CN118184658A - USP1 inhibitors - Google Patents

Abstract

The present invention provides a novel class of compounds having USP1 inhibitory activity represented by formula (I'), pharmaceutical compositions containing the compounds, useful intermediates for preparing the compounds, and methods of treating cancer using the compounds of the present invention.

Description

USP1 inhibitors

Technical Field

The present invention is in the field of pharmaceutical chemistry and relates to novel compounds having USP1 inhibitory activity, pharmaceutical compositions containing the compounds, useful intermediates for preparing the compounds, and methods of treating cancer using the compounds of the present invention.

Background

Ubiquitin is a small, highly conserved protein of 76 amino acids, a posttranslationally conjugated substrate protein, including itself, through a three-step enzymatic reaction. The initial covalent attachment occurs primarily between the C-terminal glycine of ubiquitin and the epsilon-amino group of the lysine residue of the target protein. 1a further ubiquitin molecule can be linked to one of seven internal lysines of ubiquitin, resulting in a different ubiquitin chain topology. The biological outcome of ubiquitination is determined by length and connection topology. Like other types of post-translational modifications, ubiquitination is a reversible process of enzyme deregulation called deubiquitinating enzymes (DUBs), which catalyzes the removal of ubiquitin from modified proteins. More importantly, dysfunction of the ubiquitin-dependent signaling pathway is associated with various human diseases, suggesting that inhibition of ubiquitin pathway components is a novel therapeutic target for drug discovery.

The ubiquitin-proteasome system provides additional opportunities for therapeutic intervention, increasing specificity and improving the likelihood of clinical outcome. The most obvious targets include enzymes involved in ubiquitin conjugation and de-conjugation (i.e. ubiquitin ligase and DUB), the upstream process of proteasome mediated protein degradation. In DUBs, ubiquitin-specific protease 1 (USP 1) is an attractive anticancer target because of its involvement in regulating the DNA damage response pathway. USP1 binds to UAF1 (USP 1 related factor 1) to produce the heterodimeric USP1/UAF1 complex required for deubiquitinase activity. The USP1/UAF1 complex has been shown to regulate DNA cross-linker induced tolerance to DNA damage by deubiquitination of PCNA (proliferating cell nuclear antigen) 11 and FANCD2 (Fanconi anemia complement D2), proteins that function in the trans-injury synthesis and Fanconi anemia pathways, respectively.

Many studies are currently being conducted based on such mechanisms of action, but USP1 inhibitors are not found to be marketed, and thus development of effective USP1 inhibitors for clinical patients is urgently required.

Disclosure of Invention

The present invention provides compounds of formula (I'), isomers thereof, and pharmaceutically acceptable salts thereof:

Wherein,

X ₁ is CH, N; x ₂、X₃ is each independently CH, N, or CR ', wherein R' is substituted or unsubstituted C _3-6 cycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, C _1-4 haloalkyl, hydroxy C _1-4 alkyl, -NH-Ar, 4-6 membered heterocyclyl, -NH-CO-C _3-6 cycloalkyl, 8-14 membered fused heterocyclyl, 7-11 membered spiroheterocyclyl, 7-14 membered bridged heterocyclyl;

R _a is hydrogen or C _1-4 alkyl;

ring a is a 5-6 membered heteroaryl, R _b each independently being halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl; m is 0, 1,2, 3 or 4;

Ring B is phenyl or 11-18 ternary fused heterocyclic group; r _c is halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, Or two adjacent R _c form a substituted or unsubstituted C _3-6 membered cycloalkyl;

The ring C is 5-10 membered heteroaryl containing 1-4 nitrogen atoms and 8-14 membered fused heterocyclic group; each R _d is independently C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, halogen, C _3-6 cycloalkyl; n is 1,2, 3 or 4; p is 1,2, 3 or 4; l ₁ is C _1-4 alkylene, C _3-6 cycloalkylene.

The present invention provides compounds of formula (I'), isomers thereof, and pharmaceutically acceptable salts thereof:

Wherein,

X ₁ is CH, N; x ₂、X₃ is each independently CH, N, or CR ', wherein R' is a substituted or unsubstituted C _3-6 cycloalkyl, 5-6 membered heteroaryl;

R _a is hydrogen or C _1-4 alkyl;

ring a is a 5-6 membered heteroaryl, R _b each independently being halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl; m is 0, 1,2, 3 or 4;

Ring B is phenyl or 11-18 membered tricyclic fused heterocyclyl; r _c is C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, Or a halogen, or a halogen atom,

The ring C is 5-10 membered heteroaryl containing 1-4 nitrogen atoms and 8-14 membered fused heterocyclic group; each R _d is independently C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, halogen, C _3-6 cycloalkyl; n is 1,2, 3 or 4; p is 1,2, 3 or 4; l ₁ is C _1-4 alkylene, C _3-6 cycloalkylene.

The present invention provides compounds of formula (I') and pharmaceutically acceptable salts thereof:

Wherein,

X ₁ is CH, N; x ₂、X₃ is each independently CH, N, or CR ', wherein R' is a substituted or unsubstituted C _3-6 cycloalkyl, 5-6 membered heteroaryl;

R _a is hydrogen or C _1-4 alkyl;

Ring a is a 5-6 membered heteroaryl, R _b each independently being halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl; m is 1, 2, 3 or 4;

Ring B is phenyl or 11-14 membered tricyclic fused heterocyclyl; r _c is C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or The ring C is a 5-10 membered heteroaryl group containing 1-4 nitrogen atoms; each R _d is independently C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy; n is 1,2, 3 or 4; p is 1,2, 3 or 4;

L ₁ is C _1-4 alkylene, C _3-6 cycloalkylene.

In some embodiments of the present invention, the above-mentioned compound of formula (I '), isomers thereof, and pharmaceutically acceptable salts thereof, wherein R' is

In some embodiments of the present invention, the compound of formula (I '), isomers thereof, and pharmaceutically acceptable salts thereof, wherein R' is-Cl、-CHF₂、

In some embodiments of the present invention, the compound of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, wherein ring A is

In some embodiments of the present invention, the compounds of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, wherein ring A is

In some embodiments of the present invention, the compounds of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, wherein R _b is Cl-, CH ₃-、CH(CH₃)₂-、CH₃ O-,

In some embodiments of the present invention, the compounds of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, are characterized by structural unitsFor

In some embodiments of the present invention, the compounds of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, are characterized by structural unitsFor

In some embodiments of the invention, the compounds of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, wherein ring B is phenyl and R _c is ring C, wherein ring C may be substituted with p R _d; the ring C is 5-10 membered heteroaryl containing 1-4 nitrogen atoms and 5-10 membered heterocyclic group; each R _d is independently C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, halogen, C _3-6 cycloalkyl; n is 1,2, 3 or 4; p is 1,2, 3 or 4.

In some embodiments of the invention, the compounds of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, wherein ring B is phenyl and R _c is ring C, wherein ring C may be substituted with p R _d; the ring C is a 5-10 membered heteroaryl group containing 1-4 nitrogen atoms; each R _d is independently C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, halogen, C _3-6 cycloalkyl; n is 1, 2,3 or 4; p is 1, 2,3 or 4.

In some embodiments of the present invention, the compounds of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, wherein ring B is an 11-18 membered tricyclic fused heterocyclyl; r _c is C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, halogen; n is 1,2,3 or 4.

In some embodiments of the present invention, the compounds of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, wherein ring B is an 11-14 membered tricyclic fused heterocyclyl; r _c is C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy; n is 1, 2, 3 or 4.

In some embodiments of the present invention, the compound of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, wherein ring B is

In some embodiments of the present invention, the compound of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, wherein ring B is

In some embodiments of the present invention, the compounds of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, wherein R _c is-CF ₃、-OCH₃, -F,

In some embodiments of the present invention, the compounds of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, are characterized by structural unitsFor

In some embodiments of the invention, the compounds of formula (I'), isomers and pharmaceutically acceptable salts thereof, are described above, wherein R _d is-CH ₃、-CH(CH₃)₂、-CF₃、-OCH₂CH₃.

In some embodiments of the present invention, the compounds of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, wherein R _d is-Cl, -F,

In some embodiments of the present invention, the compounds of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, wherein ring C is

In some embodiments of the present invention, the compounds of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, are characterized by structural unitsIs that

In some embodiments of the invention, the compounds of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, are characterized in that L ₁ is-CH ₂ -.

In some embodiments of the present invention, the compounds of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, are characterized by structural unitsIs that

In some embodiments of the present invention, the compound of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, wherein the compound, isomers thereof, and pharmaceutically acceptable salts thereof are selected from the group consisting of,

Wherein ring a, ring B, R _a、R_b、R_c、R'、L₁, m, n are as defined above.

In some embodiments of the present invention, the compounds of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, are selected from,

Wherein ring A, ring C, R _a、R_b、R'、L₁、R_d, p, m are as defined above.

In some embodiments of the present invention, the compounds of formula (I') above, isomers thereof, and pharmaceutically acceptable salts thereof, are selected from,

Wherein R' is as defined above.

The invention also provides the compounds shown in the following, isomers and pharmaceutically acceptable salts thereof,

The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

"Pharmaceutically acceptable carrier" refers to a medium commonly accepted in the art for delivery of biologically active agents to animals, particularly mammals, and includes, for example, adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow modifying agents, disintegrants, wetting agents, emulsifying agents, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersing agents, depending on the mode of administration and the nature of the dosage form. Pharmaceutically acceptable carriers are formulated within the purview of one of ordinary skill in the art according to a number of factors. Including but not limited to: the type and nature of the active agent formulated, the subject to which the composition containing the agent is to be administered, the intended route of administration of the composition, and the therapeutic indication of interest. Pharmaceutically acceptable carriers include both aqueous and nonaqueous media and a variety of solid and semi-solid dosage forms. Such carriers include many different ingredients and additives in addition to the active agent, and such additional ingredients included in the formulation for a variety of reasons (e.g., stabilizing the active agent, adhesive, etc.) are well known to those of ordinary skill in the art.

The invention also provides application of the compound or pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing medicines for treating USP1 mediated diseases, including cancers.

Technical effects

The compound has obvious USP1 enzymatic inhibition activity and can be used for treating cancers.

Description and definition of the invention

The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present invention prepared with relatively non-toxic acids or bases. These salts may be prepared during synthesis, isolation, purification of the compound, or the purified compound may be used alone in free form to react with a suitable acid or base. When the compound contains relatively acidic functional groups, reaction with alkali metal, alkaline earth metal hydroxides or organic amines gives base addition salts, including salts based on alkali metal and alkaline earth metal cations and non-toxic ammonium, quaternary ammonium and amine cations, as well as amino acid salts and the like. When the compound contains a relatively basic functional group, it is reacted with an organic acid or an inorganic acid to give an acid addition salt.

The term "pharmaceutically acceptable carrier" refers to a medium commonly accepted in the art for delivery of biologically active agents to animals, particularly mammals, and includes, for example, adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifying agents, suspending agents, sweetening, flavoring, perfuming, antibacterial, antifungal, lubricating and dispersing agents, depending on the mode of administration and nature of the dosage form. Pharmaceutically acceptable carriers are formulated within the purview of one of ordinary skill in the art according to a number of factors. Including but not limited to: the type and nature of the active agent formulated, the subject to which the composition containing the agent is to be administered, the intended route of administration of the composition, and the therapeutic indication of interest. Pharmaceutically acceptable carriers include both aqueous and nonaqueous media and a variety of solid and semi-solid dosage forms. Such carriers include many different ingredients and additives in addition to the active agent, and such additional ingredients included in the formulation for a variety of reasons (e.g., stabilizing the active agent, adhesive, etc.) are well known to those of ordinary skill in the art.

The term "excipient" generally refers to the carrier, diluent, and/or medium required to make an effective pharmaceutical composition.

The term "prophylactically or therapeutically effective amount" refers to a sufficient amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to treat a disorder at a reasonable effect/risk ratio applicable to any medical treatment and/or prophylaxis. It will be appreciated that the total daily amount of the compounds of formula I' or pharmaceutically acceptable salts and compositions of the present invention will be determined by the physician within the scope of sound medical judgment. For any particular patient, the particular therapeutically effective dose level will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; age, weight, general health, sex and diet of the patient; the time of administration, route of administration and rate of excretion of the particular compound employed; duration of treatment; a medicament for use in combination with or simultaneously with the particular compound employed; and similar factors well known in the medical arts. For example, it is common in the art to start doses of the compound at levels below that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

Unless otherwise specified, in the general formulaRefers to either single bond or double bond.

Unless otherwise specified, "Ar" in the formula refers to a monocyclic or bicyclic group having a conjugated pi-electron system. Examples of the "Ar" include, but are not limited to, phenyl, naphthyl.

The term "5-10 membered heteroaryl" means, unless otherwise specified, a monocyclic or bicyclic group of 5-10 ring atoms having a conjugated pi-electron system, 1,2,3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms. Wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) _p, p is 1 or 2). The 5-10 membered heteroaryl group may be attached to the remainder of the molecule through a heteroatom or carbon atom. The "5-10 membered heteroaryl" may be a fused heteroaryl, may be preferably a 5-6 membered heteroaryl and 5-6 membered heteroaryl, a phenyl and 5-6 membered heteroaryl, and may be more preferably a 5-membered heteroaryl and 5-membered heteroaryl, a 5-membered heteroaryl and 6-membered heteroaryl. Examples of the 5-to 10-membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1, 2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furanyl (including 2-furanyl, 3-furanyl, etc.), thienyl (including 2-thienyl, 3-thienyl), pyridyl, pyrimidyl, etc.

Unless otherwise specified, the term "tricyclic fused heterocyclyl" refers to a cyclic structure formed by three rings sharing two adjacent ring atoms with each other, and wherein at least one ring is a heterocycle; the fused heterocyclic group may be fused from a cyclic group selected from phenyl, cycloalkyl, heterocyclyl, heteroaryl, and at least one of which is a heterocyclic or heteroaryl ring, and specific fused means include, but are not limited to, benzoheterocyclyl-heteroaryl, benzoheteroaryl-heteroaryl, heteroaryl-heterocyclo-heteroaryl, and the like. Examples of tricyclic fused heterocyclyl groups include, but are not limited to

The term "C _1-4 alkylene" is used to denote a C _1-4 straight or branched saturated alkylene group, unless otherwise specified. Examples of alkylene include, but are not limited to -CH₂-、-(CH₂)₂-、-(CH₂)₃、-(CH₂)₄-、-CH(CH₃)-、-C(CH₃)₂-.

Unless otherwise specified, the term "hydroxy C _1-4 alkyl" refers to a structure in which a hydrogen atom in the C _1-4 alkyl group is optionally substituted with a hydroxy group, examples of "C _1-4 alkyl-OH" include, but are not limited to -CH₂OH、-CH₂CH₂OH、-CH(OH)CH₃、-CH₂CH₂CH₂OH、-CH₂CH(OH)CH₃、、-CH₂CH₂CH₂CH₂OH、-CH₂CH(OH)CH₂CH₃、-CH₂CH₂CH(OH)CH₃、Etc.

The term "C _3-6 cycloalkylene" is used to denote a C _3-6 cyclic alkylene group, unless otherwise specified. Examples of cyclic hydrocarbylene groups include, but are not limited to

The term "halogen" means a fluorine, chlorine, bromine or iodine atom unless otherwise specified.

The term "alkyl of C _1-4" is used to denote a C _1-4 straight or branched saturated hydrocarbon group unless otherwise specified. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, and the like.

The term "C _1-4 alkoxy" refers to a C _1-4 alkyl group attached through an oxygen bridge, unless otherwise specified, and compounds include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy.

