-N-(1-Imino-1-oxyhexahydro-1λ ⁶ -thiopyran-4-yl)-2-methylpropane-2-sulfinamide

Referring to the synthesis method of intermediate I-B6, tetrahydrothiopyran-4-one is used instead of thiophene-3-one, and a two-step reaction is carried out to obtain intermediate I-B7.

Synthesis of Intermediate I-B8: 4-(Chloromethyl)-2-(methylthio)oxazole

Step 1: I-B8-1 (1 g, 4.55 mmol) was dissolved in EtOH (15 mL), and then MeSNa (530.94 mg, 6.82 mmol, 90% purity) was added. The temperature was raised to 80 ° C under nitrogen protection for 2 hours. The LC-MS results showed that the raw material reacted completely. The above reaction solution was concentrated and then added with water (10 mL) and ethyl acetate (10 mL * 3) for extraction. The organic phase was washed with saturated brine, then dried over anhydrous sodium sulfate and concentrated to obtain I-B8-2 (0.566 g, yield: 62.56%) as a yellow solid.

LC-MS [M+1] ⁺ = 174.19

Step 2: I-B8-2 (0.436 g, 2.33 mmol) was dissolved in THF (16 mL) and EtOH (4 mL), and then NaBH ₄ (88.10 mg, 2.33 mmol) was added, replaced with nitrogen 3 times, heated to 60°C under nitrogen protection, and stirred for 4 hours. The reaction solution was cooled to 0°C, quenched with saturated aqueous ammonium chloride solution, and the pH of the reaction solution was adjusted to neutral. After concentration, water (2 mL) and ethyl acetate (10 mL*2) were added for extraction, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purification by TLC plate (ethyl acetate) finally gave I-B8-3 (0.234 g, yield: 66.44%) as a yellow oil.

LC-MS [M+1] ⁺ = 146.18

Step 3: Add SOCl ₂ (106.53 mg, 895.44 μmol) to I-B8-3 (130 mg, 895.44 μmol), then heat to 80°C and reflux for 0.5 hours. TLC spot (PE:EA=1:3), the reaction is complete, concentrated, dissolved in acetonitrile and concentrated again to obtain intermediate I-B8 (130 mg, crude product).

Synthesis of Intermediate I-B9: 4-(Chloromethyl)-5-(methylthio)oxazole

Step 1: Dissolve I-B9-1 (5 g, 35.43 mmol) in acetonitrile (50 mL), add NBS (9.46 g, 53.14 mmol) and AIBN (581.79 mg, 3.54 mmol). The reaction was carried out at 85 ° C for 16 hours. After the reaction solution was concentrated, it was purified by column (petroleum ether/ethyl acetate = 5/1) to obtain I-B9-2 (1.6 g, yield: 18.47%), which was a yellow oily liquid. 1H-NMR (400 MHz, Chloroform-d) δ8.25 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). LC-MS [M + H] ⁺ = 220.0/222.0

Step 2: Dissolve I-B9-2 (1.6 g, 7.27 mmol) in ethanol (8 mL), add sodium thiomethoxide (611.63 mg, 8.73 mmol). The mixture is reacted at 80°C for 2 hours. The reaction solution is concentrated and passed through a column (petroleum ether/ethyl acetate = 5/1) to obtain I-B9-3 (1.1 g, yield: 76.76%) as a yellow solid.

¹ H-NMR (400MHz, Chloroform-d) δ8.18 (s, 1H), 4.38 (q, J = 7.1Hz, 2H), 2.71 (s, 3H), 1.38 (t, J = 7.1Hz, 3H) .LC-MS[M+H] ⁺ =187.9

Step 3: Dissolve I-B9-3 (0.6 g, 3.20 mmol) in ethanol and add NaBH ₄ (242.48 mg, 6.41 mmol). Heat the mixture to 70°C for two hours. Slowly pour the reaction solution into 100 mL of water and add ethyl acetate (50 mL). The aqueous phase is extracted three times with ethyl acetate, and the organic phases are combined and washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain I-B9-4 (450 mg, 2.76 mmol, yield: 86.08%), which is a colorless oily liquid and used directly in the next step.

Step 4: Dissolve I-B9-4 (450 mg, 3.10 mmol) in dichloromethane (9.55 mL) and add SOCl ₂ (737.52 mg, 6.20 mmol, 449.71 μL). The reaction was carried out at 40°C for 2 hours. LCMS detected that the reaction was complete. After the mixture was concentrated, I-B9 (400 mg, 2.08 mmol, yield: 67.04%) was obtained as a colorless oily liquid, which was directly used in the next step. MS (ESI) m/z = 164 [M + H] ⁺

Synthesis of Intermediate I-B10: 2-Chloro-6-(chloromethyl)pyrazine

The raw material I-B10-1 (1 g, 7.78 mmol) was dissolved in acetonitrile (15 mL), and then AIBN and NCS were added, and the mixture was heated to 85°C and stirred for 16 hours, and concentrated. The concentrated mixture was purified by column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain the product I-B10 (1.21 g, yield: 71.81%), which was a yellow oily liquid. LC-MS [M+1] ⁺ = 163

Synthesis of intermediate B11: 1-imino-4-(pyridin-2-yl)-1λ ⁶ -thiomorpholine-1-oxo

Step 1: Dissolve B11-1 (200 mg, 2.06 mmol, 177.30 μL) and thiomorpholine (637.67 mg, 6.18 mmol, 621.51 μL) in DMA (5 mL), stir at 60 ° C for 4 hours, and monitor the completion of the reaction by LCMS. Add water (30 mL) and extract with ethyl acetate (20 mL * 3). Wash the organic phase with saturated brine (20 mL * 3). The organic phase is mixed and purified by normal phase column (petroleum ether: ethyl acetate = 15: 1) to obtain the target product B11-2 (90.00 mg, yield: 24.24%), which is a transparent oil.

LC-MS [M+1] ⁺ = 181.1

Step 2: B11-2 (90 mg, 499.25 μmol), [acetoxy(phenyl)-iodanyl]acetate (402.02 mg, 1.25 mmol), NH ₂ COONH ₄ (42.84 mg, 549.18 μmol) were added to MeOH (2 mL), and the reaction was stirred at room temperature for 2 hours. After completion of the reaction under LCMS monitoring, the reaction solution was mixed and purified by normal phase column (petroleum ether: ethyl acetate = 0:1) to obtain the target product B11 (40.00 mg, yield: 37.92%) as a white solid.

LC-MS [M+1] ⁺ = 212.1

Synthesis of intermediate B12: 6-Imino-2-oxo-6λ ⁴ -thiospiro[3.3]heptane-6-oxo

Referring to the synthesis method of intermediate I-B1, a one-step reaction was performed to obtain intermediate B12.

Synthesis of intermediate B14: benzyl 2-imino-2λ ⁶ -thio-6-azaspiro[3.3]heptane-6-carbonyloxy-2-oxo

Step 1: Dissolve B14-1 (800 mg, 3.16 mmol) in tetrahydrofuran (2 mL), add HBr aqueous solution (532.34 mg, 3.16 mmol, 1 mL, 48% purity) at 0°C, and react for 1 hour. Add saturated NaHCO ₃ aqueous solution, adjust pH to 8, extract with methyl tert-butyl ether (10 mL*3), wash with saturated brine (10 mL*3), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the target product B14-2 (1.0 g, crude) as a white solid. LC-MS [M+23] ⁺ = 334.10

Step 2: Dissolve B14-2 (1.0 g, 2.99 mmol) and CBr ₄ (1.59 g, 4.79 mmol) in dichloromethane (20 mL), add PPh ₃ (1.26 g, 4.79 mmol) at 0°C, raise the temperature to room temperature (20°C) and continue the reaction for 12 hours. Concentrate the reaction solution under reduced pressure, and obtain the target product B14-3 (700 mg, yield: 53.02%) as a white solid by column chromatography (ethyl acetate/petroleum ether = 0-30%).

¹ H NMR (400MHz, Chloroform-d) δ7.72 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 7.5 Hz, 2H), δ 3.58 (d, J = 0.9 Hz, 4H), 3.52(d,J＝1.1Hz,4H),2.46(s,3H).

Step 3: Compound B14-3 (700 mg, 1.76 mmol) was dissolved in acetonitrile (20 mL) and water (2 mL), and Na ₂ S (343.90 mg, 4.41 mmol) was added, and stirred at 50°C for 3 hours. The reaction solution was concentrated under reduced pressure, water (30 mL) was added, and extracted with ethyl acetate (10 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product B14-4 (300 mg, crude) as a white solid. LC-MS [M+1] ⁺ = 270.10

Step 4: Dissolve B14-4 (240 mg, 890.93 μmol) in methanol (5 mL), add magnesium powder (129.95 mg, 5.35 mmol), and react at room temperature 20°C for 3 hours. The reaction solution was filtered to obtain the target product B14-5 (102.63 mg, crude) as a colorless methanol solution, which was directly used in the next step. LC-MS [M+1] ⁺ = 116.10

Step 5: Dissolve compound B14-5 (102.63 mg, 890.91 μmol) in methanol (20 mL), add CbzCl (222.03 mg, 890.91 μmol) and triethylamine (450.76 mg, 4.45 mmol) at 20°C, and react for 12 hours. The reaction solution was directly concentrated under reduced pressure, and the target product B14-6 (220 mg, crude) was obtained by column chromatography (ethyl acetate/petroleum ether = 0-16%) as a colorless oil. LC-MS [M+1] ⁺ = 250.10

Step 6: Dissolve B14-6 (220 mg, 882.37 μmol) in methanol (5 mL), add carbamate (68.89 mg, 882.37 μmol) and iodobenzene acetate (284.21 mg, 882.37 μmol), and react at room temperature 20°C for 1 hour. The reaction solution was concentrated under reduced pressure and column chromatography (ethyl acetate/petroleum ether = 0-100%) was performed to obtain the target product B14 (180.00 mg, yield: 58.21%) as a colorless oil. LC-MS [M+1] ⁺ = 281.20

Synthesis of intermediate B15: 5-Imino-2-methyl-4,5,6,7-tetrahydro-2H-5λ ⁴ -thiopyrano[4,3-c]pyrazole-5-oxo

Step 6: Compound B15-1 (5.0 g, 43.04 mmol) was dissolved in toluene (40 mL) and B15-2 (8.25 g, 47.34 mmol) was added. The mixture was stirred at 20°C for 18 hours. The reaction solution was concentrated to obtain intermediate B15-3 (6.0 g, crude product) as a yellow oil. LC-MS [M-1] ^- = 143.0

Step 7: Compound B15-3 (6 g, crude product) was dissolved in solvent EtOH (60 mL), and hydrazine hydrate (7.02 g, 175.17 mmol) was added. The mixture was stirred at 90°C for 12 hours. The solvent was evaporated to obtain intermediate B15-4 (8.00 g, crude product) as a light yellow solid. LC-MS [M+1] ⁺ = 141.1

Step 8: B15-4 (4 g, 28.53 mmol) was dissolved in DMF (40 mL) and t-BuOK (3.51 g, 31.38 mmol) was added. The reaction solution was stirred evenly. MeI (4.05 g, 28.53 mmol) was added at 0°C, and the temperature was raised to 20°C and stirred for 16 hours. The reaction solution was poured into 200 mL of water for quenching, extracted with ethyl acetate (40 mL*3), washed with saturated brine (30 mL*3), dried over anhydrous sodium sulfate, and separated by column chromatography (petroleum ether/tetrahydrofuran = 2/1) to obtain intermediate B15-5 (2.00 g, crude product) as a light yellow oil. LC-MS [M+1] ⁺ = 155.1

Step 9: B15-5 (1.9 g, crude product) was dissolved in MeOH (20 mL), and NH ₂ COONH ₄ (2.11 g, 27.10 mmol) and (Diacetoxyiodo)benzene (11.11 g, 34.49 mmol) were added. The mixture was stirred at 30°C for 16 hours. The solvent was evaporated and separated by column chromatography (methanol/tetrahydrofuran = 3/17) to obtain 1.70 g of crude product. 400 mg of the crude product was used for Prep-HPLC to obtain intermediate B15 (50.00 mg) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.44 (s, 1H), 4.10 (s, 2H), 3.78 (s, 1H), 3.72 (s, 3H), 3.21 (ddt, J = 25.7, 13.9, 6.5Hz, 2H), 2.96 (t, J = 6.4Hz, 2H).

LC-MS [M+1] ⁺ = 186.10

Refer to the above synthesis method to synthesize intermediate B13

Example 1: Synthesis of Compound I-1:

3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((dimethyl(oxo)-λ ⁶ -sulfoxyl)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

Step 1: Add cesium carbonate (2.79 g, 8.57 mmol, 2.0 eq) to a 40 mL acetonitrile solution of I-A1 (1.5 g, 4.28 mmol) and intermediate I-1-1 (698 mg, 4.28 mmol, 1.0 eq) at room temperature. The mixed solution was stirred at 40 ° C for two hours. TLC detection showed that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain the product I-1-2 (0.8 g, yield: 39%).

Step 2: At room temperature, toluene (1 mL), I-1-2 (20 mg, 0.04 mmol), dimethylsulfenyl imide (4.69 mg, 5.50 mmol), palladium acetate (0.94 mg, 0.004 mmol), 2-dicyclohexylphosphine-2', 6'-diisopropoxy-1,1'-biphenyl (3.91 mg, 0.008 mmol) and cesium carbonate (20.50 mg, 0.063 mmol) were added to the reaction bottle in sequence. Nitrogen was replaced three times, then the temperature was raised to 100 ° C and stirred for 12 hours. After the reaction was complete, it was filtered and the filtrate was prepared by HPLC to obtain a white solid compound I-1 (5 mg, yield: 22.34%).

¹ H NMR (400MHz, DMSO-d6) δ8.45 (s, 1H), 7.63 (d, J = 2.4Hz, 1H), 7.57 (d, J = 2.4Hz, 1H), 7.19 (t, J = 8.4 Hz,2H),6.98–6.91(m,2H),6.66(d,J＝8.4Hz,1H),5.04(s,2H),4.45–4.37(m,2H),3.99–3.92(m,2H) ,3.39(s,6H),1.24(s,6H).

LCMS [M+H] ⁺ = 533.1

Example 2: Synthesis of Compound I-2:

3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((1-oxotetrahydro-1λ ⁶ -thiophen-1-ylidene)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

At room temperature, toluene (1 mL), intermediate I-1-2 (60 mg, 0.088 mmol), intermediate I-B1 (21.0 mg, 0.176 mmol), palladium acetate (1.98 mg, 0.009 mmol), 2-dicyclohexylphosphine-2', 6'-diisopropoxy-1,1'-biphenyl (8.22 mg, 0.018 mmol) and cesium carbonate (43.05 mg, 0.132 mmol) were added to the reaction bottle in sequence. Nitrogen was replaced three times, and then the temperature was raised to 100 ° C and stirred for 12 hours. After the reaction was complete, it was filtered and the filtrate was prepared by HPLC (formic acid system) to obtain white solid compound I-2 (5 mg, yield: 10.14%).

¹ H NMR (400MHz, DMSO-d6) δ8.51-8.40(m,1H),7.70-7.54(m,2H),7.23-7.13(m,2H),7.00-6.97(m,3H),5.03( s,2H),4.49-4.36(m,2H),3.99-3.91(m,2H),2.29-1.98(m,4H),1.71-1.57(m,4H),1.24(s,6H).

LCMS [M+H] ⁺ = 559.1

According to the synthesis methods of compound I-1 and compound I-2 above or references, the following compounds were synthesized respectively:

Example 3: Synthesis of Compound I-3:

3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((4-oxo-1,4λ ⁶ -oxo-4-ylidene)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

Referring to the synthesis method of compound I-1, intermediate I-B4 is used to replace dimethylsulfonyl imine, and compound I-3 is obtained by a one-step reaction.

¹ H NMR(400MHz,MeOD-d4)δ8.45(s,1H),7.54-7.45(m,2H),7.25–7.13(m,2H),7.11–7.02(m,1H),6.99–6.87( m,2H),5.08(s,2H),4.47–4.37(m,2H),4.22–4.12(m,2H),4.07–3.98(m,2H),3.92–3.87(m,2H),3.87– 3.79(m,2H),3.62-3.49(m,2H),1.66(s,6H).

LCMS [M+H] ⁺ = 575.1

Example 4: Synthesis of Compound I-4:

3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((1-oxido-1λ ⁶ -thiazane-1-ylidene)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

Referring to the synthesis method of compound I-1, intermediate I-B2 is used to replace dimethylsulfonyl imine, and a one-step reaction is carried out to obtain compound I-4.

¹ H NMR (400MHz, MeOD-d4) δ8.43(d,J＝5.2Hz,1H),7.48(dd,J＝16.0,2.4Hz,2H),7.21–7.11(m,2H),7.07(d ,J＝5.2Hz,1H),6.96–6.83(m,2H),5.05(s,2H),4.44–4.23(m,6H),3.88(t,J＝5.6Hz,2H),2.53-2.32( m,2H),1.64(s,6H).

LCMS [M+H] ⁺ = 545.1

Example 5: Synthesis of Compound I-5:

3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((1-oxytrihydro-2H-1λ ⁶ -thiopyran-1-ylidene)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

Referring to the synthesis method of compound I-1, intermediate I-B3 is used to replace dimethylsulfonyl imine, and a one-step reaction is carried out to obtain compound I-5.

LCMS [M+H] ⁺ = 573.1

Example 6: Synthesis of Compound I-6:

3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((1-oxo-1λ ⁶ -thiomorpholin-1-ylidene)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

Step 1: At room temperature, toluene (1 mL), I-1-2 (50 mg, 0.105 mmol), intermediate I-B5 (24.60 mg, 0.105 mmol), palladium acetate (2.36 mg, 0.01 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (9.79 mg, 0.021 mmol) and cesium carbonate (51.25 mg, 0.157 mmol) were added to the reaction bottle in sequence. Nitrogen was replaced three times, and then the temperature was raised to 100 ° C and stirred for 12 hours. After the reaction was complete, the filtrate was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (0-4% methanol/dichloromethane) to obtain a yellow oily intermediate I-6-1 (40 mg, yield: 56.47%).

LCMS [M+H-Boc] ⁺ = 574.1

Step 2: Add intermediate I-6-1 (40 mg, 0.06 mmol), dichloromethane (1 mL) and hydrochloric acid/dioxane solution (1 mL) to the reaction bottle in sequence, stir at 25°C for 12 hours, concentrate under reduced pressure after the reaction is complete, and prepare by HPLC (formic acid system) to obtain white solid compound I-6 (30 mg, yield: 82.81%).

¹ H NMR (400MHz, MeOD-d4) δ8.45 (d, J＝5.2Hz, 1H), 7.50 (dd, J＝18.0, 2.4Hz, 2H), 7.19 (d, J＝8.8Hz, 2H), 7.10(s,1H),6.95(d,J＝8.8Hz,2H),5.08(s,2H),4.46–4.36(m,2H),3.90(t,J＝5.6Hz,2H),3.87–3.76 (m,2H),3.54–3.37(m,4H),3.36-3.32(m,2H),1.67(s,6H).

LCMS [M+H] ⁺ = 574.1

Example 7: Synthesis of Compound I-7:

3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((4-methyl-1-oxido-1λ ⁶ -thiomorpholin-1-ylidene)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

Step 1: At room temperature, add acetonitrile (1 mL), compound I-6 (40 mg, 0.07 mmol), potassium carbonate (19.2 mg, 0.14 mmol) and iodomethane (4.36 uL, 0.070 mmol) to the reaction bottle, stir at 25 ° C for 12 hours, after the reaction is complete, concentrate under reduced pressure, and separate the residue by column chromatography (0-5% methanol/dichloromethane) to obtain white solid compound I-7 (10 mg, yield: 24.27%).

