CN114181199B

CN114181199B - 2, 4-disubstituted pyrimidine derivative, preparation method and application thereof

Info

Publication number: CN114181199B
Application number: CN202111096199.9A
Authority: CN
Inventors: 陈俐娟
Original assignee: Chengdu Zeiling Biomedical Technology Co ltd
Current assignee: Chengdu Zeiling Biomedical Technology Co ltd
Priority date: 2020-09-15
Filing date: 2021-09-15
Publication date: 2023-09-26
Anticipated expiration: 2041-09-15
Also published as: CN114181199A

Abstract

The invention relates to a 2, 4-disubstituted pyrimidine derivative, a preparation method and application thereof, belonging to the field of chemical medicine. The invention provides a 2, 4-disubstituted pyrimidine derivative or pharmaceutically acceptable salt thereof, the structure of which is shown as a formula I. The invention also provides a preparation method and application of the 2, 4-disubstituted pyrimidine derivative. The invention provides a 2, 4-disubstituted pyrimidine derivative. Biological experiments show that the compounds can be used as JAK kinase inhibitors, and provide a new choice for preparing medicines for treating and/or preventing tumor and immune diseases.

Description

2, 4-disubstituted pyrimidine derivative, preparation method and application thereof

Technical Field

The invention relates to a 2, 4-disubstituted pyrimidine derivative, a preparation method and application thereof, belonging to the field of chemical medicine.

Background

Over the last 20 years, new therapies for the treatment of autoimmune diseases have evolved rapidly, with impressive success in terms of biologicals. Inhibition of different cytokine pathways can cope with different situations, and has proved to have good therapeutic effects. For example, anti-IL 12/IL23 or more selective anti-IL 23 therapies have been approved for the treatment of psoriasis and psoriatic arthritis, which exhibit significant efficacy and good safety profiles, and are now approved for use in the treatment of crohn's disease patients in europe and the united states. Inflammatory bowel disease (Inflammatory bowel disease, IBD) is a recurrent disease characterized by chronic inflammation of the gastrointestinal tract, which is commonly affected by both genetic and environmental factors, resulting in diarrhea and abdominal pain. The main types of IBD are Crohn's Disease (CD) and Ulcerative Colitis (UC). Typically, patients require life-long medication and other procedures depending on the severity of the disease. Studies have shown that about 25% of patients with crohn's disease will require additional bowel surgery within 5 years after the first treatment. The risk of requiring surgery after diagnosis has been reduced over the last 60 years, but is still a significant burden. Since 1997, treatments for IBD have been mainly using steroids to induce remission and immunomodulatory drugs such as azathioprine, mercaptopurine, and methotrexate to maintain remission. anti-Tumor Necrosis Factor (TNF) infliximab is effective in treating IBD, resulting in a shift in treatment pattern. However, up to one third of patients receiving anti-tumor necrosis factor treatment are major non-responders, while a significant portion (10% -15% per year) is lost due to antibody formation (immunogenicity failure). In addition, these biological agents are associated with significant adverse events such as opportunistic infections and immune complications. With our knowledge of the major inflammatory pathways of inflammatory bowel disease, a variety of new therapeutic approaches are becoming possible. These include the development of new oral drugs, inhibiting cytokine signaling, lymphocyte influx and mast cell activity, and promoting the activity of innate immunosuppressive pathways for specific pathways found to be associated with other immune-mediated diseases. There remains a great clinical need for new effective, tolerated, economical and oral drugs.

JAK (JAK) is a family of intracellular tyrosine kinases with four known members JAK1, JAK2, JAK3 and TYK2, which are associated with various cytokine-mediated signal transduction pathways. Upon binding of the ligand to its corresponding receptor, JAK activation will be induced, followed by receptor phosphorylation. Activated JAKs phosphorylate signal transduction and transcriptional activator proteins (signal transducer and activator of transcription, STAT), which form dimers, translocate to the nucleus, promoting cytokine response gene expression. JAK kinase inhibitors are small molecule drugs that are currently marketed or under development for the treatment of several immune diseases, including psoriasis, rheumatoid arthritis (rheumatoid arthritis, RA) and IBD. It has been demonstrated that different cytokine receptors are associated with heterodimers or homodimers of specific JAK enzymes, and that each JAK is linked to more than one receptor. In mammals, JAK1, JAK2 and TYK2 are widely expressed, except that JAK3 is mainly expressed in hematopoietic cells. JAK1 is the most widely expressed JAK kinase because it is involved in the signaling process of a variety of cytokines, such as gamma common, yc, gp130, type I interferon (IFN-a/β) and type II interferon (IFN- γ), IL-6 and IL-10 families, and is thus involved in Rheumatoid Arthritis (RA), inflammation and immunodeficiency. JAK2 is the only JAK family member paired with itself. JAK2 plays a decisive role in myelopoiesis, erythropoiesis, megakaryopoiesis and mammary gland development by forming unique homodimers through signal transduction associated with cytokines IL-3, IL-5, granulocyte-macrophage colony stimulating factor (granulocyte macrophage colony-stimulating factor, GM-CSF), erythropoietin (EPO) and Thrombopoietin (TPO). The absence of JAK3 may lead to indications of some immune systems such as rheumatoid arthritis, graft rejection and severe combined immunodeficiency of the X-linkage.

TYK2 is paired with JAK2, through its signaling pathways with IL-12 and IL-23, which interact with the IL-12 receptor β1 receptor chain, and coordinates phosphorylation of STAT3 and STAT4. Clinical data indicate that there is a need to reduce activity on JAK2 in HWB to reduce the risk of hematopoietic effects. Human Tyk2 gene deficiency can lead to defective signaling of various cytokines (including IL-6, IL-10, IL-12 and IL-23) and reduced IFNγ production; and the lack of TYK2 expression is manifested in a significant imbalance in the signaling attenuation of various pro-inflammatory cytokines and helper T cell differentiation. TYK2 deficiency is clinically diagnosed as hyper-IgE Syndrome (HIEs) and chronic mucosal cutaneous candidiasis (chronic mucocutaneous candidiasis, CMC). Given the importance of TYK 2-dependent downstream cytokine signaling in this and other diseases (such as rheumatoid arthritis and crohn's disease), selective TYK2 inhibitors are the most potential small molecule inhibitors for the treatment of immune diseases.

Disclosure of Invention

The invention aims to provide a 2, 4-disubstituted pyrimidine derivative or a pharmaceutically acceptable salt thereof, the structure of which is shown as a formula I:

X ₁ 、X ₂ independently selected from N or CR ₄ ，X ₁ And X is ₂ Not both are N;

ring a is selected from substituted or unsubstituted pyrazolyl, substituted or unsubstituted furanyl;

R ₂ 、R ₃ independently selected from H, halogen, -O- (CH) ₂ ) _m -R ₅ 、-(CH ₂ ) _n -R ₆ or-NHC (O) - (CH) ₂ ) _p -R ₇ M, n, p=1 to 3; alternatively, R ₂ 、R ₃ Linking to form a five-membered nitrogen-containing heterocycle;

R ₁ 、R ₄ independently selected from H, halogen, C ₁ ～C ₆ Alkyl, C ₁ ～C ₆ Alkoxy or-C (O) NHR ₈ ；

R ₅ 、R ₆ 、R ₇ Are independently selected from

R ₈ Selected from C ₁ ～C ₆ An alkyl group.

As a preferable technical scheme of the invention, the structure of the 2, 4-disubstituted pyrimidine derivative or the pharmaceutically acceptable salt thereof is shown as a formula II:

R ₂ 、R ₃ independently selected from H, halogen, -O- (CH) ₂ ) _m -R ₅ 、-(CH ₂ ) _n -R ₆ or-NHC (O) - (CH) ₂ ) _p -R ₇ ，m、n、p＝1～3；

R ₄ Selected from halogen, C ₁ ～C ₆ Alkyl or C ₁ ～C ₆ An alkoxy group;

R ₅ 、R ₆ 、R ₇ are independently selected from

Further, the above 2, 4-disubstituted pyrimidine derivative or a pharmaceutically acceptable salt thereof satisfies at least one of the following:

R ₂ selected from H or halogen;

R ₃ selected from the group consisting of-O- (CH) ₂ ) _m -R ₅ 、-(CH ₂ ) _n -R ₆ or-NHC (O) - (CH) ₂ ) _p -R ₇ ，m、n、p＝1～3；

Preferably, R ₃ Selected from the group consisting of-O- (CH) ₂ ) ₂ -R ₅ 、-(CH ₂ ) _n -R ₆ or-NHC (O) - (CH) ₂ ) ₂ -R ₇ N=1 or 2;

R ₄ selected from halogen.

As a preferred technical scheme of the invention, the structure of the 2, 4-disubstituted pyrimidine derivative or the pharmaceutically acceptable salt thereof is shown as a formula III:

ring a is selected from substituted or unsubstituted pyrazolyl, furanyl;

the ring B is selected from five-membered nitrogen-containing heterocycle, and the five-membered nitrogen-containing heterocycle is tetrahydropyrrole, pyrrolidone or pyrrole;

R ₈ Selected from C ₁ ～C ₆ An alkyl group;

r is connected with N on the B ring, R is H、C ₁ ～C ₆ Alkyl, hydroxy substituted C ₁ ～C ₆ Alkyl, -C (O) - (CH) ₂ ) _q -R ₉ 、-C(O)NH-R ₁₀ or-SO ₂ R ₁₁ ，q＝0、1；

R ₉ 、R ₁₀ 、R ₁₁ Independently selected from C ₁ ～C ₆ Alkyl, halogen substituted C ₁ ～C ₆ Alkyl, substituted or unsubstituted cyclopropane, substituted or unsubstituted benzene ring, substituted or unsubstituted 2-indolone, substituted or unsubstituted pyridyl, The substituted cyclopropane, the substituted benzene ring, the substituted 2-indolone and the substituted pyridyl respectively contain at least one substituent as follows: halogen, cyano, pyrazole, C ₁ ～C ₆ Alkyl, halogen substituted C ₁ ～C ₆ Alkyl, C ₁ ～C ₆ Alkoxy or halogen substituted C ₁ ～C ₆ An alkoxy group.

