CN118812445A - Benzenesulfonamide WDR5-MYC interaction inhibitors and pharmaceutical compositions and uses thereof - Google Patents

Abstract

The present disclosure provides benzenesulfonamide WDR5-MYC interaction inhibitors and pharmaceutical compositions and uses thereof. The compounds have the structure of formula (I), and the compounds and pharmaceutical compositions can be used to prevent or treat diseases, conditions or disorders associated with MYC.

Description

Benzenesulfonamide WDR5-MYC interaction inhibitors and pharmaceutical compositions and uses thereof

Technical Field

The present disclosure relates to benzenesulfonamide compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, metabolites, isotope-labeled compounds or prodrugs thereof that inhibit WDR5-MYC protein-protein interaction, preparation methods thereof and pharmaceutical compositions containing the same, and the use of the compounds and pharmaceutical compositions for preventing or treating diseases, conditions or disorders associated with MYC.

Background Art

MYC is a type of oncoprotein with transcription factor function. It is overexpressed in most malignant tumors and is considered a highly validated anti-cancer target, causing hundreds of thousands of cancer deaths worldwide each year. MYC's cancer-promoting potential is mainly due to its ability to bind to the regulatory sequences of thousands of target genes, regulate target gene expression, affect cell growth, proliferation, metabolism, genome stability and apoptosis, and this potential also depends on the interaction between myc and its binding factor MAX to form a heterodimer, thereby achieving binding to DNA.

Recent studies have found that the extensive binding of MYC to chromatin also depends on the interaction with the WD40-repeat protein WDR5. WDR5 belongs to the WD40 domain repeat family (WD40-repeat) protein, which usually acts as a scaffold protein and participates in the interaction of various oncogenic proteins. As a protein that assembles the histone modifier complex into the nucleus, WDR5 can recruit MYC to chromatin, and MYC can interact with the shallow hydrophobic cleft on the surface of WDR5 through its evolutionary conserved "MYC box IIIb" sequence, bind together, and ultimately control the expression of genes related to protein synthesis. Structure-guided mutations in MYC that cannot interact with WDR5 reduce MYC binding to chromatin and weaken its tumorigenic potential. Therefore, breaking the interaction between MYC and its chromatin co-factor WDR5 can treat MYC-related cancers.

Therefore, the development of new inhibitors of WDR5-MYC interaction is needed.

Summary of the invention

The present disclosure provides novel WDR5-MYC protein-protein interaction (WDR5-MYC PPI) inhibitors.

The novel WDR5-MYC PPI inhibitor disclosed herein has high affinity for WDR5 and can inhibit WDR5-MYC PPI, and thus has the potential to prevent and treat diseases, disorders or conditions associated with MYC. The compounds disclosed herein have improved pharmacokinetic properties (e.g., improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (e.g., reduced cardiac toxicity) and/or fewer side effects), less prone to drug resistance and other more excellent properties.

In one aspect, the present disclosure provides benzenesulfonamide compounds of formula (I) as defined below:

or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof.

In another aspect, the present disclosure provides the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, which is used as a medicament, preferably a WDR5-MYC PPI inhibitor.

In another aspect, the present disclosure provides use of the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof in the preparation of a drug, preferably a WDR5-MYC protein protein interaction (WDR5-MYC PPI) inhibitor.

In another aspect, the present disclosure provides a pharmaceutical composition comprising the compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.

In another aspect, the present disclosure provides a method for preventing or treating a disease, disorder or condition associated with MYC in an individual, wherein the method comprises: administering to the individual a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof; or administering to the individual a therapeutically effective amount of the pharmaceutical composition.

In another aspect, the present disclosure provides the use of the compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or the pharmaceutical composition in the preparation of a medicament for preventing or treating a disease, disorder or condition associated with MYC in an individual.

In some embodiments, the disease, disorder or condition is a tumor (e.g., cancer), including solid tumors and hematological tumors. In some embodiments, the solid tumor is ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, gastric cancer, or uterine cancer. In some embodiments, the hematological tumor is leukemia.

DETAILED DESCRIPTION

definition

Unless otherwise defined below, the meanings of all technical terms and scientific terms used herein are intended to be the same as those generally understood by those skilled in the art. Reference to the technology used herein is intended to refer to the technology generally understood in the art, including those changes in technology or replacement of equivalent technology that are obvious to those skilled in the art. Although it is believed that the following terms are well understood by those skilled in the art, the following definitions are still set forth to better explain the present invention.

The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps (i.e., these terms also encompass the terms "consisting essentially of" and "consisting of").

As used herein, the term "alkane" means a straight-chain or branched saturated aliphatic hydrocarbon.

As used herein, the term "alkyl" means a straight or branched monovalent saturated aliphatic hydrocarbon, which can be regarded as a group obtained by losing 1 hydrogen atom from an alkane. In some embodiments, the alkyl group has 1 to 12, such as 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. For example, as used herein, the term "C _1-8 alkyl" refers to a straight or branched group of 1 to 8 carbon atoms, including "C _1-6 alkyl", "C _2-6 alkyl", "C _2-5 alkyl", "C _1-4 alkyl" and "C _1-2 alkyl". Examples of "C _1-6 alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. The alkyl group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents such as halogen (in this case _, the group is referred to as "haloalkyl", for example _CF3 , _C2F5 , _CHF2 , _{CH2F , CH2CF3} , _CH2Cl or _-CH2CH2CF3 , etc.). The term " _C1-4alkyl " refers to an alkyl group having 1 to 4 carbon atoms (i.e. _, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- _butyl or tert-butyl).

As used herein, the term "alkylene" refers to a linear or branched divalent saturated aliphatic hydrocarbon. In some embodiments, the alkylene group has 1 to 12 carbon atoms, preferably 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, such as methylene, ethylene, propylene or butylene.

As used herein, the term "alkenyl" means a linear or branched monovalent aliphatic hydrocarbon group containing one or more double bonds. In some embodiments, the alkenyl group has 2-8 carbon atoms (" _C2-8 alkenyl"), for example, 2-6 carbon atoms (" _C2-6 alkenyl") or 2-4 carbon atoms (" _C2-4 alkenyl"). The alkenyl group is, for example, -CH= _CH2 , _-CH2CH = _CH2 , -C( _CH3 )= _CH2 , _-CH2- CH=CH- _CH3 , 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the invention contain an alkenyl group, the compounds may be present in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof.

As used herein, the term "alkynyl" means a linear or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds. In some embodiments, the alkynyl group has 2, 3, 4, 5, 6, 7 or 8 carbon atoms (" _C2-8 alkynyl"), such as ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. The alkynyl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents.

As used herein, the terms "cycloalkyl", "hydrocarbon ring" and "cycloalkylene" refer to saturated (i.e., "cycloalkyl" and "cycloalkylene") or partially unsaturated (i.e., having one or more double bonds (i.e., "cycloalkenyl" and "cycloalkenylene") and/or triple bonds in the ring) monocyclic or polycyclic fused hydrocarbon rings having, for example, 3-10 (suitably 3-8, more suitably 3-7, 3-6, 4-6 or 5-6) ring carbon atoms. The ring includes, but is not limited to, cyclopropyl (ring), cyclobutyl (ring), cyclopentyl (ring), cyclohexyl (ring), cycloheptyl (ring), cyclooctyl (ring), cyclononyl (ring), cyclobutenyl (ring), cyclopentenyl (ring), cyclohexenyl (ring), cycloheptenyl (ring), cyclooctenyl (ring), cyclononenyl (ring), etc.

As used herein, the term "fused" means that two or more ring structures share two adjacent atoms with each other.

As used herein, the terms "cycloalkyl" and "cycloalkylene" refer to a saturated monocyclic or polycyclic (such as bicyclic) fused hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring such as ). The cycloalkyl and cycloalkylene groups have 3 to 10 carbon atoms, suitably 3-8, for example 3-7, 3-6, 4-6 or 5-6. The cycloalkyl and cycloalkylene groups are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g. methyl or halogen), for example methyl-substituted cyclopropyl.

As used herein, the terms "cycloalkenyl" and "cycloalkenylene" refer to monocyclic or polycyclic (such as bicyclic) fused hydrocarbon rings (e.g., monocyclic, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or bicyclic) having one or more double bonds in the ring. The cycloalkenyl and "cycloalkenylene" have 3 to 10 carbon atoms, suitably 3-8, such as 3-7, 3-6, 4-6 or 5-6. The cycloalkenyl and cycloalkenylene are optionally substituted with 1 or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopentenyl.

As used herein, the terms "heterocyclyl", "heterocycle" and "heterocyclylene" refer to a saturated (i.e., "heterocycloalkyl" and "heterocycloalkylene") or partially unsaturated (e.g., having one or more double bonds within the ring (i.e., "heterocycloalkenyl" and "heterocycloalkenylene")) monovalent monocyclic or bicyclic fused ring structure having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and 1 or more (e.g., 1, 2, 3 or 4) heteroatom-containing groups selected from O, S, S(=O), S(=O) ₂ and NR', wherein R' is a hydrogen atom or a _C1-6 alkyl or a halo- _C1-6 alkyl. The heterocyclyl group can be attached to the rest of the molecule via any of the carbon atoms or the nitrogen atom, if present. In particular, the 3-10 membered heterocyclic group is a group having 3-10 (e.g. 3-8, 3-7, 3-6, 4-6 or 5-6) carbon atoms and heteroatoms in the ring. The heterocyclic group is optionally substituted by 1 or more (e.g. 1 to 3) suitable substituents (e.g. halogen, OH, NH ₂ , oxo (═O), C _1-6 alkyl, C _1-6 haloalkyl). Examples that may be mentioned include, but are not limited to, oxirane, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, azocanyl, dihydropyrrolyl, dihydroimidazolyl, azooctenyl.

As used herein, the term "monospiro heterocyclyl" refers to a cyclic structure formed by a cycloalkyl as defined herein and a heterocyclyl as defined herein, or two heterocyclyls as defined herein, which share a ring atom, and which has 3, 4, 5, 6, 7, 8 or 9 carbon atoms and 1 or more (e.g., 1, 2, 3 or 4) heteroatom-containing groups selected from O, S, S(=O), S(=O) ₂ and NR', wherein R ^' is as defined above. The monospiro heterocyclyl can be connected to the rest of the molecule through any of the carbon atoms or nitrogen atom (if present). In particular, a 5-11-membered monospiro heterocyclyl is a group having 5-11 carbon atoms and heteroatoms in the ring, including but not limited to a 6-11-membered monospiro heterocyclyl, a 7-11-membered monospiro heterocyclyl, a 7-9-membered monospiro heterocyclyl or an 8-10-membered monospiro heterocyclyl. The monospiro heterocyclyl group may be saturated (i.e., "monospiro heterocycloalkyl") or partially unsaturated (e.g., having one or more double bonds in the ring (i.e., "monospiro heterocycloalkenyl")). The monospiro heterocyclyl group includes, but is not limited to, a 5-11-membered monospiro heterocycloalkyl group, a 7-11-membered monospiro heterocycloalkyl group, a 7-11-membered nitrogen-containing monospiro heterocycloalkyl group, a 7-10-membered oxygen-containing monospiro heterocycloalkyl group, a 7-10-membered sulfur-containing monospiro heterocycloalkyl group; and a 5-11-membered monospiro heterocycloalkenyl group, a 7-11-membered monospiro heterocycloalkenyl group, a 7-11-membered nitrogen-containing monospiro heterocycloalkenyl group, a 7-11-membered oxygen-containing monospiro heterocycloalkenyl group, and a 7-11-membered sulfur-containing monospiro heterocycloalkenyl group. The monospiro heterocyclic group may include, for example, a 3-membered/5-membered ring system, a 4-membered/4-membered ring system, a 4-membered/5-membered ring system, a 4-membered/6-membered ring system, a 5-membered/5-membered ring system, a 5-membered/6-membered ring system, and a 6-membered/6-membered ring system, wherein the count of each ring includes the spiro atom. The monospiro heterocyclic group may be optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g., methyl, ethyl, or oxo). Examples that may be cited include, but are not limited to

The "nitrogen-containing monospiro heterocyclic group", "oxygen-containing monospiro heterocyclic group" and "sulfur-containing monospiro heterocyclic group" optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur. The term "7-11-membered nitrogen-containing monospiro heterocyclic group" refers to a monospiro heterocyclic group containing a total of 7-11 ring atoms and at least one of the ring atoms being a nitrogen atom.

As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, as used herein, the term "C _6-14 aryl" means an aromatic group containing 6 to 14 (e.g., 6 to 12) carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituted with 1 or more (e.g., 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO ₂ , C _1-6 alkyl, etc.).

As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having 5 to 14 ring atoms, e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and 1, 2, 3, 4 or 5 identical or different heteroatoms independently selected from N, O, S and S(O) ₂ . One or more ring carbon atoms in the heteroaryl may be replaced by C(O). The heteroaryl may be benzo-fused. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridonyl, pyrimidinyl, pyrimidonyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, quinolyl, indolyl, pyrrolopyridazinyl, benzo The heteroaryl group may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

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

The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form stable compounds.

If a group is described as "optionally substituted with" or "optionally substituted," the group may be: (1) unsubstituted or (2) substituted. If a carbon of a group is described as optionally substituted with one or more of the listed substituents, one or more hydrogens on that carbon (to the extent of any hydrogens present) may be replaced, individually and/or together, with independently selected optional substituents. If a nitrogen of a group is described as optionally substituted with one or more of the listed substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent. The optional substituents may be selected from the group consisting of halogen, OH, SH, CN, _NO2 , _C1-6 alkyl, _C1-6 haloalkyl, _C2-6 alkenyl, _C2-6 alkynyl, _-OC1-6 alkyl, -O- _haloC1-6 alkyl, _-OC2-6 alkenyl, _{-OC2-6 alkynyl, -SC1-6 alkyl} , _NH2 , -NH( _C1-6 alkyl), -N( _C1-6 alkyl) ₂ , _-C1-6 alkylene-OH, _-C1-6 alkylene-SH, _-C1-6 alkylene-CN, _-C1-6 alkylene- _NH2 , _-C1-6 alkylene-NH( _C1-6 alkyl), _-C1-6 alkylene-N( _C1-6 alkyl) ₂ , _-C1-6 alkyl- _OC1-6 alkyl, -C1-6 _{-C 0-6} alkylene-C(O)OH, -C _0-6 alkylene-C(O)OC _1-6 alkyl, -C _0-6 alkylene-C(O)NH ₂ , -C _0-6 alkylene-C(O)NH(C _1-6 alkyl), -C _0-6 alkylene-C(O)N(C _1-6 alkyl) ₂ , -C _0-6 alkylene-S(O) ₂ C _1-6 alkyl, -C _0-6 alkylene-S(O) ₂ NH ₂ , -C _0-6 alkylene-S(O) ₂ NH(C _1-6 alkyl), -C _0-6 alkylene-S(O) ₂ N(C _1-6 alkyl) ₂ , -NH-C(O)C _1-6 alkyl, -N(C _1-6 alkyl)-C(O)C _{-C 1-6} alkyl, -NH—C(═O)OH, -NH—C(═O)OC _1-6 alkyl, -N(C _1-6 alkyl)-C(═O)OC _1-6 alkyl, -NH—C(O)NH ₂ , -NH—C(O)NH(C _1-6 alkyl), -NH—C(O)N(C _1-6 alkyl) ₂ , -NH—S(O) ₂ -C _1-6 alkyl, -N(C _1-6 alkyl)-S(O) ₂ -C _1-6 alkyl, -C _0-6 alkylene-C _3-10 cycloalkyl, -C _0-6 alkylene-(3-10 membered heterocyclyl), -C _0-6 alkylene-phenyl and -C _0-6 alkylene-(5-10 membered heteroaryl).

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

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

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

When a bond to a substituent is shown as passing through a bond connecting two atoms in a ring (a "floating bond"), such a substituent may be bonded to any ring-forming atom in the substitutable ring, unless otherwise indicated. Where an available ring member is shown to carry a substitutable hydrogen atom, the substitutable hydrogen atom is substantially substituted (i.e., not present) when the floating bond is bonded to the available ring member.

The present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D, ² H), tritium (T, ³ H)); isotopes of carbon (e.g., ¹¹ C, ¹³ C, and ¹⁴ C); isotopes of chlorine (e.g., ³⁶ Cl); isotopes of fluorine (e.g., ¹⁸ F); isotopes of iodine (e.g., ¹²³ I and ¹²⁵ I); isotopes of nitrogen (e.g., ¹³ N and ¹⁵ N); isotopes of oxygen (e.g., ¹⁵ O, ¹⁷ O, and ¹⁸ O); isotopes of phosphorus (e.g., ³² P); and isotopes of sulfur (e.g., ³⁵ S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioisotopes) can be used in drug and/or substrate tissue distribution studies (e.g., analysis). The radioisotopes tritium (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) are particularly useful for this purpose because they are easily incorporated and easily detected. Substitution with positron emitting isotopes (e.g., ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N) can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the invention can be prepared by methods similar to those described in the accompanying routes and/or examples and preparations by using appropriate isotopically labeled reagents instead of previously employed non-labeled reagents. Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent can be isotopically substituted, for example, D ₂ O, acetone-d ₆ , or DMSO-d _6. In some embodiments, the isotopically labeled compounds of the invention are deuterated.

The term "stereoisomer" means an isomer formed due to at least one asymmetric center, which has the same chemical composition but different spatial arrangements of atoms or groups. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, it can produce a racemic mixture, a single enantiomer, a diastereomeric mixture, and a single diastereomer. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structures in rapid equilibrium in different forms. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of the present application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

"Diastereomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical methods such as electrophoresis and chromatography.

"Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

The term "chiral" refers to molecules that have the property of non-superimposability of mirror image pairs, whereas the term "achiral" refers to molecules that are superimposable on their mirror image pairs.

The compounds of the invention may be prepared in racemic form, or individual enantiomers may be prepared by enantioselective synthesis or by resolution.

As used herein, the term "cis-trans isomers" or "geometric isomers" is caused by the inability to rotate freely around double bonds or single bonds of ring-forming carbon atoms. The compounds provided herein include all cis, trans, cis (syn), anti (anti), entgegen (E) and zusammen (Z) isomers and their corresponding mixtures.

In this article, solid lines can be used Solid wedge Virtual wedge Depicting chemical bonds of the compounds of the invention. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown are present. When present in a racemic mixture, the solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the invention are intended to exist in the form of stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereoisomer pairs).

It should also be understood that certain compounds of the present invention may exist in free form for treatment, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which, after being administered to a patient in need thereof, can directly or indirectly provide a compound of the present invention or a metabolite or residue thereof. Therefore, when referring to "compounds of the present invention" herein, the above-mentioned various derivative forms of the compounds are also intended to be covered.

As used herein, a wavy line Represents the point of attachment of a substituent to another group.

The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients making up the formulation and/or the mammal to be treated therewith.