Unless otherwise specified, "C _3-6 cycloalkyl" refers to 3-6 membered monocyclic alkyl, preferably 5-6 membered cycloalkyl, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

Unless otherwise specified, the term "5-6 membered heteroaryl containing 1-4 nitrogen atoms" refers to a 5-6 membered heteroaryl ring in which the ring atom contains 1,2,3 or 4 nitrogen atoms, examples include, but are not limited to

Unless otherwise specified, "substituted or unsubstituted C _3-6 cycloalkyl, 5-6 membered heteroaryl" means that the C _3-6 cycloalkyl, 5-6 membered heteroaryl may or may not be substituted with one or more substituents selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl, and the like; examples of such "substituted or unsubstituted C _3-6 cycloalkyl, 5-6 membered heteroaryl" groups include, but are not limited to

Unless otherwise specified, the term "heterocyclyl" refers to a non-aromatic cyclic group derived from the removal of one hydrogen atom containing at least one heteroatom as a ring atom, the heteroatom selected from CO, N, O, S, NO, SO, S (O) ₂. Including saturated or partially saturated monocyclic heterocyclyl and polycyclic heterocyclyl; the heterocyclic group is independent of the attachment position (i.e., may be bound through a carbon atom or heteroatom). The polycyclic heterocyclic group includes a condensed heterocyclic group, a spiro heterocyclic group, and a bridged heterocyclic group. The "heterocyclyl" is preferably a 5-6 membered mono-heterocyclyl, 8-14 membered fused heterocyclyl, 7-11 membered spiro heterocyclyl, 5-to 14 membered bridged heterocyclyl. Specific examples of such "heterocyclyl" groups include, but are not limited to

Unless otherwise specified, the term "fused heterocyclic group" refers to a saturated or partially saturated non-aromatic cyclic group containing at least one ring atom as a heteroatom, formed by two or more cyclic structures sharing two adjacent atoms with each other; the heteroatom is generally selected from CO, N, O, S, NO, SO, S (O) ₂. The "8-14 membered fused heterocyclic group" as used herein includes "8-14 membered saturated fused heterocyclic group" and "8-14 membered partially saturated fused heterocyclic group". The condensed mode can be 5-6 membered heterocyclic group, 5-6 membered cycloalkyl, 5-6 membered heterocyclic group, 5-6 membered heteroaryl, 5-6 membered heterocyclic group and benzo 5-6 membered heterocyclic group. Specific examples of the fused heterocyclic group include, but are not limited to:

unless otherwise specified, the term "spiroheterocyclyl" refers to a saturated or partially saturated cyclic structure containing at least one ring atom as a heteroatom, formed by two or more cyclic structures sharing one ring atom with each other. The heteroatom is generally selected from CO, N, O, S, NO, SO, S (O) ₂. The "7-11 membered spiroheterocyclic group" includes "7-11 membered saturated spiroheterocyclic group" and "7-11 membered partially saturated spiroheterocyclic group". Specific examples include, but are not limited to: Etc.

Unless otherwise specified, the term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly attached, which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more of the ring atoms are heteroatoms selected from CO, N, O, S, NO, SO, S (O) ₂ and the remaining ring atoms are carbon. Preferably 5 to 14 membered, more preferably 7 to 14 membered. The number of constituent rings may be classified into a double ring and a triple ring. Specific examples include, but are not limited to:

the compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.

The solvent used in the present invention is commercially available.

The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS), or ultra-efficient liquid chromatography-mass spectrometry (UPLC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using Bruker Neo 400M or Bruker Ascend 400 nuclear magnetic instruments with deuterated dimethyl sulfoxide (DMSO-D ₆), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃), heavy water (D ₂ O), and internal standard Tetramethylsilane (TMS).

Agilent 1260-6125B single quadrupole mass spectrometer for LC-MS determination, mass spectrometer (ion source is electrospray ionization).

Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was performed using a Waters UPLC H-class SQD mass spectrometer (electrospray ionization as the ion source).

HPLC measurements were performed using Waters e2695-2998 or WATERS ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.

Preparation HPLC was performed using Waters 2555-2489 (10 μm, ODS250 cm. Times.5 cm) or GILSON Trilution LC.

Chiral HPLC assay using waters acquity UPC2; the column was DAICEL CHI ring Clpak AD-H (5 um, 4.6X250 mm).

Supercritical Fluid Chromatography (SFC) uses WATERS SFC to 80Q.

The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.

All reactions of the invention were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, with the solvent being a dry solvent and the reaction temperature being in degrees celsius, without specific description.

Detailed Description

The present invention is described in detail below by way of examples, but is not meant to be limiting in any way. The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention. Various changes and modifications to the specific embodiments of the invention will be apparent to those skilled in the art without departing from the spirit and scope of the invention.

1. Preparation method

Intermediate INT-1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol

Step A3, 3-dibromo-1, 1-trifluoropropan-2-one (144 g,0.54 mol) and sodium acetate (80 g,0.67 mol) were dissolved in water (320 mL) at room temperature. Subsequently, the above solution was heated to 90℃and stirred for 0.5 hours. Then, the reaction system was cooled to 0℃and a mixed solution of methyl 4-formylbenzoate (80 g,0.49 mol) and 28% wt ammonia water (400 mL) in methanol (120 mL) was slowly added dropwise to the above reaction solution. Finally, the reaction system was stirred at room temperature for 16 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction was filtered and the filter cake rinsed with ethyl acetate (100 mL x 3 times). The filtrate was then collected and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel to give 104g of methyl 4- (4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate.

MS(ESI)M/Z:271.0[M+H]⁺.

And (B) step (B): methyl 4- (4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate (69 g,0.25 mol) and cesium carbonate (250 g,0.76 mol) were dissolved in acetonitrile (1.2L) at room temperature and stirred for 2 hours. Subsequently, 2-iodopropane (64.9 g,0.38 mol) was added to the above solution, and the reaction system was heated to 50℃and stirred for 24 hours. The reaction was then lowered to 0℃and 2-iodopropane (21.6 g,0.13 mo) was added continuously. The reaction system was then stirred at 50℃for 4 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction solution was quenched by addition of ice water (1.5L), the mixture was extracted with ethyl acetate (500 ml×3 times), the organic phases were combined and the organic phase was washed with saturated brine (150 mL). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 33g of methyl 4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate.

MS(ESI)M/Z:313.2[M+H]⁺.

Step C: methyl 4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate (33 g,0.11 mol) was dissolved in dry tetrahydrofuran (528 mL) at room temperature under nitrogen. Subsequently, a 2.5M lithium aluminum hydride solution (85 mL,0.22 mol) was slowly added dropwise to the above solution at 0deg.C. The reaction was then stirred at room temperature for 1 hour.

After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by slowly dropping ice water (1L), filtered and the filter cake was washed with ethyl acetate (100 mL x 3 times). The filtrate was extracted with ethyl acetate (500 mL. Times.3), and the organic phases were combined and washed with saturated brine (150 mL). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 28g of (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol.

MS(ESI)M/Z:285.1[M+H]⁺.

¹H NMR(400MHz,CDCl₃)δ7.47-7.32(m,5H),4.72(s,2H),4.59-4.46(m,1H),2.97(br,1H),1.44(d,J＝6.8Hz,6H).

Intermediate INT-2- (4- (bromomethyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole

Step A (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol (700 mg,2.46 mmol) was dissolved in dichloromethane (12.5 mL) at room temperature. Triphenylphosphine (1.29 g,4.93 mmol), sodium bicarbonate (414 mg,4.93 mmol) and carbon tetrabromide (1.63 g,4.93 mmol) were then added to the above solution in that order. The reaction was then stirred at room temperature for 2 hours.

After LCMS monitoring showed the disappearance of starting material, quench the reaction by adding water (20 mL), extract the mixture with dichloromethane (10 mL. Times.3), combine the organic phases and wash the organic phase with saturated brine (60 mL). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 82mg of 2- (4- (bromomethyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole.

MS(ESI)M/Z:347.2[M+H]⁺.

Intermediate INT-3:2- (4- (bromomethyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole

Step A: the compound 4-chloro-6-methoxypyrimidine (25 g,172.94 mmol), cyclopropylboronic acid (25.25 g, 254 mmol), 1' -bis-diphenylphosphino ferrocene palladium dichloride (6.3 g,8.68 mmol), potassium phosphate (73.42 g,345.88 mmol) and silver oxide (20.04 g,86.47 mmol) were dissolved in 1, 4-dioxane (868 mL) at room temperature under nitrogen. The solution was then warmed to 90℃and stirred for 16 hours.

LCMS monitoring showed the disappearance of starting material, filtering while hot and concentrating the filtrate under reduced pressure. To the resulting residue was added water (500 mL), the mixture was extracted with methylene chloride (100 mL. Times.3), and the organic phases were combined and washed with saturated brine (150 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 18.3g of 4-cyclopropyl-6-methoxypyrimidine.

MS(ESI)M/Z:151.2[M+H]⁺.

And (B) step (B): 4-cyclopropyl-6-methoxypyrimidine (45 g,299.64 mmol) was dissolved in ethanol (1.5L) at-20℃under nitrogen. Subsequently, bromine (240 g,1.5 mol) was slowly added dropwise to the above solution. The reaction was then stirred at room temperature for a further 16 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. The crude product is pulped by ethyl acetate, filtered and the filter cake is collected. The filter cake was then added to water (150 mL) and stirred at 0 ℃ and saturated sodium bicarbonate solution was added dropwise to the solution system pH to 7. Finally, the mixture was filtered, the filter cake was rinsed with water (150 mL. Times.2 times), the filter cake was collected, and concentrated under reduced pressure to give 56g of 5-bromo-4-cyclopropyl-6-methoxypyrimidine.

MS(ESI)M/Z:230.1[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ8.53(s,1H),3.99(s,3H),2.50-2.44(m,1H),1.16-1.09(m,2H),1.08-1.02(m,2H).

Step C: 5-bromo-4-cyclopropyl-6-methoxypyrimidine (15.0 g,65.79 mmol) and triisopropyl borate (16.08 g,85.53 mmol) were dissolved in toluene/tetrahydrofuran (150 mL/45 mL) at room temperature under nitrogen. Subsequently, the above reaction solution was stirred at-78℃for 30 minutes, and 2.5M n-butyllithium solution (34.2 mL,85.53 mmol) was slowly added dropwise, followed by stirring for 30 minutes. Then the reaction system was warmed to-20℃and stirred for 1 hour.

After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by adding ice water (100 mL) and the mixture was filtered, and the filter cake was rinsed with water (20 mL. Times.3) to give 9.7g (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid.

MS(ESI)M/Z:195.0[M+H]⁺.

Intermediate INT-4:2- (4- (bromomethyl) phenyl) -1-methyl-4- (trifluoromethyl) -1H imidazole

Step A methyl 4- (4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate (5 g,18.45 mmol) and potassium carbonate (5.1 g,36.7 mmol) were dissolved in N, N-dimethylformamide (92 mL) at room temperature. Subsequently, the reaction system was cooled to 0℃and methyl iodide (3.14 g,22.14 mmol) was slowly added dropwise, and then the reaction system was stirred at room temperature for 1 hour.

After LCMS monitoring showed the disappearance of starting material, quench the reaction by adding water (200 mL), extract the mixture with ethyl acetate (60 mL. Times.3), combine the organic phases and wash the organic phase with saturated brine (100 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel to give 3.2g of methyl 4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate.

MS(ESI)M/Z:285.0[M+H]⁺.

And (B) step (B): methyl 4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate (3.2 g,11.26 mmol) was dissolved in tetrahydrofuran (28 mL) at room temperature. Subsequently, the reaction system was cooled to 0℃and lithium aluminum hydride (2.14 g,56.32 mmol) was slowly added dropwise. The reaction system was then stirred at room temperature for 2 hours.

After LCMS monitoring showed the disappearance of starting material, ice water (100 mL) was added to the reaction solution to quench, the mixture was extracted with ethyl acetate (60 ml×3 times), the organic phases were combined and the organic phase was washed with saturated brine (30 ml×2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2.6g of (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol.

MS(ESI)M/Z:257.0[M+H]⁺.

Step C: (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol (2.6 g,10.12 mmol), sodium bicarbonate (1.7 g,20.24 mmol), triphenylphosphine (5.3 g,20.24 mmol) were dissolved in dichloromethane (51 mL) at room temperature under nitrogen. Subsequently, the reaction system was cooled to 0℃and carbon tetrabromide (6.7 g,20.24 mmol) was slowly added. The reaction was then warmed to room temperature and stirred for an additional 2 hours.

After LCMS monitoring showed the disappearance of starting material, ice water (100 mL) was added to the reaction solution to quench, the mixture was extracted with dichloromethane (50 ml×3 times), the organic phases were combined and the organic phase was washed with saturated brine (80 ml×2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2.4g of (2- (4- (bromomethyl) phenyl) -1-methyl-4- (trifluoromethyl) -1H-imidazole.

MS(ESI)M/Z:319.0[M+H]⁺.

Intermediate INT-5- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) -3-methoxyphenyl) methanol

Step A3, 3-dibromo-1, 1-trifluoropropan-2-one (40.2 g,0.15 mol) and sodium acetate (12.25 g,0.15 mol) were dissolved in water (36 mL) at room temperature. Subsequently, the above solution was heated to 90℃and stirred for 0.5 hours. Then, the reaction system was cooled to 0℃and a mixed solution of methyl 4-formyl-3-methoxybenzoate (10 g,51.54 mmol), 28% wt ammonia (45 mL) and methanol (135 mL) was slowly added dropwise to the above reaction solution. Finally, the reaction system was stirred at room temperature for 16 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction was filtered and the filter cake was rinsed with ethyl acetate/petroleum ether (v/v, 3/1), the filtrate was collected and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 10.85g of methyl 3-methoxy-4- (4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate.

MS(ESI)M/Z:301.0[M+H]⁺.

And (B) step (B): methyl 3-methoxy-4- (4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate (500 mg,1.67 mmol) and potassium carbonate (463mg, 3.34 mmol) were dissolved in N, N-dimethylformamide (9 mL) at room temperature. Subsequently, 2-iodomethane (355 mg,2.50 mmol) was added dropwise to the above solution under ice-water bath conditions. The reaction system was then stirred at room temperature for 1 hour.

After LCMS monitoring showed the disappearance of starting material, ice water (50 mL) was added to the reaction solution to quench, the mixture was extracted with ethyl acetate (25 ml×3 times), the organic phases were combined and the organic phase was washed with saturated brine (40 mL). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 500mg of methyl 3-methoxy-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate.

MS(ESI)M/Z:315.0[M+H]⁺.

Step C: 3-methoxy-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzoic acid methyl ester (500 mg,1.60 mmol) was dissolved in dry tetrahydrofuran (8 mL) at room temperature under nitrogen. Subsequently, a 2.5M lithium aluminum hydride solution (3.2 mL,8 mmol) was slowly added dropwise to the above solution at 0 ℃. The reaction was then stirred at room temperature for 2 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by slowly dropping the solution into ice water (50 m L), filtered and the filter cake rinsed with ethyl acetate (30 mL x 3 times). The resulting filtrate was then separated, the aqueous phase was extracted with ethyl acetate (30 mL. Times.3), all organic phases were combined and the organic phase was washed with saturated brine (30 mL). Finally, the mixture is dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 400mg of (3-methoxy-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol.

MS(ESI)M/Z:287.0[M+H]⁺.

Intermediate INT-6:4-chloro-1-isopropyl-5- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) -1H pyrazole

Step A4-chloro-1H-pyrazole (5 g,0.049 mol), 2-iodopropane (20 g,0.118 mol) and cesium carbonate (33 g,0.1 mol) were dissolved in acetonitrile (40 mL) at room temperature. The reaction system was then stirred at 80℃for 2 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction mixture was quenched by adding ice water (100 mL), the mixture was extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined and the organic phase was washed with saturated brine (30 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 3.62g of 4-chloro-1-isopropyl-1H-pyrazole.