¹ H NMR (400MHz, MEOD-D4) δ8.45(s,1H),7.50(dd,J＝17.2,2.0Hz,2H),7.18(d,J＝8.8Hz,2H),7.10(s,1H ),6.95(d,J＝8.8Hz,2H),5.08(s,2H),4.42(t,J＝5.6Hz,2H),3.90(t,J＝5.6Hz,2H),3.85-3.74(m ,2H),3.64–3.51(m,2H),3.14-2.94(m,4H),2.45(s,3H),1.66(s,6H).

LCMS [M+H] ⁺ = 588.1

Example 8: Synthesis of Compound I-8:

3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((5-((1-oxytrihydro-1λ ⁶ -thiophen-1-ylidene)amino)thiazol-2-yl)methoxy)phenyl)propan-2-yl)benzonitrile

Step 1: Refer to the synthesis steps of compound I-1, replace intermediate I-1-1 with intermediate I-8-1 to obtain intermediate I-8-2.

Step 2: At room temperature, toluene (1 mL), intermediate I-8-2 (50 mg, 0.095 mmol), intermediate I-B1 (16.99 mg, 0.14 mmol), Pd ₂ (dba) ₃ (17.40 mg, 0.019 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (21.99 mg, 0.038 mmol) and cesium carbonate (46.43 mg, 0.143 mmol) were added to the reaction bottle in sequence. Nitrogen was replaced three times, and then the temperature was raised to 100 ° C and stirred for 12 hours. After the reaction was complete, the filtrate was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (0-80% ethyl acetate/petroleum ether) to obtain a yellow solid compound I-8 (40 mg, yield: 74.57%).

¹ H NMR (400MHz, MEOD-D4) δ7.51 (d, J = 2.4Hz, 1H), 7.46 (d, J = 2.4Hz, 1H), 7.17 (d, J = 8.4Hz, 2H), 6.96 ( d,J＝8.4Hz,2H),6.71(d,J＝8.4Hz,1H),5.20(s,2H),4.42(t,J＝5.6Hz,2H),3.89(t,J＝5.6Hz, 2H),3.46–3.36(m,2H),3.26-3.18(m,2H),2.40–2.18(m,4H),1.66(s,6H).

LCMS [M+H] ⁺ = 564.1

Example 9: Synthesis of Compound I-9:

3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(2-hydroxyethyl)-1-oxido-1λ ⁶ -thiomorpholin-1-ylidene)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

Step 1: At room temperature, add acetonitrile (1 mL), compound I-6 (40 mg, 0.07 mmol), potassium carbonate (19.2 mg, 0.14 mmol) and 2-bromoethanol (7.42 uL, 0.10 mmol) to the reaction bottle, stir at 80 ° C for 48 hours, after the reaction is complete, concentrate under reduced pressure, and separate the residue by column chromatography (0-5% methanol/dichloromethane) to obtain white solid compound I-9 (12 mg, yield: 27.86%).

¹ H NMR (400MHz, MEOD-D4) δ8.44(s,1H),7.50(dd,J＝2.0&15.6Hz,2H),7.18(d,J＝8.8Hz,2H),7.07(d,J ＝4.4Hz,1H),6.95(d,J＝8.8Hz,2H),5.07(s,2H),4.42(t,J＝5.2Hz,2H) ,3.90(t,J＝5.2Hz,2H),3.82-3.73(m,2H),3.66(t,J＝5.2Hz,2H),3.60–3.47(m,2H),3.19-3.12(m,2H ),3.11–2.98(m,2H),2.69(t,J＝5.2Hz,2H),1.66(s,6H).LCMS[M+H] ⁺ ＝618.1

Example 10: Synthesis of Compound I-10:

5-(2-(4-((2-((3-amino-1-oxytrihydro-1λ ⁶ -thiophen-1-ylidene)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile

Referring to the synthesis method of compound I-6, intermediate I-B6 was used instead of intermediate I-B5 to carry out a two-step reaction to obtain compound I-10.

¹ H NMR (400MHz, MeOD-d4) δ8.46 (d, J = 5.2 Hz, 1H), 7.49 (dt, J = 13.6, 6.8 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 7.10(d,J＝5.2Hz,1H),6.95(d,J＝8.8Hz,2H),5.08(s,2H),4.42(t,J＝5.6Hz,2H),3.98-3.84(m,4H ),3.81–3.69(m,1H),3.52–3.39(m,2H),2.62–2.53(m,1H),2.09-1.99(m,1H),1.66(s,6H).

LCMS [M+H] ⁺ = 574.1

Example 11: Synthesis of Compound I-11:

5-(2-(4-((2-((4-amino-1-oxytrihydro-2H-1λ ⁶ -thiopyran-1-ylidene)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile

Referring to the synthesis method of compound I-6, intermediate I-B7 was used to replace intermediate I-B5, and compound I-11 was obtained by two-step reaction.

Product I-11-A (cis or trans): ¹ H NMR (400MHz, MeOD-d4) δ8.47 (d, J = 5.2Hz, 1H), 7.57-7.39 (m, 3H), 7.25–7.08 (m,4H),6.96(d,J＝8.8Hz,2H),5.08(s,2H),4.58(s,2H),4.42(t,J＝5.6Hz,2H),4.08(d,J＝ 12.0Hz,2H),3.96–3.85(m,2H),3.48(t,J＝13.6Hz,3H),2.34(d,J＝13.6Hz,2H),2.22–2.13(m,2H),1.66( s,6H).

Product I-11-B (trans or cis): ¹ H NMR (400MHz, MeOD-d4) δ8.43 (d, J = 5.2Hz, 1H), 7.56–7.38 (m, 3H), 7.29–7.06 (m,4H),6.94(d,J＝8.8Hz,2H),5.07(s,2H),4.58(s,2H),4.42(t,J＝5.6Hz,2H),3.89(t,J＝ 5.6Hz,3H),3.55(t,J＝13.5Hz,2H),2.38(d,J＝13.7Hz,2H),2.25(d,J＝8.8Hz,2H),1.66(s,6H).

LCMS [M+1] ⁺ = 588.1

Example 12: Synthesis of Compound I-12:

3-Chloro-2-(2-hydroxyethoxy)-5-(2-(4-((2-((1-oxido-1λ ⁶ -thiomorpholin-1-ylidene)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

Step 1: At room temperature, dimethyl sulfoxide (1 mL), intermediate I-6-1 (100 mg, 0.15 mmol), tetrabutylammonium fluoride (0.005 mL, 0.015 mmol) and sodium formate (25.20 mg, 0.37 mmol) were added to the reaction bottle in sequence, and the reaction solution was stirred at 110 ° C for two hours. Then cooled to 25 ° C, sodium hydroxide aqueous solution (0.024 mL, 0.296 mmol, 12.5 M) was added and stirred for 12 hours. After the reaction was complete, the reaction solution was extracted with water (10 mL) and dichloromethane (5 mL * 3), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, it was purified by column chromatography (0-5% methanol/dichloromethane) to obtain a white solid I-12-1 (50 mg, yield: 51.41%).

Step 2: At room temperature, dichloromethane (1 mL), intermediate I-12-1 (50 mg, 0.076 mmol) and trifluoroacetic acid (1 mL) were added to the reaction bottle in sequence, and the reaction solution was stirred at 25 ° C for 12 hours. After the reaction was complete, the residue was concentrated under reduced pressure and the pH was adjusted to 8 with a saturated sodium bicarbonate solution, and then extracted with dichloromethane (10 mL * 3), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (0-10% methanol/dichloromethane), and then purified by preparative thick silica gel plate (methanol/dichloromethane = 1/10) to obtain compound I-12 (15 mg, yield: 35.40%).

¹ H NMR (400MHz, MeOD-d4) δ8.43(d,J＝5.2Hz,1H),7.48(dd,J＝17.6,2.4Hz,2H),7.19–7.15(m,2H),7.07(d ,J＝5.2Hz,1H),7.01–6.91(m,2H),5.07(s,2H),4.24(t,J＝4.8Hz,2H),3.91(t,J＝4.8Hz,2H),3.84 –3.71(m,2H),3.52–3.32(m,4H),3.21(ddd,J＝14.0,8.8,2.8Hz,2H),1.65(s,6H).

LCMS [M+H] ⁺ = 556.1

Example 13: Synthesis of Compound I-13:

1-((4-((4-(2-(7-chloro-1-(2-chloroethyl)-1H-indazol-5-yl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)imino)tetrahydro-1H-1λ ⁶ -thiophene-1-oxo

Step 1: Dissolve intermediate I-A3 (300 mg, 0.859 mmol), intermediate I-1-1 (150 mg, 0.920 mmol) and cesium carbonate (560 mg, 1.72 mmol) in acetonitrile (5 mL) and react at room temperature for 3 hours. Concentrate the reaction mixture and separate by column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain product I-13-1 (300 mg, yield: 62%) as a yellow oil.

LCMS [M+1] ⁺ = 474.9

Step 2: Dissolve intermediate I-13-1 (50 mg, 0.105 mmol), intermediate I-B1 (63 mg, 0.525 mmol), cesium carbonate (103 mg, 0.315 mmol) and t-BuXPhos Pd G3 (8 mg, 0.009 mmol) in dioxane (1 mL), and react with microwave at 100 ° C for 1 hour. After the reaction mixture is concentrated, HPLC separation is performed to obtain the product compound I-13 (20 mg, yield: 17%), which is a white solid.

¹ H NMR (400MHz, Chloroform-d) δ8.47 (d, J = 4.0Hz, 1H), 7.98 (s, 1H), 7.55 (s, 1H), 7.15-7.12 (m, 3H), 7.07 (d ,J＝4.0Hz,1H),6.87-6.83(m,2H),5.05-5.02(m,4H),3.92(t,J＝8.0Hz,2H),3.73-3.66(m,2H),3.44- 3.38(m,2H),2.39-2.26(m,4H),1.69(s,6H).

LCMS [M+1] ⁺ = 558.2

Example 14: Synthesis of Compound I-14:

1-((4-((4-(2-(7-chloro-2-(2-chloroethyl)-2H-indazol-5-yl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)imino)tetrahydro-1H-1λ ⁶ -thiophene-1-oxo

Referring to the synthesis steps of compound I-13, intermediate I-A5 was used instead of intermediate I-A3 to synthesize compound I-14 in two steps.

¹ H NMR (400MHz, Chloroform-d) δ8.47 (d, J = 4.0Hz, 1H), 8.03 (s, 1H), 7.52 (s, 1H), 7.16-7.12 (m, 2H), 7.06 (d ,J＝8.0Hz,1H),7.04(s,1H),6.86-6.83(m,2H),5.05(s,2H),4.74(t,J＝8.0Hz,2H),4.04(t,J＝ 8.0Hz,2H),3.73-3.66(m,2H),3.44-3.37(m,2H),2.39-2.23(m,4H),1.67(s,6H).

LCMS [M+1] ⁺ = 558.2

Example 15: Synthesis of Compound I-15:

1-(2-Chloroethyl)-5-(2-(4-((2-((1-oxotetrahydro-1λ ⁶ -thiophen-1-ylidene)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-1H-indazole-7-carbonitrile

Referring to the synthesis steps of compound I-13, intermediate I-A10 was used instead of intermediate I-A3 to synthesize compound I-15 in two steps.

¹ H NMR (400MHz, Chloroform-d) δ8.52–8.41(m,1H),8.07(s,1H),7.94–7.85(m,1H),7.60–7.51(m,1H),7.15–7.07( m,2H),7.07–6.99(m,1H),6.85(d,J＝9.9Hz,2H),5.04(s,2H),5.00(t,J＝6.1Hz,2H),4.05–3.95(m ,2H),3.71-3.64(m,2H),3.42-3.35(m,2H),2.37-2.23(m,4H),1.70(s,6H).

LC-MS [M+1] ⁺ = 549.2

Example 16: Synthesis of Compound I-16:

3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((4-(methylamino)-1-oxotrihydro-2H-1λ ⁶ -thiopyran-1-ylidene)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

Step 1: At 0°C, the intermediate I-11-1 (100 mg, 0.144 mmol) was dissolved in N,N-dimethylacetamide (1 mL), and then sodium hydride (11.55 mg, 0.289 mmol) was added, and stirring was continued for 0.5 hours, and then methyl iodide (0.027 mL, 0.433 mmol) was added, and stirring was continued for 12 hours at room temperature. After the reaction was complete, the reaction solution was extracted with water (20 mL) and ethyl acetate (10 mL*3), and the combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain a yellow oil I-16-1 (80 mg, yield: 78.42%).

LCMS [M+H] ⁺ = 706.1

Step 2: Add dichloromethane (1 mL), intermediate I-16-1 (80 mg, 0.113 mmol) and trifluoroacetic acid (1 mL) to the reaction bottle in sequence and stir at 25°C for 12 hours. After the reaction is complete, concentrate under reduced pressure, adjust the pH to 8 with saturated sodium bicarbonate aqueous solution, and then extract with dichloromethane (10 mL*3), wash the combined organic phase with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure and purify by column chromatography (0-10% methanol/dichloromethane) to obtain white solid compound I-16 (30 mg, yield: 43.98%).

¹ H NMR (400MHz, DMSO-d6) δ8.47-8.42(m,1H),7.54-7.43(m,2H),7.18(dd,J＝8.8,2.0Hz,2H),7.12-7.06(m, 1H)6.95(dd,J＝8.8,4.0Hz,2H),5.07(d,J＝2.4Hz,2H),4.42(t,J＝5.6Hz,2H),4.06(d,J＝14.0Hz,1H ),3.93–3.85(m,2H),3.67–3.37(m,4H),262(s,3H),2.48-2.36(m,2H),2.24-1.99(m,2H),1.66(s,6H) ).

LCMS [M+H] ⁺ = 602.1

Example 17: Synthesis of Compound I-17:

3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((4-((2-hydroxyethyl)amino)-1-oxotrihydro-2H-1λ ⁶ -thiopyran-1-ylidene)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

Referring to the synthesis method of compound I-9, compound I-11 is used instead of compound I-6 to carry out a one-step reaction to obtain compound I-17.

¹ H NMR (400MHz, MEOD-D4) δ8.44 (dd, J＝9.2, 5.2Hz, 1H), 7.58–7.40 (m, 2H), 7.25–7.13 (m, 2H), 7.08 (dd, J＝ 9.2,5.2Hz,1H),7.01–6.90(m,2H),5.07(d,J＝2.0Hz,2H),4.58(s,1H),4.42(t,J＝5.6Hz,2H),4.03( d,J＝14.4Hz,1H),3.96–3.78(m,3H), 3.73(q,J＝7.2,6.4Hz,2H),3.57(t,J＝12.0Hz,1H),3.44(d,J＝12.8Hz,1H),3.17(s,1H),2.93(t,J =5.6Hz,2H),2.37(s,2H),2.24–2.04(m,2H),1.66(s,6H).

LCMS [M+1] ⁺ = 632.1

The following compounds were synthesized according to the above synthesis method or references:

If the final product needs to remove the N-Boc protecting group, the following conditions can be used for removal: 1) 4N HCl/1,4-dioxane/methanol (1/1) solution, room temperature or heating and stirring until the reaction is completed, the reaction solution is concentrated and separated by preparative HPLC to obtain the target product; 2) trifluoroacetic acid/dichloromethane (1/10) solution is reacted at room temperature until the reaction is completed, the reaction solution is concentrated and separated by preparative HPLC to obtain the target product.

Example 19: Synthesis of Compound I-56:

3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((6-((2-hydroxyethyl)amino)-2-((1-oxotetrahydro-1λ ⁶ -thiophen-1-ylidene)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

Step 1: Add an aqueous solution (12.5 mL) of sodium thiomethoxide (1.04 g, 14.78 mmol) to a toluene (75 mL) solution of the intermediate I-56-1 (3 g, 14.49 mmol) and react at room temperature for 12 hours. The reaction solution was extracted with ethyl acetate (20 mL * 2), the organic phases were combined, washed with saturated brine (20 mL * 2), the organic phases were dried over anhydrous sodium sulfate, and dried by column (petroleum ether/ethyl acetate = 8/1) to obtain crude I-56-2 (1.2 g, yield: 37.9%) as a white solid.

LC-MS[M+1] ^- =219.00

Step 2: At room temperature, intermediate I-56-2 (1.2 g, 5.49 mmol) and intermediate I-B1 (687 mg, 5.76 mmol) were dissolved in anhydrous dioxane (10 mL), and then Cs ₂ CO ₃ (4.47 g, 13.72 mmol) and t-BuXPhos Pd G3 (397 mg, 0.5 mmol) were added. After the addition, nitrogen was blown in for protection, and then microwaved at 100 ° C for 1 hour. The reaction solution was filtered. The filtrate was dried and passed through a column (petroleum ether/ethyl acetate = 0/1) to obtain intermediate I-56-3 (800 mg, yield: 48.50%), which was a light orange oily liquid.

LC-MS [M+1] ⁺ = 302.10

Step 3: Dissolve I-56-3 (800 mg, 2.65 mmol) in anhydrous ethanol (10 mL), add sodium borohydride (301.27 mg, 7.96 mmol), stir at room temperature for 4 hours, and then stir at 70°C for 4 hours. Concentrate the reaction solution and perform column chromatography separation (dichloromethane/methanol = 10/1) to obtain the desired product (I-56-4, 700 mg, yield: 96.5%) as an orange oily liquid.

LC-MS [M+1] ⁺ = 274.10

Step 4: Add dichlorothionyl (391.67 mg, 3.29 mmol) to a dichloromethane solution (10 mL) of I-56-4 (300 mg, 1.1 mmol) at 0°C, react for 30 minutes at 0°C, and then react for 30 minutes at room temperature. The reaction mixture is slowly added to a saturated sodium bicarbonate solution and extracted with dichloromethane (10 mL*3). The organic phase is washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated to give a crude product I-56-5 (320 mg, yield: 93.7%) as an orange oily liquid.

LC-MS [M+1] ⁺ = 292.1

Step 5: Add cesium carbonate (1.07 g, 3.3 mmol, 3.0 eq) to an acetonitrile solution (10 mL) of I-56-5 (320 mg, 1.1 mmol) and intermediate I-A1 (384.06 mg, 1.1 mmol, 1.0 eq) at room temperature. The mixed solution was stirred at 40 ° C for 1 hour. The reaction solution was filtered and the filtrate was concentrated to obtain the product I-56-6 (600 mg, yield: 90.4%) as a light yellow oil.

Step 6: Add m-chloroperbenzoic acid (216 mg, 0.94 mmol, 0.95 eq) in dichloromethane (2 mL) dropwise to a dichloromethane solution (6 mL) of I-56-6 (600 mg, 0.99 mmol) at 0°C. The mixed solution was stirred at 0°C for 30 minutes. TLC detection revealed that the reaction was complete. The reaction solution was quenched with saturated sodium bicarbonate solution (10 mL), extracted twice with dichloromethane (20 mL), the mixed organic phase was washed with saturated brine (20 mL), dried and filtered, and the filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 0/1) to obtain the product I-56-7 (500 mg, yield: 81.2%) as a white solid.

¹ H NMR (400MHz, Chloroform-d) δ7.79 (s, 1H), 7.43 (d, J = 2.3Hz, 1H), 7.32 (d, J = 2.3Hz, 1H), 7.14–7.06 (m, 2H ),6.93–6.85(m,2H),5.10(s,2H),4.41(t,J＝6.2Hz,2H),3.86(t,J＝6.2Hz,2H),3.75–3.56(m,2H) ,3.45–3.32(m,2H),2.89(s,3H),2.43–2.19(m,4H),1.63(s,6H).

LC-MS [M+1] ⁺ = 621.30

Step 7: At room temperature, sodium carbonate (143.23 mg, 1.35 mmol) was added to a solution of I-56-7 (60 mg, 0.096 mmol) and 2-aminoethyl-1-hydroxy hydrochloride (47.17 mg, 0.772 mmol) in NMP (3 mL), and then microwaved at 150 ° C for 1 hour. LC-MS detection showed that the reaction was complete. Extracted twice with ethyl acetate (20 mL), the mixed organic phase was washed with saturated brine (20 mL), dried and filtered, and the filtrate was concentrated and prepared by HPLC (TFA) to obtain compound I-56 (4.99 mg, yield: 8.4%) as a white solid.