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

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

The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol. The amount of polar solvents, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compounds of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may have less pharmacological activity or no pharmacological activity themselves, and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Such prodrugs are usually functional group derivatives of the compounds that are easily converted into the desired therapeutically active compounds in vivo. For additional information on the use of prodrugs, see "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E. B. Roche, ed., American Pharmaceutical Association). The prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moiety" (e.g., "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

The present invention also encompasses compounds of the present invention containing protecting groups. In any process of preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Using methods known in the art, the protecting group can be removed at an appropriate subsequent stage. The term "protecting group" includes, but is not limited to, an "amino protecting group", a "hydroxy protecting group" or a "sulfhydryl protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions of the hydroxy group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

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

Compounds

In one aspect, the present disclosure provides compounds of formula (I):

or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof,

in:

CyA is a structure of formula (a-i), (a-ii), (a-iii) or (a-iv):

in:

^X1, at each occurrence, is independently selected from CR ^X1 and N;

^X2 is selected from ^CR1 and N;

X ³ is selected from CR ² or N;

^X4 is selected from CR ^X2 and N;

R ^X1 and R ^X2 are each independently selected from H, halogen and C _1-8 alkyl;

R ¹ is independently selected at each occurrence from H, halogen, OH, -OC _1-8 alkyl, -OC _1-8 haloalkyl, -OC _3-6 cycloalkyl, NH ₂ , -NHC _1-8 alkyl, -N(C _1-8 alkyl) ₂ , -NHC _3-6 cycloalkyl, -N(C _1-8 alkyl)(C _3-6 cycloalkyl), and -N(C _3-6 cycloalkyl) ₂ ;

R ² is independently selected at each occurrence from: H; -P(＝O)H(C _1-8 alkyl), -P(O)(C _1-8 alkyl) ₂ ; 5- or 6-membered monocyclic heteroaryl, and 8-, 9- or 10-membered bicyclic heteroaryl, wherein the monocyclic heteroaryl and the bicyclic heteroaryl each have 0, 1, 2, 3 or 4 nitrogen atoms as ring members and 0, 1 or 2 ring members independently selected from O and S, and the monocyclic heteroaryl and the bicyclic heteroaryl are optionally substituted by 1, 2, 3 or 4 R ⁵ , wherein optionally, R ⁵ is an N-substituent;

each R ⁵ is independently selected from the group consisting of C _1-8 alkyl, halogen, OH, -OC _1-8 alkyl, -OC _1-8 haloalkyl, NH ₂ , -NHC _1-8 alkyl, and -N(C _1-8 alkyl) ₂ substituents;

R ³ is independently selected at each occurrence from H, C _1-8 alkyl, halogen, OH, -OC _1-8 alkyl, -OC _1-8 haloalkyl, -P(=O)H(C _1-8 alkyl) and -P(O)(C _1-8 alkyl) ₂ ;

R ⁴ is independently selected at each occurrence from: H, halogen, CN, SF ₅ , C _1-8 alkyl, C _2-8 alkenyl, C _1-8 haloalkyl, -OC _1-8 alkyl, -OC _1-8 haloalkyl, -P(═O)H(C _1-8 alkyl) and -P(O)(C _1-8 alkyl) ₂ ; and C _3-6 cycloalkyl, C _4-6 cycloalkenyl, phenyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl, wherein said C _3-6 cycloalkyl, C _4-6 cycloalkenyl, phenyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 R ⁶ ;

Each R ⁶ is independently selected from halogen, CN, oxo, C _1-8 alkyl and C _1-8 haloalkyl;

or

^R1 and ^R2 in the formula (ai) and (a-ii) together with the two ring carbon atoms to which they are attached form a heterocyclic group Het1; or

^R2 and ^R3 in the formula (ai) and (a-iii) together with the two ring carbon atoms to which they are attached form a heterocyclic group Het2; or

R ³ and R ⁴ in the formula (ai) and (a-iii) together with the two ring carbon atoms to which they are attached form a heterocyclic group Het3;

The heterocyclyls Het1, Het2 and Het3 are each independently selected from 5 or 6-membered monocyclic heterocycloalkyl, 5 or 6-membered monocyclic heterocycloalkenyl, 5 or 6-membered monocyclic heteroaryl, 7-11-membered monospiro heterocycloalkyl, and 7-11-membered monospiro heterocycloalkenyl, wherein the 5 or 6-membered monocyclic heterocycloalkyl, the 5 or 6-membered monocyclic heterocycloalkenyl, the 5 or 6-membered monocyclic heteroaryl, the 7-11-membered monospiro heterocycloalkyl and the 7-11-membered monospiro heterocycloalkenyl each optionally have 1 C(O) as a ring member and are optionally substituted by 1, 2, 3, 4 or more substituents ^Ra , wherein when ^Ra is present, 1 ^Ra is optionally an N-substituent;

each ^{Ra is} independently selected from halogen, CN, OH, _NH2 , _C1-8 alkyl, _C2-8 alkenyl, _C1-8 haloalkyl, _-NHC1-8 alkyl, -N( _C1-8 alkyl) ₂ , _-OC1-8 alkyl, -OC1-8 haloalkyl, _-C1-8 alkylene-(optionally substituted C3-6 cycloalkyl), _-C1-8 alkylene-(optionally substituted C4-6 cycloalkenyl), _-C1-8 alkylene-(optionally substituted _4-6 membered _{heterocycloalkyl), -C1-8 alkylene-} (optionally substituted _4-6 membered heterocycloalkenyl), _-C1-8 alkylene-(optionally substituted _C6-10 aryl), and _-C1-8 alkylene-(optionally substituted 5- or 6-membered heteroaryl);

^R7 is selected from H, halogen, OH, CN, -C(O)OH, _-SF5 , _-NO2 , _C1-8 alkyl, _C1-8 haloalkyl, _-OC1-8 alkyl, _-OC1-8 haloalkyl, -C1-8 _alkylene -OH, _{-C1-6 alkylene-OC1-6 alkyl, -C1-6 alkylene-OC1-6 alkylene-OC1-6 alkyl, -C1-6 alkylene-OC1-6 alkylene-NH2, -C1-6 alkylene-OC1-6 alkylene-NH(C1-6 alkyl), -C1-6 alkylene - OC1-6 alkylene - N ( C1-6 alkyl ) 2 , C3-6 cycloalkyl ,} 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkenyl and 5-10 heteroaryl, wherein the C1-6 _3-6 membered cycloalkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkenyl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from halogen, CN, C _1-8 alkyl and C _1-8 haloalkyl; and

^R8 is selected from H, halogen, CN, _C1-8 alkyl, _C1-8 haloalkyl, _-OC1-8 alkyl, _-OC1-8 haloalkyl, _C2-8 alkynyl and _C2-8 haloalkynyl.

In some embodiments, the present disclosure provides a compound of formula (I) as described above, wherein the compound of formula (I) is a compound of formula (I-i):

In other embodiments, the present disclosure provides a compound of formula (I) as described above, wherein the compound of formula (I) is a compound of formula (I-ii):

In other embodiments, the present disclosure provides a compound of formula (I) as described above, wherein the compound of formula (I) is a compound of formula (I-iii):

In some embodiments, the present disclosure provides compounds as described above, wherein X ¹ at each occurrence is independently CR ^X1 .

In some embodiments, the present disclosure provides a compound as described above, wherein ^RX1 is selected from H, F, Cl and C _1-6 alkyl. In some embodiments, ^RX1 is H or C _1-4 alkyl. Preferably, ^RX1 is H.

In some embodiments, the present disclosure provides compounds as described above, wherein X ¹ is independently CH at each occurrence.

In other embodiments, the present disclosure provides compounds as described above, wherein X ¹ is independently N at each occurrence.

In other embodiments, the present disclosure provides the compound of formula (I), which is a compound of formula (I-iv):

In some embodiments of the compound of Formula (I) or Formula (I-iv), X ² is CR ¹ . In other embodiments, X ² is N.

In some embodiments of the compound of Formula (I) or Formula (I-iv), X ³ is CR ² . In other embodiments, X ³ is N.

In some embodiments of the compound of Formula (I) or Formula (I-iv), ^X4 is CR ^X2 . In other embodiments, ^X4 is N.

In some embodiments of the compound of Formula (I) or Formula (I-iv), ^X2 is N, ^X3 is ^CR2 , and ^X4 is ^CRX2 .

In some embodiments of the compound of formula (I) or formula (I-iv), ^RX2 is selected from H, F, Cl and _C1-6 alkyl. In some embodiments, ^RX2 is H or _C1-4 alkyl. Preferably, ^RX2 is H.

In some embodiments of the compound of Formula (I) or Formula (I-iv), X ² is N, X ³ is CR ² , and X ⁴ is CH.

In some embodiments, the present disclosure provides a compound as described above, wherein:

R ¹ at each occurrence is independently selected from H, F, Cl, OH, -OC _1-6 alkyl, -OC _1-6 haloalkyl, -OC _3-6 cycloalkyl, NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -NHC _3-6 cycloalkyl, -N(C _1-6 alkyl)(C _3-6 cycloalkyl), and -N(C _3-6 cycloalkyl) ₂ .

In some such embodiments, R ¹ at each occurrence is independently selected from H, F, Cl, OH, NH ₂ , -NHC _1-4 alkyl, and -N(C _1-4 alkyl) _2. Preferably, R ¹ at each occurrence is independently hydrogen or OH.

In some embodiments, the present disclosure provides a compound as described above, wherein:

R ² is independently selected at each occurrence from: -P(＝O)H(C _1-8 alkyl), -P(O)(C _1-8 alkyl) ₂ ; 5- or 6-membered nitrogen-containing monocyclic heteroaryl, and 8-, 9- or 10-membered nitrogen-containing bicyclic heteroaryl, wherein the nitrogen-containing monocyclic heteroaryl and the nitrogen-containing bicyclic heteroaryl each have 1, 2, 3 or 4 nitrogen atoms as ring members and 0, 1 or 2 ring members independently selected from O and S, and the nitrogen-containing monocyclic heteroaryl and the nitrogen-containing bicyclic heteroaryl are each optionally substituted by 1, 2, 3 or 4 R ⁵ , wherein optionally, R ⁵ is an N-substituent.

In some such embodiments, R ² is independently selected at each occurrence from: -P(＝O)H(C _1-6 alkyl), -P(O)(C _1-6 alkyl) ₂ ; 5- or 6-membered nitrogen-containing monocyclic heteroaryl, and 8-, 9- or 10-membered nitrogen-containing bicyclic heteroaryl, wherein the nitrogen-containing monocyclic heteroaryl and the nitrogen-containing bicyclic heteroaryl each have 1, 2, 3 or 4 nitrogen atoms as ring members and 0 or 1 ring member selected from O and S, and the nitrogen-containing monocyclic heteroaryl and the nitrogen-containing bicyclic heteroaryl are each optionally substituted by 1, 2 or 3 R ⁵ , wherein optionally, R ⁵ is an N-substituent.

In some embodiments, R ² is independently selected at each occurrence from: -P(O)(C _1-4 alkyl) ₂ ; 5 or 6 membered nitrogen-containing monocyclic heteroaryl, and 8, 9 or 10 membered nitrogen-containing bicyclic heteroaryl, wherein the nitrogen-containing monocyclic heteroaryl and the nitrogen-containing bicyclic heteroaryl each have 1, 2 or 3 nitrogen atoms as ring members and 0 or 1 ring member selected from O and S, and the nitrogen-containing monocyclic heteroaryl and the nitrogen-containing bicyclic heteroaryl are each optionally substituted by 1 or 2 R ⁵ , wherein optionally, R ⁵ is an N-substituent.

In some embodiments, R ² is independently selected at each occurrence from: -P(O)(C _1-2 alkyl) ₂ ; 5 or 6 membered nitrogen-containing monocyclic heteroaryl, and 8, 9 or 10 membered nitrogen-containing bicyclic heteroaryl, wherein the nitrogen-containing monocyclic heteroaryl and the nitrogen-containing bicyclic heteroaryl each have 1, 2 or 3 nitrogen atoms as ring members and 0 or 1 ring members selected from O and S, and the nitrogen-containing monocyclic heteroaryl and the nitrogen-containing bicyclic heteroaryl are optionally substituted by 1 R ⁵ , wherein optionally, R ⁵ is an N-substituent.

In some such embodiments, the nitrogen-containing monocyclic heteroaryl is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl. In some embodiments, the nitrogen-containing monocyclic heteroaryl is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl. In some embodiments, the nitrogen-containing monocyclic heteroaryl is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl.

In some such embodiments, the nitrogen-containing bicyclic heteroaryl is selected from the group consisting of pyrrolopyrazolyl, pyrroloimidazolyl, imidazoimidazolyl, imidazopyrazolyl, imidazothiazolyl, pyrazolothiazolyl, imidazooxazolyl, pyrazolooxazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, imidazopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrazinyl, quinolyl, isoquinolyl, indolyl, isoindolyl, Indole, pyrrolopyridinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrazolopyrazinyl, pyrazolopyridazinyl, oxazolopyridinyl, oxazolopyridazinyl, oxazolopyrimidinyl, oxazolopyrazinyl, thiazolopyridinyl, thiazolopyridazinyl, thiazolopyrimidinyl, thiazolopyrazinyl, indazolyl, quinazolinyl, triazolopyridinyl, cinnolinyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, furazanyl and quinoxalinyl. In some embodiments, the nitrogen-containing bicyclic heteroaryl is selected from the group consisting of imidazopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrazinyl, pyrrolopyridinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrazolopyrazinyl, pyrazolopyridazinyl, oxazolopyridinyl, oxazolopyridazinyl, oxazolopyrimidinyl, oxazolopyrazinyl, thiazopyridinyl, thiazopyridazinyl, thiazopyrimidinyl and thiazopyrazinyl. In some embodiments, the nitrogen-containing bicyclic heteroaryl is selected from the group consisting of imidazopyridinyl, imidazopyridazinyl, imidazopyrimidinyl and imidazopyrazinyl. Preferably, the nitrogen-containing bicyclic heteroaryl is selected from the group consisting of imidazo[1,2]pyridazinyl, imidazo[1,2]pyrimidinyl and imidazo[1,2]pyrazinyl.

When the nitrogen-containing bicyclic heteroaryl group comprises one 5-membered heteroaryl ring and one 6-membered ring, the nitrogen-containing bicyclic heteroaryl group is preferably linked to the rest of the molecule via the 5-membered heteroaryl ring.

In some embodiments, each R ⁵ is independently selected from the group consisting of C _1-6 alkyl, halogen, OH, -OC _1-6 alkyl, -OC _1-6 haloalkyl, NH ₂ , -NHC _1-6 alkyl, and -N(C _1-6 alkyl) _2. In some embodiments, each R ⁵ is independently selected from the group consisting of C _1-4 alkyl, F, Cl, OH, -OC _1-4 alkyl, -OC _1-4 haloalkyl, NH ₂ , -NHC _1-4 alkyl, and -N(C _1-4 alkyl) _2. Preferably, each R ⁵ is independently selected from the group consisting of C _1-4 alkyl, more preferably methyl.

In some preferred embodiments, ^R2 at each occurrence is independently selected from

In some embodiments, the present disclosure provides a compound as described above, wherein:

R ³ at each occurrence is independently selected from H, C _1-6 alkyl, halogen, OH, -OC _1-6 alkyl, -OC _1-6 haloalkyl, -P(=O)H(C _1-6 alkyl) and -P(O)(C _1-6 alkyl) ₂ .

In some such embodiments, R ³ is independently selected at each occurrence from H, C _1-4 alkyl, F, Cl, OH, -OC _1-4 alkyl, -OC _1-4 haloalkyl, -P(=O)H(C _1-4 alkyl), and -P(O)(C _1-4 alkyl) _2. Preferably, R ³ is independently H at each occurrence.

In some embodiments, the present disclosure provides a compound as described above, wherein:

R ⁴ is independently selected at each occurrence from: H, halogen, CN, SF ₅ , C _1-6 alkyl, C _2-6 alkenyl, C _1-6 haloalkyl, -OC _1-6 alkyl, -OC _1-6 haloalkyl, -P(＝O)H(C _1-6 alkyl) and -P(O)(C _1-6 alkyl) ₂ ; and C _3-6 cycloalkyl, C _4-6 cycloalkenyl, phenyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl, wherein said C _3-6 cycloalkyl, C _4-6 cycloalkenyl, phenyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 R ⁶ .

In some such embodiments, R ⁴ is independently selected at each occurrence from: H, F, Cl, CN, SF ₅ , C _1-4 alkyl, C _2-4 alkenyl, C _1-4 haloalkyl, -OC _1-4 alkyl, -OC _1-4 haloalkyl, -P(＝O)H(C _1-4 alkyl) and -P(O)(C _1-4 alkyl) ₂ ; and C _3-6 cycloalkyl, C _4-6 cycloalkenyl, phenyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl, wherein said C _3-6 cycloalkyl, C _4-6 cycloalkenyl, phenyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 R ⁶ .

In some embodiments, R ⁴ at each occurrence is independently selected from: H; C _3-6 cycloalkyl, C _4-6 cycloalkenyl, and 4-6 membered heterocycloalkyl, wherein said C _3-6 cycloalkyl, C _4-6 cycloalkenyl, and 4-6 membered heterocycloalkyl are each optionally substituted with 1 R ⁶ .

In some embodiments, R ⁴ at each occurrence is independently selected from: H; cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are each optionally substituted with 1 R ⁶ .

In some embodiments, each R ⁶ is independently selected from independently selected from halogen, CN, oxo, C _1-6 alkyl and C _1-6 haloalkyl. In some embodiments, each R ⁶ is independently selected from independently selected from F, Cl, CN, oxo, C _1-4 alkyl and C _1-4 haloalkyl. In some embodiments, each R ⁶ is independently selected from independently selected from F, Cl and CN. Preferably, each R ⁶ is independently selected from independently CN.

In some preferred embodiments, ^R4 at each occurrence is independently selected from H, More preferred

In some embodiments, the present disclosure provides a compound as described above, which is a compound of formula (I-v), (I-vi) or (I-vii):

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁷ and R ⁸ are each as defined above.

In some such embodiments, ^R1 is selected from H, F, Cl, OH, and _NH2 , preferably hydrogen or OH.

In some embodiments, R ² is selected from: -P(O)(C _1-4 alkyl) ₂ ; 5 or 6-membered nitrogen-containing monocyclic heteroaryl, and 8, 9 or 10-membered nitrogen-containing bicyclic heteroaryl, wherein the nitrogen-containing monocyclic heteroaryl and the nitrogen-containing bicyclic heteroaryl each have 1, 2 or 3 nitrogen atoms as ring members and 0 or 1 ring members selected from O and S, and the nitrogen-containing monocyclic heteroaryl and the nitrogen-containing bicyclic heteroaryl are each optionally substituted by 1 R ⁵ , wherein R ⁵ is selected from C _1-4 alkyl and is optionally an N-substituent.

In some embodiments, R ² is selected from: -P(O)(C _1-4 alkyl) ₂ ; pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, imidazopyridinyl, imidazopyridazinyl, imidazopyrimidinyl and imidazopyrazinyl, wherein the pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, imidazopyridinyl, imidazopyridazinyl, imidazopyrimidinyl and imidazopyrazinyl are each optionally substituted with 1 R ⁵ , wherein R ⁵ is selected from C _1-4 alkyl and is optionally an N-substituent.

In some embodiments, R ² is selected from: -P(O)(C _1-2 alkyl) ₂ ; pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl and thiazolyl, imidazo[1,2]pyridazinyl, imidazo[1,2]pyrimidinyl and imidazo[1,2]pyrazinyl, wherein said pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, imidazo[1,2]pyridazinyl, imidazo[1,2]pyrimidinyl and imidazo[1,2]pyrazinyl are each optionally substituted with 1 R ⁵ , wherein R ⁵ is selected from C _1-4 alkyl and is optionally an N-substituent.

In some preferred embodiments, ^R2 is selected from

More preferably, ^R2 is selected from

In some embodiments, ^R3 is H.

In some embodiments, ^R4 is _C3-6 cycloalkyl, wherein the _C3-6 cycloalkyl is optionally substituted by 1 F, Cl or CN. In some embodiments, ^R4 is selected from cyclobutyl, cyclopentyl and cyclohexyl, wherein the cyclobutyl, cyclopentyl and cyclohexyl are each optionally substituted by 1 F, Cl or CN.

In some preferred embodiments, ^R4 is More preferably

In other embodiments, the present disclosure provides a compound as described above, which is a compound of formula (I-viii):

wherein X ² , X ⁴ , R ² , R ⁴ , R ⁷ and R ⁸ are each as defined above.

In some such embodiments, X ² is CH or N, preferably N.

In some embodiments, ^X4 is CH or N, preferably CH.