MS(ESI)M/Z:145.2[M+H]⁺.

And (B) step (B): 4-chloro-1-isopropyl-1H-pyrazole (2 g,0.014 mol) was dissolved in tetrahydrofuran (14 mL) at 0deg.C under nitrogen. Subsequently, n-butyllithium (11.2 mL,0.017 mol) was added dropwise to the above solution, and the mixture was warmed to room temperature and stirred for 1 hour. Then, the reaction mixture was cooled to-78℃and 2-isopropoxy-4, 5-tetramethyl-1, 3, 2-dioxaborolan (3.45 g,0.018 mol) was slowly added dropwise thereto, and the mixture was stirred for 2 hours at room temperature.

After LCMS monitoring showed the disappearance of starting material, the reaction solution was quenched by addition of saturated aqueous ammonium chloride (40 mL). The mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 2.4g of 4-chloro-1-isopropyl-5- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) -1H-pyrazole.

MS(ESI)M/Z:271.0[M+H]⁺.

Intermediate INT-7:1- (4- (bromomethyl) phenyl) -5-ethoxy-3- (trifluoromethyl) -1H-pyrazole

Step A4-hydrazinobenzoic acid (5 g,32.9 mmol) and ethyl 4, 4-trifluoro-3-oxobutanoate (6 g,32.9 mmol) were dissolved in methanol/hydrochloric acid (73 mL/14.6 mL) at room temperature. The reaction system was then stirred at room temperature for 3 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel to give 8.3g of methyl 4- (5-hydroxy-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzoate.

MS(ESI)M/Z:287.0[M+H]⁺.

And (B) step (B): methyl 4- (5-hydroxy-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzoate (5 g,17.5 mmol) was dissolved in N, N-dimethylformamide (87 mL) at room temperature under nitrogen. Subsequently, sodium hydride (1.39 g,34.96 mmol) was added to the above solution, and stirred for 30 minutes. Then, ethyl iodide (5.4 g,34.96 mmol) was slowly added dropwise thereto, and stirred at room temperature for 1 hour.

After LCMS monitoring showed the disappearance of starting material, ice water (250 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (80 mL. Times.3), and the organic phases were combined and washed with saturated brine (250 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 3.7g of methyl 4- (5-ethoxy-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzoate.

MS(ESI)M/Z:315.0[M+H]⁺.

Step C: methyl 4- (5-ethoxy-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzoate (3.7 g,11.78 mmol) was dissolved in tetrahydrofuran (59 mL) at 0deg.C under nitrogen. Subsequently, lithium aluminum hydride (9.4 mL,23.56 mmol) was added to the above solution, and stirring was continued for 30 minutes.

After LCMS monitoring showed the disappearance of starting material, the reaction solution was quenched by slowly dropping into ice water (150 mL), filtered, the filtrate extracted with ethyl acetate (50 ml×3 times), the organic phases combined and the organic phase washed with saturated brine solution (150 ml×2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 3g of (4- (5-ethoxy-3- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) methanol.

MS(ESI)M/Z:287.0[M+H]⁺.

Step D: (4- (5-ethoxy-3- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) methanol (1.5 g,5.24 mmol) was dissolved in dichloromethane (26 mL) at 0deg.C under nitrogen. Subsequently, triphenylphosphine (2.7 g,10.48 mmol), sodium bicarbonate (880 mg,10.48 mmol) and carbon tetrabromide (3.46 g,10.48 mmol) were added sequentially to the above solution. The reaction was then stirred at room temperature for a further 30 minutes.

After LCMS monitoring showed the disappearance of starting material, ice water (150 mL) was added to the reaction solution to quench. The mixture was extracted with dichloromethane (50 mL. Times.3), and the organic phases were combined and washed with saturated aqueous saline (150 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 1.8g of 1- (4- (bromomethyl) phenyl) -5-ethoxy-3- (trifluoromethyl) -1H-pyrazole.

MS(ESI)M/Z:348.8[M+H]⁺.

Intermediate INT-8:1- (4- (bromomethyl) phenyl) -5-methyl-3- (trifluoromethyl) -1H pyrazole

Step A: methyl 4-hydrazinobenzoate hydrochloride (1 g,4.93 mmol) was dissolved in ethanol (25 mL) at room temperature. Subsequently, 1-trifluoropentane-2, 4-dione (912 mg,5.92 mmol) was added to the above solution under ice-water bath conditions. The reaction system was then stirred at room temperature for 2 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure and the resulting residue was quenched by addition to ice water (50 mL). The mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined and washed with saturated brine (30 mL). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 170mg of methyl 4- (5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzoate.

MS(ESI)M/Z:285.0[M+H]⁺.

And (B) step (B): methyl 4- (5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzoate (170 mg,0.60 mmol) was dissolved in dry tetrahydrofuran (3 mL) at room temperature under nitrogen. Subsequently, a 2.5M lithium aluminum hydride solution (1.2 mL,3 mmol) was slowly added dropwise to the above solution at 0 ℃. The reaction was then stirred at room temperature for 2 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by slowly dropping the solution into ice water (50 mL), filtered and the filter cake rinsed with ethyl acetate (30 mL x 3 times). The filtrate was then collected, separated, the aqueous phase extracted with ethyl acetate (30 mL. Times.3), the organic phases combined and the organic phase washed with saturated brine (50 mL). Finally, the mixture is dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 120mg of (4- (5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) methanol.

MS(ESI)M/Z:257.2[M+H]⁺.

Step C: (4- (5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) methanol (120 mg,0.47 mmol) was dissolved in dichloromethane (2.5 mL) at room temperature. Subsequently, sodium hydrogencarbonate (79 mg,0.94 mmol), triphenylphosphine (247 mg,0.94 mmol) and carbon tetrabromide (312 mg,0.94 mmol) were added to the above solution in this order. The reaction system was then stirred at room temperature for 1 hour.

After LCMS monitoring showed the disappearance of starting material, ice water (40 mL) was added to the reaction solution to quench, the mixture was extracted with ethyl acetate (30 ml×3 times), the organic phases were combined and the organic phase was washed with saturated brine (30 mL). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 140mg of 1- (4- (bromomethyl) phenyl) -5-methyl-3- (trifluoromethyl) -1H pyrazole.

MS(ESI)M/Z:319.0[M+H]⁺.

EXAMPLE 1 3-cyclopropyl-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1H pyrazolo [3,4-d ] pyrimidine

The reaction route is as follows:

the operation steps are as follows:

Step A6-chloro-1H-pyrazolo [3,4-d ] pyrimidine (1 g,6.49 mmol), 3.4 dihydro-2H-pyran (1.1 g,12.98 mmol) and 4-methylbenzenesulfonic acid pyridine (163 mg,0.65 mmol) are dissolved in dichloromethane (2 mL) at room temperature. The reaction system was then stirred at 60℃for 2 hours.

After LCMS monitoring showed the disappearance of starting material, ice water (40 mL) was added to the reaction solution for quenching, the mixture was extracted with ethyl acetate (20 ml×3 times), the organic phases were combined and the organic phase was washed with saturated brine (20 ml×2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue obtained was purified by silica gel column chromatography to give 1.4g of intermediate 1-1.

MS(ESI)M/Z:239.2[M+H]⁺.

Step B6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d ] pyrimidine (800 mg,2.27 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (1.71 g,8.82 mmol), potassium phosphate (1.37 g,6.47 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (694 mg,0.88 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) [2- (2 ' -amino-1, 1' -biphenyl) ] palladium (II) (50 mg,0.06 mmol) are dissolved in 1, 4-dioxane/water (21 mL/7 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air and the reaction was stirred at 90℃for 2 hours.

After LCMS monitoring showed the disappearance of starting material, quench the reaction solution by adding ice water (40 mL), extract the mixture with ethyl acetate (20 mL x 3 times), combine the organic phases and wash the organic phase with saturated brine (20 mL x 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was purified by silica gel column chromatography to give 800mg of intermediate 1-2.

MS(ESI)M/Z:353.0[M+H]⁺.

Step C: 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d ] pyrimidine (800 mg,2.27 mmol) is dissolved in dichloromethane (12 mL) at room temperature. Subsequently, trifluoroacetic acid (12 mL) was added to the above solution at 0deg.C. The reaction system was then stirred at room temperature for 16 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction solution was concentrated under reduced pressure, ice water (20 mL) was added to the resulting residue to quench, the mixture was extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined and the organic phase was washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 740mg of intermediate 1-3 were obtained.

MS(ESI)M/Z:269.2[M+H]⁺.

Step D: 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine (200 mg,0.75 mmol) is dissolved in N, N-dimethylformamide (2 mL) at room temperature. Subsequently, N-bromosuccinimide (267 mg,1.5 mmol) was added to the above solution. The reaction system was then stirred for an additional 2 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction solution was quenched by addition to ice water (40 mL), the mixture was extracted with ethyl acetate (30 mL x 3 times), the organic phases were combined and the organic phase was washed with saturated aqueous sodium chloride (20 mL x 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 230mg of intermediate 1-4.

MS(ESI)M/Z:347.0[M+H]⁺.

Step E: 3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine (230 mg,0.67 mmol), (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol (208 mg,0.73 mmol) and triphenylphosphine (262 mg,1.0 mmol) were dissolved in tetrahydrofuran (4.0 mL) at room temperature under nitrogen. Subsequently, diisopropyl azodicarboxylate (202 mg,1.0 mmol) was added to the above solution under ice water bath conditions. The reaction system was then stirred at room temperature for 2 hours.

After LCMS monitoring showed the disappearance of starting material, ice water (20 mL) was added to the reaction solution to quench, the mixture was extracted with ethyl acetate (30 ml×3 times), the organic phases were combined and the organic phase was washed with saturated aqueous sodium bicarbonate (20 mL). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 230mg of intermediate 1-5.

MS(ESI)M/Z:613.0[M+H]⁺.

Step F: 3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1H pyrazolo [3,4-d ] pyrimidine (100 mg,0.16 mmol), cyclopropylboronic acid (30 mg,0.28 mmol), potassium phosphate (70 mg,0.32 mmol), silver oxide (20 mg,0.08 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (20 mg,0.02 mmol) are dissolved in 1, 4-dioxane (4 mL) at room temperature. The nitrogen was replaced 3 times with vacuum air and the reaction was stirred at 100 degrees celsius for 3 hours.

After LCMS monitoring showed the disappearance of starting material, quench the reaction solution with ice water (20 mL), extract the mixture with ethyl acetate (30 mL. Times.3), combine the organic phases and wash the organic phase with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 63.21mg of Compound 1 were obtained.

MS(ESI)M/Z:575.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.46(s,1H),8.70(s,1H),8.17(d,J＝0.8Hz,1H),7.52(d,J＝8.4Hz,2H),7.39(d,J＝8.4Hz,2H),5.67(s,2H),4.48-4.37(m,1H),3.85(s,3H),2.47-2.40(m,1H),1.69-1.61(m,1H),1.38(d,J＝6.8Hz,6H),1.15-1.10(m,4H),1.08-1.02(m,2H),0.88-0.81(m,2H).

EXAMPLE 2 5-cyclopropyl-2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -7H-pyrrole [2,3-d ] pyrimidine

The reaction route is as follows:

the operation steps are as follows:

Step A5-bromo-2-chloro-7H-pyrrolo [2,3-d ] pyrimidine (200 mg,0.87 mmol), (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol (270 mg,0.95 mmol) and triphenylphosphine (292 mg,1.31 mmol) were dissolved in tetrahydrofuran (4.5 mL) at room temperature. Subsequently, diisopropyl azodicarboxylate (264 mg,1.31 mmol) was added to the above solution under ice water bath conditions. The reaction system was then stirred at room temperature for 2 hours.

After LCMS monitoring showed the disappearance of starting material, ice water (40 mL) was added to the reaction solution for quenching, the mixture was extracted with ethyl acetate (20 ml×3 times), the organic phases were combined and the organic phase was washed with saturated brine (20 ml×2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 400mg of intermediate 2-1.

MS(ESI)M/Z:497.8[M+H]⁺.

And (B) step (B): 5-bromo-2-chloro-7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -7H-pyrrolo [2,3-d ] pyrimidine (400 mg,0.80 mmol), cyclopropylboronic acid (118 mg,1.37 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (98 mg,0.12 mmol), silver oxide (93 mg,0.40 mmol) and potassium phosphate (340 mg,1.60 mmol) were dissolved in 1, 4-dioxane (10 mL) at room temperature. Then, the nitrogen was replaced with vacuum-evacuated gas 4 times, heated to 100℃and stirred for 4 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction solution was quenched by addition to ice water (40 mL), the mixture was extracted with ethyl acetate (20 ml×3 times), the organic phases were combined, washed with saturated brine (20 ml×2 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was purified by silica gel column chromatography to give 200mg of intermediate 2-2.

MS(ESI)M/Z:460.0[M+H]⁺.

Step C: 2-chloro-5-cyclopropyl-7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -7H-pyrrolo [2,3-d ] pyrimidine (100 mg,0.22 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (86 mg,0.44 mmol), cesium carbonate (144 mg,0.44 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (35 mg,0.04 mmol) were dissolved in 1, 4-dioxane/water (2.7 mL/0.3 mL) at room temperature. Then the reaction system was vacuum-evacuated to replace nitrogen 3 times, heated to 100℃and stirred for 3 hours.

After LCMS monitoring showed the disappearance of starting material, quench the reaction solution with ice water (20 mL), extract the mixture with ethyl acetate (30 mL. Times.3), combine the organic phases and wash the organic phase with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 8.42mg of Compound 2 was obtained.

MS(ESI)M/Z:574.0[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.16(s,1H),8.67(s,1H),8.16(d,J＝0.8Hz,1H),7.57(s,1H),7.51(d,J＝8.4Hz,2H),7.39(d,J＝8.4Hz,2H),5.48(s,2H),4.46-4.35(m,1H),3.83(s,3H),2.13-2.04(m,1H),1.67-1.59(m,1H),1.37(d,J＝6.8Hz,6H),1.05-1.00(m,2H),0.99-0.92(m,2H),0.84-0.74(m,4H).

EXAMPLE 3-cyclopropyl-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- (4- (5-ethoxy-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzyl) -1H-pyrazolo [3,4-d ] pyrimidine

Reference example 1 preparation method to give Compound 3

MS(ESI)M/Z:577.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d6)δ9.45(s,1H),8.70(s,1H),7.61(d,J＝8.4Hz,2H),7.40(d,J＝8.4Hz,2H),6.44(s,1H),5.64(s,2H),4.26(q,J＝6.8Hz,2H),3.85(s,3H),2.46-2.39(m,1H),1.70-1.59(m,1H),1.33(t,J＝7.0Hz,3H),1.16-1.08(m,4H),1.08-1.01(m,2H),0.90-0.78(m,2H).

EXAMPLE 4 3-cyclopropyl-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1H pyrazolo [3,4-d ] pyrimidine

Reference example 1 preparation method to give Compound 4

MS(ESI)M/Z:547.0[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆):δ9.45(s,1H),8.70(s,1H),7.92(s,1H),7.67(d,J＝8.0Hz,2H),7.38(d,J＝8.4Hz,2H),5.66(s,2H),3.85(s,3H),3.75(s,3H),2.46-2.40(m,1H),1.71-1.59(m,1H),1.12(d,J＝6.8Hz,4H),1.09-1.02(m,2H),0.89-0.82(m,2H).

EXAMPLE 5 6- (4-chloro-1-isopropyl-1H-pyrazol-5-yl) -3-cyclopropyl-1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1H pyrazolo [3,4-d ] pyrimidine

Compound 5 is prepared according to the method of reference example 1

MS(ESI)M/Z:569.1[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.51(s,1H),8.16(d,J＝0.8Hz,1H),7.75(s,1H),7.54(d,J＝8.0Hz,2H),7.43(d,J＝8.4Hz,2H),5.69(s,2H),5.31-5.19(m,1H),4.49-4.36(m,1H),2.48-2.40(m,1H),1.43-1.35(m,12H),1.14(d,J＝6.8Hz,4H).