Further, the above-mentioned 2, 4-disubstituted pyrimidine derivative or a pharmaceutically acceptable salt thereof,

when ring B is pyrrolidone, R is H;

when ring B is tetrahydropyrrole or pyrrole, R is H, C ₁ ～C ₃ Alkyl, hydroxy substituted C ₁ ～C ₃ Alkyl, -C (O) - (CH) ₂ ) _q -R ₉ 、-C(O)NH-R ₁₀ or-SO ₂ R ₁₁ ，q＝0、1；

R ₉ 、R ₁₀ 、R ₁₁ Independently selected from C ₁ ～C ₆ Alkyl, halogen substituted C ₁ ～C ₆ Alkyl, substituted or unsubstituted cyclopropane, substituted or unsubstituted benzene ring, substituted or unsubstituted 2-indolone, substituted or unsubstituted pyridyl, The substituted cyclopropane, the substituted benzene ring, the substituted 2-indolone and the substituted pyridyl respectively contain at least one substituent as follows: halogen, cyano, pyrazole, C ₁ ～C ₆ Alkyl, halogen substituted C ₁ ～C ₆ Alkyl, C ₁ ～C ₆ Alkoxy or halogen substituted C ₁ ～C ₆ An alkoxy group;

preferably, when ring B is tetrahydropyrrole or pyrrole, R is H, methyl, 1, 2-propanediol, -C (O) - (CH) ₂ ) _q -R ₉ 、-C(O)NH-R ₁₀ or-SO ₂ R ₁₁ ，q＝0、1；

more preferably, when ring B is tetrahydropyrrole or pyrrole, R is H, methyl, 1, 2-propanediol, -C (O) - (CH) ₂ ) _q -R ₉ 、-C(O)NH-R ₁₀ or-SO ₂ R ₁₁ ，q＝0、1；

R ₉ 、R ₁₀ 、R ₁₁ Independently selected from C ₁ ～C ₃ Alkyl, halogen substituted C ₁ ～C ₃ Alkyl, substituted or unsubstituted cyclopropane, substituted benzene ring, substituted or unsubstituted 2-indolone, substituted pyridyl, The substituted cyclopropane, the substituted benzene ring, the substituted 2-indolone and the substituted pyridyl respectively contain at least one substituent as follows: halogen, cyano, pyrazole, C ₁ ～C ₆ Alkyl, halogen substituted C ₁ ～C ₆ Alkyl, C ₁ ～C ₆ Alkoxy or halogen substituted C ₁ ～C ₆ An alkoxy group;

further preferred, when ring B is tetrahydropyrrole or pyrrole, R is H, methyl, 1, 2-propanediol, -C (O) - (CH) ₂ ) _q -R ₉ 、-C(O)NH-R ₁₀ or-SO ₂ R ₁₁ ，q＝0、1；

R ₉ 、R ₁₀ 、R ₁₁ Independently selected from methyl, ethyl, propyl, trifluoromethyl, substituted or unsubstituted cyclopropane, substituted benzene ring, substituted or unsubstituted 2-indolone, substituted pyridyl,The substituted cyclopropane, the substituted benzene ring, the substituted 2-indolone and the substituted pyridyl respectively contain at least one substituent as follows: halogen, cyano, pyrazole, methyl, t-butyl, trifluoromethyl, methoxy or trifluoromethoxy;

most preferably, when ring B is tetrahydropyrrole or pyrrole, R is H, methyl, 1, 2-propanediol, -C (O) - (CH) ₂ ) _q -R ₉ 、-C(O)NH-R ₁₀ or-SO ₂ R ₁₁ ，q＝0、1；

R ₉ Selected from methyl, substituted or unsubstituted cyclopropane, substituted benzene ring, substituted pyridyl, The substituted cyclopropane, the substituted benzene ring and the substituted pyridyl each contain at least one substituent of the following: halogen, cyano, pyrazole, tert-butyl, trifluoromethyl or trifluoromethoxy;

R ₁₀ A benzene ring selected from trifluoromethyl;

R ₁₁ selected from ethyl, propyl, trifluoromethyl, cyclopropane, substituted benzene ring, substituted or unsubstituted 2-indolone; the substituted cyclopropane, the substituted benzene ring and the substituted 2-indolone respectively contain at least one substituent as follows: methyl, trifluoromethyl or methoxy.

Further, the 2, 4-disubstituted pyrimidine derivative or a pharmaceutically acceptable salt thereof is characterized in that:

ring a is selected from substituted or unsubstituted pyrazolyl, furanyl; the substituted pyrazolyl contains at least one of the following substituents: c (C) ₁ ～C ₆ Alkyl, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₆ Phenyl ring substituted by alkyl, C ₁ ～C ₆ Alkylnitriles, diethyl ether or cyclopropanecarbaldehyde;

preferably, ring a is selected from substituted or unsubstituted pyrazolyl, furanyl; the substituted pyrazolyl contains at least one of the following substituents: methyl, isopropyl, propyl, propionitrile, cyclobutane, cyclopropane, benzyl, diethyl ether or cyclopropanecarbaldehyde.

R ₁ selected from H, C ₁ ～C ₃ Alkyl or C ₁ ～C ₃ An alkoxy group;

preferably, R ₁ Selected from H, methyl or methoxy;

X ₁ 、X ₂ Independently selected from N or CR ₄ ，X ₁ And X is ₂ Not simultaneously N, R ₄ Selected from H, halogen, C ₁ ～C ₃ Alkyl, C ₁ ～C ₃ Alkoxy or-C (O) NHR ₈ ，R ₈ Selected from C ₁ ～C ₃ An alkyl group;

preferably, X ₁ 、X ₂ Independently selected from N or CR ₄ ，X ₁ And X is ₂ Not simultaneously N, R ₄ Selected from H, halogen, methyl, methoxy or-C (O) NHCH ₃ ；

Most preferably, X ₁ Selected from N, X ₂ Selected from CR ₄ ，R ₄ Selected from H, halogen, methyl or methoxy.

The structural formula of the 2, 4-disubstituted pyrimidine derivative or the pharmaceutically acceptable salt thereof is as follows:

the invention also provides a pharmaceutically acceptable pharmaceutical composition of the 2, 4-disubstituted pyrimidine derivative, which is a preparation prepared by adding pharmaceutically acceptable auxiliary components into the 2, 4-disubstituted pyrimidine derivative shown in the formulas I-III and salts thereof. Such as cyclodextrin, arginine or meglumine. The cyclodextrin is selected from alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, (C) _1-4 Alkyl) -alpha-cyclodextrin, (C _1-4 Alkyl) -beta-cyclodextrin, (C) _1-4 Alkyl) -gamma-cyclodextrin, (hydroxy-C _1-4 Alkyl) -alpha-cyclodextrin, (hydroxy-C _1-4 Alkyl) -beta-cyclodextrin, (hydroxy-C _1-4 Alkyl) -gamma-cyclodextrin, (carboxy-C _1-4 Alkyl) -alpha-cyclodextrin, (carboxy-C _1-4 Alkyl) -beta-cyclodextrin, (carboxy-C _1-4 Alkyl) -gamma-cyclodextrin, saccharide ethers of alpha-cyclodextrin, saccharide ethers of beta-cyclodextrin, saccharide ethers of gamma-cyclodextrin, sulfobutyl ethers of alpha-cyclodextrin, sulfobutyl ethers of beta-cyclodextrin, and sulfobutyl ethers of gamma-cyclodextrin. The adjunct ingredients further comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. Can be used for pharmaceutically acceptable pharmaceutical compositions, such as ion exchangers, aluminum oxide, aluminum stearate and egg gel; buffer substances include phosphates, glycine, arginine, sorbic acid, and the like.

The pharmaceutical composition may be in liquid form or in solid form. Wherein the liquid form may be in the form of an aqueous solution. The solid form may be in the form of a powder, granules, tablets or a lyophilized powder. The pharmaceutical composition further comprises water for injection, saline solution, aqueous dextrose solution, saline for injection/infusion, dextrose for injection/infusion, or a Grignard solution comprising lactate.

The use of 2, 4-disubstituted pyrimidine derivatives of formula I-III or pharmaceutically acceptable salts thereof, pharmaceutical compositions in the preparation of JAK kinase inhibitors; preferably, the JAK kinase inhibitor is a JAK1 kinase inhibitor, a JAK2 kinase inhibitor, a JAK3 kinase inhibitor or a TYK2 kinase inhibitor.

Use of 2, 4-disubstituted pyrimidine derivatives shown in formulas I-III or pharmaceutically acceptable salts thereof and pharmaceutical compositions in preparation of medicaments for treating and/or preventing tumors;

preferably, the tumor comprises a solid tumor and a hematological tumor;

more preferably, the solid tumor comprises: lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic lymphoma, lymphoplasmacytic lymphoma, ovarian cancer, breast cancer, prostate cancer, bladder cancer, renal cancer, esophageal cancer, neck cancer, pancreatic cancer, colorectal cancer, gastric cancer, non-small cell lung cancer, thyroid cancer, brain cancer, lymphoma, epidermal transitional hyperplasia, psoriasis, or prostate cancer, and combinations thereof;

the hematological neoplasm comprises: acute myelogenous leukemia, chronic myelogenous leukemia, myeloma, acute lymphoblastic leukemia, acute myelogenous leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic neutrophilic leukemia, acute undifferentiated leukemia, myelodysplastic syndrome, myelodysplastic disorder, myelofibrosis, multiple myeloma or spinal sarcoma, and combinations thereof.

Use of a 2, 4-disubstituted pyrimidine derivative represented by formulas I-iii or a pharmaceutically acceptable salt thereof, a pharmaceutical composition for the preparation of a medicament for the treatment and/or prevention of an immune disease;

Preferably, the immune disease comprises: psoriasis, rheumatoid arthritis, inflammatory bowel disease (e.g., crohn's disease, ulcerative colitis, etc.), sjogren's syndrome, behcet's disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, polymyositis, dermatomyositis (DM), peri-arteritis nodosa (PN), mixed Connective Tissue Disease (MCTD), scleroderma, lupus erythematosus, chronic thyroiditis, graves' disease, autoimmune gastritis, type I and type II diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, graft versus host disease, additi, abnormal immune responses, arthritis, dermatitis, radiation dermatitis, etc.), especially psoriasis, rheumatoid arthritis, inflammatory bowel disease, sjogren's syndrome, behcet's disease, multiple sclerosis, and systemic lupus erythematosus.