In some embodiments, R ² is -P(O)(C _1-4 alkyl) ₂ , preferably -P(O)(C _1-2 alkyl) ₂ , more preferably

In some embodiments, R ⁴ is C _3-6 cycloalkyl, wherein the C _3-6 cycloalkyl is optionally substituted by 1 F, Cl or CN. In some embodiments, R ⁴ is selected from cyclobutyl, cyclopentyl and cyclohexyl, wherein the cyclobutyl, cyclopentyl and cyclohexyl are each optionally substituted by 1 F, Cl or CN. Preferably, R ⁴ is More preferred

In other embodiments, the present disclosure provides compounds of formula (I), wherein the compound is:

Compounds of formula (I-ix) or (I-x):

Or a compound of formula (I-xi) or (I-xii):

or a compound of formula (I-xiii) or (I-xiv):

In some embodiments, the present disclosure provides compounds of formula (I), including compounds of formula (I-ix), (I-x), (I-xi), (I-xii), (I-xiii) and (I-xiv), wherein:

The heterocyclyl groups Het1, Het2 and Het3 are each independently selected from 5- or 6-membered nitrogen-containing monocyclic heterocycloalkyl, 5- or 6-membered nitrogen-containing monocyclic heterocycloalkenyl, 5- or 6-membered nitrogen-containing monocyclic heteroaryl, 7-11-membered nitrogen-containing monospiro heterocycloalkyl, and 7-11-membered nitrogen-containing monospiro heterocycloalkenyl, wherein the 5- or 6-membered nitrogen-containing monocyclic heterocycloalkyl, the 5- or 6-membered nitrogen-containing monocyclic heterocycloalkenyl, the 5- or 6-membered nitrogen-containing monocyclic heteroaryl, the 7-11-membered nitrogen-containing monospiro heterocycloalkyl and the 7-11-membered nitrogen-containing monospiro heterocycloalkenyl each have 1, 2 or 3 nitrogen atoms as ring members and 0 or 1 ring member selected from O and S and optionally have 1 C(O) as a ring member, and are optionally substituted by 1, 2, 3, 4 or more substituents ^Ra , wherein when ^Ra is present, 1 ^Ra is optionally an N-substituent.

In some embodiments, the heterocyclyls Het1, Het2 and Het3 are each independently selected from 5 or 6-membered nitrogen-containing monocyclic heterocycloalkyl, 5 or 6-membered nitrogen-containing monocyclic heterocycloalkenyl, 5 or 6-membered nitrogen-containing monocyclic heteroaryl, 7-11-membered nitrogen-containing monospiro bicyclic heterocycloalkyl, and 7-11-membered nitrogen-containing monospiro bicyclic heterocycloalkenyl, wherein the 5 or 6-membered nitrogen-containing monocyclic heterocycloalkyl, the 5 or 6-membered nitrogen-containing monocyclic heterocycloalkenyl, the 5 or 6-membered nitrogen-containing monocyclic heteroaryl, the 7-11-membered nitrogen-containing monospiro bicyclic heterocycloalkyl and the 7-11-membered nitrogen-containing monospiro bicyclic heterocycloalkenyl each have 1, 2 or 3 nitrogen atoms as ring members and 0 or 1 ring member selected from O and S and optionally have 1 C(O) as a ring member, and are optionally substituted by 1, 2, 3 or 4 substituents ^Ra , wherein when ^Ra is present, 1 ^Ra is optionally an N-substituent.

In some embodiments, the heterocyclyls Het1, Het2 and Het3 are each independently selected from a 5- or 6-membered nitrogen-containing monocyclic heteroaryl, a 7-11-membered nitrogen-containing monospiro bicyclic heterocycloalkyl and a 7-11-membered nitrogen-containing monospiro bicyclic heterocycloalkenyl, wherein the 6-membered nitrogen-containing monocyclic heteroaryl, the 7-11-membered nitrogen-containing monospiro bicyclic heterocycloalkyl and the 7-11-membered nitrogen-containing monospiro bicyclic heterocycloalkenyl each have 1 C(O) as a ring member and 1, 2 or 3 nitrogen atoms as the only ring heteroatoms, and are optionally substituted by 1, 2, 3 or 4 substituents ^Ra , wherein when ^Ra is present, 1 ^Ra is optionally an N-substituent.

In some such embodiments, the 5-membered monocyclic heteroaryl described for Het1, Het2 or Het3 is selected from: furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl, wherein the furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl are each optionally substituted with 1, 2 or 3 substituents ^Ra , wherein when ^Ra is present, 1 ^Ra is optionally an N-substituent. In some embodiments, the 5-membered nitrogen-containing monocyclic heteroaryl is selected from: pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl, wherein the pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl are each optionally substituted with 1, 2 or 3 substituents ^Ra , wherein when ^Ra is present, 1 ^Ra is optionally an N-substituent.

In some preferred embodiments, the 5-membered nitrogen-containing monocyclic heteroaryl group is selected from wherein n1 is 0, 1, 2 or 3, wherein when n1 is not 0, 1 ^Ra is optionally an N-substituent; and n2 is 0, 1 or 2.

or

In other such embodiments, the 6-membered monocyclic heteroaryl described for Het1, Het2 or Het3 is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl, wherein the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl each optionally has 1 C (O) as a ring member and is optionally substituted by 1 or 2 substituents ^Ra , wherein when ^Ra is present, 1 ^Ra is optionally an N-substituent. In some embodiments, the 6-membered heteroaryl is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl, wherein the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl each has 1 C (O) as a ring member and is optionally substituted by 1 or 2 substituents ^Ra , wherein when ^Ra is present, 1 ^Ra is optionally an N-substituent.

In some preferred embodiments, the 6-membered heteroaryl group is selected from:

wherein n3 is 0, 1, 2 or 3, wherein when n3 is not 0, 1 ^Ra is optionally an N-substituent; Where n4 is 0, 1, 2 or 3;

wherein n5 is 0, 1 or 2, wherein when n5 is not 0, 1 ^Ra is optionally an N-substituent; and

Where n6 is 0 or 1.

In other such embodiments, the 7-11 membered monospiro heterocycloalkyl for Het1, Het2 or Het3 is selected from: a spiro ring system having one 5- or 6-membered monocyclic heterocycloalkyl and one monocyclic cycloalkyl selected from cyclopropane, cyclobutane, cyclopentane or cyclohexane, and a spiro ring system having one 5- or 6-membered monocyclic heterocycloalkyl and one 3-, 4-, 5- or 6-membered monocyclic heterocycloalkyl, wherein the 5- or 6-membered monocyclic heterocycloalkyl optionally has 1 C(O) as a ring member; and wherein the 7-11 membered monospiro heterocycloalkyl has 1, 2 or 3 nitrogen atoms as ring members and 0 or 1 ring member selected from O and S, and is optionally substituted by 1, 2, 3 or 4 substituents ^Ra , wherein when ^Ra is present, 1 ^Ra is optionally an N-substituent.

In other embodiments, the 7-11 membered nitrogen-containing monospiro bicyclic heterocycloalkyl for Het1, Het2 or Het3 is selected from: a spiro ring system having a 5- or 6-membered nitrogen-containing monocyclic heterocycloalkyl selected from pyrrolidinyl and 6-membered nitrogen-containing monocyclic heterocycloalkyl and a monocyclic cycloalkyl selected from cyclopropane, cyclobutane, cyclopentane or cyclohexane, and a spiro ring system having a 5- or 6-membered nitrogen-containing monocyclic heterocycloalkyl selected from pyrrolidinyl and 6-membered nitrogen-containing monocyclic heterocycloalkyl and a 3-, 4-, 5- or 6-membered monocyclic heterocycloalkyl, wherein the 5- or 6-membered nitrogen-containing monocyclic heterocycloalkyl has 1 C(O) as a ring member; and wherein the 7-11 membered nitrogen-containing monospiro bicyclic heterocycloalkyl has 1, 2 or 3 nitrogen atoms as ring members and 0 or 1 ring member selected from O and S, and is optionally substituted by 1, 2, 3 or 4 substituents ^Ra , wherein when ^Ra is present, 1 ^Ra is optionally an N-substituent.

In some preferred embodiments, the 7-11 membered nitrogen-containing monospiro bicyclic heterocycloalkyl is selected from:

wherein n7 is 0 or 1, wherein when n7 is 1, 1 ^Ra is optionally an N-substituent; and n8 is 0, 1, 2 or 3.

In some embodiments, the 7-11 membered monospiro heterocycloalkenyl described for Het1, Het2 or Het3 is selected from: a spiro ring system having one 5 or 6 membered monocyclic heterocycloalkenyl and a monocyclic cycloalkyl selected from cyclopropane, cyclobutane, cyclopentane or cyclohexane, and a spiro ring system having one 5 or 6 membered monocyclic heterocycloalkenyl and a 3, 4, 5 or 6 membered monocyclic heterocycloalkyl, wherein the 5 or 6 membered monocyclic heterocycloalkenyl optionally has 1 C(O) as a ring member; and wherein the 7-11 membered monospiro heterocycloalkenyl has 1, 2 or 3 nitrogen atoms as ring members and 0 or 1 ring member selected from O and S, and is optionally substituted by 1, 2, 3 or 4 substituents ^Ra , wherein when ^Ra is present, 1 ^Ra is optionally an N-substituent.

In some embodiments, the 7-11 membered nitrogen-containing monospiro bicyclic heterocycloalkenyl described for Het1, Het2 or Het3 is selected from: a spiro ring system having a 5 or 6 membered nitrogen-containing monocyclic heterocycloalkenyl selected from dihydropyrrolyl and 6 membered nitrogen-containing monocyclic heterocycloalkenyl and a monocyclic cycloalkyl selected from cyclopropane, cyclobutane, cyclopentane or cyclohexane, and a spiro ring system having a 5 or 6 membered nitrogen-containing monocyclic heterocycloalkenyl selected from dihydropyrrolyl and 6 membered nitrogen-containing monocyclic heterocycloalkenyl and a 3, 4, 5 or 6 membered monocyclic heterocycloalkyl, wherein the 5 or 6 membered nitrogen-containing monocyclic heterocycloalkenyl has 1 C(O) as a ring member; and wherein the 7-11 membered nitrogen-containing monospiro bicyclic heterocycloalkenyl has 1, 2 or 3 nitrogen atoms as ring members and 0 or 1 ring member selected from O and S, and is optionally substituted by 1, 2, 3 or 4 substituents ^Ra , wherein when ^Ra is present, 1 R ^a is optionally an N-substituent.

In some preferred embodiments, the 7-11 membered nitrogen-containing monospiro bicyclic heterocycloalkenyl is selected from:

Wherein n9 is 0 or 1, and n10 is 0, 1, 2 or 3.

In some embodiments, each ^Ra _is independently selected from halogen, CN, OH, _NH2 , _C1-6 alkyl, _C2-6 alkenyl, _C1-6 haloalkyl, _-NHC1-6 alkyl, -N( _C1-6 alkyl) ₂ , -OC1-6 alkyl, _-OC1-6 haloalkyl, -C1-6 alkylene-(optionally substituted _C3-6 cycloalkyl), _-C1-6 alkylene-(optionally substituted C4-6 cycloalkenyl), _-C1-6 alkylene-(optionally substituted _4-6 membered heterocycloalkyl), _-C1-6 alkylene-(optionally substituted _4-6 membered heterocycloalkenyl), _-C1-6 alkylene-(optionally substituted _C6-10 aryl), and _-C1-6 alkylene-(optionally substituted 5 or 6 membered heteroaryl).

In some embodiments, each ^Ra is independently selected from F, Cl, CN, OH, _NH2 , _C1-4 alkyl, _C2-4 alkenyl, _C1-4 haloalkyl, _-NHC1-4 alkyl, -N _{( C1-4} alkyl) ₂ , _-OC1-4 alkyl, _-OC1-4 haloalkyl, -C1-4 alkylene-(optionally substituted _C3-6 cycloalkyl), -C1-4 alkylene-(optionally substituted _C4-6 cycloalkenyl), -C1-4 alkylene-(optionally substituted _4-6 membered heterocycloalkyl), _-C1-4 alkylene-(optionally substituted 4-6 membered _{heterocycloalkenyl), -C1-4 alkylene-} (optionally substituted _C6-10 aryl), and _-C1-4 alkylene-(optionally substituted 5 or 6 membered heteroaryl).

In some embodiments, each ^Ra is independently selected from _C1-2 alkyl, _-C1-2 alkylene-(optionally substituted phenyl), and _-C1-2 alkylene-(optionally substituted 5- or 6-membered heteroaryl).

In some preferred embodiments, each ^Ra is independently selected from methyl, ethyl and

In some embodiments, the compound of formula (I-ix) Parts are:

wherein ^Ra is preferably a C _1-4 alkyl group or a -C _1-4 alkylene group-(5- or 6-membered heteroaryl group), more preferably a methyl group or

Preferably

In some embodiments, the compound of formula (I-xi) Parts are:

wherein ^Ra is preferably a C _1-4 alkyl group or a -C _1-4 alkylene group-(5- or 6-membered heteroaryl group), more preferably a methyl group or

Preferably

In some embodiments, the compound of formula (I-xiii) Parts are: Wherein ^Ra is preferably a _C1-4 alkyl group, more preferably a methyl group or an ethyl group;

Preferably

In some embodiments, the present disclosure provides compounds of formula (I-xi) and (I-xiii) as described above, wherein R ¹ at each occurrence is independently selected from H, F, Cl, OH and NH ₂ , preferably hydrogen.

In some embodiments, the present disclosure provides compounds of formula (I-xiii) and (I-xiv) as described above, wherein R ² is independently selected at each occurrence from: -P(O)(C _1-4 alkyl) ₂ and 5 or 6-membered nitrogen-containing monocyclic heteroaryl, wherein the nitrogen-containing monocyclic heteroaryl has 1, 2 or 3 nitrogen atoms as ring members and 0 or 1 ring members selected from O and S, and is optionally substituted by 1 R ⁵ , wherein R ⁵ is selected from C _1-4 alkyl and is optionally an N-substituent.

In some such embodiments, R ² is independently selected at each occurrence from: -P(O)(C _1-4 alkyl) ₂ ; pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, and thiazolyl, wherein said pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, and thiazolyl are each optionally substituted with 1 R ⁵ , wherein R ⁵ is selected from C _1-4 alkyl and is optionally an N-substituent.

In some embodiments, ^R2 at each occurrence is independently selected from

In some preferred embodiments, ^R2 at each occurrence is independently selected from

In some embodiments, the present disclosure provides a compound of formula (I-xi) as described above, wherein R ³ is H.

In some embodiments, the present disclosure provides compounds of formula (I-ix), (Ix), (I-xi) and (I-xii) as described above, wherein R ⁴ is independently C _3-6 cycloalkyl at each occurrence, wherein the C _3-6 cycloalkyl is optionally substituted with 1 F, Cl or CN.

In some such embodiments, R ⁴ at each occurrence is independently selected from cyclobutyl, cyclopentyl, and cyclohexyl, wherein said cyclobutyl, cyclopentyl, and cyclohexyl are each optionally substituted with 1 F, Cl, or CN.

In some preferred embodiments, R ⁴ is independently at each occurrence More preferred

In some embodiments, the present disclosure provides compounds of formula (I)-(I-xiv) as described above, wherein:

^R7 is selected from H, halogen, OH, CN, -C(O)OH, _-SF5 , _-NO2 , _C1-6 alkyl, _C1-6 haloalkyl, _-OC1-6 alkyl, -OC1-6 haloalkyl, _{-C1-6 alkylene} -OH, -C1-4 alkylene- _OC1-4 alkyl, _-C1-4 alkylene- _OC1-4 alkylene- _OC1-4 alkyl, -C1-4 alkylene-OC1-4 alkylene- _NH2 , _-C1-4 alkylene- _OC1-4 alkylene _- NH( _C1-4 alkyl), _{-C1-4 alkylene} - _OC1-4 alkylene _- N( _C1-4 alkyl) ₂ , _C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkenyl and 5-10 heteroaryl, wherein the C1-6 _3-6 membered cycloalkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkenyl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from halogen, CN, C _1-6 alkyl and C _1-6 haloalkyl.

In some such embodiments, ^R7 is selected from H, halogen, OH, CN, _-NO2 , _{C1-4 alkyl} , _C1-4 haloalkyl, _-OC1-4 alkyl, -OC1-4 haloalkyl, -C1-4 alkylene- _{OH, -C1-4 alkylene-OC1-4 alkyl, -C1-4 alkylene-OC1-4 alkylene-OC1-4 alkyl , -C1-4 alkylene - OC1-4 alkylene} -NH2, _-C1-4 alkylene- _OC1-4 alkylene-NH( _C1-4 alkyl), and _-C1-4 alkylene- _OC1-4 alkylene _- N( _C1-4 alkyl) ₂ .

In some embodiments, R ⁷ is selected from H, halogen, -C _1-2 alkylene-OC _1-2 alkyl, -C _1-2 alkylene-OC _1-2 alkylene-OC _1-2 alkylene, -C _1-2 alkylene-OC _1-2 alkylene-NH ₂ , -C _1-2 alkylene-OC _1-2 alkylene-NH(C _1-4 alkyl), and -C _1-2 alkylene-OC _1-2 alkylene-N(C _1-2 alkyl) ₂ .

In some embodiments, R ⁷ is selected from H, halogen, -C _1-2 alkylene-OC _1-2 alkylene-OC _1-2 alkyl, -C _1-2 alkylene-OC _1-2 alkylene-NH ₂ , -C _1-2 alkylene-OC _1-2 alkylene-NH(C _1-4 alkyl), and -C _1-2 alkylene-OC _1-2 alkylene-N(C _1-2 alkyl) ₂ .

In some preferred embodiments, ^R7 is selected from H, F, Cl, Br, I, More preferably, H, Cl,

In some embodiments, the present disclosure provides compounds of formula (I)-(I-xiv) as described above, wherein:

R ⁸ is selected from H, halogen, CN, C _1-6 alkyl, C _1-6 haloalkyl, -OC _1-6 alkyl, -OC _1-6 haloalkyl, C _2-6 alkynyl and C _2-6 haloalkynyl.

In some such embodiments, R ⁸ is selected from H, halogen, C _2-4 alkynyl, and C _2-4 haloalkynyl.

In some preferred embodiments, R ⁸ is selected from H, F, Cl, Br, I, More preferably, H, Br and

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

In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound is selected from:

The compounds provided by the present disclosure can be prepared by a variety of synthetic methods known to those skilled in the art, including the examples listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples below.

Pharmaceutical compositions and uses

The compounds of formula (I) disclosed in the present invention, including the compounds of formula (I-i)-(I-xiv), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, metabolites, isotope-labeled compounds or prodrugs thereof are inhibitors of WDR5, which can inhibit the binding of WDR5 to MYC, and can also inhibit the activity of WDR5 itself. Therefore, the compounds of the present invention can be used to prevent or treat diseases, conditions or disorders mediated by WDR5, and can also be used to prevent or treat diseases, conditions or disorders related to MYC.

In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) described in the present disclosure, including a compound of formula (I-i)-(I-xiv), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition may be a solid preparation, a liquid preparation or a transdermal preparation.

In some embodiments, the pharmaceutical compositions described herein may further comprise one or more additional therapeutically active agents.

In another aspect, the present disclosure provides a drug combination, which includes a compound of formula (I) described in the present disclosure, including a compound of formula (I-i)-(I-xiv), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, and another therapeutically active agent. In some embodiments, the additional therapeutically active agent is a known other anticancer chemotherapeutic agent, including but not limited to taxanes, vinca alkaloids, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, vinflunine, cisplatin, 5-fluorouracil, 5-fluoro-2-4 (1H, 3H)-pyrimidinedione (5FU), flutamide and gemcitabine, etc.

In another aspect, the present disclosure provides a compound of formula (I) described in the present disclosure, including a compound of formula (I-i)-(I-xiv), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition according to the present disclosure, which is used as a drug, including WDR5 inhibitors and WDR5-MYC PPI inhibitors.

In another aspect, the present disclosure provides the use of the compounds of formula (I) described in the present disclosure, including the compounds of formula (I-i)-(I-xiv), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, metabolites, isotope-labeled compounds or prodrugs thereof in the preparation of drugs, including WDR5 inhibitors and WDR5-MYC PPI inhibitors.