1H NMR (400MHz, Methanol-d4) δ7.49(d,J＝2.3Hz,1H),7.42(d,J＝2.3Hz,1H), 7.21–7.16(m,2H),6.97–6.91(m, 2H),6.35(s,1H),4.96(d,J＝0.8Hz,2H),4.43–4.35(m,2H),3.90–3.83(m,2H),3.82–3.69(m,4H),3.62 –3.45(m,4H),2.47–2.03(m,4H),1.64(s,6H).

LC-MS [M+1] ⁺ = 618.40

The following compounds were synthesized according to the above synthesis method or references:

If the final product needs to remove the N-Boc protecting group, the following conditions can be used for removal: 1) 4N HCl/1,4-dioxane/methanol (1/1) solution, room temperature or heating and stirring until the reaction is completed, the reaction solution is concentrated and separated by preparative HPLC to obtain the target product; 2) trifluoroacetic acid/dichloromethane (1/10) solution is reacted at room temperature until the reaction is completed, the reaction solution is concentrated and separated by preparative HPLC to obtain the target product.

Example 20: Synthesis of Compound I-66:

1-(2-chloroethyl)-5-(2-(4-((5-fluoro-2-((1-oxotetrahydro-1λ ⁶ -thiophen-1-ylidene)amino)pyrimidin-4-yl)methoxy)phenyl)propyl-2-yl)-1H-indazole-7-cyano

Step 1: Add methylmagnesium bromide in THF (4.20 mL, 4.20 mmol) to a solution of I-66-1 (500 mg, 2.99 mmol), Fe(acac) ₂ (211 mg, 0.60 mmol) and NMP (356 mg, 3.60 mmol) in THF (17 mL) at -78 °C. The mixture was stirred at -78 °C for 2 hours. The reaction was complete by TLC. The reaction solution was quenched with water (30 mL), extracted with ethyl acetate (30 mL*3), the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain the desired product I-66-2 (400 mg, yield: 92%) as a light yellow solid.

LC-MS [M+1] ⁺ = 147.0

Step 2: Add selenium dioxide (3.0 g, 27.3 mmol) to a solution of I-66-2 (1.0 g, 6.82 mmol) in dioxane (20 mL) at room temperature. The mixed solution was stirred at 108 ° C for 36 hours. LCMS detection showed that the reaction was complete. The reaction solution was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain the product I-66-3 (410 mg, yield: 37%) as a brown oil.

LC-MS[M+1] ⁺ ＝161.00

Step 3: Sodium acetate borohydride (1.6 g, 7.48 mmol) was added to a methanol (20 mL) solution of I-66-3 (400 mg, 2.49 mmol) at room temperature. The mixed solution was stirred at 25 ° C for 2 hours. LCMS detection showed that the reaction was complete. The reaction solution was quenched with water (30 mL), extracted with ethyl acetate (30 mL*3), and the combined organic phase was washed with saturated brine (30 mL) and dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain the desired product I-66-4 (200 mg, yield: 49%) as a colorless oil.

LC-MS [M+1] ⁺ = 163.10

Step 4: Add MsCl (86 mg, 0.74 mmol) dropwise to a solution of I-66-4 (100 mg, 0.62 mmol) and triethylamine (125 mg, 1.23 mmol) in dichloromethane (5 mL) at 0°C. Stir the mixture at 0°C to room temperature for 2 hours. TLC indicates that the reaction is complete. The reaction solution is concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain the product I-66-5 (80 mg, yield: 38%) as a brown oil.

LC-MS [M+1] ⁺ = 240.90

Step 5: Add cesium carbonate (76 mg, 0.23 mmol) to a solution of I-66-5 (80 mg, 0.23 mmol) and intermediate I-A10 (79 mg, 0.23 mmol) in acetonitrile (3 mL) at room temperature. The above mixture was stirred at room temperature for 2 hours. TLC detected that the reaction was complete. The reaction solution was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain the product I-66-6 (75 mg, yield: 66%) as a colorless oil.

LC-MS [M+1] ⁺ = 484.30

Step 6: Add t-Buxphos Pd G3 (8 mg, 0.014 mmol) to a solution of I-66-6 (70 mg, 0.14 mmol), intermediate I-B1 (24 mg, 0.20 mmol) and cesium carbonate (47 mg, 0.14 mmol) in dioxane (3 mL) at room temperature. The mixed solution was replaced with nitrogen three times and stirred at 100 ° C for 1 hour using a microwave. LCMS detection showed that the reaction was complete. The reaction solution was concentrated and prepared by HPLC to obtain compound I-66 (10 mg, yield: 12%) as a white solid.

¹ H NMR (400MHz, Chloroform-d) δ8.35 (s, 2H), 8.09 (s, 1H), 7.89 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.13–7.09(m,2H), 6.92–6.88(m,2H), 5.15(s,2H), 5.02(t,J＝6.0Hz,2H)4.01(t,J＝6.0Hz,2H)3.65–3.58 (m,2H), 3.36–3.29(m,2H), 2.36–2.20(m,4H), 1.71(s,6H).

LC-MS [M+1] ⁺ = 567.50

The following compounds were synthesized according to the above synthesis method or references:

Example 21: Synthesis of Compound 187:

((4-((4-(2-(1-(2-chloroethyl)-7-methyl-1H-indazol-5-yl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)imino)dimethyl-λ ⁶ -sulfinyl

Step 1: A34 (200 mg, 608.21 μmol) was dissolved in acetonitrile (10 mL), and I-1-1 (297.42 mg, 1.82 mmol) and cesium carbonate (296.50 mg, 912.31 μmol) were added, and the mixture was reacted at 25°C for 6 hours. The reaction solution was poured into 10 mL of water, extracted twice with ethyl acetate (20 mL*2), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was subjected to column chromatography (petroleum ether/tetrahydrofuran = 3/1) to obtain compound 187-1 (250 mg, yield: 63.32%) as a colorless oil.

LC-MS [M+1] ⁺ = 455.30

Step 2: 187-1 (240 mg, 528.18 μmol) was dissolved in 1,4-dioxane (5.0 mL), cesium carbonate (120.16 mg, 369.73 μmol), t-BuxphosPdG3 (41.94 mg, 52.82 μmol), dimethylsulfenyl imide (147.60 mg, 1.58 mmol) were added, nitrogen was replaced, and microwave reaction was performed at 100°C for 1 hour. The crude product was concentrated to obtain a crude product, 2 mL of acetonitrile was added to the crude product, filtered, purified by Prep-HPLC (250*20.0 mml. DS-5 μm, 12 nm. ACN/H ₂ O (0.05% FA) = 0% to 95%) and freeze-dried to obtain the product 187 (120.0 mg, yield: 43.20%), which was freeze-dried to a light yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.41(s,1H),8.02(s,1H),7.46(s,1H),7.24–7.05(m,2H),6.90(s,1H), 6.86(d,J＝11.3Hz,3H),4.98(s,2H),4.78(s,2H),4.01(s,2H),3.35(s,6H),2.56(s,3H),1.61(s ,6H).

LC-MS [M+1] ⁺ = 512.30

Example 22: Synthesis of Compound 188:

((4-((4-(2-(1-(2-chloroethyl)-7-fluoro-1H-indazol-5-yl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)imino)dimethyl-λ ⁶ -sulfinyl

Step 1: A35 (200 mg, 600.96 μmol) was dissolved in acetonitrile (5 mL), and I-1-1 (200 mg, 600.96 μmol) and cesium carbonate (292.97 mg, 901.45 μmol) were added, and the mixture was reacted at 15 °C for 5 hours. The reaction solution was poured into 10 mL of water, extracted twice with ethyl acetate (20 mL*2), and the organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was subjected to column chromatography (petroleum ether/tetrahydrofuran = 3/1) to obtain compound 188-1 (130 mg, yield: 33.91%), which was a colorless oil.

LC-MS [M+1] ⁺ = 459.30

Step 2: Dissolve 188-1 (100 mg, 217.70 μmol) in 1,4-dioxane (5 mL), add dimethylsulfenyl imide (60.84 mg, 653.11 μmol), cesium carbonate (70.75 mg, 217.70 μmol), t-BuxphosPdG3 (17.29 mg, 21.77 μmol), replace with nitrogen, and react at 100°C for 1 hour by microwave. Concentrate to obtain a crude product, add 2 mL of acetonitrile to the crude product, filter, purify by Prep-HPLC (250*20.0 mml. DS-5 μm, 12 nm. ACN/H ₂ O (0.05% FA) = 0% to 95%) and freeze-dry to obtain product 188 (40.00 mg, yield: 34.89%), which is freeze-dried to a light yellow solid.

¹ H NMR (400MHz, Acetonitrile-d ₃ ) δ8.37(s,1H),8.00(s,1H),7.50(s,1H),7.15(s,2H),6.92(s,1H),6.84( d,J＝13.3Hz,2H),4.98(s,2H),4.73(d,J＝5.8Hz,2H),3.97(d,J＝6.5Hz,2H),3.28(s,6H),1.66( s,6H).

LC-MS [M+1] ⁺ = 516.10

The following compounds were synthesized according to the above synthesis method or references:

Example 23: Synthesis of Compound I-73:

1-(5-chloro-7-(2-(4-((2-((1-1-oxotetrahydro-1λ ⁶ -thiophen-1-ylidene)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propyl-2-en-1-one

Step 1: Add triphosgene (14.63 g, 49.29 mmol) in dichloromethane (50 mL) to I-73-1 (30 g, 197.18 mmol) and pyridine (93.58 g, 1183 mmol) at 0°C. The reaction solution was reacted at 0-25°C for 2 hours. The reaction solution was slowly poured into a mixture of saturated aqueous ammonium chloride solution (200 mL) and water (400 mL), extracted with DCM (200 mL*2), and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain an oily liquid, which was added to petroleum ether (200 mL) to precipitate a white solid. The product I-73-2 (33 g, yield: 50.7%) was obtained by filtration as a white solid.

LC-MS[M+23] ⁺ ＝353.20

Step 2: At room temperature, add I-73-2 (33 g, 99.91 mmol) in THF (350 mL) dropwise to a solution of I-73-3 (19.99 g, 99.91 mmol) in THF (50 mL). The reaction solution was stirred at room temperature for 16 hours. The reaction solution was spin-dried, and petroleum ether (200 mL) was slowly added, stirred for 10 minutes, and then filtered. The filter cake was dried to obtain the desired product (I-73-4, 35 g, yield: 86.14%) as a white solid.

LC-MS[M+1] ⁺ ＝400.30

Step 3: TfOH (121.42 g, 809.06 mmol) was added dropwise to DCM (200 mL) of I-73-4 (34.0 g, 89.90 mmol) under nitrogen protection at 0°C, and the mixture was reacted at room temperature for 1 hour. The reaction solution was poured into ice water and extracted with dichloromethane (200 mL*3). The organic phase was washed with saturated brine (200 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography (dichloromethane/ethyl acetate = 1/1) to obtain the desired product I-73-5 (14.5 g, yield: 71.35%) as a white solid.

LC-MS [M+1] ⁺ = 226.10

Step 4: n-BuLi (2.55 g, 39.81 mmol, 16 mL) was added dropwise to a solution of I-73-5 (3.0 g, 13.27 mmol) in tetrahydrofuran (40 mL) at -78 °C, the reaction solution was stirred at -78 °C for 1 hour, then dry ice (1.75 g, 39.81 mmol) was added, slowly warmed to room temperature, and reacted for 4 hours. Water (100 mL) was added to quench, extracted with ethyl acetate (30 mL*3), the aqueous phase was adjusted to pH 4 with 0.5 N HCl, a large amount of solid was produced, filtered, and the filter cake was freeze-dried to obtain the desired product I-73-6 (1.2 g, yield: 47.30%) as a white solid.

LC-MS [M+1]+＝192.00

Step 5: Add I-73-7 (4.95 g, 25.11 mmol) to a solution of I-73-6 (1.2 g, 6.28 mmol) in TfOH (10 mL). The mixture was stirred at 80 ° C for 12 hours. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (20 mL * 3), the combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated and separated by column chromatography (dichloromethane/methanol = 10/1) to obtain the desired product I-73-8 (1.10 g, yield: 35.73%) as a white solid.

LC-MS [M+1]+＝225.90

Step 6: Add SOCl ₂ (1.16 g, 9.75 mmol) to a methanol solution (10 mL) of I-73-8 (1.1 g, 4.88 mmol) at room temperature. Stir the reaction solution at 80°C for 2 hours. The reaction solution is directly concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain the product I-73-9 (600 mg, yield: 41.08%) as a white solid.

LC-MS[M+1] ⁺ ＝240.00

Step 7: At room temperature, MeMgBr (746.32 mg, 6.26 mmol) was added dropwise to a THF (10 mL) solution of I-73-9 (500 mg, 2.09 mmol), and the mixture was reacted at 60 ° C for 3 hours. LCMS showed that the reaction was complete. The reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (10 mL) at 0 ° C, extracted with ethyl acetate (15 mL * 3), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain the desired product (I-73-10, 400 mg, yield: 79.99%) as a white solid.

LC-MS [M+1] ⁺ = 240.10

Step 8: At room temperature, I-73-10 (250 mg, 1.04 mmol) and phenol (294.47 mg, 3.13 mmol) were dissolved in DCM (3 mL), and BF ₃ (282.90 mg, 4.17 mmol) was added dropwise at -78 °C under nitrogen protection. After the addition, the temperature was naturally raised to room temperature 25 °C for 12 hours. LCMS showed that the reaction was complete. The reaction solution was poured into water (20 mL) and extracted with dichloromethane (10 mL*3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain the desired product (I-73-11, 180 mg, yield: 54.65%) as a colorless oil.

LC-MS [M+1] ⁺ = 316.30

Step 9: At room temperature, I-73-11 (180 mg, 0.57 mmol) was dissolved in THF (2 mL), BH ₃ (39.42 mg, 2.85 mmol) was added, and the mixture was reacted at 60° C. for 12 hours. The reaction solution was concentrated to obtain a crude product (I-73-12, 170 mg, yield: 98.8%) as a white solid.

LC-MS [M+1] ⁺ = 302.30

Step 10: I-73-12 (160 mg, 0.53 mmol) was dissolved in HCl/MeOH (4 mL) at room temperature, stirred at room temperature for 5 minutes, dried by rotation, and then dissolved in DCM (8 mL), and then triethylamine (160.59 mg, 1.59 mmol) and Boc ₂ O (347.10 mg, 1.59 mmol) were added, and the mixture was reacted at 25° C. for 12 hours. The reaction solution was concentrated and passed through a column (petroleum ether/ethyl acetate = 5/1) to obtain the product (I-73-13, 55 mg, yield: 25.8%) as a colorless oil.

LC-MS[M-56+1] ⁺ =346.30

Step 11: At room temperature, I-73-16 (4.0 g, 23.18 mmol) was dissolved in dioxane (20 mL), and then intermediate I-B1 (2.76 g, 23.18 mmol), Cs ₂ CO ₃ (15.10 g, 46.36 mmol) and t-BuXPhos Pd G3 (1.84 g, 2.32 mmol) were added, and the mixture was heated to 80°C under nitrogen protection for 2.5 hours. The reaction solution was concentrated, filtered, and the filter cake was washed with ethyl acetate and passed through a column to obtain the product (I-73-17, 3.10 g, yield: 41.94%) as a yellow solid.

LC-MS [M+1] ⁺ = 256.10

Step 12: At room temperature, I-73-17 (3.0 g, 11.75 mmol) was dissolved in THF (15 mL) and EtOH (15 mL), then cooled to 0°C, and NaBH _{4 (666.82 mg, 17.63 mmol) was added in batches, and then reacted at 0°C for 0.5 hours. Then NaBH 4 (} 666.82 mg, 17.63 mmol) was added and reacted at 0°C for 0.5 hours. TLC (EA/MeOH=10/1) showed that the raw material was basically reacted, and water (3 mL) was added, and then anhydrous magnesium sulfate was added to dry, filtered, and concentrated. The product (I-73-18, 1.47 g, yield: 50.64%) was obtained by column (DCM/MeOH=10/1) as a yellow oily solid.

LC-MS [M+1] ⁺ = 228.60

Step 13: At room temperature, I-73-18 (300.0 mg, 1.32 mmol) and DIEA (667.82 mg, 6.60 mmol) were dissolved in DCM (5 mL), and methanesulfonyl chloride (302.40 mg, 2.64 mmol) was added at 0°C, and then reacted at 0°C for 1 hour. The reaction solution was directly spin-dried and TLC (petroleum ether/ethyl acetate = 10/1) was used to obtain the product (I-73-19, 310.00 mg, yield: 69.22%) as a light orange oil.

LC-MS [M+1] ⁺ = 306.8

Step 14: At room temperature, I-73-13 (50.0 mg, 0.124 mmol) was dissolved in ACN (2 mL), and then Cs ₂ CO ₃ (40.43 mg, 0.124 mmol) and I-73-19 (151.96 mg, 0.498 mmol) were added and reacted at room temperature for 12 hours. The reaction solution was directly spin-dried and passed through a column (petroleum ether/ethyl acetate = 0-100%) to obtain the product (I-73-14, 45.00 mg, yield: 53.27%) as a colorless oil.

LC-MS [M+2] ⁺ = 611.70

Step 15: At room temperature, I-73-14 (45.0 mg, 0.073 mmol) was dissolved in DCM (2.5 mL), and then TFA (0.5 mL) was added and reacted at room temperature for 0.5 hours. The reaction solution was adjusted to pH 7 with saturated sodium bicarbonate, and then extracted with dichloromethane (10 mL*2), washed with saturated brine, and the organic phase was dried over sodium sulfate and spin-dried to obtain the target product (I-73-15, 24.00 mg, yield: 63.8%) as a colorless oil.

LC-MS [M+2] ⁺ = 512.50

Step 16: At room temperature, I-73-15 (24.0 mg, 0.047 mmol) was dissolved in DCM (3 mL), and then DIEA (18.21 mg, 0.141 mmol) and I-73-20 (17.77 mg, 0.141 mmol) were added at 0°C and reacted for 0.5 hours. The reaction solution was extracted with dichloromethane (10 mL*2), washed with saturated brine, and the organic phase was dried with sodium sulfate, spin-dried, dissolved in methanol and DMF, and prepared by HPLC to obtain the product compound I-73 (3.00 mg, yield: 11.3%) as a white solid.

1H NMR(400MHz, Acetonitrile-d3)δ8.38(d,J＝5.1Hz,1H),7.16–7.11(m,2H),7.03(m,2H),6.94(d,J＝5.1Hz,1H) ,6.89–6.85(m,2H),6.80–6.63(m,1H),6.14(dd,J＝15.6,2.0Hz,1H),,5.6 5(dd,J＝10.3,1.9Hz,1H),4.99(s,2H),4.64(s,2H),3.78(t,J＝6.1Hz,2H),3.59–3.49(m,2H),3.27 –3.20(m,2H),2.86–2.74(m,2H),2.30–2.19(m,2H),2.11–2.09(m,2H),1.59(s,6H).

LC-MS [M+1] ⁺ = 565.50

Example 24: Synthesis of Compound I-74:

4-Acryloyl-7-(2-(4-((2-((1-oxotetrahydro-1λ ⁶ -thiophen-1-ylidene)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-cyano

Step 1: I-74-1 (5.0 g, 29.91 mmol) was dissolved in DCM (100 mL) and DMF (10 mL), and NBS (6.92 g, 38.88 mmol) was added in batches at 0°C. The reaction solution was stirred at 30°C for 2 hours, and H ₂ O (50 mL) was added. The aqueous layer was extracted three times with DCM (100 mL), and the organic phases were combined, dried, concentrated, and purified by SGC (petroleum ether/ethyl acetate = 3/1) to obtain the desired product (I-74-2, 2.50 g, 8.10 mmol, yield: 27.09%) as a brown solid.