Definition of terms:

the compounds and derivatives provided by the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstract service, columbus, OH) naming system.

The term "alkyl" is a radical of a straight or branched saturated hydrocarbon radical. C (C) ₁ ～C ₆ Examples of alkyl groups include, but are not limited toLimited to methyl (C) ₁ ) Ethyl (C) ₂ ) N-propyl (C) ₃ ) Isopropyl (C) ₃ ) N-butyl (C) ₄ ) Tert-butyl (C) ₄ ) Sec-butyl (C) ₄ ) Isobutyl (C) ₄ ) N-pentyl (C) ₅ ) 3-pentyl (C) ₅ ) Amyl (C) ₅ ) Neopentyl (C) ₅ ) 3-methyl-2-butyl (C) ₅ ) Tert-amyl (C) ₅ ) And n-hexyl (C) ₆ )。

The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group, which may be a monocyclic structure, or may be more than two rings, with or without heteroatoms selected from phosphorus, sulfur, oxygen, and/or nitrogen.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), iodine (I).

The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising the pharmaceutical dosage form, and physiologically compatible with the recipient.

The term "pharmaceutically acceptable salts" refers to the acidic and/or basic salts of the compounds of the invention with inorganic and/or organic acids and bases, and also includes zwitterionic salts (inner salts), and also includes quaternary ammonium salts, such as alkylammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. Or by mixing the above-mentioned compound with a certain amount of an acid or a base as appropriate (for example, equivalent). These salts may be obtained by precipitation in solution and collected by filtration, or recovered after evaporation of the solvent, or by lyophilization after reaction in an aqueous medium. The salts of the present invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoric, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate salts of the compounds.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or solubilisers, for example starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.

In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.

The invention provides a 2, 4-disubstituted pyrimidine derivative with a novel structure. Biological experiments show that the compounds can be used as JAK kinase inhibitors, and provide a new choice for preparing medicines for treating and/or preventing tumor and immune diseases.

Detailed Description

The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.

Route one:

example 1

2- (1, 1-dioxothiomorpholine) -1- (5- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) indol-1-yl) ethan-1-one

Step 1: preparation of 1-isopropyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole (Compound of formula 2)

Pinacol 4-borate (1.9 g,10 mmol), 2-iodopropane (3.4 g,20 mmol), cesium carbonate (6.5 g,20 mmol) was added to acetonitrile (50 ml) and reacted in an oil bath at 85℃for 2 hours. After the reaction, the mixture was filtered while it was still hot and the filtrate was concentrated to give the compound of formula 2.

Step 2: preparation of 2-chloro-4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidine (Compound of formula 3)

The compound of formula 2 (1.9 g,10 mmol), 2, 4-dichloro-5-methylpyrimidine (1.7 g,10 mmol), potassium carbonate (3.4 g,25 mmol) and dppf (Pd) ₂ Cl ₂ ) (0.75 g,1 mmol) was added to a 250mL three-necked flask, dioxane/water=4: 1 (70 mL in total) was used as a solvent, replaced with nitrogen three times, and then transferred into an oil bath at 98℃for 2 hours. Concentrating the reaction solution to be dry after the reaction is finished, and separating the mixture by a silica gel column to obtain the compound of the formula 3 as an off-white solid.

Step 3: preparation of tert-butyl 5- (((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) indoline-1-carboxylate (compound of formula 4), compound of formula 3 (2.4 g,10 mmol), tert-butyl 5-aminoindoline-1-carboxylate (2.8 g,12 mmol), pd ₂ (DBA) ₃ (0.45 g,0.5 mmol), dppf (0.9 g,1 mmol) and cesium carbonate (8.2 g,25 mmol) were placed in a 250mL three-necked flask, dioxane (100 mL total) was added as a solvent, nitrogen was replaced three times, and the mixture was transferred to an oil bath at 110℃for 3 hours. Concentrating the reaction solution to be dry after the reaction is finished, and separating the mixture by a silica gel column to obtain the compound of the formula 4.

Step 4: preparation of N- (4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) indol-5-amine (compound of formula 5), deamination protection of the compound of formula 4 in a 4M solution of 1, 4-dioxane hydrochloride.

Step 5: thiomorpholinoacetic acid-1 ',1' -dioxide, wherein the monohydrate is activated with HATU (1.2 eq) and DIEA (2 eq) in N, N-dimethylformamide for 30 minutes, then the compound of formula 5 is added for reaction for 12 hours at normal temperature, after the reaction is finished, the reaction solution is concentrated to dryness, and then the mixture is stirred and separated by a silica gel column to obtain the CLJ-3 compound.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.27(s,1H),8.32(s,1H),8.26(s,1H),8.07(s,1H),7.97(d,J＝8.7Hz,1H),7.77(d,J＝2.2Hz,1H),7.51(dd,J＝8.8,2.3Hz,1H),4.66–4.54(m,1H),4.16–4.07(m,2H),3.55(s,2H),3.21–3.06(m,10H),2.31(s,3H),1.49(s,3H),1.47(s,3H). ¹³ C NMR(101MHz,DMSO)δ167.48,159.87,158.93,157.72,139.32,137.54,137.21,132.25,129.46,120.66,117.19,116.39,116.32,115.55,59.11,53.82,51.18,50.49,47.25,28.36,23.05,17.16.HRMS-ESI:calcd for C ₂₅ H ₃₁ N ₇ NaO ₃ S[M+Na] ⁺ 532.2107,found:532.2210.

Example 2

(2, 2-difluorocyclopropyl) (5- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) indol-1-yl) methanone

Steps 1, 2, 3, 4 are the same as steps 1, 2, 3, 4 of example 1.

Step 5: the compound of formula 5 is reacted with 2, 2-difluorocyclopropanecarboxylic acid as in example 1, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.31(s,1H),8.33(s,1H),8.27(s,1H),8.08(s,1H),7.94(d,J＝8.7Hz,1H),7.81(s,1H),7.53(dd,J＝8.8,2.2Hz,1H),4.63(hept,J＝6.6Hz,1H),4.36(td,J＝10.1,7.0Hz,1H),4.12(td,J＝9.9,6.9Hz,1H),3.27–3.08(m,3H),2.31(s,3H),2.12–1.88(m,2H),1.48(d,J＝6.6Hz,6H). ¹³ C NMR(101MHz,DMSO)δ161.16,159.37,158.40,157.24,138.82,137.46,136.21,132.23,128.98,120.15,116.72,115.99,115.88,115.07,53.32,47.89,27.53,26.65,22.54,16.66.HRMS-ESI:calcd for C ₂₃ H ₂₅ F ₂ N ₆ O[M+H] ⁺ 439.2058,found:439.2051.

Example 3

((1S, 2S) -2-fluorocyclopropyl) (5- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) indol-1-yl) methanone

Steps 1, 2, 3, 4 are the same as steps 1, 2, 3, 4 of example 1.

Step 5: the compound of formula 5 is reacted with (1S, 2S) -2-fluorocyclopropane carboxylic acid as in example 1, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.27(s,1H),8.32(s,1H),8.26(s,1H),8.08(s,1H),7.94(d,J＝8.7Hz,1H),7.79(s,1H),7.51(d,J＝9.1Hz,1H),5.14–4.89(m,1H),4.63(p,J＝6.7Hz,1H),4.33(q,J＝9.5Hz,1H),4.20(q,J＝9.3Hz,1H),3.21(s,2H),2.31(s,3H),2.22(p,J＝7.0Hz,1H),1.73–1.58(m,1H),1.48(d,J＝6.6Hz,6H),1.18–1.00(m,1H). ¹³ C NMR(101MHz,DMSO)δ163.40,159.37,158.44,157.22,138.81,137.01,136.73,131.94,128.97,120.17,116.72,115.89,115.74,115.10,72.98,70.76,53.31,47.56,27.55,22.54,21.67,21.55,16.66.HRMS-ESI:calcd for C ₂₃ H ₂₆ FN ₆ O[M+H] ⁺ 421.2152,found:421.2143.

Example 4

1- (5- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) indol-1-yl) ethan-1-one

Steps 1, 2, 3, 4 are the same as steps 1, 2, 3, 4 of example 1.

Step 5: the compound of formula 5 and DIEA (1.3 eq) are dissolved in dichloromethane, acetyl chloride (1.2 eq) is added dropwise under ice bath, the reaction is carried out for 4 hours, water quenching is added after the reaction is finished, dichloromethane extraction is carried out, an organic phase is concentrated to dryness, and a sample is stirred and separated by a silica gel column, thus obtaining the CLJ-6 compound.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.24(s,1H),8.33(s,1H),8.26(s,1H),8.08(s,1H),7.95(d,J＝8.7Hz,1H),7.76(d,J＝2.1Hz,1H),7.49(dd,J＝8.7,2.2Hz,1H),4.64(p,J＝6.6Hz,1H),4.08(t,J＝8.4Hz,2H),3.16(t,J＝8.5Hz,2H),2.31(s,3H),2.14(s,3H),1.49(d,J＝6.6Hz,6H). ¹³ C NMR(101MHz,DMSO)δ168.02,159.86,158.96,157.71,139.32,137.28,137.25,132.36,129.46,120.68,117.24,116.33,116.16,115.63,53.81,48.67,28.13,24.25,23.04,17.15.HRMS-ESI:calcd for C ₂₁ H ₂₅ N ₆ O[M+H] ⁺ 377.2090,found:377.2083.

Example 5

Cyclopropyl (5- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) indol-1-yl) methanone

Steps 1,2, 3, 4 are the same as steps 1,2, 3, 4 of example 1.