In one aspect, the present disclosure provides a method for preventing or treating a WDR5-mediated disease, disorder or condition in an individual, wherein the method comprises: administering to the individual a therapeutically effective amount of a compound of formula (I) described in the present disclosure, including a compound of formula (I-i)-(I-xiv), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof; or administering to the individual a therapeutically effective amount of a pharmaceutical composition described in the present disclosure.

In another aspect, the present disclosure provides a method for preventing or treating a disease, disorder or condition associated with MYC in an individual, wherein the method comprises: administering to the individual a therapeutically effective amount of a compound of formula (I) described in the present disclosure, including a compound of formula (I-i)-(I-xiv), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof; or administering to the individual a therapeutically effective amount of a pharmaceutical composition described in the present disclosure.

In another aspect, the present disclosure provides the use of the compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or the pharmaceutical composition in the preparation of a medicament for preventing or treating a WDR5-mediated disease, disorder or condition in an individual.

In another aspect, the present disclosure provides a compound of formula (I) described in the present disclosure, including a compound of formula (I-i)-(I-xiv), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition described in the present disclosure for use in the preparation of a medicament for preventing or treating a disease, disorder or condition associated with MYC in an individual.

In some embodiments, the disease, disorder or condition is a tumor (e.g., cancer), including solid tumors and hematological tumors. In some embodiments, the solid tumor is ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, gastric cancer, or uterine cancer. In some embodiments, the hematological tumor is leukemia.

In the present disclosure, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with a therapeutic agent and is suitable, within the scope of sound medical judgment, for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.

As used herein, unless otherwise indicated, the terms "treat," ...

As used herein, "individual" includes humans or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals. "Non-human animals" in the present disclosure include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

Technical Effects

The compounds disclosed herein are inhibitors of WDR5, which can inhibit the binding of WDR5 to MYC, and thus can be used to prevent or treat WDR5-mediated diseases, conditions or disorders, and can also be used to prevent or treat diseases, conditions or disorders related to MYC. The compounds disclosed herein have improved pharmacokinetic properties (e.g., improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (e.g., reduced cardiotoxicity) and/or fewer side effects), less prone to drug resistance and other more excellent properties.

Example

The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

The structure of the compounds disclosed herein can be confirmed by conventional methods known to those skilled in the art. If the disclosure relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) can be used, wherein the cultured single crystal is used to collect diffraction intensity data using a Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is: After collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

The following abbreviations are used in the present disclosure: aq represents water; HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphonium salt; eq represents equivalent; DCM represents dichloromethane; PE represents petroleum ether; DMSO represents dimethyl sulfoxide; EtOAc or EA represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; Cbz represents benzyloxycarbonyl, which is an amine protecting group; BOC represents tert-butyloxycarbonyl, which is an amine protecting group; rt represents room temperature; O/N represents overnight; THF represents tetrahydrofuran; Boc ₂ O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; iPrOH represents 2-propanol; mp represents melting point; Prep-HPLC represents preparative high-performance liquid chromatography; TLC represents thin-layer chromatography; AIBN represents azobisisobutyronitrile; NBS represents N-bromosuccinimide; Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Pd ₂ (dBa) ₃ represents tris(dibenzylideneacetone) dipalladium; EA represents ethyl acetate; Py represents pyridine; dppf represents 1,1'-bis(diphenylphosphino)ferrocene; LiAlH ₄ represents lithium aluminum hydride; PPh ₃ represents triphenylphosphine; Pd(dppf)Cl ₂ represents [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride.

Compounds are named according to the conventional nomenclature in the art or using The software names were used, and commercially available compounds were named using the supplier's catalog names.

Example 1: Synthesis of C001

Step 1: Preparation of C1-2

C1-1 (40 g, 174.7 mmol) was dissolved in carbon tetrachloride (500 mL) solution, followed by the addition of AIBN (2.87 g, 17.5 mmol). After nitrogen replacement three times, NBS (31 g, 174.7 mmol) was added in batches at room temperature and reacted for 2 h. After the reaction, the reaction solution was washed twice with sodium sulfite and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated, and compound C1-2 was obtained after column chromatography.

Step 2: Preparation of C1-3

C1-2 (20 g, 65 mmol) was dissolved in DMF/H ₂ O (120 mL/12 mL), cooled to 0°C, and then NaCN (3.2 g, 65 mmol) was added in batches, and stirred at 0°C for 1 h. The reaction solution was quenched with saturated sodium chloride aqueous solution, the organic phase was concentrated, and compound C1-3 was obtained after purification by column chromatography.

Step 3: Preparation of C1-4

C1-3 (1 g, 3.9 mmol) and 1,3-diiodopropane (1.16 g, 3.9 mmol) were dissolved in THF (16 mL), cooled to 0°C with an ice-water bath, and then t-BuOK (1.1 g, 2.5 mmol) was added in batches. After the addition, the temperature was maintained for 2 h. Ethyl acetate and water were added, the organic phase was concentrated, and then purified by column chromatography to obtain compound C1-4.

Step 4: Preparation of C1-5

C1-4 (500 mg, 1.7 mmol), trifluoroacetamide (384 mg, 3.4 mmol), cesium carbonate (1.66 g, 5.1 mmol), xantphos (197 mg, 0.34 mmol) and Pd ₂ (dba) ₃ (156 mg, 0.17 mmol) were added to a reaction flask, and then dioxane (500 mL) was added, and nitrogen was replaced three times, and the reaction was carried out at 110° C. for 16 h. Ethyl acetate and water were added, the organic phase was concentrated, and then purified by column chromatography to obtain compound C1-5.

Step 5: Preparation of C1-6

C1-5 (1 g, 3.1 mmol) was dissolved in concentrated H ₂ SO ₄ (8 mL) at room temperature, cooled to 0°C, and then potassium nitrate (345 mg, 3.41 mmol) was added. After nitrogen substitution, the reaction was stirred at room temperature for 0.5 h. Saturated sodium bicarbonate was added to the reaction solution to adjust the pH to 7-8, and ethyl acetate was added for extraction. Compound C1-6 was obtained after purification by silica gel column chromatography.

Step 6: Preparation of C1-7

C1-6 (400 mg, 3.84 mmol) was dissolved in 7M NH ₃ /MeOH (10 mL) solution, the reaction solution was placed in a sealed tube, and the temperature was raised to 80° C. for reaction for 16 h. The reaction solution was concentrated and subjected to silica gel column chromatography to obtain compound C1-7.

Step 7: Preparation of C1-8

At room temperature, C1-7 (100 mg, 0.16 mmol) was dissolved in trimethyl orthoformate (15 mL), and then p-toluenesulfonic acid monohydrate (1 mg, 0.0016 mmol) was added, and the temperature was raised to 100°C for 2 h after nitrogen replacement. After concentration, the product C1-8 was obtained by purification by silica gel column chromatography.

Step 8: Preparation of C1-9

At room temperature, C1-8 (85 mg, 0.16 mmol) was dissolved in methanol (5 mL), and then Pd/C (40 mg) was added. After hydrogen replacement, the mixture was warmed to room temperature and reacted for 2 h. After filtration, the filtrate was concentrated to obtain the product C1-9.

Step 9: Preparation of C001

At room temperature, C1-9 (70 mg, 0.3 mmol) was dissolved in dichloromethane (5 mL), and then pyridine (0.5 mL) was added, followed by 5-bromo-3-chloro-2-hydroxybenzenesulfonyl chloride (92 mg, 0.3 mmol), and the mixture was reacted at room temperature for 2 h. After concentration to dryness, the product C001 was obtained by reverse phase Prep-HPLC.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.61 (s, 1H), 8.19 (s, 1H), 7.93 (d, J = 2.4Hz, 1H), 7.90 (d, J = 2.4Hz, 1H) ,7.79(d,J＝2.1Hz,1H),7.73(d,J＝2.1Hz,1H),2.82-2.75(m,2H),2.57-2.49(m,2H),2.37-2.22(m,1H ),2.11-1.92(m,1H).MS m/z(ESI): 509.1[M+H] ⁺ .

Example 2: Synthesis of C002

Step 1: Preparation of C2-2

Under nitrogen protection, C2-1 (12.0 g, 50.19 mmol) was added to the N, N-dimethylacetamide (12 mL) solution in the reaction bottle, the temperature was controlled at 0-5 ° C in an ice bath, sodium hydride (2.21 g, 55.21 mmol) was added, and stirred at 0-5 ° C for 0.5 h. Iodomethane (8.55 g, 60.23 mmol) was added to the reaction solution and reacted at room temperature for 2 h. The reaction was quenched with a saturated sodium chloride solution, extracted with ethyl acetate, and the organic phases were combined. The organic phase was concentrated and then purified by silica gel column chromatography to obtain compound C2-2. MS m/z (ESI): 369.1 [M + H] ⁺ .

Step 2: Preparation of compound C2-3

Compound C2-2 (12.0 g, 47.41 mmol), N-bromosuccinimide (8.44 g, 47.41 mmol) and azobisisobutyronitrile (0.78 g, 4.74 mmol) were added to the reaction flask in sequence, and carbon tetrachloride (120 mL) was added to replace the hydrogen, and then stirred at 80°C for 12 h. The reaction was quenched with a saturated sodium chloride solution, extracted with DCM, and the organic phases were combined. The organic phase was concentrated and then purified by silica gel column chromatography to obtain compound C2-3. MS m/z (ESI): 447.0 [M+H] ⁺ .

Step 3: Preparation of compound C2-4

Under nitrogen protection, compound C2-3 (5.80 g, 17.46 mmol) was added to a mixed solution of N,N-dimethylformamide (60 mL) and water (6 mL), and sodium cyanide (1.03 g, 20.96 mmol) was added, reacted at room temperature for 2 h, and quenched with an aqueous solution (120 mL). The reaction solution was filtered, the filter cake was washed with water, and purified by column chromatography to obtain compound C2-4. MS m/z (ESI): 394.1 [M+H] ⁺ .

Step 4: Preparation of Compound C2-5

Compound C2-4 (5.00 g, 13.39 mmol) was added to the reaction flask under nitrogen protection, and then THF (50 mL) solution was added, and the temperature was cooled to 0-5 ° C in an ice bath. The temperature was maintained, and a THF solution (15 mL) of potassium tert-butoxide with a concentration of 1 mlo/L was added and stirred for 0.5 h. Diiodopropane (2.50 g, 14.73 mmol) was added, and the mixture was heated to room temperature and reacted for 2 h. The reaction was quenched with a saturated sodium chloride solution, extracted with EA, and the organic phases were combined. The organic phase was concentrated and then purified by silica gel column chromatography to obtain compound C2-5. MSm/z (ESI): 433.9 [M+H] ⁺ .

Step 5: Preparation of Compound C2-6

Compound C2-5 (2.0 g, 6.29 mmol) was dissolved in 1,4-dioxane (20 mL) at room temperature, and then Pd ₂ (dba) ₃ (0.13 g, 0.63 mmol), Xantpbos (0.08 g, 0.63 mmol) and NH ₂ Boc (0.736 g, 6.29 mmol) were added in sequence. Potassium carbonate (1.74 g, 12.58 mmol) was dissolved in 3 mL of water and added to the reaction solution. The reaction was stirred at 100°C for 10 h. The reaction solution was cooled to room temperature and concentrated to remove most of the solvent. The residue was purified by silica gel column chromatography to obtain compound C2-6. MS m/z (ESI): 471.0 [M+H] ⁺ .

Step 6: Preparation of Compound C2-7

Compound C2-6 (0.10 g, 0.28 mmol) was dissolved in DCM (2 mL), and boron tribromide (0.1 mL) was added and stirred at room temperature for 1.5 h. The reaction was quenched with saturated sodium bicarbonate solution, extracted with DCM, and the organic phases were combined. The organic phases were concentrated to obtain compound C2-7. MS m/z (ESI): 241.1 [M+H] ⁺ .

Step 7: Synthesis of Compound C002

Compound C2-7 (0.071 g, 0.28 mmol) was dissolved in DCM (3 mL), triethylamine (0.1 mL) was added, and 5-bromo-3-chloro-2-hydroxybenzenesulfonyl chloride (0.086 g, 0.28 mmol) was added and stirred at room temperature for 1.0 h. The reaction solution was concentrated and then subjected to reverse phase chromatography to obtain compound C002.

¹ H NMR (400MHz, DMSO) δ8.34 (s, 1H), 7.82 (s, 1H), 7.80 (d, J = 2.5Hz, 1H), 7.74 (s, 1H), 7.51 (d, J = 2.4 Hz,1H),3.45(s,3H),2.83(t,J＝8.9Hz,2H),2.60–2.52(m,2H),2.31(dd,J＝19.9,9.0Hz,1H),1.95–1.84 (m,1H). MS m/z(ESI):509.0[M+H] ⁺ .

Example 3: Synthesis of C003

In addition to replacing C2-7 with Compound C003 was prepared according to the method described in Example 2.

C003: ¹ H NMR (400MHz, DMSO) δ8.34 (s, 1H), 7.82 (s, 1H), 7.80 (d, J = 2.5Hz, 1H), 7.74 (s, 1H),

7.51(d,J＝2.4Hz,1H),3.45(s,3H),2.83(t,J＝8.9Hz,2H),2.60–2.52(m,2H),2.31(dd,J＝19.9,9.0Hz ,1H),1.95–1.84(m,1H).MS m/z(ESI):522.8[M+H] ⁺ .

Example 4: Synthesis of C004

Step 1: Synthesis of C4-2

Compound C4-1 (25 g, 98 mmol) was dissolved in DMF (250 mL), cesium carbonate (47.9 g, 147 mmol) was added, and iodomethane (13.9 g, 98 mmol) was added after stirring for 10 minutes, and then the mixture was reacted at 25°C for 2 hours. After the reaction, the reaction solution was extracted with water and ethyl acetate, the organic phase was concentrated, and then purified by silica gel column chromatography to obtain compound C4-2. MS m/z (ESI): 269.1 [M+H] ⁺ .

Step 2: Preparation of C4-3

Compound C4-2 (7 g, 26 mmol) was dissolved in THF (70 mL), cooled to 0°C, and then LiAlH ₄ (988 mg, 26 mmol) was slowly added in batches, and stirred at 0°C for 1 hour. After the reaction was completed, Na ₂ SO ₄ .10H ₂ O was added, and after stirring for 10 minutes, the mixture was directly filtered by vacuuming, and the filtrate was concentrated to obtain compound C4-3. MS m/z (ESI): 241.1 [M+H] ⁺ .

Step 3: Preparation of C4-4

Compound C4-3 (5 g, 20.75 mmol) was dissolved in DCM (50 mL), and dichlorothionyl (4.94 g, 41.5 mmol) was added. After half an hour of reaction, the reaction solution was concentrated, then washed with saturated sodium bicarbonate solution, and extracted with dichloromethane. The organic phases were combined and concentrated to obtain compound C4-4. MS m/z (ESI): 259.2 [M+H] ⁺ .

Step 4: Preparation of C4-5

Compound C4-4 (3.2 g, 12.3 mmol) was dissolved in DMF (30 mL), sodium cyanide (605 mg, 12.3 mmol) was added, and then reacted at 25° C. for 2 h. After the reaction, the reaction solution was quenched with water, extracted three times with ethyl acetate, and the organic phases were combined, concentrated, and purified by silica gel column chromatography to obtain compound C4-5. MS m/z (ESI): 250.1 [M+H] ⁺ .

Step 5: Preparation of C4-6

At 0°C, compound C4-5 (1.3 g, 5.2 mmol) was dissolved in tetrahydrofuran (20 mL), and then LiHMDS (10.4 mL, 10.4 mmol) was added. After stirring for 30 minutes, 1,3-dibromopropane (1.05 g, 5.2 mmol) was slowly dripped into the reaction solution, and then stirred for another 3 hours. The reaction solution was quenched with water, extracted three times with ethyl acetate, the organic phases were combined, then concentrated, and purified by silica gel column chromatography to obtain compound C4-6. MS m/z (ESI): 290.1 [M+H] ⁺ .

Step 6: Preparation of C4-7

Compound C4-6 (0.8 g, 2.76 mmol) was dissolved in 1,4-dioxane (10 mL) at room temperature, and then tert-butyl carbamate (315 mg, 2.76 mmol), cesium carbonate (1.7 g, 5.19 mmol), 9,9-dimethyl-9H-xanthene-4,5-diphenylphosphine (151 mg, 0.26 mmol), 3,2-benzylideneacetone dipalladium (120 mg, 0.13 mmol) were added, and the temperature was raised to 90°C after nitrogen replacement for 16 h, and the mixture was concentrated and then purified by chromatography to obtain compound C4-7. MS m/z (ESI): 327.1 [M+H] ⁺ .

Step 7: Preparation of C4-8

Compound C4-7 (0.5 g, 1.53 mmol) was dissolved in DCM (10 mL) at room temperature, TFA (1 mL) was added, and then reacted at 20°C for 3 h. After the starting material disappeared, the reaction solution was directly concentrated to dryness to obtain compound C4-8. MS m/z (ESI): 227.1 [M+H] ⁺ .

Step 8: Preparation of C004

Compound C4-8 (0.3 g, 1.33 mmol) was dissolved in DCM (10 mL) at room temperature, and then pyridine (0.1 mL) and 5-bromo-3-chloro-2-hydroxybenzenesulfonyl chloride (407 mg, 1.33 mmol) were added. The reaction solution was stirred at 20 °C for 1 hour. After the reaction was completed, the reaction solution was directly concentrated and then purified by preparative HPLC to obtain C004.

¹ H NMR(400MHz,MeOD)δ8.70(s,1H),7.91-7.63(m,2H),7.52(s,1H),7.16(s,1H),3.95(s,3H),2.94(s ,2H),2.74(dd,J＝19.3,8.8Hz,2H),2.42(dd,J＝19.6,8.7Hz,1H),2.04(s,1H).MS m/z(ESI):495.0[M +H] ⁺ .

Example 5: Synthesis of C005

In addition to C4-1 Replace with Compound C005 was prepared according to the method described in Example 4.

¹ H NMR(400MHz,MeOD)δ8.70(s,1H),7.91-7.63(m,2H),7.52(s,1H),7.16(s,1H),3.95(s,3H),2.94(s ,2H),2.74(dd,J＝19.3,8.8Hz,2H),2.42(dd,J＝19.6,8.7Hz,1H),2.04(s,1H).MS m/z(ESI):495.0[M +H] ⁺ .

Example 6: Synthesis of C006

Step 1: Preparation of C6-1

C2-5 (5 g, 11.52 mmol) was dissolved in tetrahydrofuran (60 mL) at room temperature, and then tetrabutylammonium fluoride (12.1 g, 46.07 mmol) was added. After nitrogen replacement, the temperature was raised to 70°C and reacted for 16 h. Extraction was performed with ethyl acetate, and the organic phase was concentrated and purified by column chromatography to obtain C6-1.

Step 2: Preparation of C6-2

C6-1 (3.5 g, 11.55 mmol) was dissolved in N, N-dimethylformamide (35 mL) at room temperature, and then 5-bromomethyloxazole (2.81 g, 17.33 mmol) and cesium carbonate (7.6 g, 23.1 mmol) were added, and the mixture was reacted at room temperature for 16 h. Water and ethyl acetate were added for extraction, and the organic phase was concentrated and purified by column chromatography to obtain compound C6-2.

Step 3: Preparation of C6-3

At room temperature, C6-2 (1 g, 2.6 mmol) was dissolved in 1,4-dioxane (10 mL), and then tert-butyl carbamate (305 mg, 2.6 mmol), cesium carbonate (1.7 g, 5.19 mmol), 9,9-dimethyl-9H-xanthene-4,5-diphenylphosphine (151 mg, 0.26 mmol), 3,2-benzylideneacetone dipalladium (120 mg, 0.13 mmol) were added, and the temperature was raised to 90 ° C for 16 hours after nitrogen replacement. The mixture was concentrated to dryness and purified by chromatography to obtain compound C6-3.