LC-MS [M+1] ⁺ = 245.9

Step 2: Dissolve I-74-2 (2.3 g, 9.35 mmol) and K ₂ CO ₃ (6.45 g, 46.74 mmol) in DMF (140 mL), add 1,2-dibromoethane (4.39 g, 23.37 mmol). The reaction solution was stirred at 80°C for 18 hours, concentrated, and purified by column (petroleum ether/ethyl acetate = 5/1) to obtain the desired product (I-74-3, 1.10 g, 3.84 mmol, yield: 41.09%) as a light yellow solid.

LC-MS [M+1] ⁺ = 272.0

Step 3: Dissolve I-74-3 (200 mg, 916.56 μmol), DMAP (55.99 mg, 458.28 μmol) and DIEA (278.24 mg, 2.75 mmol, 383.51 μL) in dioxane (5 mL), add (Boc) ₂ O (400.08 mg, 1.83 mmol), stir the reaction solution at 30 ° C for 18 hours, concentrate, and purify by preparative TLC (petroleum ether/ethyl acetate = 5/1) to obtain the desired product (I-74-4, 150.00 mg, 447.66 μmol, yield: 48.84%) as a white solid.

LC-MS [M+1] ⁺ = 319.1

Step 4: At 30°C, a solution of I-74-4 (40 mg, 125.66 μmol) in THF (1 mL) was added dropwise to MeMgBr (1 M, 2.01 mL). The reaction solution was reacted at 30°C for 1 hour. TLC detected that all the raw materials had reacted. After quenching with saturated NH ₄ Cl solution (5 mL) at 0°C, it was extracted twice with ethyl acetate (20 mL). The organic phases were combined, dried, and concentrated to obtain the desired product (I-74-5, 40.00 mg, 125.64 μmol, yield: 99.99%) as a white solid.

LC-MS[M+1] ⁺ ＝,319.20

Step 5: I-74-5 (40 mg, 125.64 μmol) and phenol (23.65 mg, 251.28 μmol) were dissolved in anhydrous DCM (1 mL), and BF ₃ ·Et ₂ O (53.50 mg, 376.92 μmol) was added at -78°C. The reaction solution was naturally warmed to 0°C and stirred for 3 hours; at 0°C, it was quenched with saturated NaHCO ₃ (5 mL), extracted three times with DCM (20 mL), the organic phases were combined and concentrated, and then preparative TLC (petroleum ether/ethyl acetate = 3/1) was used to obtain the desired product (I-74-6, 15.00 mg, 48.41 μmol, yield: 38.53%) as a white solid.

LC-MS [M+1] ⁺ = 295.1

Step six: I-74-6 (35 mg, 118.91 μmol) and I-73-19 (145.24 mg, 475.63 μmol) were dissolved in ACN (1 mL) and DMF (0.3 mL), and Cs ₂ CO ₃ (232.58 mg, 713.44 μmol) was added; the reaction solution was reacted at 45°C for 18 hours, and H ₂ O (15 mL) was added. The aqueous phase was extracted three times with ethyl acetate (30 mL), and the organic phases were combined and concentrated, and purified by preparative TLC (petroleum ether/ethyl acetate = 0:1) to obtain the desired product (I-74-7, 45.00 mg, 60.76 μmol, yield: 51.10%) as a white solid.

LC-MS [M+1] ⁺ = 504.2

Step 7: I-74-7 (40 mg, 79.43 μmol), DMAP (1.94 mg, 15.89 μmol) and DIEA (102.65 mg, 794.26 μmol) were dissolved in DCM (1 mL), and acrylic anhydride I-73-20 (20.03 mg, 158.85 μmol) was added at 0°C. The reaction solution was reacted at 30°C for 18 hours, quenched with MeOH (2 mL), and H ₂ O (10 mL) was added. The mixed solution was extracted three times with ethyl acetate (30 mL), and the organic phases were combined, concentrated, and purified by preparative HPLC to obtain compound I-74 (1.61 mg, 2.89 μmol, yield: 3.63%) as a white solid.

¹ H NMR (400MHz, MeCN-d6) δ8.38 (d, J = 4.8Hz, 1H), 7.16-7.13 (m, 3H), 6.97-6.87 (m, 4H), 6.35-6.30 (m, 2H) ,5.82(d,J＝10.8Hz,1H),5.00(s,2H),4.25(s,2H),3.58-3.51(m,2H),3.28-3.17(m,4H),2.16-2.07(m ,4H),1.60(s,6H).

LC-MS [M+1] ⁺ = 558.4

The following compounds were synthesized according to the above synthesis method or references:

Example 25: Synthesis of Compound I-77:

1-(2-chloroethyl)-5-(2-(4-((2-((1-oxotetrahydro-1λ ⁶ -thiophen-1-ylidene)amino)pyrimidin-4-yl)oxy)phenyl)propan-2-yl)-1H-indazole-7-cyano

Step 1: Add cesium carbonate (57.53 mg, 0.17 mmol, 1.0 eq) to a DMF solution (2 mL) of intermediate I-A10 (60 mg, 0.17 mmol) and 2,4-dichloropyrimidine (26.3 mg, 0.17 mmol, 1.0 eq) at room temperature. The mixed solution was stirred at 50°C for 1 hour. LCMS detection showed that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain the product I-77-1 (70 mg, yield: 87.6%), which was a colorless liquid.

LC-MS [M+1] ⁺ = 452.2

Step 2: At room temperature, I-77-1 (70.0 mg, 0.155 mmol) and intermediate I-B1 (18.44 mg, 0.155 mmol) were dissolved in anhydrous dioxane (2 mL), and then Cs ₂ CO ₃ (50.42 mg, 0.155 mmol) and t-BuXPhos Pd G3 (12.3 mg, 0.016 mmol) were added. After the addition, nitrogen was blown in for protection, and then microwaves were used at 100°C for 1 hour. LCMS detected the MS of the target product. The reaction mixture was dried and then prepared by HPLC to obtain compound I-77 (23.92 mg, yield: 29.0%) as a white solid.

1H NMR (400MHz, MeOD-d4) δ8.25(d,J＝5.8Hz,1H),8.21(s,1H),8.11(d,J＝1.8Hz,1H),7.66(d,J＝1.8Hz ,1H),7.33-7.31(m,2H),7.10–7.06(m,2H),6.52(d,J＝5.8Hz,1H),5.05(t,J＝6.1Hz,2H),4.03(t, J＝5.9Hz,2H),3.47–3.35(m,2H),2.97–2.81(m,2H),2.17–1.97(m,4H),1.76(s,6H).

LC-MS [M+1] ⁺ = 535.40

Example 26: Synthesis of Compound I-78:

1-(2-chloroethyl)-5-(2-(4-((5-((1-oxotetrahydro-1λ ⁶ -thiophen-1-ylidene)amino)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)-1H-indazole-7-cyano

Step 1: Add cesium carbonate (69 mg, 0.21 mmol) to a DMF (1.5 mL) solution of intermediate I-A10 (60 mg, 0.18 mmol) and 2-chloro-5-bromopyrimidine (41 mg, 0.21 mmol) at room temperature. The mixed solution was stirred at 50 ° C for 1 hour. LCMS detection showed that the reaction was complete. The reaction solution was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain the product (I-78-1, 70 mg, yield: 79.8%) as a colorless oil.

LC-MS [M+1] ⁺ = 496.20

Step 2: Add t-Buxphos Pd G3 (11 mg, 0.014 mmol) to a solution of I-78-1 (70 mg, 0.14 mmol), intermediate I-B1 (24 mg, 0.20 mmol) and cesium carbonate (55 mg, 0.17 mmol) in dioxane (2 mL) at room temperature. The mixed solution was replaced with nitrogen three times and stirred at 100 ° C for 1 hour using a microwave. LCMS detection showed that the reaction was complete. The reaction solution was concentrated and then prepared by HPLC to obtain compound I-78 (10 mg, yield: 13%) as a white solid.

¹ H NMR (400MHz, Chloroform-d) δ8.31 (s, 2H), 8.10 (s, 1H), 7.92 (d, J = 2.0Hz, 1H), 7.65 (d, J = 1.6Hz, 1H), 7.24–7.22(m,2H),7.14–7.10(m,2H),5.03(t,J＝6.0Hz,2H),4.01(t,J＝6.0Hz,2H),3.39–3.32(m,2H) ,3.22–3.15(m,2H),2.38–2.25(m,4H),1.76(s,6H).

LC-MS [M+1]+＝535.3

The following compounds were synthesized according to the above synthesis method or references:

Example 27: Synthesis of Compound I-79:

1-((4-((4-(2-(1-(2-chloroethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)imino)-4-(prop-2-yn-1-yl)-1λ ⁶ -thiomorpholine-1-oxo

Step 1: Add I-A22 (0.35 g, 1.11 mmol), I-1-1 (361.32 mg, 2.22 mmol) and Cs ₂ CO ₃ (541.66 mg, 1.66 mmol) to ACN (3.5 mL) and stir at 40°C for 4 hours. The product was detected by LC-MS. The reaction solution was separated by column chromatography (petroleum ether/tetrahydrofuran = 4/1) to obtain the desired product I-79-1 (340.00 mg, yield: 67.97%) as a light yellow oil.

¹ H NMR (400MHz, DMSO-d6) δ8.75 (d, J = 5.1Hz, 1H), 8.30 (d, J = 2.3Hz, 1H), 8.11 (s, 1H), 8.09 (d, J = 2.2 Hz,1H),7.59(d,J＝5.1Hz,1H),7.16(d,J＝9.0Hz,2H),6.93(d,J＝9.0Hz,2H),5.17(s,2H),4.69( d,J＝5.9Hz,2H),4.07(t,J＝5.8Hz,2H),1.68(s,6H).

LC-MS [M+1] ⁺ = 442.1

Step 2: Compound I-79-1 (0.3 g, 678.21 μmol), I-B5 (206.59 mg, 881.67 μmol), Cs ₂ CO ₃ (220.97 mg, 678.21 μmol) and t-BuXphos Pd G ₃ (53.85 mg, 67.82 μmol) were added to a solvent dioxane (15 mL), replaced with nitrogen, and microwaved at 90° C. for 1 hour. LC-MS detection showed that the reaction was complete, and column chromatography separation (petroleum ether/tetrahydrofuran = 9/1) gave compound I-79-2 (220.00 mg, yield: 34.46%) as a yellow oil.

LC-MS [M+1] ⁺ = 640.6

Step 3: Dissolve I-79-2 (0.2 g, 312.41 μmol) in DCM (6 mL) at room temperature, then add TFA (1.5 mL). Stir at room temperature for 5 hours, adjust the pH of the reaction solution to neutral with sodium bicarbonate solution, extract with dichloromethane (20 mL*3), wash with saturated brine, dry with anhydrous sodium sulfate, and evaporate the solvent to obtain intermediate I-79-3 (150 mg, crude product) as a yellow oil.

LC-MS [M+1] ⁺ = 540.40

Step 4: I-79-3 (80 mg, 148.13 μmol), 3-bromoacetylene (52.86 mg, 444.38 μmol) and K ₂ CO ₃ (102.36 mg, 740.63 μmol) were added to acetonitrile (8 mL) and stirred at room temperature for 12 hours. LC-MS detection showed that the reaction was complete, and the reaction solution was concentrated, filtered, and prepared by HPLC to obtain compound I-79 (10.12 mg, yield: 11.11%) as a light yellow solid.

¹ H NMR (400MHz, Acetonitrile-d3) δ8.37(d,J＝5.1Hz,1H),8.30(d,J＝2.2Hz,1H),8.06(d,J＝2.3Hz,1H),7.99( s,1H),7.17(d,J＝9.0Hz,2H),6.94(d,J＝5.1Hz,1H),6.88(d,J＝9.0Hz,2H),4. 99(s,2H),4.72(t,J＝5.9Hz,2H),4.05(t,J＝5.9Hz,2H),3.71–3.62(m,2H),3.46–3.38(m,4H),3.04 –2.96(m,2H),2.91(ddd,J＝12.2,8.4,3.2Hz,2H),2.53(t,J＝2.4Hz,1H),1.71(s,6H).

LC-MS [M+1] ⁺ = 578.20

According to the above synthesis method of compound I-79, the following compounds were synthesized respectively:

Example 30: Synthesis of Compound I-103:

1-(2-chloroethyl)-5-(2-(4-((2-((1-oxo-λ ⁶ -sulfoxide)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-1H-indazole-7-cyano

To a solution of I-15-1 (60 mg, 0.128 mmol), I-B2 (27.06 mg, 0.257 mmol) and cesium carbonate (41.92 mg, 0.128 mmol) in dioxane (2 mL) was added t-Buxphos Pd G3 (10.18 mg, 0.013 mmol) at room temperature. The mixed solution was replaced with nitrogen three times and stirred at 100 ° C for 1 hour using microwaves. The reaction solution was concentrated and then prepared by HPLC to obtain compound I-103 (14.16 mg, yield: 20.6%) as a white solid.

¹ H NMR (400MHz, Methanol-d4) δ8.42(d,J＝5.2Hz,1H),8.16(s,1H),8.03(d,J＝1.7Hz,1H),7.58(d,J＝1.7 Hz,1H),7.23–7.12(m,2H),7.06(d,J＝5.2Hz,1H),6.90(d,J＝6.7Hz,2H),5.03(s,2H),4.98(t,J ＝5.9Hz,2H),4.41–4.27(m,4H),4.01(t,J＝5.9Hz,2H),2.45–2.26(m,2H),1.71(s,6H).

LC-MS [M+1] ⁺ = 535.3

Example 31: Synthesis of Compound I-104:

2-(2-Chloroethoxy)-3-fluoro-5-(2-(4-((2-((1-oxo-λ ⁶ -sulfoxide)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

Step 1: Add cesium carbonate (146.05 mg, 0.449 mmol, 1.0 eq) to an ACN solution (2 mL) of intermediate I-A24 (150 mg, 0.449 mmol) and intermediate I-1-1 (73.25 mg, 0.449 mmol, 1.0 eq) at room temperature. The mixed solution was stirred at 40 ° C for 1 hour. The reaction solution was filtered, and the filtrate was concentrated and separated by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain I-104-1 (120 mg, yield: 52.21%) as a colorless liquid.

LC-MS [M+1]+＝460.20

Step 2: Dissolve I-104-1 (120.0 mg, 0.261 mmol) and intermediate I-B1 (31.07 mg, 0.261 mmol) in anhydrous dioxane (2 mL) at room temperature, then add Cs ₂ CO ₃ (84.72 mg, 0.261 mmol) and t-BuXPhos Pd G3 (20.70 mg, 0.026 mmol). After the addition, blow in nitrogen for protection, then use microwave at 100°C for 1 hour. The reaction mixture is spin-dried and then prepared by preparative HPLC to obtain compound I-104 (14.74 mg, yield: 10.2%) as a white solid.

¹ H NMR (400MHz, Methanol-d4) δ8.41 (d, J＝5.2Hz, 1H), 7.34–7.21 (m, 2H), 7.21–7.10 (m, 2H), 7.03 (s, 1H), 6.99 –6.85(m,2H),5.04(s,2H),4.53–4.39(m,2H),3.96–3.76(m,2H),3.63(m,2H),3.36(m,2H),2.36–2.14 (m,4H),1.62(s,6H).

LC-MS [M+1]+＝544.50

Example 33: Synthesis of Compound I-18:

3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((1-oxido-1λ ⁶ -thiomorpholin-1-ylidene)amino)pyrimidin-5-yl)ethynyl)phenyl)propan-2-yl)benzonitrile

Step 1: Under nitrogen protection, anhydrous tetrahydrofuran (2 mL), intermediate I-A2 (50 mg, 0.140 mmol), intermediate I-18-1 (33.66 mg, 0.140 mmol), triethylamine (0.039 mL, 0.280 mmol), ditriphenylphosphine palladium dichloride (9.83 mg, 0.014 mmol) and cuprous iodide (5.32 mg, 0.028 mmol) were added to the reaction bottle in sequence, and the reaction solution was stirred at 25 ° C for 6 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (0-20% ethyl acetate/petroleum ether) to obtain a yellow solid I-18-2 (55 mg, yield: 83.71%).

LCMS [M+H] ⁺ = 470.1

Step 2 and 3: Referring to the synthesis method of compound I-6, use intermediate I-18-2 instead of intermediate I-1-2 to carry out two-step reaction to obtain compound I-18.

¹ H NMR (400MHz, Chloroform-d) δ8.70-8.55 (m, 2H), 7.46 (d, J = 8.4Hz, 2H), 7.42 (d, J = 2.4Hz, 1H), 7.33 (d, J ＝2.4Hz,1H),7.17(d,J＝8.4Hz,2H),4.43(t,J＝6.0Hz,2H),3.88(t,J＝6.0Hz,2H),3.67-3.41(m,8H ),1.67(s,6H).

LCMS [M+H] ⁺ = 568.1

Example 34: Synthesis of Compound I-19:

3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((1-oxytrihydro-1λ ⁶ -thiophen-1-ylidene)amino)pyrimidin-4-yl)ethynyl)phenyl)propan-2-yl)benzonitrile

Referring to the synthesis method of compound I-18, intermediate I-19-1 is used instead of intermediate I-18-1, and intermediate I-B1 is used instead of intermediate I-B5, and a two-step reaction is carried out to obtain compound I-19.

1H NMR(400MHz,MeOD-d4)δ8.49(brs,1H),7.63–7.50(m,4H),7.33(d,J＝8.4Hz,2H),7.09(brs,1H),4.44(t, J＝5.6Hz,2H),3.90(t,J＝5.6Hz,2H),3.78–3.61(m,2H),3.45–3.41(m,2H),2.42–2.21(m,4H),1.71(s ,6H).

LCMS [M+H] ⁺ = 553.1

Example 35: Synthesis of Compound I-20:

2-(2-Chloroethoxy)-5-(2-(4-((2-((1-oxytetrahydro-1λ ⁶ -thiophen-1-ylidene)amino)pyrimidin-5-yl)ethynyl)phenyl)propan-2-yl)isophthalonitrile

Step 1: Add intermediate I-A12 (100 mg, 0.29 mmol) and intermediate I-20-1 (68 mg, 0.35 mmol), Pd(PPh ₃ ) ₄ (35 mg, 0.03 mmol), cuprous iodide (6 mg, 0.03 mmol), N,N-diisopropylethylamine (748 mg, 5.8 mmol) to acetonitrile (2 ml). The mixture was stirred at 75°C under nitrogen protection for 16 hours, and the reaction was complete by TLC detection. The reaction mixture was concentrated and purified by column chromatography to obtain the product I-20-2 (64 mg, yield: 48.5%) as a yellow oily liquid.

LC-MS [M+1]+＝461.1

Step 2: Add intermediate I-20-2 (64 mg, 0.14 mmol) and intermediate I-B1 (25 mg, 0.21 mmol), t-Buxphos Pd G3 (11 mg, 0.014 mmol), cesium carbonate (137 mg, 0.42 mmol) to 1,4-dioxane (2 mL). The mixture was replaced with nitrogen three times and reacted at 100 ° C in a microwave reactor for 1 hour. LC-MS detected that the reaction was complete. The reaction mixture was concentrated and separated and purified by HPLC to obtain compound I-20 (2.5 mg, yield: 3.3%) as a white solid.

¹ H NMR (400MHz, Chloroform-d) δ8.60 (s, 2H), 7.61 (s, 2H), 7.47 (d, J = 7.3Hz, 2H), 7.15 (d, J = 8.2Hz, 2H), 4.68(s,2H),3.88(t,J＝5.7Hz,2H),3.68(d,J＝13.8Hz,2H),3.42(d,J＝10.6Hz,2H),2.32(d,J＝40.0 Hz,4H),1.68(s,6H).