Step 5: the compound of formula 5 is reacted with cyclopropanecarbonyl chloride according to example 4, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.25(s,1H),8.32(s,1H),8.26(s,1H),8.07(s,1H),7.93(d,J＝8.7Hz,1H),7.77(s,1H),7.48(d,J＝9.1Hz,1H),4.63(hept,J＝6.6Hz,1H),4.28(t,J＝8.0Hz,2H),3.19(t,J＝8.3Hz,2H),2.31(s,3H),1.92(s,1H),1.48(d,J＝6.7Hz,6H),0.93–0.73(m,4H). ¹³ C NMR(101MHz,DMSO)δ170.65,159.86,158.96,157.71,139.31,137.48,137.22,132.36,129.44,120.68,117.20,116.34,115.59,53.81,48.19,28.10,23.04,17.16,13.43,8.00.HRMS-ESI:calcd for C ₂₃ H ₂₆ N ₆ NaO[M+Na] ⁺ 425.2066,found:425.2063.

Example 6

N- (4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) -1- ((trifluoromethyl) sulfonyl) indol-5-amine

Steps 1,2, 3, 4 are the same as steps 1,2, 3, 4 of example 1.

Step 5: the compound of formula 5 is reacted with trifluoromethanesulfonyl chloride according to example 4, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.44(s,1H),8.34(s,1H),8.29(s,1H),8.09(s,1H),7.88(d,J＝2.2Hz,1H),7.63(dd,J＝8.9,2.2Hz,1H),7.24(d,J＝8.8Hz,1H),4.63(p,J＝6.6Hz,1H),4.23(t,J＝8.2Hz,2H),3.24(t,J＝8.2Hz,2H),2.32(s,3H),1.48(d,J＝6.7Hz,6H). ¹³ C NMR(101MHz,DMSO)δ159.88,158.78,157.81,139.48,139.36,133.05,132.44,129.56,120.54,117.96,116.88,116.11,114.41,53.82,52.24,28.41,23.02,17.17.HRMS-ESI:calcd for C ₂₀ H ₂₂ F ₃ N ₆ O ₂ S[M+H] ⁺ 467.1477,found:467.1477.

Example 7

(S) -3- (5- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) indol-1-yl) propane-1, 2-diol

Steps 1,2, 3, 4 are the same as steps 1,2, 3, 4 of example 1.

Step 5: and (3) reacting the compound shown in the formula 5 with (R) - (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde (2 eq) in acetonitrile for 30 minutes, adding sodium triacetoxyborohydride (3.5 eq), performing a reaction at normal temperature overnight, performing spin-drying reaction liquid after the reaction is finished, extracting dichloromethane, concentrating an organic phase until the organic phase is dried, adding hydrochloric acid ethanol solution, performing a reaction at normal temperature overnight, performing spin-drying reaction liquid after the reaction is finished, extracting dichloromethane, and separating a mixed sample by a silica gel column to obtain the CLJ-9. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.84(s,1H),8.28(s,1H),8.18(s,1H),8.04(s,1H),7.47(d,J＝2.1Hz,1H),7.32(dd,J＝8.4,2.1Hz,1H),6.43(d,J＝8.5Hz,1H),4.68(s,1H),4.61(dt,J＝13.5,6.7Hz,2H),3.71(s,1H),3.44–3.32(m,4H),3.09(dd,J＝13.6,4.8Hz,1H),2.94–2.83(m,3H),2.28(s,3H),1.47(d,J＝6.6Hz,6H). ¹³ CNMR(101MHz,DMSO)δ159.79,159.39,157.60,148.40,139.28,132.05,129.66,129.28,120.83,118.63,117.14,115.40,106.79,70.71,64.61,55.06,54.09,53.77,29.05,23.05,17.10.HRMS-ESI:calcd for C ₂₂ H ₂₈ N ₆ NaO ₂ [M+Na] ⁺ 431.2171,found:431.2164.

Example 8

(R) -1- (2- (5- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) indole-1-carbonyl) pyrrolidine-1-carbonyl) cyclopropane-1-carbonitrile

Step 1: CLJ-2With 1-cyano-1-cyclopropanecarboxylic acid according to example 1, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.28(s,1H),8.32(s,1H),8.27(s,1H),8.07(s,1H),7.93(d,J＝8.8Hz,1H),7.78(s,1H),7.50(d,J＝8.9Hz,1H),4.74–4.56(m,2H),4.30–4.06(m,2H),4.00–3.81(m,2H),3.19(t,J＝8.4Hz,2H),2.31(s,3H),2.19–1.84(m,4H),1.69–1.53(m,2H),1.48(d,J＝6.6Hz,6H),1.49–1.42(m,2H). ¹³ C NMR(101MHz,DMSO)δ168.73,162.45,159.88,158.91,157.71,139.31,137.72,137.04,132.41,129.47,120.67,120.35,117.08,116.60,116.42,115.43,60.16,53.82,48.60,47.79,28.67,28.30,25.22,23.05,17.17,16.29,15.80,13.69.HRMS-ESI:calcd for C ₂₉ H ₃₃ N ₈ O ₂ [M+H] ⁺ 525.2726,found:525.2726.

Example 9

1- (ethylsulfo) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) indol-5-amine

Steps 1, 2, 3, 4 are the same as steps 1, 2, 3, 4 of example 1.

Step 5: the compound of formula 5 is reacted with ethanesulfonyl chloride according to example 4, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.28(s,1H),8.32(s,1H),8.26(s,1H),8.07(s,1H),7.77(d,J＝2.2Hz,1H),7.55(dd,J＝8.7,2.2Hz,1H),7.17(d,J＝8.7Hz,1H),4.62(h,J＝6.6Hz,1H),3.96(t,J＝8.4Hz,2H),3.20–3.09(m,4H),2.31(s,3H),1.48(d,J＝6.7Hz,6H),1.20(t,J＝7.3Hz,3H). ¹³ C NMR(101MHz,DMSO)δ159.86,158.93,157.74,139.34,137.75,136.07,132.57,129.48,120.63,117.98,116.46,116.27,114.11,53.81,50.55,42.86,28.46,23.04,17.15,7.94.HRMS-ESI:calcd for C ₂₁ H ₂₇ N ₆ O ₂ S[M+H] ⁺ 427.1916,found:427.1916.

Example 10

N- (4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) -1- (propylsulfonyl) indol-5-amine

Steps 1, 2, 3, 4 are the same as steps 1, 2, 3, 4 of example 1.

Step 5: the compound of formula 5 is reacted with propane sulfonyl chloride according to example 4, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.28(s,1H),8.33(s,1H),8.26(s,1H),8.08(d,J＝1.8Hz,1H),7.77(d,J＝2.1Hz,1H),7.55(dd,J＝8.6,1.8Hz,1H),7.17(d,J＝8.7Hz,1H),4.63(p,J＝6.6Hz,1H),3.95(t,J＝8.4Hz,2H),3.17–3.01(m,4H),2.30(d,J＝2.9Hz,3H),1.69(h,J＝7.4Hz,2H),1.48(dd,J＝6.7,1.8Hz,6H),0.95(t,J＝7.4Hz,3H). ¹³ C NMR(101MHz,DMSO)δ159.87,158.93,157.75,139.34,137.77,136.02,132.62,129.49,120.62,117.98,116.47,116.27,114.15,53.81,50.46,49.54,28.44,23.04,17.15,16.85,13.22.HRMS-ESI:calcd for C ₂₂ H ₂₉ N ₆ O ₂ S[M+H] ⁺ 441.2073,found:441.2072.

Example 11

1- (cyclopropylsulfonyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) indol-5-amine

Steps 1, 2, 3, 4 are the same as steps 1, 2, 3, 4 of example 1.

Step 5: the compound of formula 5 is reacted with cyclopropanesulfonyl chloride according to example 4, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.30(s,1H),8.33(s,1H),8.26(s,1H),8.08(s,1H),7.80(s,1H),7.55(d,J＝8.9Hz,1H),7.21(d,J＝8.7Hz,1H),4.63(p,J＝6.7Hz,1H),3.98(t,J＝8.3Hz,2H),3.13(s,2H),2.31(s,3H),1.48(d,J＝6.6Hz,6H),1.27–1.16(m,1H),1.02–0.95(m,2H),0.97–0.86(m,2H). ¹³ C NMR(101MHz,DMSO)δ159.87,158.93,157.75,139.34,137.99,136.04,133.17,129.48,120.63,117.94,116.49,116.11,115.01,53.82,50.92,28.76,26.22,23.04,17.16,4.41.HRMS-ESI:calcd for C ₂₂ H ₂₆ N ₆ NaO ₂ S[M+Na] ⁺ 461.1736,found:461.1741.

Example 12

N- (4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) -1- ((4-methoxyphenyl) sulfonyl) indol-5-amine

Steps 1, 2, 3, 4 are the same as steps 1, 2, 3, 4 of example 1.

Step 5: the compound of formula 5 is reacted with p-methoxybenzenesulfonyl chloride according to example 4, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.30(s,1H),8.31(s,1H),8.25(s,1H),8.07(s,1H),7.75–7.65(m,3H),7.60(dd,J＝8.7,2.3Hz,1H),7.42(d,J＝8.7Hz,1H),7.06(d,J＝8.9Hz,2H),4.63(hept,J＝6.5Hz,1H),3.86(t,J＝8.2Hz,2H),3.78(s,3H),2.83(t,J＝8.2Hz,2H),2.30(s,3H),1.48(d,J＝6.7Hz,6H). ¹³ C NMR(101MHz,DMSO)δ163.52,159.84,158.85,157.74,139.34,138.20,135.39,133.22,129.91,129.50,128.10,120.58,117.84,116.55,115.82,115.39,114.97,56.11,53.81,50.58,28.18,23.03,17.15.HRMS-ESI:calcd for C ₂₆ H ₂₉ NO ₃ S[M+H] ⁺ 505.2022,found:505.1999.

Example 13

5- ((5- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) indol-1-yl) sulfonyl) indol-2-one

Steps 1, 2, 3, 4 are the same as steps 1, 2, 3, 4 of example 1.