EXAMPLE 6- (4-chloro-1-isopropyl-1H-pyrazol-5-yl) -3-cyclopropyl-1- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1H pyrazolo [3,4-d ] pyrimidine

Reference example 1 preparation method to give Compound 6

MS(ESI)M/Z:541.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.51(s,1H),7.92(d,J＝1.4Hz,1H),7.75(s,1H),7.69(d,J＝8.3Hz,2H),7.42(d,J＝8.3Hz,2H),5.68(s,2H),5.25(p,J＝6.6Hz,1H),3.75(s,3H),2.48-2.41(m,1H),1.40(d,J＝6.6Hz,6H),1.14(d,J＝6.7Hz,4H).

EXAMPLE 7 6- (4-chloro-1-isopropyl-1H-pyrazol-5-yl) -3-cyclopropyl-1- (3-methoxy-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1H pyrazolo [3,4-d ] pyrimidine

Reference example 1 preparation method to give Compound 7

MS(ESI)M/Z:571.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.52(s,1H),7.88(d,J＝1.3Hz,1H),7.75(s,1H),7.31(d,J＝7.7Hz,1H),7.20(d,J＝1.6Hz,1H),6.87(dd,J＝7.8,1.5Hz,1H),5.68(s,2H),5.35-5.17(m,1H),3.78(s,3H),3.46(s,3H),2.49-2.42(m,1H),1.40(d,J＝6.6Hz,6H),1.17-1.11(m,4H).

EXAMPLE 8 3-cyclopropyl-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- (4- (5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzyl) -1H pyrazolo [3,4-d ] pyrimidine

Reference example 1 preparation method Compound 8 was prepared

MS(ESI)M/Z:547.4[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.46(s,1H),8.70(s,1H),7.53(d,J＝8.4Hz,2H),7.42(d,J＝8.8Hz,2H),6.74(s,1H),5.68(s,2H),3.85(s,3H),2.46-2.41(m,1H),2.31(s,3H),1.69-1.61(m,1H),1.13(d,J＝6.4Hz,4H),1.08-1.01(m,2H),0.90-0.81(m,2H).

EXAMPLE 9 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -3- (furan-3-yl) -1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1H-pyrazolo [3,4-d ] pyrimidine

The reaction route is as follows:

the operation steps are as follows:

Step A: 3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine (150 mg,0.43 mmol), (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol (124 mg,0.43 mmol) and triphenylphosphine (170 mg,0.65 mmol) were dissolved in dry tetrahydrofuran (2.5 mL) at room temperature under nitrogen. Subsequently, diisopropyl azodicarboxylate (130 mg,0.65 mmol) was slowly added dropwise to the above solution under ice water bath conditions. The reaction system was then stirred at room temperature for 2 hours.

After LCMS monitoring showed the disappearance of starting material, ice water (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated aqueous sodium bicarbonate (20 mL). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 200mg of 3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1H pyrazolo [3,4-d ] pyrimidine.

MS(ESI)M/Z:613.0[M+H]⁺.

And (B) step (B): 3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1H pyrazolo [3,4-d ] pyrimidine (100 mg,0.16 mmol), 2- (furan-3-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (54 mg,0.28 mmol), potassium phosphate (70 mg,0.32 mmol), silver oxide (20 mg,0.08 mmol) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (20 mg,0.02 mmol) are dissolved in 1, 4-dioxane (1 mL) at room temperature. The nitrogen was replaced 3 times with vacuum air and the reaction was stirred at 100 degrees celsius for 3 hours.

After LCMS monitoring showed the disappearance of starting material, quench the reaction solution with ice water (50 mL), extract the mixture with ethyl acetate (30 mL. Times.3), combine the organic phases and wash the organic phase with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 63.21mg of Compound 9 are obtained.

MS(ESI)M/Z:601.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.83(s,1H),8.74(s,1H),8.72(s,1H),8.16(d,J＝1.4Hz,1H),7.91(t,J＝1.7Hz,1H),7.54(d,J＝8.3Hz,2H),7.45(d,J＝8.2Hz,2H),7.13(d,J＝1.9Hz,1H),5.81(s,2H),4.48-4.35(m,1H),3.87(s,3H),1.77-1.64(m,1H),1.37(d,J＝6.6Hz,6H),1.11-1.04(m,2H),0.92-0.79(m,2H).

EXAMPLE 10 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -3- (1H-pyrazol-3-yl) -1H-pyrazolo [3,4-d ] pyrimidine

Reference example 9 preparation method Compound 10 was prepared

MS(ESI)M/Z:601.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ13.34(s,1H),9.76(s,1H),8.72(s,1H),8.16(d,J＝1.4Hz,1H),7.94(s,1H),7.54(d,J＝8.2Hz,2H),7.45(d,J＝8.0Hz,2H),6.88(s,1H),5.82(s,2H),4.48-4.35(m,1H),3.87(s,3H),1.78-1.66(m,1H),1.37(d,J＝6.6Hz,6H),1.09-1.03(m,2H),0.90-0.82(m,2H).

EXAMPLE 11 3-cyclopropyl-6- (2-isopropylpyridin-3-yl) -1- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1H-pyrazolo [3,4-d ] pyrimidine

Reference example 1 preparation method Compound 11 was obtained

MS(ESI)M/Z:518.3[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.47(s,1H),8.66(dd,J＝4.7,1.8Hz,1H),8.10(dd,J＝7.8,1.8Hz,1H),7.69(d,J＝8.3Hz,2H),7.43-7.32(m,3H),5.68(s,2H),3.75(s,3H),3.73-3.62(m,1H),2.49-2.43(m,1H),1.20(d,J＝6.7Hz,6H),1.17-1.09(m,4H).

EXAMPLE 12 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6- (1-methyl-1H-pyrazol-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine

The reaction route is as follows:

the operation steps are as follows:

Step A2-chloro-7H-pyrrolo [2,3-d ] pyrimidine (4.0 g,25.97 mmol) and potassium carbonate (1.34 g,9.74 mmol) were dissolved in N, N-dimethylformamide (33 mL) at room temperature and stirred for 30 min. Subsequently, benzenesulfonyl chloride (6.9 g,38.96 mmol) was slowly added dropwise to the above reaction solution, and stirred at room temperature for 1 hour.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (150 mL) to the reaction. The mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined and washed with saturated brine (50 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 2g of 2-chloro-7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:294.0[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.05(s,1H),8.19-8.141(m,2H),8.04(d,J＝4.0Hz,1H),7.84-7.78(m,1H),7.75-7.66(m,2H),6.99(d,J＝4.0Hz,1H).

And (B) step (B): 2-chloro-7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine (2 g,6.83 mmol) was dissolved in dry tetrahydrofuran (34 mL) at room temperature under nitrogen. Subsequently, lithium diisopropylamide (3.27 mL,8.2 mmol) was slowly added dropwise to the above solution at-78 degrees Celsius, and stirred for 1 hour. Iodine (2.6 g,10.25 mmol) was then added to the reaction solution and stirring was continued for 1 hour.

After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by slow addition to saturated aqueous ammonium chloride (50 mL). The mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 500mg of 2-chloro-6-iodo-7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:419.9[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ8.97(s,1H),8.17-8.10(m,2H),7.90-7.83(m,1H),7.82-7.72(m,2H),7.42(s,1H).

Step C: 2-chloro-6-iodo-7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine (200 mg,0.47 mmol), 1-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (137 mg,0.66 mmol), sodium carbonate (97 mg,0.94 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (41 mg,0.05 mmol) were dissolved in 1, 4-dioxane/water (2 mL/0.2 mL) at room temperature. The nitrogen was replaced 3 times with vacuum air and the reaction was stirred at 75 degrees celsius for 16 hours.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (30 mL) to the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 120mg of 2-chloro-6- (1-methyl-1H-pyrazol-3-yl) -7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:374.1[M+H]⁺.

Step D: 2-chloro-6- (1-methyl-1H-pyrazol-3-yl) -7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine (120 mg,0.12 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (125 mg,0.64 mmol), cesium carbonate (209 mg,0.64 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (50 mg,0.06 mmol) were dissolved in 1, 4-dioxane/water (1.6 mL/0.15 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air pumping, and the reaction system was stirred for 2 hours at 90℃under microwave conditions.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (30 mL) to the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 80mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6- (1-methyl-1H-pyrazol-3-yl) -7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:488.2[M+H]⁺.

Step E: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6- (1-methyl-1H-pyrazol-3-yl) -7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine (80 mg,0.16 mmol) and potassium tert-butoxide (90 mg,0.84 mmol) were dissolved in tetrahydrofuran (0.8 mL) at room temperature. The reaction system was stirred at room temperature for 2 hours.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (30 mL) to the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 50mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6- (1-methyl-1H-pyrazol-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:348.2[M+H]⁺.

Step F: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6- (1-methyl-1H-pyrazol-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine (50 mg,0.14 mmol), potassium carbonate (28 mg,0.28 mmol) and 2- (4- (bromomethyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole (50 mg,0.14 mmol) were dissolved in N, N-dimethylformamide (0.7 mL) at room temperature. The reaction system was then stirred at 50 degrees celsius for 2 hours.

After LCMS monitoring showed the disappearance of starting material, ice water (20 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and washed with saturated saline solution (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 31.7mg of Compound 12 are obtained.

MS(ESI)M/Z:614.3[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.16(s,1H),8.66(s,1H),8.13(d,J＝1.5Hz,1H),7.84(d,J＝2.3Hz,1H),7.43(d,J＝8.2Hz,2H),7.26(d,J＝8.2Hz,2H),7.11(s,1H),6.83(d,J＝2.3Hz,1H),6.08(s,2H),4.42-4.32(m,1H),3.94(s,4H),3.83(s,4H),1.71-1.60(m,1H),1.35(d,J＝6.6Hz,6H),1.03-0.98(m,2H),0.80-0.73(m,2H).

EXAMPLE 13 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -8- (1-methyl-1H-pyrazol-3-yl) -9H-purine

The reaction route is as follows:

the operation steps are as follows:

Step A2-chloro-9H-purine (1.0 g,6.49 mmol), 2- (4- (bromomethyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole (2.24 g,6.49 mmol), potassium carbonate (1.34 g,9.74 mmol) were dissolved in N, N-dimethylformamide (33 mL) at room temperature. The nitrogen was replaced 3 times with vacuum air and the reaction was stirred at 35 degrees celsius for 2 hours.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (100 mL) to the reaction. The mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined and washed with saturated brine (50 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 1.5g of 2-chloro-9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine.

MS(ESI)M/Z:421.0[M+H]⁺.

¹H NMR(400MHz,DMS-d₆)δ9.15(s,1H),8.84(s,1H),8.18(d,J＝1.2Hz,1H),7.58(d,J＝8.4Hz,2H),7.47(d,J＝8.0Hz,2H),5.60(s,2H),4.52-4.37(m,1H),1.39(d,J＝6.4Hz,6H).

And (B) step (B): 2-chloro-9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine (800 mg,1.90 mmol) was dissolved in tetrahydrofuran (8 mL) at room temperature under nitrogen. Subsequently, lithium diisopropylamide (1.4 mL,2.92 mmol) was slowly added dropwise to the above solution at-78 degrees Celsius, and stirred for 1 hour. 1, 2-dibromo-1, 2-tetrachloroethane (1.25 g,3.90 mmol) was then added to the above solution, and stirring was continued for 1 hour.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (30 mL) to the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 300mg of 8-bromo-2-chloro-9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine.

MS(ESI)M/Z:498.8[M+H]⁺.

Step C: 8-bromo-2-chloro-9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine (100 mg,0.20 mmol), 1-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole (58 mg,0.28 mmol), sodium carbonate (42 mg,0.40 mmol) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (33 mg,0.04 mmol) were dissolved in 1, 4-dioxane/water (0.9 mL/0.1 mL) at room temperature. The nitrogen was replaced 3 times with vacuum air and the reaction was stirred at 85 degrees celsius for 16 hours.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (30 mL) to the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 80mg of 2-chloro-9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -8- (1-methyl-1H-pyrazol-3-yl) -9H-purine.

MS(ESI)M/Z:501.0[M+H]⁺.

Step D: 2-chloro-9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -8- (1-methyl-1H-pyrazol-3-yl) -9H-purine (60 mg,0.12 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (47 mg,0.24 mmol), cesium carbonate (78 mg,0.24 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (19 mg,0.02 mmol) were dissolved in 1, 4-dioxane/water (0.54 mL/0.06 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air pumping, and the reaction system was stirred for 2 hours at 90℃under microwave conditions.

After LCMS monitoring showed the disappearance of starting material, ice water (20 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and washed with saturated saline solution (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 31.73mg of Compound 13 was obtained.

MS(ESI)M/Z:615.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.29(s,1H),8.69(s,1H),8.15(d,J＝1.3Hz,1H),7.97(d,J＝2.3Hz,1H),7.53-7.42(m,4H),7.07(d,J＝2.3Hz,1H),6.12(s,2H),4.47-4.31(m,1H),4.02(s,3H),3.85(s,3H),1.75-1.62(m,1H),1.36(d,J＝6.6Hz,6H),1.06-0.99(m,2H),0.85-0.74(m,2H).

EXAMPLE 14 9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -2, 8-bis (1-methyl-1H-pyrazol-3-yl) -9H-purine

The reaction route is as follows:

the operation steps are as follows:

Step A: 8-bromo-2-chloro-9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine (100 mg,0.20 mmol), 1-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole (33 mg,0.16 mmol), sodium carbonate (42 mg,0.40 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (32 mg,0.04 mmol) were dissolved in 1, 4-dioxane/water (0.9 mL/0.1 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air pumping, and the reaction system was stirred at 75 ℃ for 2 hours under microwave conditions.

After LCMS monitoring showed the disappearance of starting material, ice water (40 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and washed with saturated saline solution (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 10.05mg of 9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -2, 8-bis (1-methyl-1H-pyrazol-3-yl) -9H-purine are obtained.

MS(ESI)M/Z:548.0[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.17(s,1H),8.14(d,J＝1.3Hz,1H),7.93(d,J＝2.3Hz,1H),7.80(d,J＝2.2Hz,1H),7.50(d,J＝8.4Hz,2H),7.40(d,J＝8.4Hz,2H),7.01(d,J＝2.3Hz,1H),6.96(d,J＝2.2Hz,1H),6.14(s,2H),4.50-4.35(m,1H),3.99(s,3H),3.95(s,3H),1.35(d,J＝6.6Hz,6H).

EXAMPLE 15 9- (3-cyclopropyl-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -2- (trifluoromethyl) -6, 7-dihydro-5H-benzo [ c ] imidazo [1,2-a ] azepine

Reference example 1 preparation method Compound 15 was obtained

MS(ESI)M/Z:573.0[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.45(s,1H),8.70(s,1H),7.97(d,J＝1.3Hz,1H),7.63(d,J＝7.9Hz,1H),7.30(d,J＝1.8Hz,1H),7.22(dd,J＝8.0,1.8Hz,1H),5.62(s,2H),3.97(t,J＝6.8Hz,2H),3.85(s,3H),2.63(t,J＝7.0Hz,2H),2.48-2.40(m,1H),2.27-2.19(m,2H),1.71-1.58(m,1H),1.12(d,J＝6.7Hz,4H),1.09-0.99(m,2H),0.89-0.78(m,2H).