LC-MS [M+1]+＝544.1

Example 36: Synthesis of Compound I-21:

2-(2-Chloroethoxy)-3-methoxy-5-(2-(4-((2-((1-oxotetrahydro-1λ ⁶ -thiophen-1-ylidene)amino)pyrimidin-5-yl)ethynyl)phenyl)propan-2-yl)benzonitrile

Step 1: At room temperature, the intermediate I-A11 (128.0 mg, 0.36 mmol) and the intermediate I-20-1 (70 mg, 0.36 mmol) were dissolved in anhydrous tetrahydrofuran (2 mL), and then DIEA (465.3 mg, 3.6 mmol), Pd(PPh ₃ ) ₄ (42 mg, 0.036 mmol) and CuI (6.9 mg, 0.036 mmol) were added. After the addition, nitrogen was blown in for protection, and the temperature was slowly raised to 80°C and stirred for 12 hours. The reaction mixture was dried and passed through a column (petroleum ether/ethyl acetate = 3/1) to obtain the desired product I-21-1 (12 mg, yield: 28%), which was a light yellow oil.

LCMS [M+1] ⁺ = 466.10

Step 2: At room temperature, intermediate I-21-1 (100.0 mg, 0.214 mmol) and intermediate I-B1 (25.56 mg, 0.214 mmol) were dissolved in anhydrous dioxane (4 mL), and then Cs ₂ CO ₃ (209.59 mg, 0.643 mmol) and t-BuXPhos Pd G3 (17 mg, 0.0214 mmol) were added. After the addition, nitrogen was blown in for protection, and then microwaves were used to react at 100 ° C for 1 hour. The reaction mixture was spin-dried and passed through a column (PE/THF=3/1) to obtain a colorless oily product, which was freeze-dried to obtain the desired product compound I-21 (51.01 mg, yield: 43.3%) as a white solid.

¹ H NMR (400MHz, Chloroform-d) δ8.58 (s, 2H), 7.43 (d, J = 8.6Hz, 2H), 7.17 (d, J = 8.6Hz, 2H), 7.05 (d, J = 2.2 Hz,1H),6.81(d,J＝2.2Hz,1H),4.40–4.33(t,J＝6.3Hz,2H),3.81–3.78(t,J＝6.3Hz,2H),3.74(s,3H ),3.71–3.64(m,2H),3.42–3.37(m,2H),2.41–2.23(m,4H),1.65(s,6H).

LCMS [M+1] ⁺ = 549.16

Example 37: Synthesis of Compound I-22:

1-((5-((4-(2-(7-chloro-1-(2-chloroethyl)-1H-indazol-5-yl)propan-2-yl)phenyl)ethynyl)pyrimidin-2-yl)imino)tetrahydro-1H-1λ ⁶ -thiophene-1-oxo

Step 1: Dissolve intermediate I-A4 (90 mg, 0.252 mmol), DIEA (4.2 g, 41.6 mmol), intermediate I-20-1 (49 mg, 0.252 mmol), CuI (10 mg, 0.05 mmol) and Pd(PPh ₃ ) ₄ (29 mg, 0.025 mmol) in THF (2 mL), and react with microwave at 80° C. for 1.5 hours. Concentrate the reaction mixture and separate by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain product I-22-1 (40 mg, yield: 34%) as a yellow solid.

LCMS [M+1] ⁺ = 469.1

Step 2: Dissolve intermediate I-22-1 (40 mg, 0.085 mmol), intermediate I-B1 (51 mg, 0.426 mmol), cesium carbonate (83 mg, 0.255 mmol) and t-BuXPhos Pd G3 (8 mg, 0.009 mmol) in dioxane (1 mL) and react with microwave at 100 ° C for 1 hour. After the reaction mixture is concentrated, the product compound I-22 (20 mg, yield: 43%) is separated by HPLC as a white solid.

¹ H NMR(400MHz,Chloroform-d)δ8.60(s,2H),7.99(s,1H),7.56(s,1H),7.45-7.42(m,2H),7.23-7.21(m,2H) ,7.11(s,1H),5.04(t,J＝8.0Hz,2H),3.92(t,J＝8.0Hz,2H),3.73-3.66(m,2H),3.46-3.39(m,2H), 2.41-2.24(m,4H),1.72(s,6H).

LCMS [M+1] ⁺ = 552.2

Example 38: Synthesis of Compound I-27:

3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((3-((1-oxido-1λ ⁶ -thiomorpholin-1-ylidene)amino)pyrazin-2-yl)ethynyl)phenyl)propan-2-yl)benzonitrile

Step 1: Referring to the synthesis method of compound I-18, intermediate I-27-1 is used instead of intermediate I-18-1 to carry out a one-step reaction to obtain intermediate I-27-2.

LCMS [M+H] ⁺ = 470.2

Step 2: At room temperature, toluene (1.5 mL), intermediate I-27-2 (50 mg, 0.11 mmol), intermediate I-B5 (37.26 mg, 0.16 mmol), Pd ₂ (dba) ₃ (9.73 mg, 0.011 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (12.29 mg, 0.021 mmol) and cesium carbonate (51.91 mg, 0.159 mmol) were added to the reaction bottle in sequence. Nitrogen was replaced three times, and then the temperature was raised to 100 ° C and stirred for 12 hours. After the reaction was complete, the filtrate was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (0-8% methanol/dichloromethane) to obtain a yellow oil I-27-3 (50 mg, yield: 70.54%).

LCMS [M+H] ⁺ = 668.1

Step 3: Add dichloromethane (1 mL), intermediate I-27-3 (50 mg, 0.075 mmol) and trifluoroacetic acid (1 mL) to the reaction bottle in sequence, and stir at 25°C for 12 hours. After the reaction is complete, concentrate under reduced pressure, adjust the pH to 8 with saturated sodium bicarbonate aqueous solution, and then extract with dichloromethane (10 mL*3), wash the combined organic phase with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure and purify by column chromatography (methanol/dichloromethane = 1/10) to obtain white solid compound I-27 (12 mg, yield: 28.23%).

¹ H NMR (400MHz, MEOD-D4) δ8.07(d,J＝2.8Hz,1H),7.99(d,J＝2.8Hz,1H),7.55(td,J＝6.8,2.4Hz,4H), 7.36–7.27(m,2H),4.44(t,J＝5.6Hz,2H),3.90(t,J＝5.6Hz,2H),3.86–3.72(m,2H),3.40(ddd,J＝16.8, 12.4,3.6Hz,4H),3.29–3.22(m,2H),1.71(s,6H).

LCMS [M+H] ⁺ = 568.1

According to the synthesis methods of compounds I-18 to 22 and compound I-27 above or references, the following compounds were synthesized respectively:

If the final product needs to remove the N-Boc protecting group, the following conditions can be used for removal: 1) 4N HCl/1,4-dioxane/methanol (1/1) solution, room temperature or heating and stirring until the reaction is completed, the reaction solution is concentrated and separated by preparative HPLC to obtain the target product; 2) trifluoroacetic acid/dichloromethane (1/10) solution is reacted at room temperature until the reaction is completed, the reaction solution is concentrated and separated by preparative HPLC to obtain the target product.

According to the synthesis methods of compounds I-18 to 22 and compound I-27 above or references, the following compounds were synthesized respectively:

If the final product needs to remove the N-Boc protecting group, the following conditions can be used for removal: 1) 4N HCl/1,4-dioxane/methanol (1/1) solution, room temperature or heating and stirring until the reaction is completed, the reaction solution is concentrated and separated by preparative HPLC to obtain the target product; 2) trifluoroacetic acid/dichloromethane (1/10) solution is reacted at room temperature until the reaction is completed, the reaction solution is concentrated and separated by preparative HPLC to obtain the target product.

Example 39: Synthesis of Compound I-28:

3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((3-((1-oxytrihydro-1λ ⁶ -thiophen-1-ylidene)amino)pyrazin-2-yl)ethynyl)phenyl)propan-2-yl)benzonitrile

Referring to the synthesis method of compound I-27, intermediate I-B1 was used instead of intermediate I-B5 to carry out a one-step reaction to obtain compound I-28.

¹ H NMR (400MHz, MeOD-d4) δ8.10(d,J＝2.4Hz,1H),7.99(d,J＝2.4Hz,1H),7.62–7.48(m,4H),7.30(d,J ＝8.4Hz,2H),4.43(t,J＝5.6Hz,2H),3.90(t,J＝5.6Hz,2H),3.77–3.63(m,2H),3.51–3.37(m,2H),2.43 –2.18(m,4H),1.70(s,6H).

LCMS [M+H] ⁺ = 553.1

Example 40: Synthesis of Compound I-106:

3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((3-((dimethyl(oxy)-1λ ⁶ -sulfonylidene)amino)pyrazin-2-yl)ethynyl)phenyl)propyl-2-yl)benzonitrile

Step 1: At room temperature, dimethylsulfenyl imide (502 mg, 5.391 mmol) and I-106-1 (730 mg, 4.9 mmol) were dissolved in anhydrous dioxane (15 mL), and then Cs ₂ CO ₃ (3.19 g, 9.8 mmol) and t-BuXPhos Pd G3 (350 mg, 0.49 mmol) were added. After the addition, nitrogen was blown in for protection, and then microwaved at 100 ° C for 1 hour. The reaction solution was filtered. The filtrate was concentrated and then separated by column chromatography (tetrahydrofuran/petroleum ether = 2/1) to obtain the desired product I-106-2 (350 mg, yield: 34.7%) as a yellow solid.

Step 2: Dissolve I-106-2 (11.5 mg, 0.05 mmol) and intermediate I-A2 (20 mg, 0.05 mmol) in acetonitrile (1 mL) at room temperature, then add Cs ₂ CO ₃ (45 mg, 0.14 mmol) and XPhos Pd G2 (6 mg, 0.005 mmol). After the addition, blow in nitrogen for protection, then use microwave at 100 ° C for 1 hour. Filter the reaction solution. After the filtrate is concentrated, the filtrate is concentrated and subjected to preparative HPLC (formic acid) to obtain compound I-106 (4.57 mg, yield: 12.42%) as a white solid.

¹ H NMR(400MHz,Chloroform-d)δ8.05(d,J＝2.6Hz,1H),8.03(d,J＝2.7Hz,1H),7.57–7.52(m,2H),7.40(d,J ＝2.4Hz,1H),7.33(d,J＝2.4Hz,1H),7.19–7.14(m,2H),4.41(t,J＝6.2Hz,2H),3.86(t,J＝6.2Hz,2H ),3.42(s,6H),1.65(s,6H).

LC-MS [M+1] ⁺ = 527.40

Example 47: Synthesis of Compound 1:

N-(5-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenyl)ethynyl)pyrimidin-2-yl)methanesulfonamide

Intermediate I-A2 (2.3 g, 5.3 mmol) and 1-1 (1.3 g, 5.3 mmol), Pd(PPh ₃ ) ₄ (613 mg, 6.4 mmol), cuprous iodide (101 mg, 0.53 mmol), N,N-diisopropylethylamine (13.7 g, 106 mmol) were added to tetrahydrofuran (13 ml). The mixture was stirred at 80°C under nitrogen protection for 16 hours. TLC detected that the reaction was complete. The reaction mixture was put into water (20 mL), extracted with ethyl acetate (20 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography. The crude product was separated by preparative high performance liquid phase to obtain compound 1 (253 mg, yield: 7.4%) as a white solid.

¹ H NMR (400MHz, Chloroform-d) δ8.74 (s, 2H), 7.50 (d, J = 7.7Hz, 2H), 7.43 (s, 1H), 7.34 (d, J = 2.3Hz, 1H), 7.20(d,J＝8.2Hz,2H),4.44(t,J＝6.3Hz,2H),3.88(t,J＝6.2Hz,2H),3.49(s,3H),1.68(s,6H).

LC-MS [M+1] ⁺ = 529.1

Example 48: Synthesis of Compound 2:

N-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenyl)ethynyl)pyrimidin-2-yl)methanesulfonamide

Step 1: Dissolve 2-1 (0.5 g, 3.8 mmol) in anhydrous tetrahydrofuran (10 mL), add NaH (0.34 g, 8.5 mmol) at 0°C, stir for 30 minutes, and then add methanesulfonyl chloride (0.88 g, 7.6 mmol) at 0°C. React at room temperature for 1 hour, pour the reaction solution into cold water, and extract with ethyl acetate (50 mL) to remove impurities. The aqueous phase is extracted with DCM/iPrOH (3/1, 30 mL*3) and concentrated to obtain the target product 2-2 (139 mg, yield: 17.4%) as a yellow solid.

¹ HNMR (400MHz, Methanol-d4) δ8.45 (d, J = 5.3Hz, 1H), 7.13 (d, J = 5.3Hz, 1H), 3.36 (s, 3H).

Step 2: At room temperature, intermediate 2-2 (116.0 mg, 0.56 mmol) and intermediate I-A2 (200 mg, 0.56 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL), and then DIEA (724 mg, 5.6 mmol), Pd(PPh ₃ ) ₄ (97 mg, 0.08 mmol), and CuI (96 mg, 0.5 mmol) were added. After the addition, nitrogen was protected and the temperature was slowly raised to 70°C, stirred for 15 hours, and the reaction was stopped. LCMS detected the MS of the target product. The reaction solution was dried and passed through a column (petroleum ether/tetrahydrofuran = 3/1) to obtain 180 mg of a brown oily crude product, which was separated by preparative liquid phase to obtain compound 2 (13 mg, yield: 4.4%) as a white solid.

¹ H NMR(400MHz,Chloroform-d)δ7.57(d,J＝8.1Hz,2H),7.42(s,1H),7.34(s,1H),7.22(d,J＝8.2Hz,4H), 4.44(t,J＝6.4Hz,2H),3.88(t,J＝6.4Hz,2H),3.50(s,3H),1.68(s,6H).

LCMS [M+1] ⁺ = 528.9

Example 49: Synthesis of Compound 3:

N-(3-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenyl)ethynyl)pyrazin-2-yl)methanesulfonamide

Step 1: Dissolve 3-1 (5 g, 38.6 mmol) in anhydrous tetrahydrofuran (50 mL), add TEA (7.5 g, 74.1 mmol) at 0°C. Then add methanesulfonyl chloride (6.6 g, 57.6 mmol). React at 0°C for 4 hours. The reaction solution is dried by column (petroleum ether/ethyl acetate = 1/1) to obtain intermediate 3-2 (4.3 g, yield: 39.1%) as a white solid.

LC-MS [M+1] ⁺ = 285.9

Step 2: At room temperature, 3-2 (2.2 g, 7.7 mmol) was dissolved in anhydrous methanol (50 mL), and then K ₂ CO ₃ (2 g, 14.5 mmol) was added. After the addition, the temperature was slowly raised to 60°C and stirred for 1 hour. K ₂ CO ₃ was filtered off, and the filtrate was dried and passed through a column (DCM/MeOH = 0-10%) to obtain intermediate 3-3 (1 g, yield: 62.9%) as a light yellow solid.

LC-MS [M+1] ⁺ = 207.8

Step 3: At room temperature, intermediate 3-3 (240.0 mg, 1.16 mmol) and intermediate I-A2 (414.1 mg, 1.16 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL), and then DIEA (1.5 g, 11.6 mmol), Pd(PPh ₃ ) ₄ (134 mg, 0.12 mmol), and CuI (22.1 mg, 0.12 mmol) were added. After the addition, nitrogen was protected and the temperature was slowly raised to 80°C and stirred for 12 hours. The reaction mixture was dried and passed through a column (petroleum ether/tetrahydrofuran = 3/1) to obtain 400 mg of a brown oily crude product, which was prepared by HPLC to obtain compound 3 (36 mg, yield: 5.9%) as a white solid.

¹ H NMR (400MHz, Chloroform-d) δ8.59 (d, J = 2.6Hz, 1H), 8.40 (d, J = 2.6Hz, 1H), 7.51 (s, 1H), 7.48 (d, J = 1.5 Hz,2H),7.37(d,J＝2.3Hz,1H),7.26–7.25(m,1H),6.81(s,1H),4.41(t,J＝6.4Hz,2H),3.86(t,J ＝6.4Hz,2H),3.54(s,3H),1.71(s,6H).

LC-MS [M+1] ⁺ = 529.1

According to the synthesis methods of compounds 1 to 3 above or references, the following compounds were synthesized respectively:

Example 50: Synthesis of Compound 10:

N-(5-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyano)propan-2-yl)phenyl)ethynyl)pyrimidin-4-yl)methanesulfonamide

Step 1: I-A2 (100 mg, 279.13 μmol) and 10-1 (100.67 mg, 418.69 μmol) were dissolved in acetonitrile (1.5 mL), and triethylamine (141.22 mg, 1.40 mmol), CuI (5.32 mg, 27.91 μmol) and Pd(PPh ₃ ) ₂ Cl ₂ (19.59 mg, 27.91 μmol) were added. The mixture was replaced with nitrogen three times and reacted at 25° C. for 16 hours. The reaction solution was filtered and concentrated, and then separated by column (petroleum ether/ethyl acetate = 0-15%) to obtain the product 10-2 (75.00 mg, yield: 57.07%) as a colorless oil.

LC-MS[M+1] ⁺ ＝470.20

Step 2: At room temperature, 10-2 (50 mg, 106.21 μmol) and methanesulfonamide (15 mg, 157.69 μmol) were dissolved in dioxane (2 mL), DIEA (68.63 mg, 531.04 μmol) and t-BuXphos Pd G3 (8.43 mg, 10.62 μmol) were added, the mixture was replaced with nitrogen three times, and microwaved at 100 ° C for 1 hour. The reaction solution was spin-dried and purified by preparative HPLC to obtain the target product compound 10 (4.24 mg, yield: 7.39%) as a white solid.

¹ H NMR (400MHz, Chloroform-d) δ9.08 (s, 1H), 9.02 (s, 1H), 7.51–7.43 (m, 3H), 7.35 (d, J = 2.3Hz, 1H), 7.26 (s ,1H),7.23(s,1H),6.62(s,1H),4.42(t,J＝6.1Hz,2H),3.86(t,J＝6.2Hz,2H),3.62(s,3H),1.70 (s,6H).

LC-MS [M+1] ⁺ = 529.30

Example 51: Synthesis of Compound 14:

N-(3-((4-(2-(7-chloro-1-(2-chloroethyl)-1H-indazol-5-yl)propan-2-yl)phenyl)ethynyl)pyrazin-2-yl)methanesulfonamide

Intermediate I-A4 (100 mg, 0.280 mmol), DIEA (362 mg, 2.80 mmol), intermediate 3-3 (76 mg, 0.364 mmol), CuI (6 mg, 0.028 mmol) and Pd(PPh ₃ ) ₄ (32 mg, 0.028 mmol) were dissolved in THF (3 mL) and reacted with microwave at 80° C. for 2 hours. The reaction mixture was concentrated and separated by HPLC to give the product N-(3-((4-(2-(7-chloro-1-(2-chloroethyl)-1H-indazol-5-yl)propan-2-yl)phenyl)ethynyl)pyrazin-2-yl)methanesulfonamide (Compound 14, 25 mg, yield: 17%) as a white solid.

¹ H NMR (400MHz, Chloroform-d) δ8.59 (s, 1H), 8.41 (d, J = 4.0Hz, 1H), 8.01 (s, 1H), 7.61 (d, J = 4.0Hz, 1H), 7.50-7.46(m,2H),7.34-7.31(m,2H),7.21(d,J＝4.0Hz,1H),6.81(s,1H),5.05(t,J＝8.0Hz,2H),3.93 (t,J＝8.0Hz,2H),3.55(s,3H),1.78(s,6H).