Step 5: the compound of formula 5 is reacted with 2-oxoindoline-5-sulfonyl chloride according to example 4, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.76(s,1H),9.28(s,1H),8.31(s,1H),8.25(s,1H),8.06(s,1H),7.66(s,1H),7.63–7.61(m,2H),7.59–7.54(m,1H),7.38(d,J＝8.8Hz,1H),6.90(d,J＝8.7Hz,1H),4.62(p,J＝6.6Hz,1H),3.87(t,J＝8.2Hz,2H),3.52(s,2H),2.87(t,J＝8.3Hz,2H),2.30(s,3H),1.47(d,J＝6.6Hz,6H). ¹³ C NMR(101MHz,DMSO)δ176.82,159.84,158.84,157.73,148.99,139.34,138.02,135.43,133.05,129.50,128.78,128.68,127.34,123.88,120.57,117.88,116.52,115.91,115.04,109.51,53.81,50.57,36.04,28.15,23.04,17.16.HRMS-ESI:calcd for C ₂₇ H ₂₈ N ₇ O ₃ S[M+H] ⁺ 530.1974,found:530.1971.

Example 14

5- ((5- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) indol-1-yl) sulfonyl) -1-methylindol-2-one

Steps 1, 2, 3, 4 are the same as steps 1, 2, 3, 4 of example 1.

Step 5: the compound of formula 5 is reacted with 1-methyl-2-oxo-5-indole Lin Huangxian chloride according to example 4, step 5. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.28(s,1H),8.31(s,1H),8.24(s,1H),8.05(s,1H),7.77–7.63(m,3H),7.57(dd,J＝8.7,2.2Hz,1H),7.40(d,J＝8.7Hz,1H),7.08(d,J＝8.3Hz,1H),4.65–4.56(m,1H),3.89(t,J＝8.3Hz,2H),3.59(s,2H),3.09(s,3H),2.86(t,J＝8.3Hz,2H),2.30(d,J＝4.5Hz,3H),1.47(d,J＝6.7Hz,6H). ¹³ C NMR(101MHz,DMSO)δ174.94,159.79,158.83,157.75,150.05,139.34,138.04,135.42,133.08,129.50,129.30,128.66,126.30,123.46,120.56,117.97,116.53,115.99,115.13,108.72,53.81,50.61,35.40,28.16,26.52,23.03,17.14.HRMS-ESI:calcd for C ₂₈ H ₂₉ N ₇ NaO ₃ S[M+H] ⁺ 566.1950,found:566.1957

Example 15

N- (4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) -1- ((4- (trifluoromethyl) phenyl) sulfonyl) indol-5-amine

Steps 1, 2, 3, 4 are the same as steps 1, 2, 3, 4 of example 1.

Step 5: the compound of formula 5 is reacted with p-trifluoromethylbenzenesulfonyl chloride according to example 4, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.34(s,1H),8.32(s,1H),8.26(s,1H),8.08(s,1H),8.02(d,J＝8.3Hz,2H),7.95(d,J＝8.3Hz,2H),7.71(d,J＝2.4Hz,1H),7.64(d,J＝8.7Hz,1H),7.45(d,J＝8.8Hz,1H),4.63(p,J＝6.6Hz,1H),3.96(t,J＝8.3Hz,2H),2.87(t,J＝8.2Hz,2H),2.31(s,3H),1.48(d,J＝6.7Hz,6H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ159.82,158.81,157.75,140.49,139.35,138.64,134.51,133.75,133.42,133.29,129.47,128.63,127.05,127.01,122.42,120.57,117.88,116.64,115.85,115.29,53.81,50.75,28.14,22.99,17.15.HRMS-ESI:calcd for C ₂₆ H ₂₆ F ₃ N ₆ O ₂ S[M+H] ⁺ 543.1790,found:543.1791

Example 16

1- (5- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) indol-1-yl) -2- (3- (trifluoromethoxy) phenyl) ethan-1-one

Steps 1, 2, 3, 4 are the same as steps 1, 2, 3, 4 of example 1.

Step 5: the compound of formula 5 is reacted with 2- (3- (trifluoromethoxy) phenyl) acetyl chloride according to example 4, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.27(s,1H),8.32(s,1H),8.26(s,1H),8.07(s,1H),7.95(d,J＝8.7Hz,1H),7.79(d,J＝2.2Hz,1H),7.53–7.42(m,2H),7.36–7.29(m,2H),7.25(d,J＝8.3Hz,1H),4.63(hept,J＝6.6Hz,1H),4.19(t,J＝8.4Hz,2H),3.92(s,2H),3.19(t,J＝8.4Hz,2H),2.31(s,3H),1.48(d,J＝6.6Hz,6H). ¹³ C NMR(101MHz,DMSO)δ168.00,159.85,158.93,157.73,148.72,139.31,138.72,137.54,137.20,132.47,130.37,129.47,129.44,122.68,121.87,120.67,119.36,117.21,116.39,116.35,115.56,53.81,48.18,41.58,28.19,23.03,17.15.HRMS-ESI:calcd for C ₂₈ H ₂₈ F ₃ N ₆ O ₃ [M+H] ⁺ 537.2226,found:537.2230.

Example 17

1- (5- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) indol-1-yl) -2- (3-methylisoxazol-5-yl) ethan-1-one

Steps 1, 2, 3, 4 are the same as steps 1, 2, 3, 4 of example 1.

Step 5: 3-methyl-5-isoxazoleacetic acid is dissolved in DCM, oxalyl chloride (2 eq) is added, anhydrous DMF with catalytic equivalent is reacted for 2 hours at normal temperature, the reaction solution is dried by spin, and the mixture is added into the mixed solution of DIEA and DCM in formula 5 dropwise, and the reaction is carried out overnight at 0 ℃ to normal temperature.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.33(s,1H),8.33(s,1H),8.26(s,1H),8.08(s,1H),7.94(d,J＝8.7Hz,1H),7.79(s,1H),7.51(dd,J＝8.8,2.2Hz,1H),6.28(s,1H),4.64(h,J＝6.6Hz,1H),4.18(t,J＝8.4Hz,2H),4.08(s,2H),3.19(t,J＝8.3Hz,2H),2.31(s,3H),2.23(s,3H),1.48(d,J＝6.6Hz,6H). ¹³ C NMR(101MHz,DMSO)δ167.01,164.87,159.96,159.46,158.67,157.96,139.38,137.59,137.02,132.62,129.57,120.60,117.36,116.46,116.38,115.68,104.81,53.83,48.21,34.08,28.16,23.04,17.16,11.46.HRMS-ESI:calcd for C ₂₅ H ₂₈ N ₇ O ₂ [M+H] ⁺ 458.2304,found:458.2307.

Example 18

(2-fluoro-5- (trifluoromethyl) phenyl) (5- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) indol-1-yl) methanone

Steps 1, 2, 3, 4 are the same as steps 1, 2, 3, 4 of example 1.

Step 5: the compound of formula 5 is reacted with 2-fluoro-5- (trifluoromethyl) benzoyl chloride according to example 4, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.39(s,1H),8.33(s,1H),8.27(s,1H),8.09(d,J＝5.1Hz,1H),8.08–7.99(m,2H),7.98–7.90(m,1H),7.85(s,1H),7.68–7.57(m,2H),4.68–4.56(m,J＝6.5Hz,1H),3.87(t,J＝8.2Hz,2H),3.14(t,J＝8.2Hz,2H),2.31(s,3H),1.48(d,J＝6.7Hz,6H). ¹³ C NMR(101MHz,DMSO)δ161.28,159.86,158.88,157.75,139.35,138.69,136.11,133.49,129.57,129.47,127.00,126.94,126.81,126.58,126.26,126.23,125.38,122.67,120.65,118.10,117.87,117.20,117.02,116.60,115.49,53.82,49.65,28.28,23.00,17.15.HRMS-ESI:calcd for C ₂₇ H ₂₅ F ₄ N ₆ O[M+H] ⁺ 525.2026,found:525.2055.

Example 19

(5- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) indol-1-yl) (3- (trifluoromethyl) phenyl) methanone

Steps 1, 2, 3, 4 are the same as steps 1, 2, 3, 4 of example 1.

Step 5: the compound of formula 5 is reacted with 3- (trifluoromethyl) benzoyl chloride according to example 4, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.34(s,1H),8.32(s,1H),8.27(s,1H),8.08(s,1H),8.06–8.00(m,1H),7.97–7.85(m,3H),7.83(s,1H),7.73(t,J＝7.8Hz,1H),7.62(s,1H),4.62(hept,J＝6.7Hz,1H),4.01(q,J＝10.5,8.8Hz,2H),3.11(t,J＝8.2Hz,2H),2.31(s,3H),1.47(d,J＝6.6Hz,6H). ¹³ C NMR(101MHz,DMSO)δ166.12,159.87,158.90,157.74,139.33,138.75,138.30,133.42,131.44,130.13,129.45,126.94,125.74,124.22,123.04,120.66,117.37,117.10,116.55,115.44,53.83,50.95,28.64,23.01,17.15.HRMS-ESI:calcd for C ₂₇ H ₂₆ F ₃ N ₆ O[M+H] ⁺ 507.2120,found:507.2151.

Example 20

N- (4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyridin-2-yl) -1- ((4- (trifluoromethyl) phenyl) sulfonyl) indol-5-amine

Step 1 is the same as step 1 of example 1.

Step 2, 4-dichloro-5-methylpyridine is reacted with formula 2 according to example 1 step 2.

Steps 3, 4, 5 were reacted as in example 15 steps 3, 4, 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.84(s,1H),8.11(s,1H),8.03–7.90(m,5H),7.76(s,1H),7.60(s,1H),7.47(dd,J＝8.7,2.2Hz,1H),7.42(d,J＝8.7Hz,1H),6.86(s,1H),4.57(hept,J＝6.8Hz,1H),3.94(t,J＝8.2Hz,2H),2.81(t,J＝8.2Hz,2H),2.27(s,3H),1.46(d,J＝6.6Hz,6H). ¹³ C NMR(101MHz,DMSO)δ155.06,148.68,141.42,140.53,139.87,137.83,133.76,133.72,133.55,133.40,128.60,127.52,127.06,127.02,126.99,126.95,125.14,122.43,120.39,119.16,117.09,115.65,114.99,108.67,53.67,50.74,28.20,23.08,17.83.HRMS-ESI:calcd for C ₂₇ H ₂₇ F ₃ N ₅ O ₂ S[M+H] ⁺ 542.1838,found:542.1854.