Step 4: Preparation of C6-4

At room temperature, C6-3 (200 mg, 0.3 mmol) was dissolved in tetrahydrofuran (5 mL), and then tetrabutylammonium fluoride (0.5 mL) was added and reacted at 80°C for 16 h. Ethyl acetate and water were added to the reaction solution for extraction, and the organic phase was dried and concentrated to obtain compound C6-4.

Step 5: Synthesis of Compound C006

At room temperature, C6-4 (100 mg, 0.32 mmol) was dissolved in pyridine (5 mL), and then 5-bromo-3-chloro-2-hydroxybenzenesulfonyl chloride (98 mg, 0.32 mL) was added, and the reaction was allowed to react for 1 h at room temperature. Ethyl acetate and water were added to the reaction solution for extraction, and the organic phase was concentrated and then purified by reverse phase preparative chromatography to obtain compound C006.

¹ H NMR(400MHz,MeOD)δ8.28(s,1H),8.14(s,1H),7.97(s,1H),7.67(s,1H),7.50(s,1H),7.43(d,J ＝23.6Hz,1H),7.22(s,1H),5.29(s,2H),2.78(s,2H),2.39(d,J＝42.9Hz,3H),1.84(s,1H).MS m/ z(ESI):589.9[M+H] ⁺ .

Example 7: Synthesis of D001

Step 1: Prepare D1-2

D1-1 (100 g, 304 mmol) was dissolved in DMF (1000 mL) solution, and NaCN (14.9 g, 304 mmol) was added in batches, and stirred at room temperature for 0.5 h. After filtration, the filter cake was washed with EA. The organic phases were combined, concentrated, and column chromatography was performed to obtain compound D1-2.

Step 2: Preparation of D1-3

To a solution of D1-2 (50 g, 181.9 mmol) in DMSO (500 mL) were added NaH (13.1 g, 545.7 mmol) and 1,3-diiodopropane (64.6 g, 218.3 mmol) in batches and reacted at room temperature for 1 h. After filtration, the filter cake was washed with EA. The organic phases were combined, concentrated, and column chromatography was performed to obtain compound D1-3.

Step 3: Preparation of D1-4

NH ₂ Boc (9.3 g, 79.4 mmol), CsCO ₃ (51.8 g, 158.8 mmol), xantPhos (4.6 g, 7.94 mmol) and Pd ₂ (dBa) ₃ (3.6 g, 3.97 mmol) were added to a solution of D1-3 (25 g, 79.4 mmol) in 1,4-dioxane (200 mL). The temperature was raised to 110° C. under nitrogen protection and the reaction was continued for 16 h. After filtration, the filter cake was washed with EA. The organic phases were combined, concentrated and purified by column chromatography to obtain compound D1-4.

Step 4: Preparation of D1-5

To a solution of D1-4 (12 g, 34.2 mmol, 1 eq) in 1,4-dioxane (100 mL) were added dimethylphosphine oxide (2.7 g, 34.2 mmol, 1 eq), CsCO ₃ (22.3 g, 68.4 mmol, 2 eq), xantPhos (2.0 g, 3.42 mmol, 0.1 eq) and Pd ₂ (dBa) ₃ (1.6 g, 1.71 mmol, 0.05 eq), and the temperature was raised to 110° C. under nitrogen protection, and the reaction was carried out for 16 h. The reaction solution was extracted, concentrated and subjected to column chromatography to obtain compound D1-5.

Step 5: Preparation of D1-6

D1-5 (200 mg, crude product) was dissolved in 5 mL of HCL/EA solution, stirred at room temperature for 0.5 h, and then the reaction solution was concentrated to obtain compound D1-6.

Step 6: Preparation of D001

To a solution of D1-6 (100 mg, 0.4 mmol) in DCM (5 mL) were added 5-bromo-3-chloro-2-hydroxybenzenesulfonyl chloride (160 mg, 0.52 mmol) and pyridine (191 mg, 2.4 mmol). The mixture was concentrated to dryness and purified by reverse phase Prep-HPLC to give product D001.

¹ H NMR (400MHz, CD ₃ OD-d ₄ ) δ7.85 (d, J = 2.2Hz, 1H), 7.72 (d, J = 2.2Hz, 1H), 7.55-7.40 (m, 3H), 2.77 ( s,2H),2.51-2.63(m,2H),2.44-2.34(m,1H),2.13-1.95(m,1H),1.74(d,J＝13.4Hz,6H).MS m/z(ESI ): 517.0[M+H] ⁺ .

Example 8: Synthesis of D002

D002 was prepared according to the method described in Example 7 except that dimethylphosphine oxide was replaced by diethylphosphine oxide.

¹ H NMR (400MHz, CD ₃ OD-d ₄ ) δ7.81 (d, J = 2.4Hz, 1H), 7.71 (d, J = 2.4Hz, 1H), 7.47 (d, J = 11.0Hz, 1H) ,7.43-7.37(m,2H),2.76(s,2H),2.57(s,2H),2.41-2.36(m,1H),2.07-2.01(m,3H),1.96-1.87(m,2H) ,1.02(t,J＝7.7Hz,3H),0.97(t,J＝7.7Hz,3H).MS m/z(ESI): 545.0[M+H] ⁺ .

Example 9: Synthesis of D003

Step 1: Prepare D3-2

D3-1 (5 g, 26.2 mmol) was dissolved in acetonitrile (50 mL) solution, followed by the addition of KI (5.2 g, 31.44 mmol), cesium carbonate (17 g, 52.4 mmol) and bromocyclopentane (7.8 g, 52.4 mmol). The reaction solution was placed in a sealed tank, nitrogen purged three times, heated to 135 ° C and reacted for 16 h, then concentrated and separated by silica gel column chromatography to obtain compound D3-2.

Step 2: Preparation of D3-3

D3-2 (500 mg, 1.92 mmol) was dissolved in toluene (10 mL), and dimethylphosphine oxide (300 mg, 3.84 mmol), cesium carbonate (1.88 g, 5.76 mmol), dppf (209 mg, 0.384 mmol) and Pd(OAc) ₂ (43 mg, 0.192 mmol) were added in sequence, and then the temperature was raised to 100° C. and stirred for 16 h. The reaction solution was concentrated and subjected to column chromatography to obtain compound D3-3.

Step 3: Preparation of D3-4

D3-3 (95 mg, 0.16 mmol) was dissolved in methanol (5 mL) at room temperature, and then Pd/C (40 mg) was added. After hydrogen replacement, the mixture was warmed to room temperature and reacted for 2 h. After filtration, the filtrate was concentrated to obtain compound D3-4.

Step 4: Preparation of D003

At room temperature, 5-bromo-3-chloro-2-hydroxybenzenesulfonyl chloride (113 mg, 0.37 mmol) was added to a pyridine solution (1 mL) of D3-4 (84 mg, 0.37 mmol) and reacted at room temperature for 2 h. After concentration, compound D003 was obtained by reverse phase Prep-HPLC.

¹ H NMR (400MHz, CDCl ₃ ) δ7.69 (d, J = 2.3Hz, 1H), 7.65 (d, J = 2.3Hz, 1H), 6.99 (s, 1H), 5.51-5.45 (m, 1H) ,2.27(d,J＝7.4Hz,2H),1.85(d,J＝5.4Hz,2H),1.81-1.66(m,10H).MS m/z(ESI): 496.0[M+H] ⁺ .

Example 10: Synthesis of D004

Step 1: Preparation of D4-2

Add CH ₃ I (45.4 g, 322 mmol) and K ₂ CO ₃ (44.5 g, 322 mmol) to a DMF solution (500 mL) of D4-1 (50 g, 161 mmol) at 25°C and continue stirring for 16 h. After the reaction is complete, filter the reaction solution and wash the filter cake with EA. Combine the organic phases, wash with water, concentrate, and purify by column chromatography to obtain compound D4-2.

Step 2: Preparation of D4-3

At 0°C, LiAlH ₄ (4.8 g, 126.6 mmol) was added in batches to a THF solution (400 mL) of D4-2 (41 g, 126.6 mmol). After the reaction was completed, the mixture was filtered and the filter cake was washed with THF. The organic phases were combined, washed with water, and concentrated to obtain a crude product of D4-3, which was used directly in the next step.

Step 3: Preparation of D4-4

To a solution of D4-3 (25 g, 79.4 mmol) in DCM (200 mL) was added PPh ₃ (9.3 g, 79.4 mmol) and CBr ₄ (51.8 g, 158.8 mmol) at 0°C. The mixture was stirred for 1 h at 0°C. After the reaction was completed, the mixture was filtered and the filter cake was washed with EA. The organic phases were combined, concentrated, and purified by column chromatography to obtain compound D4-4.

Step 4: Preparation of D4-5

To a DMF (100 mL) solution of compound D4-4 (12 g, 30 mmol) was added NaCN (3.5 g, 30 mmol) in batches at 25°C. The reaction solution was stirred for 0.5 h at 25°C. After the reaction was completed, the mixture was filtered and the filter cake was washed with EA. The organic phases were combined, washed with water, concentrated, and purified by column chromatography to obtain compound D4-5.

Step 5: Preparation of D4-6

Add t-BuOK (5.8 g, 52 mmol) and 1,3-diiodopropane (6.1 g, 21 mmol) to a DMSO solution (500 mL) of D4-5 (6 g, 21 mmol) at 25°C and continue stirring for 1 h. After the reaction is complete, filter and wash the filter cake with EA. Combine the organic phases, wash with water, concentrate, and purify by column chromatography to obtain compound D4-6.

Step 6: Preparation of D4-7

NH ₂ Boc (1 g, 8.7 mmol), CsCO ₃ (5.7 g, 17 mmol), XantPhos (503 mg, 0.89 mmol) and Pd ₂ (dBa) ₃ (398 mg, 0.43 mmol) were added to a solution of D4-6 (3 g, 8.7 mmol) in 1,4-dioxane (30 mL), and the mixture was reacted at 110° C. for 16 h under N ₂ protection. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with EA. The organic phases were combined, washed with water, concentrated, and purified by column chromatography to obtain compound D4-7.

Step 7: Preparation of D4-8

Dimethylphosphine oxide (500 mg, 1.2 mmol), CsCO ₃ (678 mg, 1.33 mmol), xantPhos (275 mg, 1.4 mmol) and Pd ₂ (dBa) ₃ (222 mg, 0.954 mmol) were added to a solution of compound D4-7 (1 g, 1 mmol, 1 eq) in 1,4-dioxane (200 mL), and the temperature was raised to 110° C. under nitrogen protection and reacted for 16 h. The reaction solution was cooled to room temperature, and EA and water were added for extraction. The organic phase was concentrated and purified by column chromatography to obtain compound D4-8.

Step 8: Preparation of D4-9

Compound D4-8 (50 mg) was added to HCL/EA (5 mL) and reacted at 25° C. for 0.5 h. The reaction solution was concentrated to obtain compound D4-9.

Step 9: Preparation of D4-10

5-Bromo-3-chloro-2-hydroxybenzenesulfonyl chloride (75 mg, 0.2 mmol) and pyridine (191 mg, 2.4 mmol) were added to a solution of compound D4-9 (50 mg, 0.2 mmol) in DCM (5 mL) at 25°C and stirred for 1 h. The reaction solution was concentrated and purified by column chromatography to obtain compound D4-10.

Step 10: Preparation of D004

BBr ₃ (2 ml) was added to a DCM (5 mL) solution of compound D4-10 (20 mg, 0.2 mmol) at 25° C., and the reaction solution was stirred for 1 h. After the reaction was completed, the reaction solution was concentrated and purified by Prep-HPLC to obtain compound D004.

¹ H NMR (400MHz, CD ₃ OD-d ₄ ) δ7.59-7.52(m,3H),7.39(s,1H),2.75-2.69(m,2H),2.57-2.51(m,2H),2.37 -2.31(m,1H),2.07-1.99(m,1H),1.79(d,J＝13.8Hz,6H).MS m/z(ESI): 533.0[M+H] ⁺ .

Example 11: Synthesis of D005

Step 1: Preparation of compound D5-2

At room temperature, compound D4-7 (0.5 g, 1.76 mmol) was dissolved in 1,4-dioxane (10 mL), and then compound D5-1 (315 mg, 2.76 mmol), cesium carbonate (1.7 g, 5.19 mmol), and Pd(dppf)Cl ₂ (151 mg, 0.26 mmol) were added. After nitrogen replacement, the temperature was raised to 90°C and the reaction was carried out for 16 hours. The reaction solution was concentrated and subjected to column chromatography to obtain compound D5-2. MSm/z (ESI): 369.1 [M+H] ⁺ .

Step 2: Preparation of compound D5-3

At room temperature, compound D5-2 (0.4 g, 1.16 mmol) was dissolved in DCM (10 mL), and then BBr ₃ (315 mg, 2.76 mmol) was added. After nitrogen substitution, the reaction was continued for 2 h. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phases were combined, concentrated, and then purified by silica gel column chromatography to obtain compound D5-3. MS m/z (ESI): 255.1 [M+H] ⁺ .

Step 3: Preparation of D005

At room temperature, compound D5-3 (0.2 g, 1.33 mmol) was dissolved in DCM (10 mL), and then pyridine (0.1 mL) and 5-bromo-3-chloro-2-hydroxybenzenesulfonyl chloride (407 mg, 1.33 mmol) were added. The reaction solution was then stirred at 20 degrees for 1 hour. After the reaction was completed, the reaction solution was directly concentrated and then purified by preparative HPLC to obtain compound D005.

¹ H NMR(400MHz,MeOD)δ8.70(s,1H),7.66(s,1H),7.58(s,1H),7.40(s,1H),6.89(s,1H),2.66(s,2H ),2.49-2.43(m,2H),2.31-2.28(m,1H),2.13-1.95(m,1H).MS m/z(ESI):523.0[M+H] ⁺ .

Example 12: Synthesis of D006

Step 1: Preparation of compound D6-2

D6-1 (1 g, 3.56 mmol) was dissolved in DMF (10 mL) solution, and dimethylphosphine oxide (278 mg, 3.56 mmol), potassium phosphate (2.27 g, 10.68 mmol), xantphos (412 mg, 0.712 mmol), palladium acetate (80 mg, 0.356 mmol) were added in sequence, and the mixture was reacted at 120°C for 16 h under nitrogen protection. After the reaction, the reaction solution was quenched with water, extracted with ethyl acetate, and the organic phases were combined, concentrated, and purified by silica gel column chromatography to obtain compound D6-2. LCMS (ESI) m/z: 278 [M+H] ⁺ .

Step 2: Preparation of compound D6-4

D6-2 (530 mg, 1.9 mmol) was dissolved in 1,4-dioxane (10 mL), and D6-3 (214 mg, 1.9 mmol), potassium carbonate (524 mg, 3.8 mmol), and Pd(dppf)Cl ₂ (139 mg, 0.19 mmol) were added. The atmosphere was replaced with nitrogen three times and stirred at 110° C. for 16 hours. The reaction solution was concentrated and separated and purified by silica gel column to obtain compound D6-4. LCMS (ESI) m/z: 266.0 [M+H] ⁺ .

Step 3: Preparation of compound D6-5

D6-4 (300 mg, 167.36 mmol) was dissolved in MeOH (10 mL), wet palladium carbon (150 mg) was added, and the mixture was reacted at room temperature for 3 h. Celite was added for filtration, and the filtrate was mixed with a sample and passed through a column to obtain compound D6-5. LCMS (ESI) m/z: 238.0 [M+H] ⁺ .

Step 4: Preparation of D006

D6-5 (60 mg, 0.253 mmol) was dissolved in DCM (5 mL) at room temperature, and then 5-bromo-3-chloro-2-hydroxybenzenesulfonyl chloride (47 mg, 0.15 mmol) and pyridine (39 mg, 0.5 mmol) were added, and the reaction was carried out at room temperature for 1 h. The reaction solution was extracted with water and ethyl acetate, the organic phase was concentrated, and then purified by reverse phase preparative chromatography to obtain compound D006.

HNMR (400MHz, CD ₃ OD) δ7.77(d,J＝2.4Hz,1H),7.71(d,J＝2.4Hz,1H),7.34–7.22(m,3H),2.99(dd,J＝10.5 ,6.7Hz,1H),2.02(td,J＝5.5,3.6Hz,2H),1.84–1.78(m,2H),1.73–1.69(m,8H),1.49(ddd,J＝11.5,6.0,2.6 Hz,2H).MS m/z(ESI):[M+H] ⁺ =506.0.

Example 13: Synthesis of D007

Step 1: Preparation of D7-2

To a solution of compound D7-1 (100 g, 304 mmol) in DMF (1000 mL) was added NaCN (14.9 g, 304 mmol) in batches, and the mixture was stirred at 25°C for 0.5 h, and then EA and water were added for extraction. The organic phase was concentrated and purified by column chromatography to obtain compound D7-2.

Step 2: Preparation of D7-3

NaH (13.1 g, 545.7 mmol) and 1,3-diiodopropane (64.6 g, 218.3 mmol) were added in batches to a solution of D7-2 (50 g, 181.9 mmol) in DMSO (500 mL), stirred at room temperature for 1 h, and then EA and water were added for extraction. The organic phase was concentrated and purified by column chromatography to obtain compound D7-3.

Step 3: Preparation of D7-4

NH ₂ BoC (9.3 g, 79.4 mmol), CsCO ₃ (51.8 g, 158.8 mmol), xantPhos (4.6 g, 7.94 mmol) and Pd ₂ (dBa) ₃ (3.6 g, 3.97 mmol) were added to a solution of D7-3 (25 g, 79.4 mmol) in 1,4-dioxane (200 mL). The temperature was raised to 110° C. under nitrogen protection and reacted for 16 h. After cooling to room temperature, the reaction solution was filtered and the filter cake was washed with EA. The organic phases were combined, concentrated, and purified by column chromatography to obtain compound D7-4.

Step 4: Preparation of D7-6

D7-5 (283 mg, 1.87 mmol), CsCO ₃ (1.108 g, 3.4 mmol), xantPhos (98 mg, 0.17 mmol) and Pd ₂ (dBa) ₃ (78 mg, 0.085 mmol) were added to a solution (10 mL) of compound D7-4 (600 mg, 1.7 mmol, 1 eq) in 1,4-dioxane. The mixture was heated to 110° C. under nitrogen protection and reacted for 16 h. The reaction solution was cooled to room temperature and extracted with EA and water. The organic phase was concentrated and purified by column chromatography to obtain compound D7-6.

Step 5: Preparation of D7-7

D7-6 (200 mg) was dissolved in HCL/EA (5 mL) and stirred at 25° C. for 0.5 h. The reaction solution was concentrated to obtain crude D7-7, which was used directly in the next step.

Step 6: Preparation of D007

To a solution of D7-7 (100 mg, 0.5 mmol) in DCM (5 mL) was added 5-bromo-3-chloro-2-hydroxybenzenesulfonyl chloride (163 mg, 0.52 mmol) and pyridine (126 mg, 1.6 mmol). The reaction mixture was continued at 25°C for 1 h. The reaction mixture was concentrated and purified by Prep-HPLC to obtain compound D007.

¹ H NMR (400MHz, CD ₃ OD-d ₄ ) δ7.92 (s, 2H), 7.81 (d, J = 2.3Hz, 1H), 7.69 (d, J = 1.6Hz, 1H), 7.31 (s, 1H),7.26(s,1H),7.06(s,1H),2.73(d,J＝8.2Hz,2H),2.63-2.55(m,2H),2.39-2.32(m,1H),2.08-2.00 (m,1H).MS m/z(ESI): 507.0[M+H] ⁺ .

Example 14: Synthesis of D008

Step 1: Preparation of compound D8-2

D7-4 (500 mg, 1.4 mmol, 1 eq) was dissolved in 1,4-dioxane (10 mL), and then D8-1 (356 mg, 1.7 mmol, 1.1 eq), K ₂ CO ₃ (394 mg, 2.8 mmol, 2 eq) and Pd(dppf)Cl ₂ (104 mg, 0.14 mmol, 0.1 eq) were added. The reaction solution was reacted at 110° C. for 16 h under nitrogen protection. Water and ethyl acetate were added to the reaction solution for extraction, the organic phase was concentrated, and then purified by silica gel column to obtain compound D8-2.