EXAMPLE 16 4' -cyclopropyl-5- (furan-3-yl) -N- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6' -methoxy- [2,5' -bipyrimidin ] -4-amine

Reference example 1 preparation method Compound 16 was prepared

MS(ESI)M/Z:576.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.31(s,1H),8.18-8.12(m,2H),7.93-7.87(m,1H),7.50-7.39(m,5H),6.94-6.90(m,1H),4.68(d,J＝6.1Hz,2H),4.48-4.38(m,1H),3.81(s,3H),1.76-1.65(m,1H),1.39(d,J＝6.6Hz,7H),1.00-0.91(m,2H),0.78-0.69(m,2H).

EXAMPLE 17- ((3-cyclopropyl-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -2- (trifluoromethyl) -5H-imidazo [2,1-a ] isoindole

The reaction route is as follows:

the operation steps are as follows:

Step A: 3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine (109 mg,0.31 mmol), (2- (trifluoromethyl) -5H-imidazo [2,1-a ] isoindol-7-yl) methanol (80 mg,0.31 mmol) and triphenylphosphine (122 mg,0.46 mmol) are dissolved in dry tetrahydrofuran (1.5 mL) at room temperature under nitrogen. Subsequently, diisopropyl azodicarboxylate (94 mg,0.46 mmol) was slowly added dropwise to the above solution under ice water bath conditions. The reaction system was then stirred at room temperature for 2 hours.

After LCMS monitoring showed the disappearance of starting material, ice water (10 mL) was added to the reaction solution to quench, the mixture was extracted with ethyl acetate (10 ml×3 times), the organic phases were combined and the organic phase was washed with saturated aqueous sodium chloride (20 mL). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 220mg of 7- ((3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -2- (trifluoromethyl) -5H-imidazo [2,1-a ] isoindole.

MS(ESI)M/Z:583.1[M+H]⁺.

And (B) step (B): 7- ((3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -2- (trifluoromethyl) -5H-imidazo [2,1-a ] isoindole (220 mg,0.38 mmol), cyclopropylboronic acid (65 mg,0.76 mmol), potassium phosphate (161 mg,0.76 mmol), silver oxide (44 mg,0.19 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (37 mg,0.05 mmol) are dissolved in 1, 4-dioxane (2 mL) at room temperature. The nitrogen was replaced with air under vacuum for 3 times, and the reaction system was stirred at 100℃for 3 hours.

After LCMS monitoring showed the disappearance of starting material, quench the reaction solution with ice water (20 mL), extract the mixture with ethyl acetate (30 mL. Times.3), combine the organic phases and wash the organic phase with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 44.31mg of 7- ((3-cyclopropyl-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -2- (trifluoromethyl) -5H-imidazo [2,1-a ] isoindole are obtained.

MS(ESI)M/Z:545.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.45(s,1H),8.71(s,1H),8.11(s,1H),7.76(d,J＝8.0Hz,1H),7.53(s,1H),7.41(d,J＝8.0Hz,1H),5.68(s,2H),5.11(s,2H),3.86(s,3H),2.48-2.38(m,1H),1.72-1.63(m,1H),1.12(d,J＝6.8Hz,4H),1.09-1.02(m,2H),0.89-0.81(m,2H).

EXAMPLE 18- ((3-cyclopropyl-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -2- (trifluoromethyl) -5, 6-dihydroimidazo [2,1-a ] isoquinoline

The reaction route is as follows:

the operation steps are as follows:

Step A: (2- (trifluoromethyl) -5, 6-dihydroimidazo [2,1-a ] isoquinolin-8-yl) methanol (23 mg,0.09 mmol), 3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine (30 mg,0.09 mmol) and triphenylphosphine (33 mg,0.13 mmol) are dissolved in dry tetrahydrofuran (0.4 mL) at room temperature. Subsequently, diisopropyl azodicarboxylate (26 mg,0.13 mmol) was added to the above solution at 0 ℃. The reaction system was then stirred at room temperature for 3 hours.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (20 mL) to the reaction. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and washed with saturated brine (30 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 37mg of 8- ((3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -2- (trifluoromethyl) -5, 6-dihydroimidazo [2,1-a ] isoquinoline.

MS(ESI)M/Z:597.0[M+H]⁺.

And (B) step (B): 8- ((3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -2- (trifluoromethyl) -5, 6-dihydroimidazo [2,1-a ] isoquinoline (37 mg,0.06 mmol), cyclopropylboronic acid (8.6 mg,0.10 mmol), potassium phosphate (25 mg,0.12 mmol), silver oxide (7 mg,0.03 mmol) and dichloro [1,1' -bis (diphenylphosphino) ferrocene ] palladium (6 mg,0.008 mmol) are dissolved in 1, 4-dioxane (0.3 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air and the reaction was stirred at 90℃for 16 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 30mg of crude product. The crude product is purified by preparative high performance liquid chromatography. 10.05mg of 8- ((3-cyclopropyl-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -2- (trifluoromethyl) -5, 6-dihydroimidazo [2,1-a ] isoquinoline are obtained.

MS(ESI)M/Z:559.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.44(s,1H),8.71(s,1H),7.86(d,J＝8.0Hz,1H),7.60(d,J＝1.2Hz,1H),7.29(s,1H),7.26(d,J＝8.0Hz,1H),5.61(s,2H),4.22(t,J＝7.0Hz,2H),3.85(s,3H),3.16(t,J＝7.0Hz,2H),2.47-2.39(m,1H),1.71-1.61(m,1H),1.12(d,J＝6.8Hz,4H),1.09-1.01(m,2H),0.89-0.80(m,2H).

EXAMPLE 19 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6- (1H-pyrazol-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine

The reaction route is as follows:

the operation steps are as follows:

step A2-chloro-6-iodo-7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine (300 mg,0.72 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole (315 mg,0.1.07 mmol), sodium carbonate (153 mg,1.44 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (74 mg,0.07 mmol) were dissolved in 1, 4-dioxane/water (3.6 mL/0.36 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air and the reaction was stirred at 75℃for 16 hours.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (30 mL) to the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 250mg of 2-chloro-7- (phenylsulfonyl) -6- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:490.1[M+H]⁺.

And (B) step (B): 2-chloro-7- (phenylsulfonyl) -6- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine (250 mg,0.51 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (199mg, 1.02 mmol), cesium carbonate (333 mg,1.02 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (164 mg,0.2 mmol) were dissolved in 1, 4-dioxane/water (2.5 mL/0.25 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air suction, and the reaction system was stirred for 2 hours at 90℃under microwave conditions.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (30 mL) to the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 150mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (phenylsulfonyl) -6- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:474.0[M+H]⁺.

Step C: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (phenylsulfonyl) -6- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine (150 mg,0.25 mmol) and potassium tert-butoxide (139 mg,1.24 mmol) were dissolved in tetrahydrofuran (1 mL) at room temperature. The reaction system was then stirred at room temperature for 2 hours.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (30 mL) to the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 70mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:464.2[M+H]⁺.

Step D: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine (70 mg,0.15 mmol), potassium carbonate (41 mg,0.3 mmol) and 2- (4- (bromomethyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole (52 mg,0.15 mmol) were dissolved in N, N-dimethylformamide (1 mL) at room temperature. The reaction system was then stirred at 50℃for 4 hours.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (30 mL) to the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 65mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:730.2[M+H]⁺.

Step D: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine (65 mg,0.09 mmol) was dissolved in trifluoroacetic acid (6 mL) at room temperature. The reaction system was then stirred at 40℃for 16 hours.

LCMS monitoring showed the disappearance of starting material followed by concentration under reduced pressure. Dissolving the residue with methanol at 0deg.C, adjusting pH to 8-9 with ammonia water, concentrating under reduced pressure, and purifying by preparative high performance liquid chromatography. 14.92mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6- (1H-pyrazol-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine are obtained.

MS(ESI)M/Z:600.3[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ13.28(s,1H),9.16(s,1H),8.66(s,1H),8.13(d,J＝0.8Hz,1H),7.91(s,1H),7.43(d,J＝8.4Hz,2H),7.22(d,J＝8.0Hz,2H),7.14(s,1H),6.89(s,1H),6.12(s,2H),4.43-4.30(m,1H),3.83(s,3H),1.69-1.59(m,1H),1.35(d,J＝6.4Hz,6H),1.04-0.95(m,2H),0.80-0.70(m,2H).

EXAMPLE 20 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -8- (1H-pyrazol-3-yl) -9H-purine

The reaction route is as follows:

the operation steps are as follows:

Step A8-bromo-2-chloro-9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine (100 mg,0.20 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole (91 mg,0.28 mmol), sodium carbonate (42 mg,0.40 mmol) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (33 mg,0.04 mmol) were dissolved in 1, 4-dioxane/water (0.9 mL/0.1 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air and the reaction was stirred at 85℃for 16 hours.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (30 mL) to the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 120mg of 2-chloro-9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -8- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) -9H-purine.

MS(ESI)M/Z:617.3[M+H]⁺.

And (B) step (B): 2-chloro-9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -8- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) -9H-purine (80 mg,0.13 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (51 mg,0.26 mmol), cesium carbonate (85 mg,0.26 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (21 mg,0.03 mmol) were dissolved in 1, 4-dioxane/water (0.54 mL/0.06 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air suction, and the reaction system was stirred for 2 hours at 90℃under microwave conditions.

After LCMS monitoring showed the disappearance of starting material, ice water (20 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and washed with saturated saline solution (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 68mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -8- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) -9H-purine.

MS(ESI)M/Z:731.2[M+H]⁺.

Step C: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -8- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) -9H-purine (60 mg,0.08 mmol) was dissolved in trifluoroacetic acid (2 mL) at room temperature. The reaction system was then stirred at room temperature for 48 hours.

LCMS monitoring showed the disappearance of starting material followed by concentration under reduced pressure. Dissolving the residue with methanol at 0deg.C, adjusting pH to 8-9 with ammonia water, concentrating under reduced pressure, and purifying by preparative high performance liquid chromatography. 31.73mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -8- (1-methyl-1H-pyrazol-3-yl) -9H-purine are obtained.

MS(ESI)M/Z:601.2[M+H]⁺.

1H NMR(400MHz,DMSO-d₆)δ13.65(s,1H),9.31(s,1H),8.68(s,1H),8.15(d,J＝0.8Hz,1H),8.03(d,J＝2.4Hz,1H),7.48(d,J＝8.4Hz,2H),7.40(d,J＝8.4Hz,2H),7.11(d,J＝1.6Hz,1H),6.16(s,2H),4.45-4.29(m,1H),3.84(s,3H),1.72-1.61(m,1H),1.35(d,J＝6.4Hz,6H),1.07-0.96(m,2H),0.85-0.72(m,2H).

EXAMPLE 21 7- ((3-cyclopropyl-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -3- (trifluoromethyl) -5H-imidazo [2,1-a ] isoindole

The reaction route is as follows:

the operation steps are as follows:

Step A: 3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine (33 mg,0.10 mmol), (3- (trifluoromethyl) -5H-imidazo [2,1-a ] isoindol-7-yl) methanol (20 mg,0.08 mmol) and triphenylphosphine (31.4 mg,0.12 mmol) are dissolved in tetrahydrofuran (0.5 mL) at room temperature under nitrogen. Subsequently, diisopropyl azodicarboxylate (24.2 mg,0.12 mmol) was slowly added dropwise to the above solution under ice water bath conditions. The reaction system was then stirred at room temperature for 2 hours.

After LCMS monitoring showed the disappearance of starting material, ice water (5 mL) was added to the reaction solution to quench, the mixture was extracted with ethyl acetate (5 ml×3 times), the organic phases were combined and the organic phase was washed with saturated aqueous sodium chloride (10 mL). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 98mg of 7- ((3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -3- (trifluoromethyl) -5H-imidazo [2,1-a ] isoindole.

MS(ESI)M/Z:583.1[M+H]⁺.

And (B) step (B): 7- ((3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -3- (trifluoromethyl) -5H-imidazo [2,1-a ] isoindole (98 mg,0.16 mmol), cyclopropylboronic acid (29 mg,0.33 mmol), potassium phosphate (71 mg,0.33 mmol), silver oxide (19.4 mg,0.08 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (17.1 mg,0.02 mmol) are dissolved in 1, 4-dioxane (1 mL) at room temperature. The nitrogen was replaced with air under vacuum for 3 times, and the reaction system was stirred at 100℃for 3 hours.

After LCMS monitoring showed the disappearance of starting material, quench the reaction solution with ice water (20 mL), extract the mixture with ethyl acetate (30 mL. Times.3), combine the organic phases and wash the organic phase with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 13.66mg of 7- ((3-cyclopropyl-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -3- (trifluoromethyl) -5H-imidazo [2,1-a ] isoindole are obtained.

MS(ESI)M/Z:545.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.45(s,1H),8.71(s,1H),7.78(d,J＝7.6Hz,1H),7.69(d,J＝1.2Hz,1H),7.54(s,1H),7.42(d,J＝8.0Hz,1H),5.69(s,2H),5.19(s,2H),3.85(s,3H),2.48-2.39(m,1H),1.70-1.61(m,1H),1.12(d,J＝6.8Hz,4H),1.09-1.02(m,2H),0.88-0.81(m,2H).

EXAMPLE 22 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (furan-3-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine

The reaction route is as follows:

the operation steps are as follows:

Step A8-bromo-2-chloro-9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine (170 mg,0.34 mmol), 2- (furan-3-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (99 mg,0.51 mmol), sodium carbonate (72 mg,0.68 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (55 mg,0.062 mmol) were dissolved in 1, 4-dioxane/water (1.7 mL/0.1 mL) at room temperature. The nitrogen was replaced with air under vacuum for 3 times, and the reaction system was stirred at 90℃for 3 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition to ice water (10 mL). The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 35mg of 2-chloro-8- (furan-3-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine.

MS(ESI)M/Z:487.2[M+H]⁺.

And (B) step (B): 2-chloro-8- (furan-3-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine (35 mg,0.07 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (28 mg,0.17 mmol), cesium carbonate (45.5 mg,0.14 mmol) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (11 mg,0.014 mmol) were dissolved in 1, 4-dioxane/water (0.5 mL/0.01 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air suction, and the reaction system was stirred for 3 hours at 90℃under microwave conditions.

After LCMS monitoring showed the disappearance of starting material, ice water (5 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (5 mL. Times.3), and the organic phases were combined and washed with saturated brine (10 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 9.88mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (furan-3-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine are obtained.

MS(ESI)M/Z:601.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆):δ9.33(s,1H),8.68(s,1H),8.47(t,J＝1.0Hz,1H),8.15(d,J＝1.2Hz,1H),7.93(t,J＝1.8Hz,1H),7.51(d,J＝8.0Hz,2H),7.28(d,J＝8.4Hz,2H),7.11(dd,J＝2.0,0.8Hz,1H),5.84(s,2H),4.44-4.34(m,1H),3.84(s,3H),1.72-1.63(m,1H),1.36(d,J＝6.8Hz,6H),1.06-0.99(m,2H),0.85-0.77(m,2H).

EXAMPLE 23 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6- (2H-1, 2, 3-triazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine

The reaction route is as follows:

the operation steps are as follows:

Step A2-chloro-6-iodo-7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine (360 mg,0.86 mmol), 2- (tetrahydro-2H-pyran-2-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaboro-2-yl) -2H-1,2, 3-triazole (360 mg,1.29 mmol) and sodium carbonate (182 mg,1.72 mmol) were dissolved in 1, 4-dioxane/water (4.1 mL/0.45 mL) at room temperature under nitrogen. Subsequently, to the above solution was added [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (70 mg,0.08 mmol). The nitrogen was replaced with air under vacuum 4 times and the reaction was stirred at 75℃for 16 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction solution was filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 280mg of 2-chloro-7- (phenylsulfonyl) -6- (2- (tetrahydro-2H-pyran-2-yl) -2H-1,2, 3-triazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:445.2[M+H]⁺.