Example 21

N- (4- (1-isopropyl-1H-pyrazol-4-yl) -5-methoxypyrimidin-2-yl) -1- ((4- (trifluoromethyl) phenyl) sulfonyl) indol-5-amine

Step 1 is the same as step 1 of example 15.

Step 2, 4-dichloro-5-methoxypyrimidine was reacted with formula 2 according to example 15 step 2.

Steps 3, 4, 5 were reacted as in example 15 steps 3, 4, 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.26(s,1H),8.36(s,1H),8.29(s,1H),8.13(s,1H),8.01(d,J＝8.4Hz,2H),7.95(d,J＝8.4Hz,2H),7.67(d,J＝2.2Hz,1H),7.62(dd,J＝8.8,2.3Hz,1H),7.43(d,J＝8.7Hz,1H),4.65–4.57(m,1H),3.96(t,J＝8.3Hz,2H),3.93(s,3H),2.85(t,J＝8.2Hz,2H),1.46(d,J＝6.6Hz,6H). ¹³ C NMR(101MHz,DMSO)δ154.88,148.58,143.63,142.65,140.49,139.39,139.01,134.18,133.72,133.34,130.09,128.64,127.07,127.03,125.15,122.44,117.58,117.29,115.39,115.22,55.71,53.73,50.75,28.16,23.02.HRMS-ESI:calcd for C ₂₆ H ₂₆ F ₃ N ₆ O ₃ S[M+H] ⁺ 559.1739,found:559.1736.

Example 22

N- (6- (1-isopropyl-1H-pyrazol-4-yl) -2-methoxypyrimidin-4-yl) -1- ((4- (trifluoromethyl) phenyl) sulfonyl) indol-5-amine

Step 1 is the same as step 1 of example 15.

Step 2,4, 6-dichloro-2-methoxypyrimidine was reacted with formula 2 according to example 15 step 2.

Steps 3, 4, 5 were reacted as in example 15 steps 3, 4, 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.52(s,1H),8.27(s,1H),8.06–7.94(m,4H),7.91(s,1H),7.57(s,1H),7.53–7.42(m,2H),6.53(s,1H),4.56(p,J＝6.6Hz,1H),3.96(t,J＝8.3Hz,2H),3.87(s,3H),2.88(t,J＝8.3Hz,2H),1.45(d,J＝6.7Hz,6H). ¹³ C NMR(101MHz,DMSO)δ165.56,162.77,158.91,140.39,137.42,137.32,135.73,133.55,128.63,127.83,127.14,127.10,121.16,119.43,117.51,115.24,94.86,54.26,53.80,50.74,28.02,23.02.HRMS-ESI:calcd for C ₂₆ H ₂₆ F ₃ N ₆ O ₃ S[M+H] ⁺ 559.1739,found:559.1738.

Example 23

N- (4- (1-isopropyl-1H-pyrazol-4-yl) -6-methylpyrimidin-2-yl) -1- ((4- (trifluoromethyl) phenyl) sulfonyl) indol-5-amine

Step 1 is the same as step 1 of example 15.

Step 2, 4-dichloro-6-methylpyrimidine is reacted with formula 2 according to example 15, step 2.

Steps 3, 4, 5 were reacted as in example 15 steps 3, 4, 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.43(s,1H),8.40(s,1H),8.06(s,1H),8.02(d,J＝8.3Hz,2H),7.95(d,J＝8.4Hz,2H),7.78–7.69(m,2H),7.45(d,J＝8.6Hz,1H),7.00(s,1H),4.57(hept,J＝6.7Hz,1H),3.95(t,J＝8.3Hz,2H),2.88(t,J＝8.2Hz,2H),2.34(s,3H),1.46(d,J＝6.7Hz,6H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ167.83,160.28,159.34,140.49,138.52,138.01,134.63,133.74,133.42,133.29,128.64,128.25,127.09,127.05,122.43,121.12,118.02,116.09,115.26,106.93,53.86,50.74,28.13,24.13,23.01.HRMS-ESI:calcd for C ₂₆ H ₂₆ F ₃ N ₆ O ₂ S[M+H] ⁺ 543.1790,found:543.1786.

Example 24

4- (1-isopropyl-1H-pyrazol-4-yl) -N-methyl-6- ((1- ((4- (trifluoromethyl) phenyl) sulfo) indol-5-yl) amino) nicotinamide

Step 1 is the same as step 1 of example 15.

Step 2,4, 6-dichloro-N-methylnicotinamide was reacted with formula 2 according to example 15 step 2.

Steps 3, 4,5 were reacted as in example 15 steps 3, 4, 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.30(s,1H),8.62(d,J＝3.4Hz,2H),8.24(s,1H),8.07(d,J＝8.2Hz,2H),7.98(d,J＝8.3Hz,2H),7.86(s,1H),7.54(d,J＝8.6Hz,1H),7.19–7.07(m,3H),4.51(hept,J＝6.8Hz,1H),4.00(t,J＝8.4Hz,2H),2.94(t,J＝8.3Hz,2H),2.79(d,J＝4.3Hz,3H),1.43(d,J＝6.6Hz,6H). ¹³ C NMR(101MHz,DMSO)δ168.66,154.17,151.73,150.05,140.47,137.60,137.38,135.99,134.58,133.89,133.57,128.66,127.40,127.20,127.16,125.13,122.50,122.21,120.22,115.67,110.63,101.93,53.69,50.81,27.87,26.43,23.04.HRMS-ESI:calcd for C ₂₈ H ₂₈ F ₃ N ₆ O ₃ S[M+H] ⁺ 585.1896,found:585.1883.

Example 25

N- (5-methyl-4- (1, 3, 5-trimethyl-1H-pyrazol-4-yl) pyrimidin-2-yl) -1- ((4- (trifluoromethyl) phenyl) sulfonyl) indol-5-amine

Step 1:1,3, 5-trimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) -1H-pyrazole was reacted with 2, 4-dichloro-5-methylpyrimidine according to example 15, step 2.

Steps 2, 3, 4 were reacted as in example 15 steps 3, 4, 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.43(s,1H),8.35(s,1H),7.99(d,J＝8.3Hz,2H),7.93(d,J＝8.3Hz,2H),7.61(d,J＝9.2Hz,2H),7.39(d,J＝8.5Hz,1H),3.93(t,J＝8.2Hz,2H),3.71(s,3H),2.81(t,J＝8.2Hz,2H),2.14(s,3H),2.05(s,3H),2.00(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ160.70,159.52,158.79,144.49,140.45,138.54,137.94,134.58,133.73,133.41,133.31,128.62,127.01,125.14,122.42,119.83,117.83,116.66,115.86,115.27,50.73,36.21,28.09,15.30,12.87,10.69.

HRMS-ESI:calcd for C ₂₆ H ₂₅ F ₃ N ₆ NaO ₂ S[M+Na] ⁺ 565.1609,found:565.1609.

Example 26

N- (4- (furan-3-yl) -5-methylpyrimidin-2-yl) -1- ((4- (trifluoromethyl) phenyl) sulfonyl) indol-5-amine

Step 1: the furan-3-boronic acid pinacol ester was reacted with 2, 4-dichloro-5-methylpyrimidine according to example 15, step 2.

Steps 2, 3, 4 were reacted as in example 15 steps 3, 4, 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.43(s,1H),8.32(s,2H),8.01(d,J＝8.3Hz,2H),7.95(d,J＝8.4Hz,2H),7.84(t,J＝1.7Hz,1H),7.70–7.62(m,2H),7.45(d,J＝8.6Hz,1H),7.07(d,J＝1.8Hz,1H),3.95(t,J＝8.2Hz,2H),2.86(t,J＝8.2Hz,2H),2.29(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ160.06,158.89,157.29,145.08,144.12,140.47,138.47,134.66,133.30,128.62,127.09,127.05,127.01,126.98,125.48,117.95,117.87,115.97,115.27,110.69,50.73,28.12,17.09.HRMS-ESI:calcd for C ₂₄ H ₂₀ F ₃ N ₄ O ₃ S[M+H] ⁺ 501.1208,found:501.1206.

Example 27

3- (4- (5-methyl-2- ((1- ((4- (trifluoromethyl) phenyl) sulfonyl) indol-5-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile

Step 1:4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole-1-carbonitrile was reacted with 2, 4-dichloro-5-methylpyrimidine according to example 15, step 2.

Steps 2, 3, 4 were reacted as in example 15 steps 3, 4, 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.38(s,1H),8.46(s,1H),8.28(s,1H),8.14(s,1H),8.02(d,J＝8.3Hz,2H),7.95(d,J＝8.4Hz,2H),7.72–7.63(m,2H),7.46(d,J＝8.6Hz,1H),4.52(t,J＝6.4Hz,2H),3.95(t,J＝8.3Hz,2H),3.15(t,J＝6.3Hz,2H),2.87(t,J＝8.2Hz,2H),2.31(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ160.03,158.83,157.38,140.42,138.56,134.56,133.75,133.33,133.42,133,33,132.41,128.63,127.08,125.14,122.43,121.19,118.93,117.84,116.76,115.86,115.33,50.74,47.52,28.12,18.89,17.12.HRMS-ESI:calcd for C ₂₆ H ₂₂ F ₃ N ₇ NaO ₂ S[M+Na] ⁺ 576.1405,found:576.1418.

Example 28

N- (4- (1-cyclobutyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) -1- ((4- (trifluoromethyl) phenyl) sulfonyl) indol-5-amine

Step 1: n-cyclopropyl-pyrazole-4-pinacol diboronate was reacted with 2, 4-dichloro-5-methylpyrimidine according to example 15, step 2.