Step 2: Preparation of compound D8-3

D8-2 (200 mg) was dissolved in HCL/EA (5 mL) and reacted at 25°C for 0.5 h. The reaction solution was concentrated to obtain compound D8-3, which was directly used in the next step.

Step 3: Preparation of compound D008

Compound D8-3 (206 mg, 0.8 mmol, 1 eq) was dissolved in DCM (5 mL), and then 5-bromo-3-chloro-2-hydroxybenzenesulfonyl chloride (249 mg, 0.8 mmol, 1.0 eq) and pyridine (193 mg, 2.4 mmol, 3 eq) were added and reacted at 25° C. for 1 h. The reaction solution was concentrated and separated and purified by reverse phase preparative chromatography to obtain compound D008.

¹ H NMR (400MHz, CD ₃ OD-d ₄ ) δ7.93 (s, 1H), 7.81 (d, J = 2.4Hz, 1H), 7.75 (d, J = 0.6Hz, 1H), 7.69 (d, J＝2.4Hz,1H),7.27(t,J＝1.6Hz,1H),7.25–7.23(m,1H),7.04(t,J＝1.8Hz,1H),3.91(s,3H),2.79- 2.70(m,2H),2.60-2.53(m,2H),2.39-2.33(m 1H),2.09-2.04(m,1H).MS m/z(ESI): 521.0[M+H] ⁺ .

Example 15: Synthesis of D009

Step 1: Preparation of D9-1

To a solution of D7-4 (327 mg, 0.931 mmol) in 1,4-dioxane (8 mL), add pinacol diboron (284 mg, 1.1 mmol), K ₂ CO ₃ (257 mg, 1.9 mmol) and Pd(dppf)Cl ₂ (136 mg, 0.19 mmol), and heat to 100°C under nitrogen protection and react for 16 h. After the reaction solution cools to room temperature, it is extracted with water and EA. The organic phase is concentrated and purified by column chromatography to obtain compound D9-1.

Step 2: Preparation of D9-3

D9-2 (50 mg, 0.25 mmol), K ₂ CO ₃ (69 mg, 0.5 mmol) and Pd(dppf)Cl ₂ (18 mg, 0.025 mmol) were added to a solution of D9-1 (100 mg, 0.25 mmol) in 1,4-dioxane (5 mL). The temperature was raised to 100°C under nitrogen protection and the reaction was continued for 16 h. After the reaction solution cooled to room temperature, it was extracted with water and EA. The organic phase was concentrated and purified by column chromatography to obtain compound D9-3.

Step 3: Preparation of D9-4

D9-3 (100 mg) was dissolved in HCL/EA (5 mL) and stirred at room temperature for 0.5 h. After the reaction was completed, the reaction solution was spin-dried to obtain a crude compound D9-4, which was directly used in the next step.

Step 4: Prepare D009

5-Bromo-3-chloro-2-hydroxybenzenesulfonyl chloride (100 mg, 0.2 mmol) and pyridine (121 mg, 2.4 mmol) were added to a DCM (5 mL) solution of D9-4 (80 mg, 0.2 mmol), and the reaction solution was stirred for 1 h at room temperature. After the reaction was completed, the reaction solution was concentrated and separated by Prep-HPLC to obtain compound D009.

¹ H NMR (400MHz, CD ₃ OD-d ₄ ) δ9.08 (s, 1H), 8.36 (d, J = 3.7 Hz, 1H), 8.00-7.96 (m, 2H), 7.88 (d, J = 2.4 Hz,1H),7.76(d,J＝2.4Hz,1H),7.45-7.42(m,2H),7.36(d,J＝1.7Hz,1H),2.83-2.76(m,2H),2.69-2.60 (m,2H),2.44-2.36(m,1H),2.11-2.07(m,1H).MS m/z(ESI): 558.0[M+H] ⁺ .

Example 16: Synthesis of D010

D010 was prepared according to the preparation method of D009 described in Example 15, except that D9-2 was replaced with 1-methyl-5-bromo-1,2,4-triazole.

¹ H NMR (400MHz, CD ₃ OD-d ₄ ) δ7.99 (d, J = 4.9 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H) ,7.51-7.40(m,3H),3.93(s,3H),2.83-2.75(m,2H),2.65-2.58(m,2H),2.44-2.32(m,1H),2.11-2.07(m, 1H).MS m/z(ESI): 522.0[M+H] ⁺ .

Example 17: Synthesis of D011

D011 was prepared according to the preparation method described in Example 15, except that D9-2 was replaced by 5-bromothiazole.

¹ H NMR(400MHz,MeOD)δ8.28(s,1H),8.14(s,1H),7.97(s,1H),7.67(s,1H),7.50(s,1H),7.43(d,J ＝23.6Hz,1H),7.22(s,1H),5.29(s,2H),2.78(s,2H),2.39(d,J＝42.9Hz,3H),1.84(s,1H).MS m/ z(ESI):524.0[M+H] ⁺ .

Example 18: Synthesis of D012

Step 1: Preparation of D12-2

D12-1 (500 mg, 8.26 mmol) was dissolved in dimethylformamide (3 mL), followed by the addition of sodium hydride (250 mg, 9.1 mmol) and 1-bromo-2-methoxyethane (100 mg, 8.26 mmol), and the mixture was reacted at room temperature for 3 h. The mixture was concentrated to dryness and the compound D12-2 was prepared by reverse phase chromatography. MS m/z (ESI): 507.0 [M+H] ⁺ .

Step 2: Preparation of D12-3

D12-2 (500 mg, 0.45 mmol) was dissolved in 1,4-dioxane (5 mL) and stirred at 80°C for 4 h. The mixture was concentrated to dryness and the compound D12-3 was prepared by reverse phase chromatography. MS m/z (ESI): 503, 0 [M+H] ⁺ .

Step 3: D12-4

D12-3 (505 mg, 0.45 mmol) was dissolved in acetonitrile/acetic acid/water solution (5 mL/5 mL/5 mL), and dichlorohydantoin was added, and the mixture was reacted at room temperature for 4 h. The mixture was concentrated to dryness and the compound D12-4 was prepared by reverse phase reaction. MS m/z (ESI): 479.0 [M+H] ⁺ .

Step 4: Preparation of D12-5

D12-4 (300 mg) was dissolved in dichloromethane (10 mL), and D8-3 (250 mg, 0.90 mmol) and pyridine (121 mg, 2.4 mmol) were added, and the reaction solution was stirred for 1 h at room temperature. The reaction solution was concentrated and separated by column chromatography to obtain D12-5. MSm/z (ESI): 695.1 [M+H] ⁺ .

Step 5: Prepare D012

D12-5 (100 mg) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at 25° C. for 1 hour. The reaction solution was concentrated and purified by preparative HPLC to obtain compound D012.

¹ H NMR (400MHz, CD ₃ OD) δ8.09(s,1H),7.80(s 1H),7.74(s,1H),7.63(s,1H),7.25(s,1H),7.19(s, 1H),6.94(s,1H),4.51(s,2H),3.85(s,3H),3.51(d,J＝8.0Hz,2H),3.43-3.28(m,2H),3.21(s,3H ),2.68(s,2H),2.50(s,2H),2.30-2.23(m,1H),2.03-1.89(m,1H).MS m/z(ESI):575.1[M+H] ⁺ .

Example 19: Synthesis of D013

In addition to Replace Compound D013 was prepared according to the method described in Example 18.

¹ H NMR (400MHz, CDCl ₃ ) δ7.80(s,1H),7.71(s,1H),7.60(s,1H),7.32(s,1H),7.18(s,2H),7.01(s, 1H),7.45(s,2H),7.71(s,1H),3.87(d,J＝8.0Hz,3H),3.76(s,2H),3.18(s,2H),2.75-2.60(m,8H ),2.54-2.50(m,2H),2.39-2.30(m,1H),2.04(s,1H). MS m/z(ESI):588.1[M+H] ⁺ .

Example 20: Synthesis of D014

Step 1: Preparation of D14-2

D14-1 (5 g, 15.001 mmol) was dissolved in DMF (50 mL), and PMBCl (3.524 g, 22.502 mmol) and K ₂ CO ₃ (4.146 g, 30.002 mmol) were added at room temperature, and the reaction mixture was reacted at 60° C. for 16 h. Water and ethyl acetate were added to the reaction solution for extraction, and the organic phase was concentrated and then purified by silica gel column chromatography to obtain compound D14-2.

Step 2: Preparation of D14-3

D14-2 (4.9 g, 10.805 mmol) was dissolved in 1,4-dioxane (50 mL), and BnSH (1.342 g, 10.805 mmol), DIEA (2.793 g, 21.61 mmol), Xantphos (1.250 g, 2.161 mmol) and Pd ₂ (dba) ₃ (1.106 g, 1.081 mmol) were added at room temperature. The atmosphere was replaced with nitrogen and reacted at 80° C. for 5 hours. Ethyl acetate and water were added to the reaction solution for extraction. The organic phase was concentrated and then purified by silica gel column chromatography to obtain compound D14-3.

Step 3: Preparation of D14-4

D14-3 (1 g, 2.223 mmol) was dissolved in ACN/AcOH/H ₂ O (10 mL/2 mL/2 mL), cooled to 0°C in an ice bath, and DCDMH (876 mg, 4.446 mmol) was added in batches. After the addition was complete, the temperature was maintained for 2 h. Ethyl acetate and water were added for extraction, the organic phases were combined, concentrated, and then purified by silica gel column chromatography to obtain compound D14-4.

Step 4: Preparation of D14-5

D14-4 (600 mg, 1.303 mmol) and D1-6 (324 mg, 1.303 mmol) were dissolved in DCM (10 mL), pyridine (309 mg, 3.909 mmol) was added at room temperature, and the reaction was carried out at room temperature for 16 h. The reaction solution was quenched with 0.5 mmol/L citric acid aqueous solution, extracted with dichloromethane, washed with saturated sodium chloride solution, and the organic phases were combined. The organic phase was concentrated and then purified by silica gel column chromatography to obtain compound D14-5.

Step 5: Preparation of D14-6

D14-5 (250 mg, 0.372 mmol) was dissolved in 1,4-dioxane (10 mL) at room temperature, and trimethyl((tributyltinyl)ethynyl)silane (288 mg, 0.744 mmol) and Pd(pph ₃ ) ₄ (43 mg, 0.037 mmol) were added at room temperature. The atmosphere was replaced with nitrogen and reacted at 100° C. for 16 hours. The reaction solution was directly concentrated and purified by silica gel column chromatography to obtain compound D14-6.

Step 6: Preparation of D014

D14-6 (150 mg, 0.218 mmol) was dissolved in DCM (10 mL) at room temperature, and then TFA (1 mL) was added. After the reaction was completed, it was quenched with saturated sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined, concentrated to dryness, and separated and purified by reverse phase preparative chromatography to obtain compound D014.

¹ H NMR (400MHz, MeOD) δ7.71 (d, J = 2.0Hz, 1H), 7.55 (d, J = 2.1Hz, 1H), 7.51 (d, J = 11.9Hz, 1H), 7.44 (d, J＝12.5Hz,2H),3.46(s,1H),2.76(s,2H),2.57(d,J＝7.7Hz,2H),2.39(dd,J＝11.2,5.0Hz,1H),2.23– 2.06(m,1H),1.74(d,J＝13.4Hz,6H).MS m/z(ESI):463.1[M+H] ⁺ .

Example 21: Synthesis of E001

Step 1: Preparation of E1-1

Indole-2-one (20 g, 150.32 mmol) was dissolved in tetrahydrofuran (200 mL) solution, cooled to -78°C, lithium diamine (56 g, 330.71 mmol) was added dropwise, and 1,4-dibromobutane (33 g, 150.32 mmol) was added after half an hour of reaction, and then the temperature was raised to 70°C for reaction for 7 hours. After the reaction, the reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was concentrated to dryness, and E1-1 was obtained by column chromatography.

Step 2: Preparation of E1-2

E1-1 (5 g, 26.73 mmol) was dissolved in trifluoroacetic acid (50 mL), potassium nitrate (2.7 g, 26.73 mmol) was added at 0°C, and stirred for 4 hours. After the reaction was completed, the reaction solution was added dropwise to ice water, filtered, and the filter cake was dissolved in ethyl acetate, concentrated, and then purified by column chromatography to obtain compound E1-2.

Step 3: Preparation of E1-3

Under an ice-salt bath, E1-2 (3.0 g, 12.92 mmol) was dissolved in a concentrated sulfuric acid solution (20 mL), and N-bromosuccinimide (2.3 g, 12.92 mmol) was slowly added, and stirred at room temperature for 3 h. Saturated sodium bicarbonate was then added to adjust the pH to 7, and then ethyl acetate was added for extraction, and the organic phases were combined. The organic phase was concentrated and then purified by silica gel column chromatography to obtain compound E1-3. MS m/z (ESI): 311.0 [M+H] ⁺ .

Step 4: Preparation of E1-4

Potassium phosphate (1637.4 mg, 7.71 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (446.3 mg, 0.77 mmol) and palladium acetate (86.6 mg, 0.39 mmol) were added to a solution of E1-3 (1200 mg, 3.86 mmol) and dimethylphosphine oxide (301.0 mg, 3.86 mmol) in nitrogen methyl pyrrolidone (20 mL), and stirred at 130° C. for 3 h. The reaction solution was cooled to room temperature, concentrated to dryness, and subjected to silica gel column chromatography to obtain compound E1-4. MS m/z (ESI): 309.1 [M+H] ⁺ .

Step 5: Preparation of E1-5

E1-4 (600 mg, 1.95 mmol) was dissolved in ethanol (20 mL) at room temperature, and then water (5 mL) was added, and ammonium chloride (208.4 mg, 3.90 mmol) and iron powder (545.5 mg, 9.74 mmol) were added. The reaction solution was stirred at room temperature for 1 h. The reaction solution was filtered and the filtrate was concentrated to obtain compound E1-5. MS m/z (ESI): 279.1 [M+H] ⁺ .

Step 6: Preparation of E001

E1-5 (300 mg, 1.08 mmol) was dissolved in dichloroethane (10 mL) at room temperature, and then 5-bromo-3-chloro-2-hydroxybenzenesulfonyl chloride (329 mg, 1.00 mmol) and pyridine (170.5 mg, 2.00 mmol) were added. The reaction solution was stirred at room temperature for 1 h, concentrated to dryness, and separated by reverse phase preparative chromatography to obtain compound E001.

¹ H NMR (400MHz, MeOD) δ7.74(d,J＝2.2Hz,1H),7.68(d,J＝2.2Hz,1H),7.14(s,1H),7.08(dd,J＝12.7,1.7 Hz, 1H), 3.32 (dd, J = 9.2, 7.7Hz, 3H), 2.09–1.92 (m, 6H), 1.73 (dd, J = 25.6, 9.6Hz, 8H). MS m/z(ESI):547.0[M+H] ⁺ .

Example 22: Synthesis of E002

Step 1: Preparation of E2-1

To a solution of E1-4 (300 mg, 0.97 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added sodium hydride (256.5 mg, 2 mmol) dropwise under an ice-salt bath, and stirred at 0°C for 1 h, and then iodomethane (276.6 mg, 2 mmol) was added. The reaction solution was returned to room temperature and stirred for 1 h. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined. The organic phase was concentrated and then purified by silica gel column chromatography to obtain compound E2-1. MS m/z (ESI): 323.1 [M+H] ⁺ .

Step 2: Preparation of E2-2

Add iron powder (243 mg, 4.35 mmol) and ammonium chloride (465 mg, 8.7 mmol) to a solution of E2-1 (280 mg, 0.87 mmol) in ethanol (10 mL) and water (2.5 mL). Stir at 80 °C for 2 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was extracted with ethyl acetate, and the organic phases were combined. The organic phase was concentrated and then chromatographed on a silica gel column to obtain compound E2-2. MS m/z (ESI): 293.1 [M+H] ⁺ .

Step 3: Preparation of compound E002

At room temperature, E2-2 (240 mg, 0.82 mmol) was dissolved in dichloromethane (2 mL), and then pyridine (1.64 mg) and 5-bromo-3-chloro-2-hydroxybenzenesulfonyl chloride (248.2 mg, 0.82 mmol) were added. The reaction solution was stirred at room temperature for 0.5 h. The reaction solution was concentrated to dryness and purified by reverse phase preparative chromatography to obtain compound E002.

¹ H NMR (400MHz, CD Cl3) δ7.6 0(s,1H),7.5 6(s,1H),7.0 5–6.9 2(m,2H),3.5 8(s,3H),2.11–1.9 7 (m,4H),1.8 4(d,J＝1 2.0Hz,8H),1.6 3(s,2H). MS m/z(ESI):561.1[M+H] ⁺ .

Example 23: Synthesis of E003

Step 1: Preparation of E3-1

E1-3 (450 mg, 1.45 mmol) was dissolved in 1,4-dioxane, 4-methyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylpyrazole (332 mg, 1.59 mmol), potassium carbonate (400 mg, 2.90 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (106 mg, 0.145 mmol) were added, nitrogen was replaced three times, and the reaction was carried out at 80°C for 16 hours. The reaction solution was concentrated and purified by silica gel column chromatography to obtain compound E3-1.

Step 2: Preparation of E3-2

E3-1 (150 mg, 0.48 mmol) was dissolved in methanol (3 mL) at room temperature, palladium carbon (75 mg) was added at room temperature, hydrogen was replaced three times, and the reaction was continued for 3 h. The palladium carbon was filtered off from the reaction solution, and E3-2 was obtained after concentration.

Step 3: Preparation of E003

At room temperature, E3-2 (150 mg, 0.53 mmol) was dissolved in dichloromethane (5 mL), and then 5-bromo-3-chloro-2-hydroxybenzenesulfonyl chloride (163 mg, 0.53 mmol) and pyridine (127 mg, 1.59 mmol) were added, and the mixture was reacted at room temperature for 1 h. The reaction solution was extracted with water and ethyl acetate, and the organic phase was concentrated and purified by reverse phase preparative chromatography to obtain E003.

¹ H NMR (400MHz, CD ₃ OD_SPE) δ7.81 (s, 1H), 7.72 (d, J = 2.4Hz, 1H), 7.66 (d, J = 2.4Hz, 1H), 7.61 (s, 1H), 6.99(d,J＝1.9Hz,1H),6.87(d,J＝2.0Hz,1H),3.93(s,3H),2.04(d,J＝4.7Hz,2H),1.95(s,2H), 1.71(s,1H),1.33(s,1H).MS m/z(ESI):561.0[M+H] ⁺ .

Experimental example

Experimental Example 1: Determination of the inhibitory effect of WDR5 inhibitors on WDR5-MYC protein-protein interaction (PPI)

1. Experimental Materials

PPI-Terbium detection buffer, MAb Anti 6HIS-Tb cryptate and streptavidin-d2 were purchased from Cisbio; biotin-MYC and HIS-WDR5 were purchased from Genscript; DMSO was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.

2. Determination of the inhibitory activity of WDR5 inhibitors on WDR5-MYC PPI

1) Add 2 μL of 10× test compound working solution in a gradient dilution into a 384-well white plate, and add 10× DMSO working solution into the blank wells and negative control wells.

2) Add 4 μL 5×HIS-WDR5 working solution and 4 μL 5×biotin-MYC working solution, and add 8 μL PPI-Terbium detection buffer to the blank wells. Incubate the 384-well plate at room temperature with shaking for 30 min.

3) Add 5 μL 1×MAb Anti 6HIS-Tb cryptate to the negative control wells, and then add 5 μL PPI-Terbium detection buffer. Add 10 μL 1× antibody working solution (MAb Anti 6HIS-Tbcryptate and streptavidin-d2 mixture) to the remaining wells, where the final concentration of MAb Anti 6HIS-Tb cryptate is 4 ng/well and the concentration of streptavidin-d2 is 25 ng/well. Incubate the 384-well plate at room temperature with shaking for 1 hour.