LC-MS [M+1] ⁺ = 527.9

Example 52: Synthesis of Compound 15:

N-(3-((4-(2-(4-(2-chloroethoxy)-3-cyano-5-methoxyphenyl)propan-2-yl)phenyl)ethynyl)pyrazin-2-yl)methanesulfonamide

At room temperature, compound 3-3 (100.0 mg, 0.48 mmol) and compound I-A11 (170.4 mg, 0.48 mmol) were dissolved in anhydrous tetrahydrofuran (4 mL), and then DIEA (620 mg, 4.8 mmol), Pd(PPh ₃ ) ₄ (57.8 mg, 0.05 mmol), and CuI (9.5 mg, 0.05 mmol) were added. After the addition, nitrogen was protected and the temperature was slowly raised to 80°C and stirred for 12 hours. The reaction mixture was dried and passed through a column (petroleum ether/tetrahydrofuran = 4/1) to obtain 220 mg of a crude product as an orange solid, which was purified by preparative HPLC to obtain compound 15 (40.67 mg, yield: 16.08%) as a white solid.

¹ H NMR (400MHz, Chloroform-d) δ8.59 (d, J = 2.4Hz, 1H), 8.40 (d, J = 2.8Hz, 1H), 7.51 (d, J = 14.4Hz, 2H), 7.30 ( d,J＝17.2Hz,2H),6.83(s,J＝9.2Hz,2H),4.39(t,J＝6.4Hz,2H),3.82(t,J＝6.4Hz,2H),3.75(s, 3H),3.54(s,3H),1.71(s,6H).

LC-MS [M+1] ⁺ = 525.20

The following compounds were synthesized according to the above synthesis method or references:

Example 55: Synthesis of Compound 217:

((4-((4-(2-(1-(2-chloroethane)-7-methoxy-1H-indazol-5-yl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)imino)dimethyl-λ ⁶ -sulfoximine

Step 1: A39 (1 g, 2.90 mmol) was dissolved in ACN (15 mL), and I-1-1 (945.41 mg, 5.80 mmol) and Cs ₂ CO ₃ (1.41 g, 4.35 mmol) were added and stirred at 30°C for 3 hours. LC-MS showed that the raw material was completely reacted, and the reaction solution was concentrated to obtain a crude product, which was separated by column chromatography (PE/THF=1/0 to 1/1) to obtain product 217-2 (800.00 mg, yield: 58.52%) as a yellow oil.

LC-MS [M+1] ⁺ = 471.1

Step 2: Dissolve 217-2 (150 mg, 318.22 μmol) and dimethylsulfenyl imide (59.28 mg, 636.43 μmol) in dioxane (2 mL), add Cs ₂ CO ₃ (206.84 mg, 636.43 μmol) and t-Buxphos Pd G3 (28.64 mg, 31.82 μmol), and react at 100° C. for 1 hour in a microwave oven under nitrogen protection. LC-MS showed that the raw material was completely reacted. 20 mL of water was added to the reaction solution, extracted twice with ethyl acetate (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated and sent to prep-HPLC reverse phase column chromatography (250*20.0 mml. DS-5 μm, 12 nm. 0.05% TFA, ACN/H ₂ O=0%-95%) for purification to obtain product 217 (46.00 mg, yield: 26.01%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.85 (s, 1H), 7.76 (s, 1H), 4.89 (s, 2H), 4.31 (dd, J＝12.5, 7.3Hz, 2H), 4.05 ( s,2H),2.71(s,3H),1.31(d,J＝6.6Hz,3H).

LC-MS [M+H] ⁺ = 528.05

Example 56: Synthesis of Compound 274:

1-((4-(4-(2-(1-(2-chloroethyl)-7-fluoro-1H-indazol-5-yl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)imino)-1λ ⁶ -thiomorpholine-1-oxide

Step 1: A35 (80 mg, 228.06 μmol) was dissolved in DMF (5 mL), and I-1-1 (74.35 mg, 456.11 μmol) and Cs ₂ CO ₃ (222.92 mg, 684.17 μmol) were added, and the mixture was stirred at 50°C for 2 hours. LC-MS showed that the target product was generated. The reaction solution was diluted with water (5 mL), extracted with ethyl acetate (5 mL x 3), washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The target product 274-2 (100.00 mg, yield: 80.97%) was isolated and purified by column chromatography (petroleum ether/ethyl acetate = 10/1) as a yellow jelly.

LC-MS [M+1] ⁺ = 477.20

Step 2: Dissolve 274-2 (100 mg, 217.70 μmol) in dioxane (2 mL), add I-B5 (51.01 mg, 217.70 μmol), Cs ₂ CO ₃ (70.93 mg, 217.70 μmol) and t-BuXphos Pd G3 (17.33 mg, 21.77 μmol), protect with nitrogen, and microwave for 1 hour at 100 ° C. LC-MS showed that the target product was generated. The reaction solution was quenched with water (3 mL), extracted with ethyl acetate (3 mL x 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 274-3 (120.00 mg, crude) as a yellow oil.

LC-MS [M+1] ⁺ = 657.40

Step 3: Dissolve 274-3 (120 mg, 182.59 μmol) in TFA (1 mL) and DCM (4 mL) and react at 25°C for 1 hour. LC-MS showed that the raw material reacted completely. The reaction solution was directly concentrated under reduced pressure, Prepared by Pre-HPLC (YMC-PACK ODS-A, 250x20mml.D.S-5um, 12nm AA12S05-2520WT, Ser.No.114ZB00083) (FA), freeze-dried to obtain the target product 274 (13.75 mg, yield: 13.27%) as a red solid.

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.49 (d, J = 5.2 Hz, 1H), 8.04 (d, J = 2.2 Hz, 1H), 7.52 (d, J = 1.1 Hz, 1H), 7.19 -7.16(m,3H),6.92-6.90(m,2H),6.82(dd,J＝14.2,1.2Hz,1H),5.09(s,2H),4.78(t,J＝5.9Hz,2H), 4.13-4.09(m,2H),3.96(t,J＝5.8Hz,2H),3.90-3.67(m,6H),1.69(s,6H).

LC-MS [M+1] ⁺ = 557.30

Example 57: Synthesis of Compound 275:

1-((4-(4-(2-(1-(2-chloroethyl)-7-fluoro-1H-indazol-5-yl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)imino)-4-(2,2-difluoroethyl)-1λ ⁶ -thiomorpholine-1-oxide

Step 1: Compound 274 (100 mg, 179.51 μmol) and 275-1 (206.73 mg, 1.08 mmol) were dissolved in DMA (5 mL), Cs ₂ CO ₃ (175.02 mg, 538.52 μmol) was added, and the mixture was reacted at 60° C. for 12 hours. LC-MS showed that the reaction was complete, and the product 275 (17.83 mg, yield: 15.35%) was obtained by purification by Prep-HPLC (0.05% NH ₃ .H ₂ O) H ₂ O-ACN) (Waters Xbridge Prep C18 OBD 5um 19mm*250mm) and freeze-dried to give a white solid.

¹ H NMR (400MHz, Methanol-d ₄ ) δ8.41 (d, J = 5.2 Hz, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.51 (d, J = 1.2 Hz, 1H), 7.17 -7.13(m,2H),7.06(d,J＝5.2Hz,1H),6.89-6.85(m,2H),6.81(dd,J＝14.2,1.4Hz,1H),6.22-5. 90(m,1H),5.04(s,2H),4.75(t,J＝6.0Hz,2H),4.31(td,J＝14.3,3.7Hz,2H),4.19-4.08(m,2H),3.94 (t,J＝5.8Hz,2H),3.84-3.71(m,4H),3.53-3.46(m,2H),1.67(s,6H).

LC-MS [M+44+1] ⁺ = 665.30

Example 58: Synthesis of Compound 278:

(4-((4-(2-(1-(2-chloroethyl)-7-fluoro-1H-indazol-5-yl)propan-2-yl)-3-fluorophenoxy)methyl)pyrimidin-2-yl)imino)dimethyl-λ ⁶ -sulfonamide

Step 1: Compound A54 (0.11 g, 313.58 μmol), I-1-1 (56.23 mg, 344.94 μmol) and Cs ₂ CO ₃ (203.83 mg, 627.16 μmol) were added to ACN (2 mL), stirred at 40° C. for 2 hours, LC-MS showed that the raw materials were reacted completely, the reaction solution was concentrated, and column chromatography (tetrahydrofuran/petroleum ether = 20-30%) was used to obtain compound 278-2 (140.00 mg, 293.30 μmol, yield: 93.53%) as a light yellow oil.

LC-MS [M+1] ⁺ = 477.1

Step 2: Compound 278-2 (100 mg, 209.50 μmol), dimethylsulfenyl imide (58.54 mg, 628.49 μmol) were dissolved in dioxane (2 mL), cesium carbonate (68.26 mg, 209.50 μmol) and t-BuXphos Pd G3 (16.64 mg, 20.95 μmol) were added, the reaction was protected with nitrogen, and then stirred at 100 ° C for 1 hour under microwave conditions. LCMS detected that the reaction was complete. The reaction solution was extracted with ethyl acetate (15 mL*3), washed with saturated NaCl (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried, and purified by prep-HPLC (FA) (YMC-PACK ODS-A, 250x20 mml.D.S-5um, 12 nm AA12S05-2520WT, Ser. No.114ZB00083) to give 278 (39.28 mg, 73.56 μmol, yield: 35.11%) as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.42(d,J＝5.0Hz,1H),8.11(d,J＝2.3Hz,1H),7.44–7.38(m,1H),7.38(d, J＝1.3Hz,1H),6.93–6.87(m,2H),6.84(dd,J＝8.6,2.6Hz,1H),6.74(dd,J＝13.7,2.7Hz,1H),5.03(s,2H ),4.72(t,J＝5.7Hz,2H),4.02(t,J＝5.6Hz,2H),3.35(s,6H),1.63(s,6H).

LC-MS [M+1] ⁺ = 534.2

Example 59: Synthesis of Compound 282:

1-((4-(4-(2-(7-chloro-1-(2-chloroethyl)-1H-indazol-5-yl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)imino)-1λ ⁶ -thiomorpholine-1-oxide

Step 1: I-A3 (280 mg, 801.71 μmol) and I-1-1 (261.36 mg, 1.60 mmol) were dissolved in ACN (3 mL), Cs ₂ CO ₃ (390.83 mg, 1.20 mmol) was added, and the reaction solution was stirred at 45° C. for 3 hours. TLC showed that the raw materials were completely reacted, and the reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (tetrahydrofuran/petroleum ether = 0-20%) to obtain the product 282-2 (280.00 mg, yield: 66.06%) as a yellow oil.

LC-MS [M+1] ⁺ = 475.80

Step 2: Dissolve 282-2 (230 mg, 483.40 μmol) in 1,4-dioxane (2 mL), add I-B5 (226.54 mg, 966.80 μmol), Cs ₂ CO ₃ (157.10 mg, 483.40 μmol), t-BuXphos Pd G3 (39.08 mg, 48.34 μmol), and react at 100°C in a microwave oven under nitrogen protection for 1 hour. TLC showed that the raw material was completely reacted, and the reaction solution was concentrated to obtain a crude product, which was separated by column chromatography (petroleum ether/tetrahydrofuran = 1/0 to 1/1) to obtain the product 282-3 (300.00 mg, yield: 87.52%) as a yellow oil.

¹ H NMR (400MHz, Acetonitrile-d ₃ ) δ8.38 (s, 1H), 8.01 (s, 1H), 7.66 (s, 1H), 7.14 (t, J = 12.4Hz, 3H), 6.96 (s, 1H),6.88(d,J＝5.2Hz,2H),4.99(s,4H),4.08(m,2H),3.65(d,J＝17.8Hz,6H),3.31(t,J＝12.9Hz, 2H),1.66(s,6H),1.42(s,9H).

Step 3: Dissolve 282-3 (60 mg, 89.07 μmol) in dichloromethane (3 mL), add TFA (1 mL), and stir at 30°C for 3 hours. Concentrate the reaction solution to obtain a crude product, add acetonitrile (2 mL) and filter, and send the filtrate to Prep-HPLC reverse phase column chromatography (250*20.0 mml. DS-5 μm, 12 nm. 0.05% NH _3. H ₂ O, ACN/H ₂ O＝0%～95%) for purification to obtain 282 (12.00 mg, yield: 22.79%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.39 (s, 1H), 8.16 (s, 1H), 7.64 (s, 1H), 7.13 (d, J = 12.8Hz, 3H), 6.96-6.83 ( m,3H),4.97(d,J＝9.8Hz,4H),4.00(s,2H),3.57(d,J＝14.9Hz,2H),3.21(s,2H),3.12(d,J＝14.7 Hz, 2H), 2.94 (dd, J = 12.3Hz, 2H), 1.63 (s, 6H).

LCMS [M+1] ⁺ = 573.2

Example 60: Synthesis of Compound 285:

(4-((4-(2-(2-(1-(2-chloroethyl)-7-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)imino)dimethyl-λ ⁶ -sulfonamide

Step 1: Add compound A38 (0.23 g, 689.06 μmol), I-1-1 (224.64 mg, 1.38 mmol) and Cs ₂ CO ₃ (224.50 mg, 689.06 μmol) into ACN (3 mL), stir at 35°C for 2 hours, and LC-MS indicates that the reaction of the raw material is complete. Filter the reaction solution, evaporate the solvent, and separate by column chromatography (tetrahydrofuran/petroleum ether = 20-50%) to obtain compound 285-2 (220.00 mg, 477.92 μmol, yield: 69.36%) as a light yellow oil.

LC-MS[M+1] ⁺ ＝460.20

Step 2: Compound 285-2 (0.09 g, 195.51 μmol), dimethylsulfenyl imide (36.42 mg, 391.02 μmol), Cs ₂ CO ₃ (63.54 mg, 195.51 μmol) and t-BuXphos Pd G3 (15.52 mg, 19.55 μmol) were added to a solvent Dioxane (1.5 mL), and the mixture was reacted at 95° C. for 1 hour under nitrogen protection. LC-MS showed that the raw materials were completely reacted, and the reaction solution was filtered, concentrated, dissolved in acetonitrile, and prepared by prep.HPLC (250*20.0 mml. DS-5 μm, 12 nm. ACN/H ₂ O (0.05% FA) = 0% to 95%) to obtain compound 285 (10.94 mg, 20.90 μmol, yield 10.69%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.40 (d, J = 5.0 Hz, 1H), 7.76 (d, J = 1.2 Hz, 1H), 7.15 (d, J = 10.4 Hz, 2H), 7.06 (d,J＝12.1Hz,1H),6.90(s,1H),6.88(d,J＝4.2Hz,2H),5.02(t,J＝5.6Hz,2H),4.99(s,2H),4.13 (t,J＝5.6Hz,2H),3.29(s,6H),1.66(s,6H).

LC-MS [M+1] ⁺ = 517.30

Example 61: Synthesis of Compound 298:

N-(5-((4-(2-(1-(2-chloroethyl)-7-fluoro-1H-indazol-5-yl)propan-2-yl)phenyl)ethynyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)methanesulfonamide

Step 1: A59 (500 mg, 1.47 mmol), 1-1 (479.41 mg, 1.91 mmol), cuprous iodide (27.94 mg, 146.70 μmol), triethylamine (1.48 g, 14.67 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (132.03 mg, 146.70 μmol) were added to N,N-dimethylformamide (10 mL) in sequence, and the mixture was reacted at 100 °C for 1 hour under nitrogen protection. After the reaction, water (10 ml) and ethyl acetate (100 ml) were added, and the mixture was washed with saturated sodium chloride (100 × 3), dried over anhydrous sodium sulfate, and the organic phase was concentrated to dryness. Purification by combiFlash gave 298-2 (219.00 mg, 406.35 μmol, yield: 27.70%) as a yellow solid.

LC-MS [M+1] ⁺ = 511.8

Step 2: 298-2 (100 mg, 195.31 μmol), 298-3 (24.25 mg, 390.63 μmol) and cyanomethylene tri-n-butylphosphine (94.28 mg, 390.63 μmol) were added to tetrahydrofuran (5 mL) in sequence, and the mixture was reacted at 100°C for 1 hour under nitrogen protection. The reaction solution was purified by Prep-HPLC (250*20.0 mml. DS-5 μm, 12 nm. ACN/H ₂ O (0.05% FA) = 0% to 95%) to obtain 298 (11.53 mg, 19.70 μmol, yield: 10.09%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.87 (s, 2H), 8.19 (s, 1H), 7.52 (d, J = 4.4Hz, 2H), 7.50 (s, 1H), 7.33 (d, J＝8.6Hz,2H),6.96(d,J＝14.1Hz,1H),4.93(s,1H),4.76(t,J＝5.7Hz,2H),4.12(t,J＝6.3Hz,2H) ,4.06(s,2H),3.57(s,2H),3.55(s,3H),1.71(s,6H).

LC-MS [M+1] ⁺ = 555.8

Reference compound AA: Synthesized according to the method of patent (WO2020081999, compound number A109) Reference compound: N-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propane-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide

Test Example 1: LNCaP cells (AR positive) PSA luciferase reporter gene assay

The intracellular AR transcriptional activity level was measured using the luciferase reporter gene assay system. The PSA (6.1 kb)-Luc luciferase reporter gene vector contains several AR binding sequences (androgen response elements, ARE), which can be regulated by AR binding under the stimulation of androgen and initiate the expression of the luciferase reporter gene (Cleutjens, K.B.J.M., van der Korput, H.A.G.M., van Eekelen, C.C.E.M., van Rooij, H.C.J., Faber, P.W., and Trapman, J. (1997). An Androgen Response Element in a Far Upstream Enhancer Region Is Essential for High, Androgen-Regulated Activity of the Prostate-Specific Antigen Promoter. Mol. Endocrinol. 11, 148–161; Ueda, T., Bruchovsky, N., and Sadar, M.D. (2002). Activation of the N-terminus of the androgen receptor by interleukin-6 via MAPK and STAT3signal transduction pathways cells. J. Biol. Chem. 277, 7076–7085). Cell viability is determined by quantifying ATP, and the cell viability signal is used to normalize the experimental results and control the errors caused by cell number or cell status.

Step 1: Transient transfection of the constructed reporter gene vector PSA (6.1 kb)-Luc into LNCaP cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) Cells were seeded into 96-well plates at a density of 10,000 cells per well, with a volume of 80 μL per well, and cultured overnight in a 37°C, 5% carbon dioxide incubator.

Step 2: Culture overnight for 24 hours. After the cells are completely attached to the wall, add the compound to treat the cells. The test compound was diluted 3 times with DMSO in advance, and a total of 8 concentration gradients were set; 10 μL of culture medium containing the corresponding concentration of the test compound or DMSO control was added to each well, and 3 replicates were set for each concentration. The final concentration of DMSO in all test wells was 0.5%. After 1 hour of compound treatment, 10 μL of culture medium containing DHT (dihydrotestosterone) was added to each well, and the final concentration of DHT was 1nM; 10 μL of culture medium containing the control solvent was added to the control group without DHT treatment, and it was placed at 37°C and 5% carbon dioxide incubator for further culture for 24 hours. Set up duplicate plates to detect reporter gene activity and cell viability respectively.

Step 3: Detect the activity of the luciferase reporter gene in the sample using the ONE-Glo ^™ Luciferase Assay System (Promega, E6120). Add 50 μL of ONE-Glo ^™ Reagent to each well and mix well. Incubate at room temperature for 3 minutes with shaking to detect the activity of firefly luciferase (Fluc). In another replicate plate, add 50 μL of CellTiter- Luminescent Cell Viability Assay (Promega, G7572) reagent, mix well, incubate at room temperature with shaking for 10 minutes, and detect the cell viability luminescent signal. Use a multifunctional microplate reader (EnVision, PerkinElmer) to read the signal. The signal ratio is the reporter gene signal value/cell viability signal value. The inhibition percentage (%) is calculated by the following formula:

Inhibition percentage (DHT-dependent, %) = (1-(signal ratio of compound treatment group-signal ratio of non-DHT treatment group)/(signal ratio of DMSO treatment group-signal ratio of non-DHT treatment group))*100. The _IC50 value was calculated using GraphPad Prism software. The results are shown in Table 1.

Test Example 2: LNCaP cell (AR positive) proliferation inhibition activity test

Cell viability was detected by quantitatively measuring intracellular ATP using the CellTiter-Glo luminescent cell viability assay kit.