Steps 2, 3, 4 were reacted as in example 15 steps 3, 4, 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.36(s,1H),8.36(s,1H),8.26(s,1H),8.10(s,1H),8.01(d,J＝8.3Hz,2H),7.95(d,J＝8.4Hz,2H),7.70–7.60(m,2H),7.44(d,J＝8.8Hz,1H),4.96(p,J＝8.3Hz,1H),3.95(t,J＝8.3Hz,2H),2.86(t,J＝8.3Hz,2H),2.61–2.51(m,2H),2.47–2.35(m,2H),2.30(s,3H),1.88–1.75(m,2H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ159.85,158.81,157.64,140.49,139.78,138.61,134.53,133.74,133.42,133.30,130.31,128.63,127.06,127.02,122.43,120.79,117.87,116.73,115.87,115.29,55.70,55.40,50.75,30.39,28.13,17.12,14.63.HRMS-ESI:calcd for C ₂₇ H ₂₆ F ₃ N ₆ O ₂ S[M+H] ⁺ 555.1790,found:555.1788.

Example 29

N- (4- (1-cyclopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) -1- ((4- (trifluoromethyl) phenyl) sulfonyl) indol-5-amine

Step 1: 1-cyclopropyl pyrazole-4-boronic acid pinacol ester and 2, 4-dichloro-5-methyl pyrimidine according to example 15, step 2.

Steps 2, 3, 4 were reacted as in example 15 steps 3, 4, 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.35(s,1H),8.34(s,1H),8.26(s,1H),8.06–7.98(m,3H),7.95(d,J＝8.3Hz,2H),7.65(d,J＝14.7Hz,2H),7.45(d,J＝8.7Hz,1H),3.95(t,J＝8.3Hz,2H),3.87(tt,J＝8.0,4.1Hz,1H),2.86(t,J＝8.3Hz,2H),2.30(s,3H),1.14(p,J＝4.5Hz,2H),1.05–0.97(m,2H). ¹³ C NMR(101MHz,DMSO)δ159.86,158.80,157.49,140.48,139.61,138.58,134.54,133.30,131.63,128.64,127.08,127.04,125.15,120.81,117.88,116.77,115.88,115.28,50.75,33.54,28.13,17.09,6.79.HRMS-ESI:calcd for C ₂₆ H ₂₄ F ₃ N ₆ O ₂ S[M+H] ⁺ 541.1634,found:541.1631.

Example 30

N- (5-methyl-4- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) -1- ((4- (trifluoromethyl) phenyl) sulfo) indol-5-amine

Step 1: 1-methyl pyrazole-4-boric acid pinacol ester and 2, 4-dichloro-5-methyl pyrimidine according to example 15 step 2 reaction.

Steps 2, 3, 4 were reacted as in example 15 steps 3, 4, 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.34(s,1H),8.32(s,1H),8.26(s,1H),8.05(s,1H),8.01(d,J＝8.3Hz,2H),7.95(d,J＝8.4Hz,2H),7.71–7.62(m,2H),7.45(d,J＝8.7Hz,1H),3.99(t,J＝8.3Hz,2H),3.94(s,3H),2.86(t,J＝8.2Hz,2H),2.29(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ159.86,158.82,157.64,140.48,139.72,138.61,134.52,133.74,133.42,133.31,132.55,128.64,127.08,127.04,122.43,120.97,117.82,116.65,115.84,115.32,50.74,28.12,17.17.HRMS-ESI:calcd for C ₂₄ H ₂₂ F ₃ N ₆ O ₂ S[M+H] ⁺ 515.1477,found:515.1474.

Example 31

N- (5-methyl-4- (1-propyl-1H-pyrazol-4-yl) pyrimidin-2-yl) -1- ((4- (trifluoromethyl) phenyl) sulfonyl) indol-5-amine

Step 1: 1-propyl-1H-pyrazole-4-boronic acid pinacol ester was reacted with 2, 4-dichloro-5-methylpyrimidine according to example 15, step 2.

Steps 2, 3, 4 were reacted as in example 15 steps 3, 4, 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.33(s,1H),8.33(s,1H),8.26(s,1H),8.09–8.05(m,1H),8.01(d,J＝8.3Hz,2H),7.95(d,J＝8.4Hz,2H),7.65(d,J＝8.8Hz,2H),7.44(d,J＝8.5Hz,1H),4.17(t,J＝6.9Hz,2H),3.95(t,J＝8.2Hz,2H),2.86(t,J＝8.2Hz,2H),2.29(s,3H),1.84(h,J＝7.2Hz,2H),0.86(t,J＝7.4Hz,3H). ¹³ C NMR(101MHz,DMSO)δ159.84,158.81,157.71,140.47,139.69,138.61,134.52,133.74,133.42,133.31,131.83,128.63,127.07,127.03,125.14,122.42,120.66,117.86,116.67,115.85,115.30,53.55,50.75,28.12,23.57,17.16,11.33.HRMS-ESI:calcd for C ₂₆ H ₂₆ F ₃ N ₆ O ₂ S[M+H] ⁺ 543.1790,found:543.1791.

Example 32

N- (5-methyl-4- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-yl) -1- ((4- (trifluoromethyl) phenyl) sulfonyl) indol-5-amine

Step 1: 1-methyl-1H-pyrazole-5-boronic acid pinacol ester was reacted with 2, 4-dichloro-5-methylpyrimidine according to example 15, step 2.

Steps 2, 3, 4 were reacted as in example 15 steps 3, 4, 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.55(s,1H),8.45(s,1H),8.01(d,J＝8.3Hz,2H),7.95(d,J＝8.4Hz,2H),7.59–7.52(m,3H),7.43(d,J＝8.6Hz,1H),6.66(d,J＝2.0Hz,1H),3.96(d,J＝8.2Hz,2H),3.93(s,3H),2.84(t,J＝8.2Hz,2H),2.18(s,3H). ¹³ C NMR(101MHz,DMSO)δ160.62,158.68,155.96,140.44,138.39,137.95,135.10,133.76,133.44,133.39,128.64,127.08,127.04,125.14,122.43,119.43,118.48,116.50,115.25,108.91,50.76,38.83,28.05,16.05.HRMS-ESI:calcd for C ₂₄ H ₂₂ F ₃ N ₆ O ₂ S[M+H] ⁺ 515.1477,found:515.1472.

Example 33

N- (4- (1-benzyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) -1- ((4- (trifluoromethyl) phenyl) sulfonyl) indol-5-amine

Step 1: 1-benzyl-1H-pyrazole-4-boronic acid pinacol ester was reacted with 2, 4-dichloro-5-methylpyrimidine according to example 15, step 2.

Steps 2, 3, 4 were reacted as in example 15 steps 3, 4, 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.35(s,1H),8.46(s,1H),8.27(s,1H),8.10(s,1H),8.01(d,J＝8.3Hz,2H),7.95(d,J＝8.5Hz,2H),7.68–7.61(m,2H),7.44(d,J＝9.4Hz,1H),7.40–7.29(m,5H),5.44(s,2H),3.94(t,J＝8.2Hz,2H),2.85(t,J＝8.2Hz,2H),2.30(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ159.95,158.80,157.52,140.47,140.16,138.57,137.53,134.52,133.74,133,42,133.31,132.12,129.06,128.63,128.27,127,96,127.09,127.05,125.14,121.25,117.81,116.73,115.83,115.29,55.54,50.74,28.11,17.15.HRMS-ESI:calcd for C ₃₀ H ₂₆ F ₃ N ₆ O ₂ S[M+H] ⁺ 591.1790,found:591.1819.

Example 34

N- (5-methyl-4- (1H-pyrazol-4-yl) pyrimidin-2-yl) -1- ((4- (trifluoromethyl) phenyl) sulfo) indol-5-amine

Step 1: the 4-pyrazoloboronic acid pinacol ester is reacted with 2, 4-dichloro-5-methylpyrimidine according to example 15, step 2.

Steps 2, 3, 4 were reacted as in example 15 steps 3, 4, 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ13.22(s,1H),9.27(s,1H),8.23(s,1H),8.19(s,1H),8.08(s,1H),7.94(d,J＝8.3Hz,2H),7.88(d,J＝8.4Hz,2H),7.60(d,J＝9.0Hz,2H),7.38(d,J＝8.5Hz,1H),3.88(t,J＝8.3Hz,2H),2.79(t,J＝8.2Hz,2H),2.24(s,3H).

¹³ C NMR(101MHz,DMSO)δ159.78,158.82,158.06,157.11,140.47,138.63,134.50,133.74,133.42,133.29,128.64,127.05,120.43,117.84,116.83,115.84,115.27,50.74,28.13,17.18.HRMS-ESI:calcd for C ₂₃ H ₂₀ F ₃ N ₆ O ₂ S[M+H] ⁺ 501.1321,found:501.1316.

Example 35

N- (4- (1- (1-ethoxyethyl) -1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) -1- ((4- (trifluoromethyl) phenyl) sulfonyl) indol-5-amine

Step 1:1- (1-ethoxyethyl) -4-pyrazoleboronic acid pinacol ester was reacted with 2, 4-dichloro-5-methylpyrimidine according to example 15, step 2.

Steps 2, 3, 4 were reacted as in example 15 steps 3, 4, 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.38(s,1H),8.45(s,1H),8.29(s,1H),8.13(s,1H),8.02(d,J＝8.3Hz,2H),7.95(d,J＝8.4Hz,2H),7.70(d,J＝2.1Hz,1H),7.65(dd,J＝8.7,2.3Hz,1H),7.45(d,J＝8.7Hz,1H),5.67(q,J＝5.9Hz,1H),3.96(t,J＝8.3Hz,2H),3.49(dq,J＝9.7,7.0Hz,1H),3.26(dq,J＝9.7,7.0Hz,1H),2.87(t,J＝8.2Hz,2H),2.32(s,3H),1.66(d,J＝6.0Hz,3H),1.06(t,J＝7.0Hz,3H). ¹³ C NMR(101MHz,DMSO)δ159.98,158.83,157.51,140.49,139.91,138.56,134.57,133.74,133.42,133.30,130.03,128.64,127.08,127.04,125.14,122.43,121.26,117.92,116.91,115.90,115.27,87.02,63.64,50.74,28.13,21.62,17.07,15.19.HRMS-ESI:calcd for C ₂₇ H ₂₈ F ₃ N ₆ O ₃ S[M+H] ⁺ 573.1896,found:573.1920.