4) Read the signal values F of 320/615 and 320/665 on the TECAN spark microplate reader.

5) Calculate the inhibition percentage (% inhibition) of the compound on WDR5-MYC PPI according to the formula

% suppression=100%-(Signal _cmpd -Signal _{Ave_PC)} /(Signal _{Ave_NC} -Signal _{Ave_PC} )×100. (Signal＝F665/F615×100)

The compound % inhibition was then fitted with a four-parameter equation using Graphpad prism 8 to obtain the IC50 value of the compound.

3. Experimental results

Compounds IC50(uM) C001 16.4 C002 5.6 C003 2.8 C004 17.1 C005 5.0 C006 1.8 D001 1.9 D002 4.8 D003 9.2 D004 8.4 D005 8.4 D006 7.0 D007 5.9 D008 5.6 D009 7.1 D010 9.2 D011 10.3 D012 2.6 D013 5.5 D014 1.3 E001 1.1 E002 2.8 E003 0.6

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

Claims (45)

1. A compound of formula (I):

or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically-labeled compound or prodrug thereof,

Wherein:

CyA is a structure of formula (a-i), (a-ii), (a-iii) or (a-iv):

Wherein:

X ¹ is independently selected at each occurrence from CR ^X1 and N;

x ² is selected from CR ¹ and N;

X ³ is selected from CR ² or N;

X ⁴ is selected from CR ^X2 and N;

r ^X1 and R ^X2 are each independently selected from H, halogen and C _1-8 alkyl;

r ¹ is independently at each occurrence selected from H, halogen, OH, -OC _1-8 alkyl, -OC _1-8 haloalkyl, -OC _3-6 cycloalkyl, NH ₂、-NHC_1-8 alkyl, -N (C _1-8 alkyl) ₂、-NHC_3-6 cycloalkyl, -N (C _1-8 alkyl) (C _3-6 cycloalkyl), and-N (C _3-6 cycloalkyl) ₂;

R ² is independently selected at each occurrence from: h is formed; -P (=o) H (C _1-8 alkyl), -P (O) (C _1-8 alkyl) ₂; a5 or 6 membered monocyclic heteroaryl, and an 8, 9 or 10 membered bicyclic heteroaryl, wherein the monocyclic heteroaryl and the bicyclic heteroaryl each have 0, 1, 2, 3 or 4 nitrogen atoms as ring members and 0, 1 or 2 ring members independently selected from O and S, and the monocyclic heteroaryl and the bicyclic heteroaryl are optionally substituted with 1, 2, 3 or 4R ⁵, wherein optionally R ⁵ is an N-substituent;

Each R ⁵ is independently selected from the group consisting of C _1-8 alkyl, halogen, OH, -OC _1-8 alkyl, -OC _1-8 haloalkyl, NH ₂、-NHC_1-8 alkyl, and a substituent of-N (C _1-8 alkyl) ₂;

r ³ is independently at each occurrence selected from H, C _1-8 alkyl, halogen, OH, -OC _1-8 alkyl, -OC _1-8 haloalkyl, -P (=O) H (C _1-8 alkyl) and-P (O) (C _1-8 alkyl) ₂;

R ⁴ is independently selected at each occurrence from: H. halogen, CN, SF ₅、C_1-8 alkyl, C _2-8 alkenyl, C _1-8 haloalkyl, -OC _1-8 alkyl, -OC _1-8 haloalkyl, -P (=o) H (C _1-8 alkyl) and-P (O) (C _1-8 alkyl) ₂; and C _3-6 cycloalkyl, C _4-6 cycloalkenyl, phenyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein each of said C _3-6 cycloalkyl, C _4-6 cycloalkenyl, phenyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl is optionally substituted with 1,2, 3, or 4R ⁶;

Each R ⁶ is independently selected from the group consisting of independently halogen, CN, oxo, C _1-8 alkyl, and C _1-8 haloalkyl;

Or alternatively

R ¹ and R ² in said formulae (a-i) and (a-ii) together with the two ring carbon atoms to which they are attached form a heterocyclyl Het1; or alternatively

R ² and R ³ in said formulae (a-i) and (a-iii) together with the two ring carbon atoms to which they are attached form a heterocyclyl Het2; or alternatively

R ³ and R ⁴ in said formulae (a-i) and (a-iii) together with the two ring carbon atoms to which they are attached form a heterocyclyl Het3;

The heterocyclyl Het1, het2 and Het3 are each independently selected from 5 or 6 membered monocyclic heterocycloalkyl, 5 or 6 membered monocyclic heterocycloalkenyl, 5 or 6 membered monocyclic heteroaryl, 7-11 membered mono-spiroheterocycloalkyl, and 7-11 membered mono-spiroheterocycloalkenyl, wherein the 5 or 6 membered monocyclic heterocycloalkyl, the 5 or 6 membered monocyclic heterocycloalkenyl, the 5 or 6 membered monocyclic heteroaryl, the 7-11 membered mono-spiroheterocycloalkyl and the 7-11 membered mono-spiroheterocycloalkenyl each optionally having 1C (O) as a ring member and optionally being substituted with 1,2, 3, 4 or more substituents R ^a, wherein when R ^a is present, 1R ^a is optionally an N-substituent;

Each R ^a is independently selected from halogen, CN, OH, NH ₂、C_1-8 alkyl, C _2-8 alkenyl, C _1-8 haloalkyl, -NHC _1-8 alkyl, -N (C _1-8 alkyl) ₂、-OC_1-8 alkyl, -OC _1-8 haloalkyl, -C _1-8 alkylene- (optionally substituted C _3-6 cycloalkyl), -C _1-8 alkylene- (optionally substituted C _4-6 cycloalkenyl), -C _1-8 alkylene- (optionally substituted 4-6 membered heterocycloalkyl), -C _1-8 alkylene- (optionally substituted 4-6 membered heterocycloalkenyl), -C _1-8 alkylene- (optionally substituted C _6-10 aryl), and-C _1-8 alkylene- (optionally substituted 5-or 6 membered heteroaryl);

R ⁷ is selected from H, halogen, OH, CN, -C (O) OH, -SF ₅、-NO₂、C_1-8 alkyl, C _1-8 haloalkyl, -OC _1-8 alkyl, -OC _1-8 haloalkyl, -C _1-8 alkylene-OH, -C _1-6 alkylene-OC _1-6 alkyl, -C _1-6 alkylene-OC _1-6 alkylene-OC _1-6 alkyl, -C _1-6 alkylene-OC _1-6 alkylene-NH ₂、-C_1-6 alkylene-OC _1-6 alkylene-NH (C _1-6 alkyl), -C _1-6 alkylene-OC _1-6 alkylene-N (C _1-6 alkyl) ₂、C_3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkenyl and 5-10 heteroaryl, wherein the C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkenyl and 5-10 heteroaryl are optionally substituted with 1,2,3 or 4 substituents independently selected from halogen, CN, C _1-8 alkyl and C _1-8 haloalkyl; And

R ⁸ is selected from H, halogen, CN, C _1-8 alkyl, C _1-8 haloalkyl, -OC _1-8 alkyl, -OC _1-8 haloalkyl, C _2-8 alkynyl and C _2-8 haloalkynyl.

2. The compound of claim 1, wherein the compound is of formula (I-I):

3. the compound of claim 1, wherein the compound is of formula (I-ii):

4. The compound of claim 1, wherein the compound is of formula (I-iii):

5. The compound of any one of claims 1-4, wherein X ¹ is independently CR ^X1 at each occurrence.

6. The compound of any one of claims 1-5, wherein R ^X1 is selected from H, F, cl and C _1-6 alkyl;

Preferably, R ^X1 is H or C _1-4 alkyl;

More preferably, R ^X1 is H.

7. The compound of any one of claims 1-6, wherein X ¹ is independently CH at each occurrence.

8. The compound of any one of claims 1-4, wherein X ¹ is independently N at each occurrence.

9. The compound of claim 1, wherein the compound is of formula (I-iv):

10. The compound of claim 1 or 9, wherein: x ² is CR ¹.

11. The compound of claim 1 or 9, wherein: x ² is N.

12. The compound of any one of claims 1 or 9-11, wherein X ³ is CR ².

13. The compound of any one of claims 1 or 9-11, wherein X ³ is N.

14. The compound of any one of claims 1 or 9-13, wherein X ⁴ is CR ^X2.

15. The compound of any one of claims 1 or 9-13, wherein X ⁴ is N.

16. The compound of any one of claims 1, 9, 11-12 and 14, wherein X ² is N, X ³ is CR ², and X ⁴ is CR ^X2.

17. The compound of any one of claims 1, 9, 11-12, 14 and 16, wherein:

R ^X2 is selected from H, F, cl and C _1-6 alkyl;

Preferably, R ^X2 is H or C _1-4 alkyl;

More preferably, R ^X2 is H.

18. The compound of any one of claims 1, 9, 11-12, 14, 16, and 17, wherein X ² is N, X ³ is CR ², and X ⁴ is CH.

19. A compound according to any one of claims 1-3 and 5-18, wherein:

R ¹ is independently at each occurrence selected from H, F, cl, OH, -OC _1-6 alkyl, -OC _1-6 haloalkyl, -OC _3-6 cycloalkyl, NH ₂、-NHC_1-6 alkyl, -N (C _1-6 alkyl) ₂、-NHC_3-6 cycloalkyl, -N (C _1-6 alkyl) (C _3-6 cycloalkyl), and-N (C _3-6 cycloalkyl) ₂;

Preferably, R ¹ is independently selected at each occurrence from H, F, cl, OH, NH ₂、-NHC_1-4 alkyl and-N (C _1-4 alkyl) ₂;

More preferably, R ¹ is independently at each occurrence hydrogen or OH.

20. A compound according to any one of claims 1-19, wherein:

R ² is independently selected at each occurrence from: -P (=o) H (C _1-8 alkyl), -P (O) (C _1-8 alkyl) ₂; a 5-or 6-membered nitrogen-containing monocyclic heteroaryl, and an 8, 9, or 10-membered nitrogen-containing bicyclic heteroaryl, wherein the nitrogen-containing monocyclic heteroaryl and the nitrogen-containing bicyclic heteroaryl each have 1,2, 3, or 4 nitrogen atoms as ring members and 0,1, or 2 ring members independently selected from O and S, and each are optionally substituted with 1,2, 3, or 4R ⁵, wherein optionally R ⁵ is an N-substituent;

Preferably, R ² is independently selected at each occurrence from: -P (=o) H (C _1-6 alkyl), -P (O) (C _1-6 alkyl) ₂; a 5-or 6-membered nitrogen-containing monocyclic heteroaryl, and an 8, 9, or 10-membered nitrogen-containing bicyclic heteroaryl, wherein the nitrogen-containing monocyclic heteroaryl and the nitrogen-containing bicyclic heteroaryl each have 1, 2, 3, or 4 nitrogen atoms as ring members and 0 or 1 ring member selected from O and S, and the nitrogen-containing monocyclic heteroaryl and the nitrogen-containing bicyclic heteroaryl each are optionally substituted with 1, 2, or 3R ⁵, wherein optionally R ⁵ is an N-substituent;

More preferably, R ² is independently selected at each occurrence from: -P (O) (C _1-4 alkyl) ₂; a 5-or 6-membered nitrogen-containing monocyclic heteroaryl, and an 8, 9, or 10-membered nitrogen-containing bicyclic heteroaryl, wherein the nitrogen-containing monocyclic heteroaryl and the nitrogen-containing bicyclic heteroaryl each have 1,2, or 3 nitrogen atoms as ring members and 0 or 1 ring members selected from O and S, and the nitrogen-containing monocyclic heteroaryl and the nitrogen-containing bicyclic heteroaryl each are optionally substituted with 1 or 2R ⁵, wherein optionally R ⁵ is an N-substituent;

More preferably, R ² is independently selected at each occurrence from: -P (O) (C _1-2 alkyl) ₂; a 5-or 6-membered nitrogen-containing monocyclic heteroaryl, and an 8, 9, or 10-membered nitrogen-containing bicyclic heteroaryl, wherein the nitrogen-containing monocyclic heteroaryl and the nitrogen-containing bicyclic heteroaryl each have 1,2, or 3 nitrogen atoms as ring members and 0 or 1 ring member selected from O and S, and the nitrogen-containing monocyclic heteroaryl and the nitrogen-containing bicyclic heteroaryl are optionally substituted with 1R ⁵, wherein optionally R ⁵ is an N-substituent.

21. A compound according to claim 20, wherein:

the nitrogen-containing monocyclic heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl;

Preferably, the nitrogen-containing monocyclic heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl;

More preferably, the nitrogen-containing monocyclic heteroaryl is selected from pyrazolyl, imidazolyl, triazolyl, oxazolyl, and thiazolyl.

22. A compound according to claim 20, wherein:

The nitrogen-containing bicyclic heteroaryl is selected from: pyrrolopyrazoles, pyrroloimidazoles, imidazoloimidazoles, imidazopyrazoles, imidazothiazoles, pyrazolothiazoles imidazo oxazolyl, pyrazolooxazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl imidazo oxazolyl, pyrazolooxazolyl, benzothiazolyl benzisothiazolyl, benzoxazolyl, and pyrrolopyrazinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrazolopyrazinyl, pyrazolopyridazinyl oxazolopyridinyl, oxazolopyridazinyl, oxazolopyrimidinyl, oxazolopyrazinyl, thiazolopyridinyl oxazolopyridinyl, oxazolopyridazinyl, oxazolopyrimidinyl oxazolopyrazinyl, thiazolopyridinyl, and;

preferably, the nitrogen-containing bicyclic heteroaryl is selected from: imidazopyridinyl, imidazopyridazinyl, imidazopyrimidinyl imidazopyrazinyl, pyrrolopyridinyl, and imidazopyrazinyl radical pyrrolopyridinyl group pyrazolopyridazinyl, oxazolopyridinyl, oxazolopyridazinyl, and oxazolopyrimidinyl, oxazolopyrazinyl, and oxazolopyrimidinyl group oxazolopyrazinyl, a process for preparing the same;

more preferably, the nitrogen-containing bicyclic heteroaryl is selected from: imidazopyridinyl group imidazopyridazinyl radical imidazopyrimidinyl radicals imidazopyrazinyl;

More preferably, the nitrogen-containing bicyclic heteroaryl is selected from: imidazo [1,2] pyridazinyl, imidazo [1,2] pyrimidinyl and imidazo [1,2] pyrazinyl.

23. A compound according to any one of claims 1-22, wherein:

Each R ⁵ is independently selected from the group consisting of C _1-6 alkyl, halogen, OH, -OC _1-6 alkyl, -OC _1-6 haloalkyl, NH ₂、-NHC_1-6 alkyl, and a substituent of-N (C _1-6 alkyl) ₂;

Preferably, each R ⁵ is independently selected from the group consisting of C _1-4 alkyl, F, cl, OH, -OC _1-4 alkyl, -OC _1-4 haloalkyl, NH ₂、-NHC_1-4 alkyl, and a substituent of-N (C _1-4 alkyl) ₂;

more preferably, each R ⁵ is independently selected from C _1-4 alkyl, preferably methyl.

24. A compound according to any one of claims 1-23, wherein:

R ² is independently at each occurrence selected from

25. The compound of any one of claims 1-2, 4-8, and 19-24, wherein:

r ³ is independently at each occurrence selected from H, C _1-6 alkyl, halogen, OH, -OC _1-6 alkyl, -OC _1-6 haloalkyl, -P (=O) H (C _1-6 alkyl) and-P (O) (C _1-6 alkyl) ₂;

Preferably, R ³ is independently at each occurrence selected from H, C _1-4 alkyl, F, cl, OH, -OC _1-4 alkyl, -OC _1-4 haloalkyl, -P (=o) H (C _1-4 alkyl) and-P (O) (C _1-4 alkyl) ₂;

Preferably, R ³ is independently at each occurrence H.

26. A compound according to any one of claims 1-25, wherein:

R ⁴ is independently selected at each occurrence from: H. halogen, CN, SF ₅、C_1-6 alkyl, C _2-6 alkenyl, C _1-6 haloalkyl, -OC _1-6 alkyl, -OC _1-6 haloalkyl, -P (=o) H (C _1-6 alkyl) and-P (O) (C _1-6 alkyl) ₂; and C _3-6 cycloalkyl, C _4-6 cycloalkenyl, phenyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein each of said C _3-6 cycloalkyl, C _4-6 cycloalkenyl, phenyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl is optionally substituted with 1,2, 3, or 4R ⁶;

Preferably, R ⁴ is independently selected at each occurrence from: H. f, cl, CN, SF ₅、C_1-4 alkyl, C _2-4 alkenyl, C _1-4 haloalkyl, -OC _1-4 alkyl, -OC _1-4 haloalkyl, -P (=o) H (C _1-4 alkyl) and-P (O) (C _1-4 alkyl) ₂; and C _3-6 cycloalkyl, C _4-6 cycloalkenyl, phenyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein each of said C _3-6 cycloalkyl, C _4-6 cycloalkenyl, phenyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl is optionally substituted with 1,2,3, or 4R ⁶;

More preferably, R ⁴ is independently selected at each occurrence from: h is formed; c _3-6 cycloalkyl, C _4-6 cycloalkenyl, and 4-6 membered heterocycloalkyl, wherein each of said C _3-6 cycloalkyl, C _4-6 cycloalkenyl, and 4-6 membered heterocycloalkyl is optionally substituted with 1R ⁶;

More preferably, R ⁴ is independently selected at each occurrence from: h is formed; cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein each of said cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl is optionally substituted by 1R ⁶.

27. A compound according to any one of claims 1-26, wherein:

Each R ⁶ is independently selected from the group consisting of independently halogen, CN, oxo, C _1-6 alkyl, and C _1-6 haloalkyl;

Preferably, each R ⁶ is independently selected from the group consisting of independently F, cl, CN, oxo, C _1-4 alkyl, and C _1-4 haloalkyl;

More preferably, each R ⁶ is independently selected from F, cl and CN;

More preferably, each R ⁶ is independently selected from CN independently.