Step 1: Inoculate LNCaP cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) in a 96-well plate at a density of 1000 cells per well, with a culture medium volume of 90 μL per well, and culture in a 37° C., 5% carbon dioxide incubator overnight.

Step 2: Culture overnight for 24 hours. After the cells are completely attached to the wall, add the compound to treat the cells. The test compound is diluted 3 times, and a total of 8 concentration gradients are set; 5 μL of culture medium containing the test compound or DMSO control at the corresponding concentration is added to each well, and 3 replicates are set for each concentration. The final concentration of DMSO in all test wells is 0.5%. After 1 hour of compound treatment, 5 μL of culture medium containing DHT (dihydrotestosterone) is added to each well, except for the group without DHT treatment, and the final concentration of DHT is 0.2nM. Place in a 37°C, 5% carbon dioxide incubator and continue to culture for 4 days.

Step 3: Cell viability was detected using the CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, G7570). 50ul of CellTiter-Glo was added to each well, mixed, and incubated at room temperature for 10 minutes. The signal was read using a multifunctional microplate reader (EnVision, PerkinElmer). The inhibition percentage (%) was calculated using the following formula:

Inhibition percentage (DHT-dependent part %) = (1-(signal value of the compound treatment group with DHT stimulation-signal value of the DMSO treatment group without DHT stimulation)/(signal value of the DMSO treatment group with DHT stimulation-signal value of the DMSO treatment group without DHT stimulation))*100;

The _IC50 values were calculated using GraphPad Prism software. The results are shown in Table 1.

Table 1: PSA-Luc reporter gene inhibitory activity and cell proliferation inhibitory activity in LNCaP cells

The experimental results show that this series of compounds has good proliferation inhibition activity on prostate cancer cells LNCaP expressing AR protein.

Test Example 3: 22Rv1 (AR positive/AR-V7 positive) cell proliferation inhibition test

Cell viability was detected by quantitatively measuring intracellular ATP using the CellTiter-Glo luminescent cell viability assay kit.

Step 1: 22Rv1 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) were inoculated into 384-well plates at a density of 1500 cells per well, with a culture medium volume of 40 μL per well, and cultured in a 37°C, 5% carbon dioxide incubator overnight.

Step 2: Incubate overnight for 24 hours. After the cells are completely attached, add the compound to treat the cells. The test compound is diluted 3 times, and a total of 10 concentration gradients are set. The test compound is added using a Mosquito instrument, and 100nL of the test compound or DMSO control containing the corresponding concentration is added to each well. Each concentration is set to 3 replicates, and the final concentration of DMSO is controlled at 0.2%. Place in a 37°C, 5% carbon dioxide incubator for 4 days.

Step 3: Cell viability was detected using the CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, G7570). 20 μL CellTiter-Glo was added to each well, mixed, and incubated at room temperature for 10 minutes. The signal was read using a multifunctional microplate reader (EnVision, PerkinElmer). The inhibition percentage (%) was calculated using the following formula:

Inhibition percentage (%)=(1-signal value of the compound-treated group/signal value of the DMSO-treated group)*100.

The IC ₅₀ values were calculated using GraphPad Prism software, and the results are shown in Table 2. Table 2-1: 22Rv1 cell proliferation inhibitory activity

Among them, the letter A represents IC ₅₀ less than 5 μM; the letter B represents IC ₅₀ between 5 μM and 10 μM; and the letter C represents IC ₅₀ greater than 10 μM.

The experimental results showed that this series of compounds had good proliferation inhibition activity against prostate cancer cell 22Rv1 that simultaneously expressed AR and AR-V7 proteins.

Test Example 4: DU145 cell (AR negative) proliferation inhibition activity test

Cell viability was detected by quantitatively measuring intracellular ATP using the CellTiter-Glo luminescent cell viability assay kit.

Step 1: Inoculate DU145 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) in a 96-well plate at a density of 1500 cells per well, with a volume of 95 μL per well, and culture in a 37° C., 5% carbon dioxide incubator overnight.

Step 2: Incubate overnight for 24 hours. After the cells are completely attached, add the compound to treat the cells. The test compound is diluted 3 times, and a total of 9 concentration gradients are set; 5 μL of culture medium containing the test compound or DMSO control at the corresponding concentration is added to each well, and 3 replicates are set for each concentration. The final concentration of DMSO is controlled at 0.5%. Place in a 37°C, 5% carbon dioxide incubator for 4 days.

Step 3: CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, G7570) was used to detect cell viability. 50 μL CellTiter-Glo was added to each well, mixed, and incubated at room temperature for 10 minutes. The signal was read using a multifunctional microplate reader (EnVision, PerkinElmer). The inhibition percentage (%) was calculated using the following formula:

Inhibition percentage (%)=(1-signal value of the compound-treated group/signal value of the DMSO-treated group)*100.

The _IC50 values were calculated using GraphPad Prism software. The results are shown in Table 3.

Table 3: DU145 cell proliferation inhibitory activity

Among them, the letter A represents IC ₅₀ less than 5 μM; the letter B represents IC ₅₀ between 5 μM and 10 μM; and the letter C represents IC ₅₀ greater than 10 μM.

The experimental results show that this series of compounds has good selectivity for prostate cancer cell DU145 (negative control cells) that do not express AR protein, and the proliferation inhibition IC ₅₀ is greater than 10 μM.

Test Example 5: PC3 cell (AR negative) proliferation inhibition activity test

Cell viability was detected by quantitatively measuring intracellular ATP using the CellTiter-Glo luminescent cell viability assay kit.

Step 1: PC3 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) were seeded into 384-well plates at a density of 1000 cells per well, with a volume of 40 μL per well, and cultured overnight in a 37° C., 5% carbon dioxide incubator.

Step 2: Incubate overnight for 24 hours. After the cells are completely attached, add the compound to treat the cells. The test compound is diluted 3 times, and a total of 10 concentration gradients are set. The test compound is added using a Mosquito instrument, and 100nL of the test compound or DMSO control containing the corresponding concentration is added to each well. Each concentration is set to 3 replicates, and the final concentration of DMSO is controlled at 0.2%. Place in a 37°C, 5% carbon dioxide incubator for 4 days.

Step 3: CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, G7570) Detect cell viability. Add 20μL CellTiter-Glo to each well, mix well, and incubate at room temperature for 10 minutes. Use a multifunctional microplate reader (EnVision, PerkinElmer) to read the signal. The inhibition percentage (%) is calculated using the following formula:

Inhibition percentage (%)=(1-signal value of the compound-treated group/signal value of the DMSO-treated group)*100.

The _IC50 values were calculated using GraphPad Prism software. The results are shown in Table 4.

Table 4: PC3 cell proliferation inhibitory activity

Among them, the letter A represents IC ₅₀ less than 5 μM; the letter B represents IC ₅₀ between 5 μM and 20 μM; and the letter C represents IC ₅₀ greater than 20 μM.

The experimental results show that this series of compounds has good selectivity for prostate cancer cells PC3 (negative control cells) that do not express AR protein, and most of the compounds have a proliferation inhibition IC ₅₀ greater than 20 μM.

Test Example 6: VCaP (AR positive/AR-V7 positive) cell proliferation inhibition activity test

Cell viability was detected by quantitatively measuring intracellular ATP using the CellTiter-Glo luminescent cell viability assay kit.

Step 1: VCaP cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) were inoculated into 384-well plates at a density of 1800 cells per well, with a volume of 40 μL per well, and cultured in a 37° C., 5% carbon dioxide incubator for 48 h.

Step 2: Compound treatment of cells. The test compound was diluted 3 times, and a total of 10 concentration gradients were set; the test compound was added using a Mosquito instrument, and 100 nL of the test compound or DMSO control containing the corresponding concentration was added to each well, and 3 replicates were set for each concentration. The final concentration of DMSO was controlled at 0.2%. The cells were placed in a 37°C, 5% carbon dioxide incubator for 6 days.

Step 3: Cell viability was detected using the CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, G7570). 20 μL CellTiter-Glo was added to each well, mixed, and incubated at room temperature for 10 minutes. The signal was read using a multifunctional microplate reader (EnVision, PerkinElmer). The inhibition percentage (%) was calculated using the following formula:

Inhibition percentage (%)=(1-signal value of the compound-treated group/signal value of the DMSO-treated group)*100.

_IC50 values were calculated using GraphPad Prism software.

Test Example 7: RT-qPCR method to detect AR or AR-V7 target gene expression in 22Rv1 cells

The effects of the compounds on AR or AR-V7 target genes were detected by real-time fluorescence quantitative PCR. The relative quantitative standard curve method was used to analyze the changes in the expression of AR or AR-V7 related target genes in the compound-treated group samples relative to the untreated reference group samples.

Step 1: 22Rv1 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) were inoculated into a 12-well cell culture plate at a density of 200,000 cells per well, with a culture medium volume of 1 mL per well, and cultured in a 37°C, 5% carbon dioxide incubator for 48 h.

Step 2: Compound treatment of cells. The test compound was diluted 4 times, and 4 concentration gradients were set; a certain volume of DMSO or test compound was added to each well, and the final concentration of DMSO was controlled at 0.5%. The cells were placed in a 37°C, 5% carbon dioxide incubator for 48 hours.

Step 3: Real-time fluorescence quantitative PCR. Sample RNA was extracted using RNeasy Mini Kit (QIAGEN, 74104). The Maxima First Strand cDNA Synthesis Kit for RT-qPCR (Thermo Scientific, K1416-2) was used to reverse RNA into cDNA. Real-time fluorescence quantitative PCR was performed using PowerUp ^™ SYBR ^™ Green Master Mix Kit (Applied Biosystems, A25743). 10 μL of working solution was added to each well of a 384-well plate, mixed, and centrifuged at 1000 rpm for 1 min. The signal was read using a qPCR instrument (QuantStudio 5 Real-Time PCR Instrument, appliedbiosysterms) according to the instructions of the PowerUp ^™ SYBR ^™ Green Master Mix Kit.

GAPDH was used as the internal reference gene and the arithmetic formula 2^(-ΔΔCT) was used to obtain the relative quantitative results of the compound-treated group samples and the untreated reference group samples.

Test Example 8: VCaP castration-resistant prostate cancer mouse model

5x 10^6 VCaP cells were subcutaneously inoculated into the right back of 6-8 week old CB-17SCID male mice. After inoculation, when the average tumor volume reached ~100mm3, the mice were castrated. When the tumor began to recover and grow to ~100mm3, they were randomly divided into groups for drug administration, and the tumor volume and mouse body weight were monitored and recorded twice a week.

Test Example 9: Compound Pharmacokinetics Experiment

Pharmacokinetics of the compounds of the present invention The present application adopts the following method to determine the pharmacokinetic parameters of the compounds of the present application.

Healthy male adult mice used in the study were given a single oral administration of 5-100 mg/Kg per group of animals. Fasting was carried out from 10 hours before administration to 4 hours after administration. Blood was collected at different time points after administration, and the plasma content of the compound was determined (LC-MS/MS). The plasma concentration-time relationship was analyzed using professional software (winnonlin) to calculate the pharmacokinetic parameters of the compound. The data showed that the compound of the present invention has good pharmacokinetic properties.

Claims (112)