And (B) step (B): 2-chloro-7- (phenylsulfonyl) -6- (2- (tetrahydro-2H-pyran-2-yl) -2H-1,2, 3-triazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine (280 mg,0.63 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (252 mg,1.29 mmol) and cesium carbonate (420 mg,1.29 mmol) are dissolved in 1, 4-dioxane/water (3.2 mL/0.35 mL) at room temperature under nitrogen. Subsequently, to the above solution was added chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (98 mg,0.13 mmol), and the nitrogen was replaced with air under vacuum for 4 times, and the reaction system was reacted at 90 ℃ for 1 hour under microwave conditions.

After LCMS monitoring showed the disappearance of starting material, the reaction mixture was quenched by addition of water (20 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases combined and washed with saturated brine (10 mL). Then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 140mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (phenylsulfonyl) -6- (2- (tetrahydro-2H-pyran-2-yl) -2H-1,2, 3-triazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:559.2[M+H]⁺.

Step C: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (phenylsulfonyl) -6- (2- (tetrahydro-2H-pyran-2-yl) -2H-1,2, 3-triazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine (140 mg,0.25 mmol) and potassium tert-butoxide (140 mg,1.25 mmol) were dissolved in tetrahydrofuran (1.3 mL) at room temperature. The reaction system was stirred at room temperature for 1 hour.

After LCMS monitoring showed the disappearance of starting material, the reaction mixture was quenched by addition of water (20 mL), extracted with ethyl acetate (20 mL. Times.3), the organic phases combined and washed with saturated brine (30 mL). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 80mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6- (2- (tetrahydro-2H-pyran-2-yl) -2H-1,2, 3-triazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:419.2[M+H]⁺.

Step D: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6- (2- (tetrahydro-2H-pyran-2-yl) -2H-1,2, 3-triazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine (80 mg,0.19 mmol), 2- (4- (bromomethyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole (99 mg,0.28 mmol) and potassium carbonate (57 mg,0.38 mmol) were dissolved in dry N, N-dimethylformamide (1 mL) at room temperature. The reaction system was stirred at 45℃for 5 hours.

After LCMS monitoring showed the disappearance of starting material, quench the reaction mixture by adding water (30 mL), extract the mixture with ethyl acetate (20 mL. Times.3), combine the organic phases and wash the organic phase with saturated brine (10 mL. Times.2). Then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 100mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6- (2- (tetrahydro-2H-pyran-2-yl) -2H-1,2, 3-triazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:685.3[M+H]⁺.

Step E: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6- (2- (tetrahydro-2H-pyran-2-yl) -2H-1,2, 3-triazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine (100 mg,0.15 mmol) and trifluoroacetic acid (2.5 mL) were dissolved in dichloromethane (5 mL) at room temperature under nitrogen. The reaction system was stirred at room temperature for a further 6 hours.

After LCMS monitoring showed disappearance of starting material, the reaction solution was concentrated under reduced pressure, then ph=7 was adjusted with aqueous ammonia. The residue was purified by preparative high performance liquid chromatography. 17.25mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6- (2H-1, 2, 3-triazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine are obtained.

MS(ESI)M/Z:601.3[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆):δ9.17(s,1H),8.66(s,1H),8.36(s,1H),8.13(d,J＝0.8Hz,1H),7.42(d,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,2H),7.12(s,1H),6.09(s,2H),4.42-4.30(m,1H),3.83(s,3H),1.70-1.61(m,1H),1.34(d,J＝6.8Hz,6H),1.03-0.96(m,2H),0.80-0.72(m,2H).

EXAMPLE 24 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (furan-2-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine

The reaction route is as follows:

the operation steps are as follows:

Step A8-bromo-2-chloro-9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine (30 mg,0.08 mmol), 2- (furan-2-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (23 mg,0.12 mmol), sodium carbonate (17 mg,0.16 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (7 mg,0.01 mmol) were dissolved in 1, 4-dioxane/water (0.5 mL/0.05 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air and the reaction was stirred at 85℃for 16 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition to ice water (10 mL). The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 27mg of 2-chloro-8- (furan-2-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine.

MS(ESI)M/Z:487.2[M+H]⁺.

And (B) step (B): 2-chloro-8- (furan-2-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine (27 mg,0.06 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (23 mg,0.12 mmol), cesium carbonate (39 mg,0.12 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (9 mg,0.012 mmol) were dissolved in 1, 4-dioxane/water (0.5 mL/0.05 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air suction, and the reaction system was stirred for 3 hours at 90℃under microwave conditions.

After LCMS monitoring showed the disappearance of starting material, ice water (15 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and washed with saturated brine (10 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 2.3mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (furan-2-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine are obtained.

MS(ESI)M/Z:601.3[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆):δ9.33(s,1H),8.69(s,1H),8.15(s,1H),8.09(d,J＝1.2Hz,1H),7.51(d,J＝8.0Hz,2H),7.42(d,J＝3.6Hz,1H),7.39(d,J＝8.0Hz,2H),6.82(dd,J＝3.6,1.6Hz,1H),5.90(s,2H),4.45-4.32(m,1H),3.85(s,3H),1.75-1.65(m,1H),1.36(d,J＝6.8Hz,6H),1.08-1.00(m,2H),0.88-0.77(m,2H).

EXAMPLE 25 2, 8-bis (furan-2-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine

The reaction route is as follows:

the operation steps are as follows:

Step A8-bromo-2-chloro-9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine (60 mg,0.12 mmol), 2- (furan-2-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (47 mg,0.24 mmol), sodium carbonate (25 mg,0.24 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (20 mg,0.024 mmol) were dissolved in 1, 4-dioxane/water (0.6 mL/0.06 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air and the reaction was stirred at 85℃for 3 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of ice water (10 mL). The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. Yield 2.66mg of 2, 8-bis (furan-2-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine

MS(ESI)M/Z:519.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆):δ9.20(s,1H),8.15(s,1H),8.04(d,J＝0.8Hz,1H),7.91(s,1H),7.52(d,J＝8.0Hz,2H),7.40-7.32(m,4H),6.78(dd,J＝3.4,1.6Hz,1H),6.71(dd,J＝3.4,1.6Hz,1H),5.92(s,2H),4.49-4.35(m,1H),1.36(d,J＝6.8Hz,6H).

EXAMPLE 26 4- (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -7H-pyrrolo [2,3-d ] pyrimidin-6-yl) -3, 5-dimethylisoxazole

The reaction route is as follows:

the operation steps are as follows:

Step A2-chloro-6-iodo-7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine (140 mg,0.33 mmol), 3, 5-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (110 mg,0.5 mmol), sodium carbonate (70 mg,0.66 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (27 mg,0.03 mmol) were dissolved in 1, 4-dioxane/water (1.6 mL/0.17 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air and the reaction was stirred at 75℃for 16 hours.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (30 mL) to the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 100mg of 4- (2-chloro-7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidin-6-yl) -3, 5-dimethylisoxazole.

MS(ESI)M/Z:389.0[M+H]⁺.

And (B) step (B): 4- (2-chloro-7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidin-6-yl) -3, 5-dimethylisoxazole (100 mg,0.26 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (101 mg,0.52 mmol), cesium carbonate (170 mg,0.52 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (41 mg,0.05 mmol) were dissolved in 1, 4-dioxane/water (1 mL/0.1 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air and the reaction was stirred at 90℃for 2 hours.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (30 mL) to the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 50mg of 4- (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidin-6-yl) -3, 5-dimethylisoxazole.

MS(ESI)M/Z:503.2[M+H]⁺.

Step C: 4- (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidin-6-yl) -3, 5-dimethylisoxazole (50 mg,0.1 mmol) and potassium tert-butoxide (56 mg,0.5 mmol) were dissolved in tetrahydrofuran (1 mL) at room temperature. The reaction system was then stirred at room temperature for 2 hours.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (30 mL) to the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 35mg of 4- (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7H-pyrrolo [2,3-d ] pyrimidin-6-yl) -3, 5-dimethylisoxazole.

MS(ESI)M/Z:363.2[M+H]⁺.

Step D: 4- (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7H-pyrrolo [2,3-d ] pyrimidin-6-yl) -3, 5-dimethylisoxazole (35 mg,0.1 mmol), potassium carbonate (28 mg,0.2 mmol) and 2- (4- (bromomethyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole (35 mg,0.1 mmol) were dissolved in N, N-dimethylformamide (1 mL) at room temperature. The reaction system was then stirred at 50℃for 1 hour.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (30 mL) to the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 5.83mg of 4- (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -7H-pyrrolo [2,3-d ] pyrimidin-6-yl) -3, 5-dimethylisoxazole are obtained.

MS(ESI)M/Z:629.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.24(s,1H),8.68(s,1H),8.15(s,1H),7.44(d,J＝8.0Hz,2H),7.01(d,J＝8.0Hz,2H),6.88(s,1H),5.41(s,2H),4.40-4.28(m,1H),3.86(s,3H),2.19(s,3H),1.90(s,3H),1.75-1.65(m,1H),1.35(d,J＝6.4Hz,6H),1.07-1.00(m,2H),0.87-0.79(m,2H).

EXAMPLE 27 2- (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -7H-pyrrolo [2,3-d ] pyrimidin-6-yl) oxazole

The reaction route is as follows:

the operation steps are as follows:

Step A2-chloro-7H-pyrrolo [2,3-d ] pyrimidine (5 g,32.56 mmol) and potassium carbonate (5.3 g,45.53 mmol) were dissolved in N, N-dimethylformamide (19.8 mL) at room temperature and stirred for 1 hour. Subsequently, benzenesulfonyl chloride (11.5 g,65.12 mmol) was added to the above solution, and the mixture was stirred at 50℃for 6 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition to water (200 mL), the mixture was extracted with ethyl acetate (50 mL x 3 times), the organic phases were combined and the organic phase was washed with saturated brine (90 mL x 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 7.6g of 2-chloro-7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:294.0[M+H]⁺.

And (B) step (B): 2-chloro-7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine (300 mg,1.02 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (297.2 mg,1.53 mmol), cesium carbonate (661mg, 2.04 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (161 mg,0.2 mmol) were dissolved in 1, 4-dioxane/water (2 mL/0.2 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air suction, and the reaction system was stirred at 90℃for 2.5 hours under microwave conditions.

After LCMS monitoring showed the disappearance of starting material, ice water (30 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined and washed with saturated brine (60 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 220mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:408.0[M+H]⁺.

Step C: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine (100 mg,0.24 mmol) was dissolved in tetrahydrofuran (2 mL) at room temperature under nitrogen. Subsequently, the above solution was cooled to-78 ℃, lithium diisopropylamide (0.16 ml,0.37 mmol) was slowly added dropwise to the above solution, and stirred for 1 hour. A solution of iodine (93 mg,0.37 mmol) in tetrahydrofuran (0.5 mL) was then slowly added dropwise and stirring continued for 2 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction solution was quenched by slow addition to ice water (10 mL), the mixture was extracted with ethyl acetate (10 mL x 3 times), the organic phases were combined and the organic phase was washed with saturated aqueous sodium chloride (10 mL x 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 39mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6-iodo-7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:534.1[M+H]⁺.

Step D: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6-iodo-7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine (30 mg,0.056 mmol), 2- (tributylstannyl) oxazole (40 mg,0.112 mmol) and tetrakis triphenylphosphine palladium (6.5 mg,0.005 mmol) were dissolved in dry toluene (2 mL) at room temperature under nitrogen. The reaction system was then stirred at 110℃for 16 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated and water (10 mL) was added to the resulting residue. The mixture was extracted with ethyl acetate (5 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 15mg of 2- (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidin-6-yl) oxazole.

MS(ESI)M/Z:475.2[M+H]⁺.

Step E: 2- (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidin-6-yl) oxazole (70 mg,0.147 mmol) and potassium tert-butoxide (83 mg,0.74 mmol) were dissolved in tetrahydrofuran (2 mL) at room temperature. The nitrogen was replaced with air under vacuum for 3 times, and the reaction system was stirred at room temperature for 1 hour.

After LCMS monitoring showed the disappearance of starting material, ice water (20 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 27mg of 2- (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7H-pyrrolo [2,3-d ] pyrimidin-6-yl) oxazole.

MS(ESI)M/Z:335.2[M+H]⁺.

Step F: 2- (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7H-pyrrolo [2,3-d ] pyrimidin-6-yl) oxazole (26 mg,0.077 mmol) and potassium carbonate (21.5 mg,0.155 mmol) were dissolved in N, N-dimethylformamide (2 mL) at room temperature under nitrogen. Subsequently, 2- (4- (bromomethyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole (27 mg,0.077 mmol) was added to the above solution. The reaction system was then stirred at 55℃for 2 hours.

After LCMS monitoring showed the disappearance of starting material, ice water (30 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and washed with saturated saline solution (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 12.61mg of 2- (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -7H-pyrrolo [2,3-d ] pyrimidin-6-yl) oxazole are obtained.

MS(ESI)M/Z:601.3[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆):δ9.34(s,1H),8.68(s,1H),8.37(s,1H),8.14(s,1H),7.54(s,1H),7.51(s,1H),7.46(d,J＝8.0Hz,2H),7.30(d,J＝8.4Hz,2H),6.15(s,2H),4.43-4.33(m,1H),3.84(s,3H),1.71-1.61(m,1H),1.35(d,J＝6.8Hz,6H),1.06-0.98(m,2H),0.84-0.73(m,2H). EXAMPLE 28 4- (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purin-8-yl) -3, 5-dimethylisoxazole

The reaction route is as follows:

the operation steps are as follows:

Step A8-bromo-2-chloro-9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine (40 mg,0.08 mmol), 3, 5-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaboro-2-yl) isoxazole (29 mg,0.12 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (7 mg,0.01 mmol) and sodium carbonate (17 mg,0.16 mmol) were added to 1, 4-dioxane/water (0.9 mL/0.1 mL) at ambient temperature. The nitrogen was replaced 3 times by vacuum air and the reaction was stirred at 85℃for 16 hours.

After LCMS monitoring showed the disappearance of starting material, ice water (10 mL) was added to the reaction to quench. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (60 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 35mg of 4- (2-chloro-9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purin-8-yl) -3, 5-dimethylisoxazole.

MS(ESI)M/Z:516.2[M+H]⁺.

Step B4- (2-chloro-9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purin-8-yl) -3, 5-dimethylisoxazole (35 mg,0.07 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (20 mg,0.11 mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (11 mg,0.01 mmol) and cesium carbonate (36 mg,0.11 mmol)) were added to 1, 4-dioxane/water (0.9 mL/0.1 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air suction, and the reaction system was stirred for 2 hours at 90℃under microwave conditions.

After LCMS monitoring showed the disappearance of starting material, ice water (10 mL) was added to the reaction to quench. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (60 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 2.78mg of 4- (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purin-8-yl) -3, 5-dimethylisoxazole.

MS(ESI)M/Z:630.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.41(s,1H),8.70(s,1H),8.16(d,J＝1.2Hz,1H),7.47(d,J＝8.4Hz,2H),7.15(d,J＝8.4Hz,2H),5.51(s,2H),4.41-4.30(m,1H),3.85(s,3H),2.37(s,3H),2.03(s,3H),1.73-1.65(m,1H),1.36(d,J＝6.8Hz,6H),1.07-1.00(m,2H),0.85-0.79(m,2H).