28. The compound of any one of claims 1-27, wherein R ⁴ is independently selected at each occurrence from H, Preferably

29. The compound of claim 2, wherein the compound is a compound of formula (I-v), (I-vi), or (I-vii):

Wherein:

R ¹ is selected from H, F, cl, OH and NH ₂, preferably hydrogen or OH;

And/or

R ² is selected from: -P (O) (C _1-4 alkyl) ₂; a 5-or 6-membered nitrogen-containing monocyclic heteroaryl, and an 8, 9, or 10-membered nitrogen-containing bicyclic heteroaryl, wherein the nitrogen-containing monocyclic heteroaryl and the nitrogen-containing bicyclic heteroaryl each have 1,2, or 3 nitrogen atoms as ring members and 0 or 1 ring member selected from O and S, and the nitrogen-containing monocyclic heteroaryl and the nitrogen-containing bicyclic heteroaryl each are optionally substituted with 1R ⁵, wherein R ⁵ is selected from C _1-4 alkyl and is optionally an N-substituent,

Preferably, R ² is selected from: -P (O) (C _1-4 alkyl) ₂; pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, imidazopyridinyl, imidazopyridazinyl, imidazopyrimidinyl and imidazopyrazinyl, wherein the pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, imidazopyridinyl, imidazopyridazinyl, imidazopyrimidinyl and imidazopyrazinyl are each optionally substituted with 1R ⁵, wherein R ⁵ is selected from C _1-4 alkyl and is optionally an N-substituent,

More preferably, R ² is selected from: -P (O) (C _1-2 alkyl) ₂; pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl and thiazolyl, imidazo [1,2] pyridazinyl, imidazo [1,2] pyrimidinyl and imidazo [1,2] pyrazinyl, wherein the pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, imidazo [1,2] pyridazinyl, imidazo [1,2] pyrimidinyl and imidazo [1,2] pyrazinyl are each optionally substituted with 1R ⁵, wherein R ⁵ is selected from C _1-4 alkyl and is optionally an N-substituent,

More preferably, R ² is selected from

More preferably, R ² is selected from

And/or

R ³ is H;

And/or

R ⁴ is C _3-6 cycloalkyl, wherein said C _3-6 cycloalkyl is optionally substituted with 1F, cl or CN,

Preferably, R ⁴ is selected from the group consisting of cyclobutyl, cyclopentyl and cyclohexyl, wherein each of said cyclobutyl, cyclopentyl and cyclohexyl is optionally substituted by 1F, cl or CN,

More preferably, R ⁴ isMore preferably

30. The compound of claim 9, wherein the compound is of formula (I-viii):

Wherein:

X ² is CH or N, preferably N;

And/or

X ⁴ is CH or N, preferably CH;

And/or

R ² is-P (O) (C _1-4 alkyl) ₂, preferably-P (O) (C _1-2 alkyl) ₂, more preferably

And/or

R ⁴ is C _3-6 cycloalkyl, wherein said C _3-6 cycloalkyl is optionally substituted with 1F, cl or CN,

Preferably, R ⁴ is selected from the group consisting of cyclobutyl, cyclopentyl and cyclohexyl, wherein each of said cyclobutyl, cyclopentyl and cyclohexyl is optionally substituted by 1F, cl or CN,

More preferably, R ⁴ isMore preferably

31. The compound of any one of claims 1-3, 5-7, and 25-28, wherein the compound is a compound of formula (I-ix) or (I-x):

or a compound of formula (I-xi) or (I-xii):

or a compound of formula (I-xiii) or (I-xiv):

32. a compound according to any one of claims 1 and 31, wherein:

The heterocyclyl Het1, het2 and Het3 are each independently selected from the group consisting of 5-or 6-membered nitrogen-containing monocyclic heterocycloalkyl, 5-or 6-membered nitrogen-containing monocyclic heterocycloalkenyl, 5-or 6-membered nitrogen-containing monocyclic heteroaryl, 7-11-membered nitrogen-containing mono-spiroheterocycloalkyl, and 7-11-membered nitrogen-containing mono-spiroheterocycloalkenyl, wherein the 5-or 6-membered nitrogen-containing monocyclic heterocycloalkyl, the 5-or 6-membered nitrogen-containing monocyclic heterocycloalkenyl, the 5-or 6-membered nitrogen-containing monocyclic heteroaryl, the 7-11-membered nitrogen-containing mono-spiroheterocycloalkyl and the 7-11-membered nitrogen-containing mono-spiroheterocycloalkenyl each have 1, 2 or 3 nitrogen atoms as ring members and 0 or 1 ring member selected from O and S and optionally have 1C (O) as ring members, and are optionally substituted with 1, 2, 3,4 or more substituents R ^a, wherein when R ^a is present, 1R ^a is optionally an N-substituent;

Preferably, the heterocyclyl Het1, het2 and Het3 are each independently selected from the group consisting of 5-or 6-membered nitrogen-containing monocyclic heterocycloalkyl, 5-or 6-membered nitrogen-containing monocyclic heterocycloalkenyl, 5-or 6-membered nitrogen-containing monocyclic heteroaryl, 7-11-membered nitrogen-containing mono-spiro-bicyclic heterocycloalkyl, and 7-11-membered nitrogen-containing mono-spiro-bicyclic heterocycloalkenyl, wherein the 5-or 6-membered nitrogen-containing monocyclic heterocycloalkyl, the 5-or 6-membered nitrogen-containing monocyclic heteroaryl, the 7-11-membered nitrogen-containing mono-spiro-bicyclic heterocycloalkyl, and the 7-11-membered nitrogen-containing mono-spiro-bicyclic heterocycloalkenyl each have 1, 2, or 3 nitrogen atoms as ring members and 0 or 1 ring member selected from O and S and optionally have 1C (O) as ring members, and are optionally substituted with 1, 2, 3, or 4 substituents R ^a, wherein when R ^a is present, 1R ^a is optionally an N-substituent;

More preferably, the heterocyclyl Het1, het2 and Het3 are each independently selected from 5-or 6-membered nitrogen containing monocyclic heteroaryl, 7-11-membered nitrogen containing mono-spiro-bicycloheterocycloalkyl and 7-11-membered nitrogen containing mono-spiro-bicycloalkenyl, wherein the 6-membered nitrogen containing monocyclic heteroaryl, the 7-11-membered nitrogen containing mono-spiro-bicycloheterocycloalkyl and the 7-11-membered nitrogen containing mono-spiro-bicycloalkenyl each have 1C (O) as ring member and 1,2 or 3 nitrogen atoms as the only ring heteroatoms and are optionally substituted with 1,2, 3 or 4 substituents R ^a, wherein when R ^a is present, 1R ^a is optionally an N-substituent.

33. The compound of any one of claims 1 and 31-32, wherein:

The 5-membered monocyclic heteroaryl group described with respect to Het1, het2 or Het3 is selected from: furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl, wherein the furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl are each optionally substituted with 1, 2 or 3 substituents R ^a, wherein when R ^a is present, 1R ^a is optionally an N-substituent; or alternatively

The 5-membered nitrogen-containing monocyclic heteroaryl group described with respect to Het1, het2 or Het3 is selected from: pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl, wherein the pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl are each optionally substituted with 1, 2 or 3 substituents R ^a, wherein when R ^a is present, 1R ^a is optionally an N-substituent;

Preferably, the 5-membered nitrogen-containing monocyclic heteroaryl group described with respect to Het1, het2 or Het3 is selected from Wherein N1 is 0,1, 2 or 3, wherein when N1 is not 0, 1R ^a are optionally N-substituents; n2 is 0,1 or 2;

Or alternatively

The 6-membered monocyclic heteroaryl group described with respect to Het1, het 2or Het3 is selected from: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl, wherein each of the pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl optionally has 1C (O) as a ring member and is optionally substituted with 1 or 2 substituents R ^a, wherein when R ^a is present, 1R ^a is optionally an N-substituent;

Preferably, the 6 membered heteroaryl group described with respect to Het1, het2 or Het3 is selected from: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl, wherein the pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl each have 1C (O) as a ring member and are optionally substituted with 1 or 2 substituents R ^a, wherein when R ^a is present, 1R ^a is optionally an N-substituent;

preferably, the 6 membered heteroaryl group described with respect to Het1, het2 or Het3 is selected from:

wherein N3 is 0, 1,2 or 3, wherein when N3 is not 0, 1R ^a is optionally an N-substituent; Wherein n4 is 0, 1,2 or 3;

wherein N5 is 0, 1 or 2, wherein when N5 is not 0, 1R ^a is optionally an N-substituent; and

Wherein n6 is 0 or 1;

Or alternatively

The 7-11 membered mono-spiroheterocycloalkyl groups described in relation to Het1, het2 or Het3 are selected from: a spiro ring system having one 5 or 6 membered monocyclic heterocycloalkyl and one monocyclic cycloalkyl selected from cyclopropane, cyclobutane, cyclopentane or cyclohexane, and a spiro ring system having one 5 or 6 membered monocyclic heterocycloalkyl and one 3,4, 5 or 6 membered monocyclic heterocycloalkyl, wherein said 5 or 6 membered monocyclic heterocycloalkyl optionally has 1C (O) as ring member; and wherein the 7-11 membered mono-spiroheterocycloalkyl has 1,2 or 3 nitrogen atoms as ring members and 0 or 1 ring member selected from O and S, and is optionally substituted with 1,2, 3 or 4 substituents R ^a, wherein when R ^a is present, 1R ^a is optionally an N-substituent; or alternatively

The 7-11 membered nitrogen-containing mono-spiro bicyclic heterocycloalkyl group described in relation to Het1, het2 or Het3 is selected from: a spiro ring system having one 5 or 6 membered nitrogen containing monocyclic heterocycloalkyl selected from pyrrolidinyl and 6 membered nitrogen containing monocyclic heterocycloalkyl and one monocyclic cycloalkyl selected from cyclopropane, cyclobutane, cyclopentane or cyclohexane, and a spiro ring system having one 5 or 6 membered nitrogen containing monocyclic heterocycloalkyl selected from pyrrolidinyl and 6 membered nitrogen containing monocyclic heterocycloalkyl and one 3, 4, 5 or 6 membered monocyclic heterocycloalkyl, wherein said 5 or 6 membered nitrogen containing monocyclic heterocycloalkyl has 1C (O) as a ring member; and wherein the 7-11 membered nitrogen containing mono-spiro bicyclic heterocycloalkyl has 1, 2 or 3 nitrogen atoms as ring members and 0 or 1 ring member selected from O and S, and is optionally substituted with 1, 2, 3 or 4 substituents R ^a, wherein when R ^a is present, 1R ^a is optionally an N-substituent;

More preferably, the 7-11 membered nitrogen containing mono-spiro bicyclic heterocycloalkyl is selected from:

Wherein N7 is 0 or 1, wherein when N7 is 1, 1R ^a are optionally N-substituents; and n8 is 0, 1,2 or 3;

Or alternatively

The 7-11 membered mono-spiroheterocyclenyl groups described in relation to Het1, het2 or Het3 are selected from: a spiro ring system having one 5 or 6 membered monocyclic heterocyclenyl group and one monocyclic cycloalkyl group selected from cyclopropane, cyclobutane, cyclopentane or cyclohexane, and a spiro ring system having one 5 or 6 membered monocyclic heterocyclenyl group and one 3, 4, 5 or 6 membered monocyclic heterocycloalkyl group, wherein said 5 or 6 membered monocyclic heterocyclenyl group optionally has 1C (O) as a ring member; and wherein the 7-11 membered mono-spiroheterocyclenyl has 1,2 or 3 nitrogen atoms as ring members and 0 or 1 ring member selected from O and S, and is optionally substituted with 1,2, 3 or 4 substituents R ^a, wherein when R ^a is present, 1R ^a is optionally an N-substituent;

preferably, the 7-11 membered nitrogen containing mono-spiro bicycloalkenyl described in relation to Het1, het2 or Het3 is selected from: a spiro ring system having one 5 or 6 membered nitrogen containing monocyclic heterocyclenyl group selected from the group consisting of dihydropyrrole groups and 6 membered nitrogen containing monocyclic heterocyclenyl groups and one monocyclic cycloalkyl group selected from the group consisting of cyclopropane, cyclobutane, cyclopentane or cyclohexane, and a spiro ring system having one 5 or 6 membered nitrogen containing monocyclic heterocyclenyl group selected from the group consisting of dihydropyrrole groups and 6 membered nitrogen containing monocyclic heterocyclenyl groups and one 3, 4, 5 or 6 membered monocyclic heterocyclenyl groups, wherein said 5 or 6 membered nitrogen containing monocyclic heterocyclenyl groups have 1C (O) as a ring member; and wherein the 7-11 membered nitrogen containing mono-spiro-bicycloalkenyl has 1,2 or 3 nitrogen atoms as ring members and 0 or1 ring member selected from O and S, and is optionally substituted with 1,2, 3 or 4 substituents R ^a, wherein when R ^a is present, 1R ^a is optionally an N-substituent;

more preferably, the 7-11 membered nitrogen containing mono-spiro bicycloalkenyl is selected from:

Wherein n9 is 0 or 1 and n10 is 0, 1,2 or 3.

34. The compound of any one of claims 1 and 31-33, wherein:

Each R ^a is independently selected from halogen, CN, OH, NH ₂、C_1-6 alkyl, C _2-6 alkenyl, C _1-6 haloalkyl, -NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂、-OC_1-6 alkyl, -OC _1-6 haloalkyl, -C _1-6 alkylene- (optionally substituted C _3-6 cycloalkyl), -C _1-6 alkylene- (optionally substituted C _4-6 cycloalkenyl), -C _1-6 alkylene- (optionally substituted 4-6 membered heterocycloalkyl), -C _1-6 alkylene- (optionally substituted 4-6 membered heterocycloalkenyl), -C _1-6 alkylene- (optionally substituted C _6-10 aryl), and-C _1-6 alkylene- (optionally substituted 5-or 6 membered heteroaryl);

Preferably, each R ^a is independently selected from F, cl, CN, OH, NH ₂、C_1-4 alkyl, C _2-4 alkenyl, C _1-4 haloalkyl, -NHC _1-4 alkyl, -N (C _1-4 alkyl) ₂、-OC_1-4 alkyl, -OC _1-4 haloalkyl, -C _1-4 alkylene- (optionally substituted C _3-6 cycloalkyl), -C _1-4 alkylene- (optionally substituted C _4-6 cycloalkenyl), -C _1-4 alkylene- (optionally substituted 4-6 membered heterocycloalkyl), -C _1-4 alkylene- (optionally substituted 4-6 membered heterocycloalkenyl), -C _1-4 alkylene- (optionally substituted C _6-10 aryl) and-C _1-4 alkylene- (optionally substituted 5-or 6 membered heteroaryl);

more preferably, each R ^a is independently selected from C _1-2 alkyl, -C _1-2 alkylene- (optionally substituted phenyl), and-C _1-2 alkylene- (optionally substituted 5 or 6 membered heteroaryl);

more preferably, each R ^a is independently selected from methyl, ethyl, and

35. A compound according to any one of claims 31-34, wherein:

Of the compounds of the formula (I-ix) The part is as follows:

Wherein R ^a is preferably C _1-4 alkyl or-C _1-4 alkylene- (5-or 6-membered heteroaryl), more preferably methyl or

Preferably is

Or alternatively

Of the compounds of the formula (I-xi)The part is as follows:

Wherein R ^a is preferably C _1-4 alkyl or-C _1-4 alkylene- (5-or 6-membered heteroaryl), more preferably methyl or

Preferably is

Or alternatively

Of the compounds of the formula (I-xiii)The part is as follows: wherein R ^a is preferably C _1-4 alkyl, more preferably methyl or ethyl,

Preferably is

36. A compound according to any one of claims 31-35, wherein:

In the compounds of formulae (I-xi) and (I-xiii), R ¹ is independently selected at each occurrence from H, F, cl, OH and NH ₂, preferably hydrogen;

And/or

In the compounds of formulas (I-xiii) and (I-xiv), R ² is independently selected at each occurrence from: p (O) (C _1-4 alkyl) ₂ and a 5-or 6-membered nitrogen-containing monocyclic heteroaryl, wherein the nitrogen-containing monocyclic heteroaryl has 1,2 or 3 nitrogen atoms as ring members and 0 or 1 ring member selected from O and S, and is optionally substituted by 1R ⁵, wherein R ⁵ is selected from C _1-4 alkyl and is optionally an N-substituent,

Preferably, R ² is independently selected at each occurrence from: -P (O) (C _1-4 alkyl) ₂; pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl and thiazolyl, wherein the pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl and thiazolyl are each optionally substituted with 1R ⁵, wherein R ⁵ is selected from C _1-4 alkyl and is optionally an N-substituent,

More preferably, R ² is independently selected at each occurrence

More preferably, R ² is independently selected at each occurrence

And/or

In the compounds of formula (I-xi), R ³ is H;

And/or

In the compounds of formulae (I-ix), (I-x), (I-xi) and (I-xii), R ⁴ is independently at each occurrence C _3-6 cycloalkyl, wherein the C _3-6 cycloalkyl is optionally substituted with 1F, cl or CN,

Preferably, R ⁴ is independently selected at each occurrence from cyclobutyl, cyclopentyl and cyclohexyl, wherein each of said cyclobutyl, cyclopentyl and cyclohexyl is optionally substituted by 1F, cl or CN,

More preferably, R ⁴ is independently at each occurrenceMore preferably

37. A compound according to any one of claims 1-36, wherein:

R ⁷ is selected from H, halogen, OH, CN, -C (O) OH, -SF ₅、-NO₂、C_1-6 alkyl, C _1-6 haloalkyl, -OC _1-6 alkyl, -OC _1-6 haloalkyl, -C _1-6 alkylene-OH, -C _1-4 alkylene-OC _1-4 alkyl, -C _1-4 alkylene-OC _1-4 alkylene-OC _1-4 alkyl, -C _1-4 alkylene-OC _1-4 alkylene-NH ₂、-C_1-4 alkylene-OC _1-4 alkylene-NH (C _1-4 alkyl), -C _1-4 alkylene-OC _1-4 alkylene-N (C _1-4 alkyl) ₂、C_3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkenyl and 5-10 heteroaryl, wherein the C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkenyl and 5-10 heteroaryl are optionally substituted with 1,2, 3 or 4 substituents independently selected from halogen, CN, C _1-6 alkyl and C _1-6 haloalkyl;

Preferably, R ⁷ is selected from H, halogen, OH, CN, -NO ₂、C_1-4 alkyl, C _1-4 haloalkyl, -OC _1-4 alkyl, -OC _1-4 haloalkyl, -C _1-4 alkylene-OH, -C _1-4 alkylene-OC _1-4 alkyl, -C _1-4 alkylene-OC _1-4 alkylene-OC _1-4 alkyl, -C _1-4 alkylene-OC _1-4 alkylene-NH ₂、-C_1-4 alkylene-OC _1-4 alkylene-NH (C _1-4 alkyl) and-C _1-4 alkylene-OC _1-4 alkylene-N (C _1-4 alkyl) ₂;

More preferably, R ⁷ is selected from H, halogen, -C _1-2 alkylene-OC _1-2 alkyl, -C _1-2 alkylene-OC _1-2 alkylene-OC _1-2 alkyl, -C _1-2 alkylene-OC _1-2 alkylene-NH ₂、-C_1-2 alkylene-OC _1-2 alkylene-NH (C _1-4 alkyl) and-C _1-2 alkylene-OC _1-2 alkylene-N (C _1-2 alkyl) ₂;

More preferably, R ⁷ is selected from H, halogen, -C _1-2 alkylene-OC _1-2 alkylene-OC _1-2 alkyl, -C _1-2 alkylene-OC _1-2 alkylene-NH ₂、-C_1-2 alkylene-OC _1-2 alkylene-NH (C _1-4 alkyl) and-C _1-2 alkylene-OC _1-2 alkylene-N (C _1-2 alkyl) ₂;

More preferably, R ⁷ is selected from H, F, cl, br, I, More preferably H, cl,

38. A compound according to any one of claims 1-37, wherein:

R ⁸ is selected from H, halogen, CN, C _1-6 alkyl, C _1-6 haloalkyl, -OC _1-6 alkyl, -OC _1-6 haloalkyl, C _2-6 alkynyl and C _2-6 haloalkynyl;

preferably, R ⁸ is selected from H, halogen, C _2-4 alkynyl and C _2-4 haloalkynyl;

more preferably, R ⁸ is selected from H, F, cl, br, I, More preferably H, br and

39. The compound of claim 1, wherein the compound is selected from the group consisting of:

40. A pharmaceutical composition comprising a compound according to any one of claims 1-39, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically-labeled compound, or prodrug thereof, and a pharmaceutically acceptable carrier.

41. A compound according to any one of claims 1-39, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically-labeled compound or prodrug thereof, for use as a medicament, preferably a WDR5-MYC protein interaction (WDR 5-MYC PPI) inhibitor.

42. Use of a compound according to any one of claims 1-39, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically-labeled compound or prodrug thereof, for the manufacture of a medicament, preferably a WDR5-MYC protein-protein interaction (WDR 5-MYC PPI) inhibitor.

43. A method of preventing or treating a MYC-related disease, disorder, or condition in a subject, wherein the method comprises: administering to the individual a therapeutically effective amount of a compound according to any one of claims 1-39, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically-labeled compound, or prodrug thereof; or administering to said individual a therapeutically effective amount of a pharmaceutical composition according to claim 40.

44. Use of a compound according to any one of claims 1-39, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically-labeled compound or prodrug thereof, or a pharmaceutical composition according to claim 40, in the manufacture of a medicament for the prevention or treatment of a MYC-related disease, disorder, or condition in a subject.

45. The use according to claim 43 or 44, wherein the disease, disorder or condition is cancer, including solid tumors and hematological tumors, wherein the solid tumors are preferably ovarian, breast, colorectal, pancreatic, gastric or uterine cancers.