The compound shown in the following formula 1-I: or a pharmaceutically acceptable salt thereof, in: Ring A and Ring B are each independently cycloalkyl, heterocyclyl, aryl or heteroaryl; Ring C is a bond, cycloalkyl, heterocyclyl, aryl or heteroaryl; X is C, N, O or S; R ₁ and R ₂ are each independently absent, H, halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, or -NR _a R _a ; Provided that when X is C, _R1 and _R2 are each independently absent, H, halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl _, optionally substituted alkynyl, optionally substituted alkoxy, or _-NRaRa , or _R1 and _R2 together with X form an optionally substituted R ₃ and R ₄ are each independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -(CH ₂ ) _r NR _a R _a or -OR _b ; Z ₁ is a bond, -O-, -S-, -CO-, -S(O)-, -SO ₂ -, -NR _a - or -(CH ₂ ) _r -NR _a -CO-; _R5 is H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; Z ₂ is **-Y ₁ -Y ₂ -*, wherein Y ₁ is a bond, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, Y ₂ is a bond, O, NH or S, "*" represents the point of attachment of Z ₂ to ring A, and "**" represents the point of attachment of Z ₂ to ring C; _R6 is N=S(O) _RcRd or -( _CH2 ) _sS (O)(= _{NRe ) Rf} ; R ₇ is each independently halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR _a , -S(O)R _f , -SO ₂ R _f or -NR _g R _g ; Each _Ra is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or _-CORb ; R _b is H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; R _c and R _d are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl or -NR _a R _a ; or R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl; R _e is H, cyano, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; _Rf is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; R _g is each independently H, -SO ₂ R _f , optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; or two R _g together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl; r is 0, 1, 2, or 3; s is 0, 1, 2, or 3; and m, n and p are each independently 0, 1, 2 or 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring C is a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 6-14 membered aryl or 5-10 membered heteroaryl, preferably selected from phenyl, naphthyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, pyrrolyl, triazolyl, triazinyl, imidazolyl, pyrazolyl, pyrrolyl, pyridinyl, pyrimidinyl or pyrazinyl; and/or Ring B is a 6-14 membered aryl or 5-10 membered heteroaryl group, preferably selected from phenyl, naphthyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, pyrrolyl, triazolyl, triazinyl, pyridonyl, benzomorpholinyl, indazolyl, dihydrobenzoxazinyl, pyrazolopyridinyl, benzotriazolyl, benzimidazolyl, pyridomorpholinyl, tetrahydroisoquinolinyl, imidazopyridinyl, pyridomorpholinyl, benzindolyl, benzisodiazolyl, indolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, decahydroisoquinolyl, dihydroindolyl, octahydroindolyl or octahydroisoindolyl; and/or Ring C is a bond, a 6-14 membered aryl group or a 5-10 membered heteroaryl group, preferably selected from phenyl, naphthyl, pyrimidinyl, pyrazinyl, pyridinyl, piperidinyl, piperazinyl, morpholinyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridazinyl, furanyl, pyrrolyl, triazolyl or triazinyl. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein ring A is phenyl. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein ring B is selected from phenyl, pyridyl, pyridonyl, indazolyl, dihydrobenzoxazinyl, benzomorpholinyl, pyridomorpholinyl, benzimidazolyl, pyrazolopyridinyl or benzotriazolyl. The compound or pharmaceutically acceptable salt thereof according to claim 3, wherein ring C is a 6-14-membered aryl group or a 5-10-membered heteroaryl group. The compound or pharmaceutically acceptable salt thereof according to claim 3, wherein ring C is pyrimidinyl. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein X is C, and R ₁ and R ₂ are each independently H, hydroxyl or optionally substituted alkyl. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R ₁ and R ₂ are each independently optionally substituted alkyl, the optionally substituted alkyl being optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano and -NR _a R _a . The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein one of R ₁ and R ₂ is optionally substituted alkyl and the other is H or hydroxy, wherein the optionally substituted alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano and -NR _a R _a . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R ₃ and R ₄ are each independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -(CH ₂ ) _r NR _a R _a or -OR _b . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein each R ₃ is independently H, halogen, optionally substituted alkyl, optionally substituted alkoxy or -OR _b . The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 10, wherein each R ₄ is independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -(CH ₂ ) _r NR _a R _a or -OR _b , wherein each R _a is independently H, optionally substituted alkenyl or -COR _b , and R _b is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, wherein the optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, alkoxy or -NR _a R _a . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein Z ₁ is a bond, -O-, -S-, -CO-, -S(O)-, -SO ₂ - or -NR _a -. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein Z ₁ is a bond, -O-, -CO-, or -NR _a -, wherein R _a is H or an optionally substituted alkyl. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein R ₅ is optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl, wherein the optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano or -NR _a R _a . The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein Z ₁ is a bond or -O-, and R ₅ is an optionally substituted C ₁ -C ₄ alkyl group, wherein the optionally substituted C ₁ -C ₄ alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano or -NR _a R _a . The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein Z ₁ is -CO-, R ₅ is an optionally substituted C ₂ -C ₄ alkenyl, and the optionally substituted C ₂ -C ₄ alkenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano or -NR _a R _a . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y ₁ is a bond, and Y ₂ is O, NH or S. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y ₁ is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, Y ₂ is a bond or O, and the optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, alkyl or oxo. The compound or pharmaceutically acceptable salt thereof according to claim 20, wherein _Y1 is _C1 - _C4 alkyl or _C2 - _C4 alkynyl, and _Y2 is a bond or O. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ₆ is -N=S(O)R _c R _d . The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ₆ is -N=S(O)R _c R _d , R _c and R _d are each independently selected from optionally substituted alkyl or -NR _{a Ra} , wherein _Ra is each independently H or optionally substituted alkyl. The compound or pharmaceutically acceptable salt thereof according to claim 23, wherein R ₆ is -N=S(O)R _c R _d , and R _c and R _d are each independently selected from optionally substituted C ₁ -C ₄ alkyl. The compound or pharmaceutically acceptable salt thereof according to claim 23 or 24, wherein R ₆ is -N=S(O)R _c R _d , and R _c and R _d are each independently an optionally substituted methyl group. The compound according to claim 23 or 24, or a pharmaceutically acceptable salt thereof, wherein R ₆ is The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein _R is -N=S( _O ) _RcRd , _Rc , _Rd together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl, the optionally substituted 4-10 membered heterocyclyl is optionally substituted by one or more _Rh , wherein _Rh is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted _alkynyl , optionally substituted cycloalkyl, optionally substituted heterocyclyl, _-NRaRa , -C(O) _Rg , -C(O) _NRaRa , -S(O _{)Rf or -SO2Rf} , wherein each _Ra is independently _H or optionally substituted alkyl, the optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano and _-ORb , wherein _Rb is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, R _g is optionally substituted alkyl or optionally substituted cycloalkyl. The compound according to claim 27 or a pharmaceutically acceptable salt thereof, wherein R ₆ is selected from the group consisting of: Each of which is optionally substituted with one or more R _h . The compound according to claim 27 or a pharmaceutically acceptable salt thereof, wherein R ₆ is selected from the group consisting of: The compound or pharmaceutically acceptable salt thereof according to any one of claims 26 to 29, wherein ring C is a heteroaryl group. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ₇ is each independently halogen, cyano, optionally substituted alkyl, -OR _a , -S(O)R _f , -SO ₂ R _f or -NR _g R _g . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula: in _V1 and _V2 are each independently N or CH; Ring C is a bond, aryl or heteroaryl; Z ₁ is a bond, -O-, -CO- or -(CH ₂ ) _r -NR _a -CO; Z ₂ is **-Y ₁ -Y ₂ -*, wherein Y ₁ is a bond, optionally substituted alkyl or optionally substituted alkynyl, and Y ₂ is a bond or O; _R1 and _R2 are each independently hydroxy or optionally substituted alkyl; or _R1 and _R2 together with the carbon atom to which they are attached form an optionally substituted _R3 is H, halogen, _-ORb or optionally substituted alkyl; R ₄ is each independently halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -(CH ₂ ) _r NR _a R _a or -OR _b ; _R5 is optionally substituted alkyl or optionally substituted alkenyl; R ₇ is each independently halogen, cyano, optionally substituted alkyl, -OR _a , -S(O)R _f , -SO ₂ R _f or -NR _g R _g ; _{Ra is} each independently H, optionally substituted alkyl or -COR _b ; R _b is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; R _c and R _d are each independently selected from optionally substituted alkyl or -NR _a R _a ; or R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group; _Rf is an optionally substituted alkyl group; _Rg is each independently H, _-SO2Rf or an optionally substituted _alkyl group; or two _Rg together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group; and r, s, m, n and p are each independently 0, 1 or 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula: in _V3 is N or CH; Ring C is a bond, aryl or heteroaryl; Ring D is a heterocyclic group or a heteroaryl group; Z ₁ is a bond, -O-, -CO- or -(CH ₂ ) _r -NR _a -CO-; Z ₂ is **-Y ₁ -Y ₂ -*, wherein Y ₁ is a bond, optionally substituted alkyl or optionally substituted alkynyl, and Y ₂ is a bond or O; _R1 and _R2 are each independently hydroxy or optionally substituted alkyl; or _R1 and _R2 together with the carbon atom to which they are attached form an optionally substituted _R3 is H, halogen, optionally substituted alkyl or optionally substituted alkoxy; R ₄ is each independently halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -(CH ₂ ) _r NR _a R _a or -OR _b ; _R5 is H, optionally substituted alkyl or optionally substituted alkenyl; R ₇ is each independently halogen, cyano, optionally substituted alkyl, -OR _a , -S(O)R _f , -SO ₂ R _f or -NR _g R _g ; R _a is each independently H, optionally substituted alkyl or -COR _b ; R _b is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; R _c and R _d are each independently selected from optionally substituted alkyl or -NR _a R _a ; or R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group; _Rf is an optionally substituted alkyl group; _Rg is each independently H, _-SO2Rf or an optionally substituted _alkyl group; or two _Rg together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group; and r, s, m, n and p are each independently 0, 1 or 2. The compound or pharmaceutically acceptable salt thereof according to claim 32 or 33, wherein the ring C is an aryl group or a heteroaryl group. The compound according to claim 34 or a pharmaceutically acceptable salt thereof, wherein ring C is a 6-14-membered aryl group or a 5-10-membered heteroaryl group. The compound according to claim 32 or 33, or a pharmaceutically acceptable salt thereof, wherein Z ₁ is a bond, -O- or -CO-. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 32 to 36, wherein R ₃ is H or an optionally substituted alkyl. The compound according to claim 32 or a pharmaceutically acceptable salt thereof, wherein It is phenyl, pyridyl or pyridonyl. The compound according to claim 33 or a pharmaceutically acceptable salt thereof, wherein Selected from: The compound according to claim 33 or a pharmaceutically acceptable salt thereof, wherein the ring D is substituted by 1, 2 or 3 R ₉ , and R ₉ is H, halogen or optionally substituted alkyl. The compound according to claim 40 or a pharmaceutically acceptable salt thereof, wherein R ₉ is selected from H, F, Cl, CH ₃ or CF ₃ . The compound according to claim 33 or 39, or a pharmaceutically acceptable salt thereof, wherein The saturated nitrogen atom on the ring D is connected to -Z ₁ R ₅ . The compound or pharmaceutically acceptable salt thereof according to claim 32 or 33, wherein each R ₃ is independently H, fluorine, chlorine, optionally substituted C ₁ -C ₄ alkyl or optionally substituted C ₁ -C ₄ alkoxy. The compound of claim 32 or 33, or a pharmaceutically acceptable salt thereof, wherein each R ₃ is independently an optionally substituted C ₁ -C ₄ alkyl or an optionally substituted C ₁ -C ₄ alkoxy group, wherein the optionally substituted C ₁ -C ₄ alkyl group or the optionally substituted C ₁ -C ₄ alkoxy group is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano and -NR _a R _a . The compound or pharmaceutically acceptable salt thereof according to claim 32 or 33, wherein each R ₃ is independently selected from halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy. The compound of claim 32 or 33, or a pharmaceutically acceptable salt thereof, wherein each R ₃ is independently selected from fluoro, chloro, methyl or methoxy. The compound or pharmaceutically acceptable salt thereof according to claim 32 or 33, wherein R _c and R _d are each independently C ₁ -C ₄ alkyl or -NH-(C ₁ -C ₄ alkyl). The compound or pharmaceutically acceptable salt thereof according to claim 32 or 33, wherein R _c and R _d are each independently an optionally substituted methyl group. The compound or pharmaceutically acceptable salt thereof according to claim 32 or 33, wherein R _c and R _d are both methyl. The compound or pharmaceutically acceptable salt thereof according to claim 32 or 33, wherein R _c and R _d together with the S atom to which they are attached form a 4-10 membered heterocyclic group optionally substituted by one or more R _h . The compound of claim 32 or 33, or a pharmaceutically acceptable salt thereof, wherein _R and _R together with the S atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted by one or more _R , wherein _R is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, -NR _{a Ra} , -C(O)R _g , -C(O)NR _{a Ra} , -S(O)R _f or -SO ₂ R _f , wherein each _Ra is independently H or optionally substituted alkyl, the optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano and -OR _b , wherein R _b is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, and R _g is optionally substituted alkyl or optionally substituted cycloalkyl. The compound or pharmaceutically acceptable salt thereof according to claim 32 or 33, wherein the 4-10 membered heterocyclic group formed by R _c and R _d together with the S atom to which they are attached is selected from the following group: wherein each of them is optionally substituted by one or more R _h , wherein R _h is selected from optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkynyl, optionally substituted C ₃ -C ₆ cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -NR _a R _a , -C(O)R _g , -C(O)NR _a R _a , -S(O)R _f or -SO ₂ R _f , wherein each R _a is independently H or optionally substituted C ₁ -C ₄ alkyl, the above optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkynyl and optionally substituted C ₃ -C ₆ cycloalkyl are optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano and -OR _b , wherein R _b is optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl, and R _g is optionally substituted C ₁ -C ₄ alkyl or an optionally substituted C ₂ -C ₄ cycloalkyl. The compound of claim 52, or a pharmaceutically acceptable salt thereof, wherein R _h is selected from the group consisting of C ₁ -C ₄ alkyl, C 2 -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, 4-9 membered heterocyclyl optionally substituted with one or more C ₁ -C ₄ alkyl, -NH 2 , -NH(C ₁ -C ₄ alkyl), -C(O)-(C ₁ -C ₄ alkyl), -C(O)-(C ₂ -C ₄ cycloalkyl), -C(O)NH ₂ and -SO ₂ (C _{1 -C 4} alkyl), wherein the C ₁ -C ₄ alkyl in -NH(C ₁ -C ₄ alkyl) and -C(O)-(C _{1 -C 4} alkyl) is optionally substituted with one _or more _halogen or hydroxyl. The compound or pharmaceutically acceptable salt thereof according to claim 32 or 33, wherein R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group selected from the following group: The compound or pharmaceutically acceptable salt thereof of claim 32 or 33, wherein Z ₂ is -O-, C ₂ -C ₄ alkynyl or **-(optionally substituted C _{1 -C 4} alkyl)-O-*, wherein the optionally substituted C ₁ -C ₄ alkyl is optionally substituted with one or more substituents selected from hydroxy, C1 -C 4 alkyl or oxo. The compound or pharmaceutically acceptable salt thereof according to claim 32 or 33, wherein ring C is phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl. The compound shown in the following formula 2-1: or a pharmaceutically acceptable salt thereof, in: Ring A and Ring B are each independently cycloalkyl, heterocyclyl, aryl or heteroaryl; Ring C is a bond, cycloalkyl, heterocyclyl, aryl or heteroaryl; X is C, N, O or S; R ₁ and R ₂ are each independently absent, H, halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, or -NR _a R _a ; R ₃ and R ₄ are each independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -(CH ₂ ) _r NR _a R _a or -OR _b ; Z ₁ is a bond, -O-, -S-, -CO-, -S(O)-, -SO ₂ -, -NR _a - or -(CH ₂ ) _r -NR _a -CO-; R ₅ is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; R ₆ is -N=S(O)R _c R _d , -(CH ₂ ) _s S(O)(=NR _e )R _f or -NR _a -SO ₂ R _g ; R ₇ is each independently halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR _a , -S(O)R _f , -SO ₂ R _f or -NR _h R _h ; Each _Ra is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or _-CORb ; R _b is H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; R _c and R _d are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OR _a or -NR _a R _a ; or R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl; R _e is H, cyano, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; _Rf is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; _Rg is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted 4-10 membered _heterocyclyl or _-NRhRh ; R _h is each independently H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; or two R _h together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl; r is 0, 1, 2, or 3; s is 0, 1, 2, or 3; and m, n and p are each independently 0, 1, 2 or 3. The compound or pharmaceutically acceptable salt thereof according to claim 57, wherein Z ₁ is a bond, -O-, -S-, -CO-, -S(O)-, -SO ₂ - or -NR _a -. The compound or pharmaceutically acceptable salt thereof according to any one of claims 56 to 58, wherein R ₆ is -N=S(O)R _c R _d or -NR _a -SO ₂ R _g . The compound or pharmaceutically acceptable salt thereof according to claim 57, wherein ring A is a 6-14 membered aryl group. The compound or pharmaceutically acceptable salt thereof according to claim 58, wherein ring A is phenyl. The compound according to claim 57 or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-10 membered heteroaryl group. The compound according to claim 62 or a pharmaceutically acceptable salt thereof, wherein ring A is pyridyl. The compound according to claim 57 or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5-10 membered heterocyclic group. The compound according to claim 64 or a pharmaceutically acceptable salt thereof, wherein ring B is pyridone. The compound according to claim 57 or a pharmaceutically acceptable salt thereof, wherein ring B is a 6-14 membered aryl group. The compound according to claim 66 or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl. The compound according to claim 57 or a pharmaceutically acceptable salt thereof, wherein ring B is a 6-14 membered heteroaryl group. The compound of claim 68 or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyridonyl, benzomorpholinyl, indazolyl, dihydrobenzoxazinyl, pyrazolopyridinyl, benzotriazolyl, benzimidazolyl, pyridomorpholinyl, tetrahydroisoquinolinyl, imidazopyridinyl, pyridomorpholinyl, benzisodiazolyl, indolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, decahydroisoquinolyl, dihydroindolyl, octahydroindolyl or octahydroisoindolyl. The compound according to claim 57 or a pharmaceutically acceptable salt thereof, wherein ring C is a 6-14 membered heteroaryl group. The compound of claim 70 or a pharmaceutically acceptable salt thereof, wherein ring C is selected from pyridinyl, pyrimidinyl or pyrazinyl. The compound of claim 57 or a pharmaceutically acceptable salt thereof, wherein X is C, R ₁ and R ₂ are each independently H, hydroxyl or optionally substituted alkyl. The compound of claim 72, or a pharmaceutically acceptable salt thereof, wherein R ₁ and R ₂ are each independently optionally substituted alkyl, the optionally substituted alkyl being optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano and -NR _a R _a . The compound of claim 72, or a pharmaceutically acceptable salt thereof, wherein one of R ₁ and R ₂ is optionally substituted alkyl and the other is H or hydroxy, wherein the optionally substituted alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano and -NR _a R _a . The compound or pharmaceutically acceptable salt thereof according to claim 57, wherein each R ₃ is independently H, halogen, cyano, optionally substituted alkyl or OR _b . The compound of claim 57, or a pharmaceutically acceptable salt thereof, wherein each R ₄ is independently H, halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -(CH ₂ ) _r NR _a R _a or -OR _b , wherein each R _a is independently H, optionally substituted alkenyl or -COR _b , and R _b is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, wherein the optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano or -NR _a R _a . The compound or pharmaceutically acceptable salt thereof according to claim 57, wherein Z ₁ is a bond, -O-, -CO-, -NR _a - or -(CH ₂ ) _r -NR _a -CO-, wherein _Ra is H or an optionally substituted alkyl group. The compound of claim 57 or a pharmaceutically acceptable salt thereof, wherein Z ₁ is a bond, -O-, -CO- or -NR _a -, wherein _Ra is H or an optionally substituted alkyl group. The compound of claim 57, or a pharmaceutically acceptable salt thereof, wherein R ₅ is optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl, wherein the optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano or -NR _a R _a . The compound of claim 57, or a pharmaceutically acceptable salt thereof, wherein Z ₁ is a bond, R ₅ is an optionally substituted C ₁ -C ₄ alkyl, the optionally substituted C ₁ -C ₄ alkyl being optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano or -NR _a R _a . The compound of claim 57 or a pharmaceutically acceptable salt thereof, wherein Z ₁ is -O-, R ₅ is an optionally substituted C ₁ -C ₄ alkyl, the optionally substituted C ₁ -C ₄ alkyl being optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano or -NR _a R _a . The compound of claim 57 or a pharmaceutically acceptable salt thereof, wherein R ₆ is -N=S(O)R _c R _d , R _c and R _d are each independently selected from optionally substituted alkyl, -OR _a or -NR _{a Ra} , wherein _Ra is each independently H, optionally substituted alkyl or optionally substituted alkynyl. The compound according to claim 57 or a pharmaceutically acceptable salt thereof, wherein R ₆ is The compound of claim 57 or a pharmaceutically acceptable salt thereof, wherein R ₆ is -N=S(O)R _c R _d , R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl, the optionally substituted 4-10 membered heterocyclyl is optionally substituted by one or more R _i , wherein each R _i is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -C(O)R _j , -NR _{a Ra} , -C(O)NR _{a Ra} , -S(O)R _f or -SO ₂ R _f , wherein each _Ra is independently H or optionally substituted alkyl, the optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted cycloalkyl are optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano and -OR _b , wherein R _b is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, wherein R _j is optionally substituted alkyl or optionally substituted cycloalkyl. The compound of claim 84 or a pharmaceutically acceptable salt thereof, wherein R ₆ is selected from the group consisting of: Each of which is optionally substituted with one or more R _i . The compound of claim 84 or 85, or a pharmaceutically acceptable salt thereof, wherein R ₆ is selected from the group consisting of: The compound or pharmaceutically acceptable salt thereof as described in any one of claims 82 to 86, wherein ring C is a heteroaryl group. [Corrected on 29.03.2023 according to Rule 26] A compound according to claim 57 or a pharmaceutically acceptable salt thereof, wherein R ₆ is -NR _a -SO ₂ R _g , _Ra is H or optionally substituted alkyl, and R _g is optionally substituted alkyl, optionally substituted 4-10 membered heterocyclyl or -NR _h R _h . The compound of claim 88, or a pharmaceutically acceptable salt thereof, wherein _Ra is H or alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxyl or cyano. The compound of claim 88, or a pharmaceutically acceptable salt thereof, wherein _Rg is alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano or -NR _{a Ra} , wherein _Ra is independently selected from hydrogen or alkyl. The compound of claim 88, or a pharmaceutically acceptable salt thereof, wherein _Rg is a 4-10 membered heterocyclyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano or -NR _{a Ra} , wherein _Ra is independently selected from hydrogen or alkyl. The compound of claim 88 or a pharmaceutically acceptable salt thereof, wherein _Rg is _-NRhRh , wherein each _Rh is independently hydrogen or _alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl or cyano, or two _Rh together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl. The compound of claim 57 or a pharmaceutically acceptable salt thereof, wherein R ₇ is each independently halogen, cyano, optionally substituted alkyl, -OR _a , -S(O)R _f , -SO ₂ R _f or -NR _g R _g . The compound of claim 57 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula: in _V1 and _V2 are each independently N or CH; Ring C is a bond, aryl or heteroaryl; Z ₁ is a bond, -O-, -CO- or -(CH ₂ ) _r -NR _a -CO-; _R1 and _R2 are each independently hydroxy or optionally substituted alkyl; _R3 is H, _ORb or optionally substituted alkyl; R ₄ is each independently halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -(CH ₂ ) _r NR _a R _a or -OR _b ; _R5 is optionally substituted alkyl or optionally substituted alkenyl; R ₇ is each independently halogen, cyano, optionally substituted alkyl, -OR _a , -S(O)R _f , -SO ₂ R _f or -NR _h R _h ; _{Ra is} each independently H, optionally substituted alkyl or -COR _b ; R _b is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; R _c and R _d are each independently selected from optionally substituted alkyl or -NR _a R _a ; or R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group; _Rf is an optionally substituted alkyl group; R _h is each independently H, -SO ₂ R _f or an optionally substituted alkyl group; or two R _h together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl group; and r, s, m, n and p are each independently 0, 1 or 2. The compound of claim 57 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula: in _V3 is N or CH; Ring C is a bond, aryl or heteroaryl; Ring D is a heterocyclic group or a heteroaryl group; Z ₁ is a bond, -O-, -CO- or -(CH ₂ ) _r -NR _a -CO-; _R1 and _R2 are each independently hydroxy or optionally substituted alkyl; _R3 is H, _ORb or optionally substituted alkyl; R ₄ is each independently halogen, cyano, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -(CH ₂ ) _r NR _a R _a or -OR _b ; _R5 is optionally substituted alkyl or optionally substituted alkenyl; R ₇ is each independently halogen, cyano, optionally substituted alkyl, -OR _a , -S(O)R _f , -SO ₂ R _f or -NR _h R _h ; R _a is each independently H, optionally substituted alkyl or -COR _b ; R _b is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; R _c and R _d are each independently selected from optionally substituted alkyl or -NR _a R _a ; or R _c , R _d together with the S atom to which they are attached form an optionally substituted 4-10 membered heterocyclic group; _Rf is an optionally substituted alkyl group; R _h is each independently H, -SO ₂ R _f or an optionally substituted alkyl group; or two R _h together with the N atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl group; and r, s, m, n and p are each independently 0, 1 or 2. The compound or pharmaceutically acceptable salt thereof according to claim 94 or 95, wherein Ring C is an aryl group or a heteroaryl group. The compound or pharmaceutically acceptable salt thereof according to claim 94 or 95, wherein ring C is a 6-14 membered aryl group or a 6-14 membered heteroaryl group. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 94 to 96, wherein Z ₁ is a bond, -O- or -CO-. The compound of claim 94 or a pharmaceutically acceptable salt thereof, wherein It is phenyl, pyridyl or pyridonyl. The compound of claim 95 or a pharmaceutically acceptable salt thereof, wherein Selected from: The compound or pharmaceutically acceptable salt thereof according to claim 95, wherein the ring D is substituted by 1, 2 or 3 R ₉ , and the R ₉ is H, halogen or optionally substituted alkyl. The compound of claim 95 or 100 or a pharmaceutically acceptable salt thereof, wherein The saturated nitrogen atom on the ring D is connected to -Z ₁ R ₅ . The compound or pharmaceutically acceptable salt thereof according to claim 94 or 95, wherein R _c and R _d are each independently C ₁ -C ₄ alkyl or -NH-(C ₁ -C ₄ alkyl). The compound of claim 94 or 95, or a pharmaceutically acceptable salt thereof, wherein _R and _R together with the S atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted by one or more _R , wherein each _R is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted 4-9 membered heterocyclyl, -C(O ₎ Rj-, _-NRaRa , _-C (O) _NRaRa , -S(O) _Rf , or _-SO2Rf , wherein each _Ra is independently H or optionally substituted alkyl, the optionally substituted alkyl, optionally substituted alkenyl _, optionally substituted alkynyl, and optionally substituted cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and _-ORb , wherein _Rb is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, wherein _Rj is optionally substituted alkyl or optionally substituted cycloalkyl. The compound or pharmaceutically acceptable salt thereof according to claim 94 or 95, wherein ring C is phenyl, pyridyl, pyrimidinyl or pyrazinyl. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 105, wherein the compound is selected from the group consisting of: A pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound according to any one of claims 1 to 106 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Use of a compound according to any one of claims 1 to 106 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 107, in the preparation of a medicament for treating or preventing androgen receptor-mediated diseases. The use as claimed in claim 108, wherein the androgen receptor-mediated diseases include: prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioblastoma, melanoma, renal cell carcinoma, mantle cell lymphoma, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, age-related macular degeneration and combinations thereof; preferably, the disease is prostate cancer, more preferably primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer or metastatic castration-resistant prostate cancer or hormone-sensitive prostate cancer. Use of a compound according to any one of claims 1 to 106 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 107, in the preparation of a medicament for treating or preventing a disease mediated by an androgen receptor variant. The use as claimed in claim 110, wherein the androgen receptor variant is an AR splice variant. The use as claimed in claim 111, wherein the androgen receptor variant is AR-V7.