EXAMPLE 29 4- (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4-trifluoromethyl) -1H-imidazol-2-yl) benzyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) isoxazole

The reaction route is as follows:

the operation steps are as follows:

Step A2-chloro-7H-pyrrolo [2,3-d ] pyrimidine (201 mg,1.31 mmol), potassium carbonate (362 mg,2.62 mmol) were dissolved in N, N-dimethylformamide (6.5 mL) at room temperature and stirred for 5 min. Subsequently, 2- (4-bromomethyl) phenyl-1-isopropyl-4-trifluoromethyl-1H-imidazole (500 mg,1.44 mmol) was added to the reaction solution, and the temperature was raised to 45℃and stirring was continued for 2 hours.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (50 mL) to the reaction. The mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 580mg of 2-chloro-7- (4- (1-isopropyl-4-trifluoromethyl-1H-imidazol-2-yl) benzyl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:420.2[M+H]⁺.

And (B) step (B): 2-chloro-7- (4- (1-isopropyl-4-trifluoromethyl-1H-imidazol-2-yl) benzyl) -7H-pyrrolo [2,3-d ] pyrimidine (500 mg,1.19 mmol), 4-cyclopropyl-6-methoxypyrimidine-5-boronic acid (416 mg,2.14 mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (94 mg,0.12 mmol) and sodium carbonate (252 mg,2.38 mmol) were dissolved in 1, 4-dioxane/water (6 mL/0.6 mL) at room temperature under nitrogen. The nitrogen was replaced 3 times by vacuum air and the reaction was stirred at 90℃for 16 hours.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (50 mL) to the reaction. The mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The organic phases were combined and the resulting residue was purified by column chromatography on silica gel to give 520mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4-trifluoromethyl-1H-imidazol-2-yl) benzyl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:534.2[M+H]⁺.

Step C: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4-trifluoromethyl-1H-imidazol-2-yl) benzyl) -7H-pyrrolo [2,3-d ] pyrimidine (520 mg,0.98 mmol) was dissolved in dichloromethane (4.9 mL) at room temperature. Subsequently, N-bromosuccinimide (208 mg,1.17 mmol) was added to the above solution. The reaction was then stirred for an additional 1 hour.

After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (20 mL). The mixture was extracted with dichloromethane (15 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 510mg of 5-bromo-2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4-isopropyl-4-trifluoromethyl-1H-imidazol-2-yl) benzyl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:612.2[M+H]⁺.

Step D: 5-bromo-2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4-isopropyl-4-trifluoromethyl-1H-imidazol-2-yl) benzyl) -7H-pyrrolo [2,3-d ] pyrimidine (210 mg,0.34 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (134 mg,0.68 mmol), sodium carbonate (109 mg,1.03 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (27 mg,0.03 mmol) were dissolved in 1, 4-dioxane/water (1.7 mL/0.2 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air suction, and the reaction system was stirred for 2 hours at 90℃under microwave conditions.

After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (50 mL). The mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined and washed with saturated brine (60 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 16.23mg of 4- (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4-trifluoromethyl) -1H-imidazol-2-yl) benzyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) isoxazolare obtained.

MS(ESI)M/Z:601.3[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.63(s,1H),9.55(s,1H),9.22(s,1H),8.69(s,1H),8.27(s,1H),8.17(d,J＝1.2Hz,1H),7.54(d,J＝8.0Hz,2H),7.44(d,J＝8.4Hz,2H),5.62(s,2H),4.45-4.35(m,1H),3.85(s,3H),1.70-1.63(m,1H),1.37(d,J＝6.4Hz,6H),1.07-1.00(m,2H),0.84-0.79(m,2H).

EXAMPLE 304 ' -cyclopropyl-5- (furan-2-yl) -N- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6' -methoxy- [2,5' -bipyrimidin ] -4-amine

The reaction route is as follows:

the operation steps are as follows:

Step A: 5-bromo-2, 4-dichloropyrimidine (1.0 g,4.83 mmol), (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methylamine (1.67 g,4.83 mmol) was dissolved in acetonitrile (25 mL) at 0deg.C under nitrogen. Subsequently, N-diisopropylethylamine (1.25 g,9.66 mmol) was slowly added dropwise to the above solution. The reaction system was then stirred at room temperature for 2 hours.

After LCMS monitoring showed the disappearance of starting material, ice (100 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined and washed with saturated brine (30 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2g of 5-bromo-2-chloro-N- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyrimidin-4-amine.

MS(ESI)M/Z:474.0[M+H]⁺.

And (B) step (B): 5-bromo-2-chloro-N- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyrimidin-4-amine (250 mg,0.53 mmol), 2- (furan-2-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (206 mg,1.06 mmol), silver oxide (25 mg,0.11 mmol), potassium phosphate (226 mg,1.06 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (41 mg,0.05 mmol) were dissolved in 1.4-dioxane (3 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air suction, and the reaction system was stirred for 4 hours at 90℃under microwave conditions.

After LCMS monitoring showed the disappearance of starting material, ice (50 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (30 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 200mg of 2-chloro-5- (furan-2-yl) -N- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyrimidin-4-amine.

MS(ESI)M/Z:462.2[M+H]⁺.

Step C: 2-chloro-5- (furan-2-yl) -N- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyrimidin-4-amine (200 mg,0.43 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (168 mg,0.86 mmol), cesium carbonate (280 mg,0.86 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (68 mg,0.086 mmol) were dissolved in 1.4-dioxane/water (2 mL/0.02 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air suction, and the reaction system was stirred for 2 hours at 90℃under microwave conditions.

After LCMS monitoring showed the disappearance of starting material, ice (50 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (30 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 85.85mg of 4' -cyclopropyl-5- (furan-2-yl) -N- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6' -methoxy- [2,5' -bipyrimidin ] -4-amine are obtained.

MS(ESI)M/Z:576.3[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆):δ8.61(s,1H),8.59(s,1H),8.16(d,J＝1.2Hz,1H),7.89(d,J＝1.6Hz,1H),7.80(t,J＝6.0Hz,1H),7.50(d,J＝8.4Hz,2H),7.44(d,J＝8.0Hz,2H),7.06(dd,J＝3.6,0.4Hz,1H),6.72(dd,J＝3.4,1.8Hz,1H),4.77(d,J＝6.0Hz,2H),4.50-4.39(m,1H),3.82(s,3H),1.78-1.68(m,1H),1.39(d,J＝6.4Hz,6H),0.99-0.91(m,2H),0.79-0.70(m,2H). EXAMPLE 31- ((2- (trifluoromethyl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] oxazin-9-yl) methyl) -3-cyclopropyl-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine

The reaction route is as follows:

the operation steps are as follows:

Step A: (2- (trifluoromethyl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] oxazin-9-yl) methanol (100 mg,0.35 mmol) and 3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine (119 mg,0.35 mmol) are dissolved in tetrahydrofuran (1.7 mL) at room temperature. Subsequently, triphenylphosphine (139 mg,0.53 mmol) and diisopropyl azodicarboxylate (202 mg,0.53 mmol) were added to the reaction system at 0℃and the mixture was warmed to room temperature and stirred for 3 hours.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (20 mL) to the reaction. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and washed with saturated brine (30 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 200mg of 1- ((2- (trifluoromethyl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] oxazepin-9-yl) methyl) -3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine.

MS(ESI)M/Z:613.0[M+H]⁺.

Step F9- (3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -2- (trifluoromethyl) -5, 6-dihydrobenzo [ F ] imidazo [1,2-d ] [1,4] oxazepine (200 mg,0.33 mmol), cyclopropylboronic acid (20 mg,0.56 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (40 mg,0.05 mmol), potassium phosphate (140 mg,0.66 mmol) and silver oxide (38 mg,0.17 mmol) are dissolved in 1, 4-dioxane (3 mL) at room temperature under nitrogen. The reaction solution was then stirred at 100℃for 16 hours.

After LCMS monitoring showed the disappearance of starting material, ice water (10 mL) was added to the reaction to quench. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (60 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 39.84mg of 1- ((2- (trifluoromethyl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] oxazin-9-yl) methyl) -3-cyclopropyl-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine.

MS(ESI)M/Z:575.0[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.45(s,1H),8.71(s,1H),8.27(d,J＝8.4Hz,1H),7.96(s,1H),7.03(d,J＝8.4Hz,1H),6.88(s,1H),5.58(s,2H),4.45(brs,4H),3.86(s,3H),2.47-2.38(m,1H),1.72-1.61(m,1H),1.19-1.09(m,4H),1.08-1.00(m,2H),0.96-0.80(m,2H).

EXAMPLE 32 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (1-isopropyl-1H-pyrazol-3-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine

The reaction route is as follows:

the operation steps are as follows:

Step A2-chloro-9H-purine (2.0 g,12.99 mmol), 3, 4-dihydro-2H-pyran (2.18 g,25.97 mmol) and pyridine 4-methylbenzenesulfonate (652 mg,1.30 mmol) were dissolved in dichloromethane solution (65 mL) at 0deg.C, warmed to room temperature and stirred for 1 hour.

After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 3.11g of 2-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine.

MS(ESI)M/Z:239.2[M+H]⁺.

Step B2-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (2.00 g,8.40 mmol) was dissolved in dry tetrahydrofuran solution (42 mL) at-78deg.C under nitrogen. Subsequently, a 2.5M lithium diisopropylamide solution (5.01 mL,12.6 mmol) was slowly added dropwise to the above solution, and stirred for 1 hour. 1, 2-dibromo-1, 2-tetrachloroethane (4.10 g,12.6 mmol) was then slowly added dropwise and stirring was continued for 1 hour.

After LCMS monitoring showed the disappearance of starting material, ice water (100 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined and washed with saturated saline solution (60 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 830mg of 8-bromo-2-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine.

MS(ESI)M/Z:233.0[M-84]⁺

Step C: 8-bromo-2-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (800 mg,2.53 mmol) and p-toluenesulfonic acid monohydrate (97 mg,0.51 mmol) were dissolved in methanol solution (13 mL) at room temperature, warmed to 65℃and stirred for 1H.

After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 320mg of 8-bromo-2-chloro-9H-purine.

MS(ESI)M/Z:233.0[M+H]⁺.

Step D: 8-bromo-2-chloro-9H-purine (320 mg,1.38 mmol), (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol (588 mg,2.07 mmol) and triphenylphosphine (588 mg,2.07 mmol) were dissolved in tetrahydrofuran (7 mL) under ice-water conditions. Subsequently, diisopropyl azodicarboxylate (319 mg,2.07 mmol) was slowly added to the above solution. The reaction system was then stirred at room temperature for 2 hours.

After LCMS monitoring showed the disappearance of starting material, ice water (10 mL) was added to the reaction to quench. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (60 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 600mg of 8-bromo-2-chloro-9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine.

MS(ESI)M/Z:499.0[M+H]⁺.

Step E: 8-bromo-2-chloro-9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine (200 mg,0.40 mmol), 1-isopropyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaboro-2-yl) -1H-pyrazole (142 mg,0.60 mmol), sodium carbonate (85 mg,0.80 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (33 mg,0.04 mmol) were dissolved in 1, 4-dioxane/water (1.8 mL/0.2 mL) at room temperature under nitrogen. The reaction system was then stirred at 85℃for 2 hours.

After LCMS monitoring showed the disappearance of starting material, ice water (10 mL) was added to the reaction to quench. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (60 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 600mg of N- (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -9H-pyrimido [4,5-b ] indol-7-yl) -N- ((2- (trimethylsilyl) ethoxy) methyl) methanesulfonamide.

MS(ESI)M/Z:529.2[M+H]⁺.

Step F N- (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -9H-pyrimido [4,5-b ] indol-7-yl) -N- ((2- (trimethylsilyl) ethoxy) methyl) methanesulfonamide (100 mg,0.19 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (55 mg,0.29 mmol), potassium phosphate (44 mg,0.21 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (18 mg,0.04 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) [2- (2 ' -amino-1, 1' -biphenyl) ] palladium (II) (23 mg,0.03 mmol) was dissolved in 1, 4-dioxane/water (2.7 mL/0.3 mL) at room temperature. The nitrogen was replaced with air under vacuum for 3 times, and the reaction system was stirred at room temperature for 2 hours.

After LCMS monitoring showed the disappearance of starting material, ice water (20 mL) was added to the reaction to quench. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined and washed with saturated brine (30 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 39.62mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (1-isopropyl-1H-pyrazol-3-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -9H-purine are obtained.

MS(ESI)M/Z:643.1[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.31(s,1H),8.69(s,1H),8.15(d,J＝1.2Hz,1H),8.03(d,J＝2.4Hz,1H),7.49(d,J＝8.4Hz,2H),7.43(d,J＝8.4Hz,2H),7.06(d,J＝2.4Hz,1H),6.12(s,2H),4.72-4.62(m,1H),4.42-4.32(m,1H),3.86(s,3H),1.76-1.67(m,1H),1.45(d,J＝6.8Hz,6H),1.35(d,J＝6.8Hz,6H),1.09-1.01(m,2H),0.87-0.78(m,2H).

EXAMPLE 33 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6- (1-isopropyl-1H-pyrazol-3-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -7H-pyrrolo [2,3-d ] pyrimidine

The reaction route is as follows:

the operation steps are as follows:

Step A2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6-iodo-7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine (50 mg,0.094 mmol), 1-isopropyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaboron-2-yl) -1H-pyrazole (29 mg,0.122 mmol), cesium carbonate (61 mg, 0.87 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (73 mg,0.18 mmol) were dissolved in 1, 4-dioxane/water (2 mL/0.2 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air suction, and the reaction system was stirred at 90℃for 2.5 hours under microwave conditions.

After LCMS monitoring showed the disappearance of starting material, ice water (30 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined and washed with saturated brine (60 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 50mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6- (1-isopropyl-1H-pyrazol-3-yl) -7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:516.2[M+H]⁺.

Step B2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6- (1-isopropyl-1H-pyrazol-3-yl) -7- (phenylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine (50 mg,0.116 mmol) and potassium tert-butoxide (65 mg, 0.552 mmol) were dissolved in tetrahydrofuran (5 mL) at room temperature, and the temperature was raised to 30℃and stirring was continued for 2 hours.

After LCMS monitoring showed the disappearance of starting material, the mixture was quenched by addition to water (20 mL), extracted with ethyl acetate (10 mL x 3 times), the organic phases combined and washed with saturated brine (10 mL x 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 40mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6- (1-isopropyl-1H-pyrazol-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine.

MS(ESI)M/Z:376.3[M+H]⁺.

Step C: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6- (1-isopropyl-1H-pyrazol-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine (40 mg,0.106 mmol) and potassium carbonate (30 mg,0.213 mmol) were dissolved in N, N-dimethylformamide (2 mL) at room temperature under nitrogen. Subsequently, 2- (4- (bromomethyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole (37 mg,0.106 mmol) was added to the above solution. The reaction system was then stirred at 45℃for 2 hours.

After LCMS monitoring showed the disappearance of starting material, ice water (30 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and washed with saturated saline solution (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 26.51mg of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6- (1-isopropyl-1H-pyrazol-3-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -7H-pyrrolo [2,3-d ] pyrimidine are obtained.

MS(ESI)M/Z:642.3[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.16(s,1H),8.67(s,1H),8.13(d,J＝0.8Hz,1H),7.90(d,J＝2.4Hz,1H),7.42(d,J＝8.4Hz,2H),7.24(d,J＝8.4Hz,2H),7.11(s,1H),6.83(d,J＝2.4Hz,1H),6.09(s,2H),4.63-4.53(m,1H),4.39-4.30(m,1H),3.84(s,3H),1.71-1.64(m,1H),1.42(d,J＝6.8Hz,6H),1.34(d,J＝6.8Hz,6H),1.05-0.98(m,2H),0.83-0.76(m,2H).

EXAMPLE 34 3- (6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) isoxazole

The reaction route is as follows:

the operation steps are as follows:

Step A3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine (2.6 g,7.51 mmol) is dissolved in tetrahydrofuran (37 mL) at room temperature, then the solution is cooled to 0deg.C, sodium hydride (360 mg,9.01 mmol) is added and stirred for 0.5 hours. (2- (chloromethoxy) ethyl) trimethylsilane (1.2 g,7.51 mmol) was then slowly added dropwise, warmed to room temperature and stirred for an additional 10 minutes.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (40 mL) to the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.2), and the organic phases were combined and washed with saturated brine (40 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 2g of 3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidine.

MS(ESI)M/Z:477.2[M+H]⁺.

And (B) step (B): 3-bromo-6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidine (1.9 g,3.99 mmol), 4, 5-tetramethyl-2-vinyl-1, 3, 2-dioxaborane (80 mg,5.99 mmol), potassium carbonate (1.1 g,7.98 mmol), 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (164 mg,0.39 mmol) and palladium acetate (87 mg,0.39 mmol) were dissolved in 1, 4-dioxane/water (20 mL/3 mL) at room temperature. The nitrogen was replaced 3 times by vacuum air and the reaction was stirred at 85℃for 16 hours.

After LCMS monitoring showed the disappearance of starting material, ice water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (25 mL. Times.2), and the organic phases were combined and washed with saturated brine (50 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel to give 1.2g of 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -3-vinyl-1H-pyrazolo [3,4-d ] pyrimidine.

MS(ESI)M/Z:425.2[M+H]⁺.

Step C: 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -3-vinyl-1H-pyrazolo [3,4-d ] pyrimidine (1.2 g,2.83 mmol) was dissolved in dichloromethane (30 mL) at room temperature. Subsequently, the temperature of the solution was lowered to-78 ℃, ozone was continuously introduced into the reaction system, and the mixture was stirred for 30 minutes.

After LCMS monitoring showed the disappearance of starting material, ice water (50 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (30 ml×3 times), the organic phases were combined, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 400mg of 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidine-3-carbaldehyde.

MS(ESI)M/Z:427.2[M+H]⁺。

Step D: 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidine-3-carbaldehyde (400 mg,441 mmol) was dissolved in ethanol (9 mL) at room temperature. Subsequently, the above solution was cooled to 0℃and triethylamine (284 mg,2.82 mmol) and hydroxylamine hydrochloride (130 mg,1.89 mmol) were added in this order. The reaction system was then stirred at room temperature for 8 hours.

After LCMS monitoring showed the disappearance of starting material, ice water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and washed with saturated brine (20 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give 370mg of crude 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidine-3-carbaldehyde oxime.

MS(ESI)M/Z:443.2[M+H]⁺.

Step E: 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidine-3-carbaldehyde oxime (370 mg,0.75 mmol) was dissolved in dichloromethane/N, N-dimethylformamide (7.5 mL/0.75 mL) at room temperature. Subsequently, the above solution was cooled to 0℃and N-chlorosuccinimide (643 mg,3.18 mmol) was added to the reaction system. The reaction system was then stirred at room temperature for 1 hour.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (20 mL) to the reaction. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and washed with saturated brine (30 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 350mg of (Z) -6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -N-hydroxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidine-3-carboxamide chloride.

MS(ESI)M/Z:476.2[M+H]⁺.

Step F: (Z) -6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -N-hydroxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidine-3-carboxamide chloro (345 mg,0.73 mmol) was dissolved in dichloromethane (7 mL) at room temperature. Subsequently, the above solution was cooled to 0℃and triethylamine (0.2 mL,1.45 mmol) and trimethylsilylacetylene (142 mg,1.45 mmol) were sequentially added to the reaction system. The reaction system was then stirred at room temperature for 1 hour.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (20 mL) to the reaction. The mixture was extracted with ethyl acetate (10 mL. Times.3), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 140mg of 3- (6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -5- (trimethylsilyl) isoxazole.

MS(ESI)M/Z:538.2[M+H]⁺.

Step G: 3- (6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -5- (trimethylsilyl) isoxazole was dissolved in dichloromethane (10 mL) at room temperature. Subsequently, the above solution was cooled to 0℃and trifluoroacetic acid (5 mL) was added to the reaction system. The reaction system was then stirred at room temperature for 4 hours.

After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure. The resulting concentrate was dissolved with tetrahydrofuran (10 mL), saturated sodium bicarbonate solution (5 mL) was added, and the mixed solution was stirred at room temperature for 1 hour. Then, water (20 mL) was added to the reaction mixture to dilute, and the mixture was extracted with ethyl acetate (10 mL. Times.3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 65mg of 3- (6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -5- (trimethylsilyl) isoxazole.

MS(ESI)M/Z:408.2[M+H]⁺.

Step H: 3- (6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -5- (trimethylsilyl) isoxazole (65 mg,0.16 mmol) and (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol were dissolved in tetrahydrofuran (1.6 mL) at room temperature under nitrogen. Subsequently, the above solution was cooled to 0℃and triphenylphosphine (84 mg,0.32 mmol) and diisopropyl azodicarboxylate (65 mg,0.32 mmol) were added to the reaction system in this order. The reaction system was then stirred at room temperature for 2 hours.

After LCMS monitoring showed the disappearance of starting material, quench was performed by adding water (20 mL) to the reaction. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and washed with saturated brine (30 mL. Times.2). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. 4.44mg of 3- (6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) isoxazole are obtained.

MS(ESI)M/Z:602.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.75(s,1H),9.22(d,J＝1.6Hz,1H),8.73(s,1H),8.17(d,J＝0.8Hz,1H),7.55(d,J＝8.4Hz,2H),7.48(d,J＝8.0Hz,2H),7.26(d,J＝2.0Hz,1H),5.90(s,2H),4.46-4.36(m,1H),3.87(s,3H),1.77-1.68(m,1H),1.37(d,J＝6.8Hz,6H),1.10-1.04(m,2H),0.90-0.82(m,2H).

2. Biological activity

Example 1: USP1 enzyme activity experimental method

Compounds were screened against USP1 in a fluorescent 384 well format. Experimental materials: recombinant human His6-USP1/His6-UAF1 complex protein (R & D, catalogue number E-568-050), ubiquitin rhodamine 110 protein, CF (Ub-Rho) (R & D, catalogue number U-555-050), 384 well plates (PERKIN ELMER, catalogue number 6007279). Test compounds were dissolved in 10mM stock solution in 100% DMSO for use.

The experimental process comprises the following steps:

1 preparation of 1x detection buffer. 1 Xdetection buffer (modified Tris buffer) was prepared.

2 Serial dilutions of compound: the compounds were transferred to assay plates by Echo. The final proportion of DMSO was 1%.

3 Preparing an enzyme solution: enzyme solutions were prepared in 1x detection buffer.

4, Preparing a substrate solution: ubiquitin rhodamine 110 (Ub-Rho) was added to the 1x assay buffer to form a substrate solution.

5 Transfer 10. Mu.L of enzyme solution to assay plate.

6 Incubated for 1 hour at room temperature.

7. Mu.L of substrate solution was added to each well to start the reaction, and the mixture was centrifuged for 30s and shaken for 30s.

8 The plate was read on Spect ring CMax Pa ring Cdigm for 30 minutes with excitation wavelength of 480nm and emission wavelength of 540nm.

9 Data was collected on Spect ring CMax Pa ring Cdigm.

10 Curve fitting

Fitting the data in Excel using equation (1) to obtain the inhibition value

Equation (1): inhibition ratio% = (maximum signal value-target signal value)/(maximum signal value-minimum signal value) ×100

Fitting the data in XL-Fit using equation (2) to obtain the IC ₅₀ value

Equation (2): y=bottom+ (top-bottom)/(1+ (IC ₅₀/X) × HillSlope)

Y is the percent inhibition and X is the compound concentration.

The compound has good inhibition effect on USP1, and the IC ₅₀ value is generally lower than 1 micromole; some of the compounds of the present invention have an IC ₅₀ value of less than 0.5. Mu. Mole, and more preferably the compounds of the present invention have an IC ₅₀ value of less than 0.3. Mu. Mole, or even less than 0.1. Mu. Mole. The inhibition results of USP1 by some of the compounds of the invention are shown in Table 1.

TABLE 1 enzymatic inhibition results

Conclusion: the data show that the substance has good inhibition effect on USP 1.

Example 2: USP1 CTG test method

The biological activity of USP1i compounds was verified using CTG assay (NCI-H1693). Experimental materials: NCI-H1693 cells were purchased from ATCC (cat# CRL-5866) and cultured in a 5% CO ₂ cell incubator at 37 ℃. NCI-H1693 complete medium: RPMI-1640 liquid medium (cat# Gibico 11875-093), 5% FBS (cat# Gibico 10099-141), 1% pen StRap (cat# Gibico 15070-063).

The experimental process comprises the following steps:

1 NCI-H1693 cells in 75cm ² flasks were digested with 2mL pancreatin for 2-3min and neutralized with 2mL complete medium, 1640 complete medium. Centrifuge 1200rpm was used and centrifuged for 5min. Cells were resuspended using 4ml 1640 complete medium. CELL counts were performed on 500ul of CELL suspension using a Vi-CELL-XR cytometer.

2 Were seeded in 384 well plates using Multidrop instruments at a density of 500 NCI-H1693 cells per well (40uL 1640Growth Media) and dosed 24 hours later.

3 Using an ultra-microscale applicator, compounds (concentration: 3.33mM, dissolved in DMSO) were sequentially diluted at a ratio of 1:3 in 9 gradients (10000 nM,33 nM,1111nM,370nM,123nM,41nM,13.7nM,4.6nM,1.5 nM) with 10uM as the highest initial concentration, and two multiplex wells were set for each concentration; each of 9 wells was set up for positive and negative controls, the positive control being a duplicate of 10uM positive compound and the negative control being DMSO duplicate.

And 4, placing the cells after the drug addition into a 37 ℃ incubator for continuous culture for 6 days, adding 25ul of CTG buffer into each hole after 6 days for CTG assay, and performing plate reading analysis by using an enzyme-labeled instrument.

5 Analysis of CTG reads.

The average value of the inhibition rates of the positive control duplicate wells was set as the relative inhibition rate of 100%;

The average value of the negative control duplicate wells was set to 0% of the relative inhibition.

CTG readings were converted to relative inhibition, and the inhibition (inhibition%) of each concentration of compound a was converted to cells according to the following formula.

Inhibition％＝(b-x)/(b-a)*100％

A=ctg value (highest concent ring Ction)

b＝CTG value(blank well)

x＝CTG value(x nM)

6 The IC ₅₀ was calculated using G-ring CPHPAD PRISM.

(1) The corresponding concentrations of 10000nM,3333nM,1111nM,370nM,123nM,41nM,13.7nM,4.6nM,1.5nM and inhibition were counted. Statistical calculations were performed on this with Log10 (Acompound concent ring Ction).

(2) The data is input to the G-ring CPHPAD PRISM, and Analysis is selected.

(3) Select Nonlinear RagRassion (cut fit)

(4) Log (inhibitor) vs. Rasponde-Variable slope was selected.

(5) A calculation formula is selected, which is calculated according to the following formula.

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC₅₀-X)*HillSlope))

X log of dose or concent Ring Ction

Y:Rasponse,decRaasing as X incRaases

Top and Bottom:Plateaus in same units as Y.

TIP:

-If X is not ALRAADY THE log of dose, go back and t circle Cnsform your data.

If you have subt ring Ccted off any basal Rasponse, consider const ring Cining Bottom to a constantvalue of 0.0.0.

(6) The data were fitted to give IC ₅₀ values.

(7) And adjusting the fitting condition according to the specific condition of the data. And (3) carrying out proper Const ring Cint condition adjustment on the Bottom, TOP and HillSlope so as to achieve the curve which is most suitable for the practical situation.

According to the determination, the compound has good inhibition effect on NCI-H1693 cells, and the IC ₅₀ value is generally lower than 1 micromole; some of the compounds of the present invention have an IC ₅₀ value of less than 0.5. Mu. Mole, and more preferably the compounds of the present invention have an IC ₅₀ value of less than 0.3. Mu. Mole, or even less than 0.1. Mu. Mole. The results of inhibition of NCI-H1693 cells by some of the compounds of the invention are shown in Table 2.

TABLE 2NCI-H1693 cell inhibition results

* And (3) injection: the bracketed data represent the values of KSQ-4279 cell inhibitory activity of the same batch.

The data show that the compounds of the present invention have superior inhibitory effects on NCI-H1693 cells compared to KSQ-4279 cells.

KSQ-4279 Compound Structure:

The source is as follows: synthesized by the preparation method of WO2020132269 patent.

Claims (20)

1. A compound of formula (I'), isomers thereof, and pharmaceutically acceptable salts thereof:

Wherein,

X ₁ is CH, N; x ₂、X₃ is each independently CH, N, or CR ', wherein R' is substituted or unsubstituted C _3-6 cycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, C _1-4 haloalkyl, hydroxy C _1-4 alkyl, -NH-Ar, 4-6 membered heterocyclyl, -NH-CO-C _3-6 cycloalkyl, 8-14 membered fused heterocyclyl, 7-11 membered spiroheterocyclyl, 7-14 membered bridged heterocyclyl;

R _a is hydrogen or C _1-4 alkyl;

ring a is a 5-6 membered heteroaryl, R _b each independently being halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl; m is 0, 1,2, 3 or 4;

Ring B is phenyl or 11-18 ternary fused heterocyclic group; r _c is halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, Or two adjacent R _c form a substituted or unsubstituted C _3-6 membered cycloalkyl;

The ring C is 5-10 membered heteroaryl containing 1-4 nitrogen atoms and 8-14 membered fused heterocyclic group; each R _d is independently C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, halogen, C _3-6 cycloalkyl; n is 1,2, 3 or 4; p is 1,2, 3 or 4; l ₁ is C _1-4 alkylene, C _3-6 cycloalkylene.

2. The compound, isomer, and pharmaceutically acceptable salt thereof according to claim 1, wherein R' is -Cl、-CHF₂、

3. The compound, isomer, and pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein ring a is

4. A compound according to any one of claims 1 to 3, wherein R _b is Cl-, CH ₃-、CH(CH₃)₂-、CH₃ O-,

5. The compound, isomer, and pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the structural unitFor

6. The compound, isomer, and pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein ring B is

7. The compound, isomer, and pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R _c is-CF ₃、-OCH₃, -F,

8. The compound, isomer, and pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein the structural unitIs that

9. The compound, isomer, and pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R _d is-CH ₃、-CH(CH₃)₂、-CF₃、-OCH₂CH₃, -Cl, -F,

10. The compound, isomer, and pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein ring C is

11. The compound, isomer, and pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein the structural unitIs that

12. The compound, isomer, and pharmaceutically acceptable salt thereof according to any one of claims 1-11, wherein L ₁ is-CH ₂ -.

13. The compound, isomer, and pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein the structural unitIs that

14. The compound, isomer thereof and pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein the compound, isomer thereof and pharmaceutically acceptable salt thereof is selected from the group consisting of,

Wherein ring a, ring B, R _a、R_b、R_c、R'、L₁, m, n are as defined in any preceding claim.

15. The compound according to any one of claims 1-14, an isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

Wherein ring a, ring C, R _a、R_b、R'、L₁、R_d, p, m are as defined in any preceding claim.

16. The compound according to any one of claims 1-15, an isomer thereof, and a pharmaceutically acceptable salt thereof, selected from

Wherein R' is as defined in any one of the preceding claims.

17. A compound, isomers thereof, and pharmaceutically acceptable salts thereof:

18. a pharmaceutical composition comprising a compound, isomer, and pharmaceutically acceptable salt thereof of any of claims 1-17 and a pharmaceutically acceptable carrier.

19. Use of a compound, isomer, pharmaceutically acceptable salt thereof of any of claims 1-17 or pharmaceutical composition of claim 18 for the manufacture of a medicament for the treatment of a USP1 target mediated related disorder.

20. The use of claim 19, wherein the USP1 target mediated related disease comprises a cell inflammatory disease, a neurodegenerative disease, cancer.