Example 36

Cyclopropyl (4- (5-methyl-2- ((1- ((4- (trifluoromethyl) phenyl) sulfonyl) indol-5-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) methanone

Step 1: cyclopropyl (4- (4, 5-tetramethyl-1, 3, 2-dioxin-2-yl) -1H-pyrazol-1-yl) methanone was reacted with 2, 4-dichloro-5-methylpyrimidine according to example 15, step 2.

Steps 2, 3, 4 were reacted as in example 15 steps 3, 4, 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.50(s,1H),8.79(s,1H),8.46(s,1H),8.37(s,1H),8.01(d,J＝8.3Hz,2H),7.95(d,J＝8.4Hz,2H),7.63(d,J＝8.8Hz,2H),7.45(d,J＝8.5Hz,1H),3.95(t,J＝8.2Hz,2H),3.13(ddd,J＝12.3,7.8,4.5Hz,1H),2.87(t,J＝8.2Hz,2H),2.35(s,3H),1.25(dd,J＝8.2,3.1Hz,2H),1.20(p,J＝4.5,3.9Hz,2H).

¹³ C NMR(101MHz,DMSO)δ172.94,160.51,158.86,156.04,144.53,140.47,138.24,134.82,133.75,133.43,133.30,128.86,128.64,127.09,127.05,125.14,124.48,118.16,118.09,116.16,115.22,50.75,28.11,16.67,12.42,11.93.HRMS-ESI:calcd for C ₂₇ H ₂₄ F ₃ N ₆ O ₃ S[M+H] ⁺ 569.1583,found:569.1584.

Route two:

example 37

3- (4- (5-fluoro-2- ((1- ((4- (trifluoromethyl) phenyl) sulfonyl) indolin-5-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile

Step 1:3- (4, 5-tetramethyl-1, 3, 2-dioxin-2-yl) -1H-pyrazol-1-yl) propionitrile (compound of formula 2) was prepared in the same manner as in step 1 of example 1.

Step 2:3- (4- (2-chloro-5-fluoropyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile (compound of formula 3) was prepared in the same manner as in example 1, step 2.

Step 3: preparation of 5-nitro-1- ((4- (trifluoromethyl) phenyl) sulfonyl) indole (compound of formula 4), reaction of 5-nitroindoline and p-trifluoromethyl benzenesulfonyl chloride at 0 ℃ is carried out overnight by using DIEA as a base, after the reaction is finished, the reaction solution is concentrated to dryness, and then the compound of formula 4 is obtained by mixing samples and separating the mixture by using a silica gel column.

Step 4: preparation of 1- ((4- (trifluoromethyl) phenyl) sulfonyl) indol-5-amine (compound of formula 5) was performed as in example 15, step 4.

Step 5: preparation of 3- (4- (5-fluoro-2- ((1- ((4- (trifluoromethyl) phenyl) sulfonyl) indolin-5-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile the procedure was as in example 1, step 3.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.62(s,1H),8.53(d,J＝1.9Hz,1H),8.50(d,J＝2.9Hz,1H),8.15(s,1H),8.02(d,J＝8.2Hz,2H),7.96(d,J＝8.2Hz,2H),7.68(dd,J＝8.6,2.3Hz,1H),7.61(d,J＝2.2Hz,1H),7.48(d,J＝8.7Hz,1H),4.55(t,J＝6.3Hz,2H),3.96(t,J＝8.2Hz,2H),3.15(t,J＝6.3Hz,2H),2.89(t,J＝8.3Hz,2H).

¹³ C NMR(101MHz,DMSO)δ156.82,150.07,147.58,146.67,146.50,146.26,140.45,139.96,138.11,134.99,133.76,133.44,133.38,132.80,132.72,128.63,127.11,127.06,125.14,122.43,118.86,117.96,116.30,116.25,116.01,115.30,50.75,47.58,28.08,18.95.HRMS-ESI:calcd for C ₂₅ H ₂₀ F ₄ N ₇ O ₂ S[M+H] ⁺ 558.1335,found:558.1332.

Route three

Example 38

3- (4- (5-fluoro-2- ((1- (4- (trifluoromethyl) benzoyl) indol-5-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile

Steps 1, 2 are identical to steps 1, 2 of example 37 to give the compound 3- (4- (2-chloro-5-fluoropyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile of formula iii.

Steps 3, 4 are identical to steps 3, 4 of example 1 to give the penta-compound 3- (4- (5-fluoro-2- (indol-5-ylamino) pyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile of formula (i).

Step 5: the compound of formula five was reacted with p-trifluoromethylbenzoyl chloride as in example 37, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.63(s,1H),8.56–8.50(m,2H),8.16(s,1H),8.07(d,J＝7.8Hz,1H),7.85(q,J＝8.2Hz,4H),7.74(s,1H),7.65(d,J＝8.6Hz,1H),4.55(t,J＝6.4Hz,2H),3.98(s,2H),3.14(dt,J＝12.7,7.4Hz,4H). ¹³ C NMR(101MHz,DMSO)δ156.92,147.58,139.93,132.78,128.27,125.96,118.86,117.30,116.38,50.88,47.58,28.58,18.95.HRMS-ESI:calcd for C ₂₆ H ₂₀ F ₄ N ₇ O[M+H] ⁺ 522.1665,found:522.1674.

Example 39

3- (4- (2- ((1- (4- (tert-butyl) benzoyl) indol-5-yl) amino) -5-fluoropyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile

Steps 1, 2, 3, 4 are the same as steps 1, 2, 3, 4 of example 38.

Step 5: the compound of formula five was reacted with p-tert-butylbenzoyl chloride as in example 38, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.59(s,1H),8.52(dd,J＝6.9,2.3Hz,2H),8.15(s,1H),7.71(d,J＝2.2Hz,1H),7.61–7.46(m,5H),4.55(t,J＝6.4Hz,2H),4.02(t,J＝7.9Hz,2H),3.12(dt,J＝21.9,7.3Hz,4H),1.32(s,9H). ¹³ C NMR(101MHz,DMSO)δ167.85,156.97,156.94,153.10,150.04,147.55,146.64,146.50,146.25,139.92,139.87,137.37,134.86,133.42,132.75,132.67,127.34,125.56,118.84,117.28,116.42,116.36,115.70,51.04,47.58,35.03,31.44,28.57,18.96.HRMS-ESI:calcd for C ₂₉ H ₂₈ FN ₇ NaO[M+Na] ⁺ 532.2237,found:532.2237.

Example 40

3- (4- (5-fluoro-2- ((1- ((trifluoromethyl) sulfonyl) indol-5-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile

Steps 1, 2,3, 4 are the same as steps 1, 2,3, 4 of example 38.

Step 5: the compound of formula five was reacted with p-trifluoromethanesulfonyl chloride as in example 38, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.72(s,1H),8.54(dd,J＝5.7,2.4Hz,2H),8.17(s,1H),7.78(d,J＝2.1Hz,1H),7.68(dd,J＝8.9,2.3Hz,1H),7.28(d,J＝8.9Hz,1H),4.55(t,J＝6.4Hz,2H),4.23(t,J＝8.2Hz,2H),3.25(t,J＝8.3Hz,2H),3.15(t,J＝6.4Hz,2H). ¹³ C NMR(101MHz,DMSO)δ156.78,147.68,146.56,146.32,139.94,138.98,133.16,132.93,132.83,132.75,118.86,118.05,116.29,116.27,116.24,114.50,52.25,47.58,28.37,18.95.HRMS-ESI:calcd for C ₁₉ H ₁₆ F ₄ N ₇ O ₂ S[M+H] ⁺ 482.1022,found:482.1015.

Example 41

3- (4- (5-fluoro-2- ((1-oxoisoindol-5-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile

Steps 1 and 2 are the same as steps 1 and 2 of example 38.

Step 3: the compound of formula III was reacted with 5-amino-2, 3-dihydro-isoindol-1-one as in example 38 step 3.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.03(s,1H),8.60(d,J＝3.0Hz,1H),8.57(d,J＝1.9Hz,1H),8.26(s,1H),8.20(s,1H),8.10(d,J＝1.9Hz,1H),7.78(dd,J＝8.3,1.9Hz,1H),7.59(d,J＝8.4Hz,1H),4.56(t,J＝6.4Hz,2H),4.37(s,2H),3.16(t,J＝6.3Hz,2H). ¹³ C NMR(101MHz,DMSO)δ170.59,156.61,150.39,147.90,146.74,146.59,146.35,145.89,144.24,140.02,132.93,132.85,125.83,123.71,118.88,118.34,116.22,116.16,112.38,47.61,45.38,18.95.HRMS-ESI:calcd for C ₁₈ H ₁₅ FN ₇ O[M+H] ⁺ 364.1322,found:364.1313.

Example 42

3- (4- (5-methyl-2- ((1-oxoisoindol-5-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile

Step 1:3- (4, 5-tetramethyl-1, 3-dioxolan-2-yl) -1H-pyrazol-1-yl) propionitrile was reacted with 2, 4-dichloro-5-methylpyrimidine according to example 1, step 1.

Step 2:3- (4- (2-chloro-5-methylpyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile was reacted with 5-amino-2, 3-dihydro-isoindol-1-one as in example 38, step 3.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.80(s,1H),8.51(s,1H),8.37(s,1H),8.23(s,1H),8.19(s,1H),8.15(s,1H),7.80(d,J＝7.6Hz,1H),7.57(d,J＝8.3Hz,1H),4.53(t,J＝6.4Hz,2H),4.36(s,2H),3.15(t,J＝6.3Hz,2H),2.35(s,3H).

¹³ C NMR(101MHz,DMSO)δ170.70,160.10,158.65,157.54,145.91,144.66,140.47,132.55,125.34,123.65,121.10,118.95,118.25,117.65,112.29,47.55,45.37,19.03,17.17.HRMS-ESI:calcd for C ₁₉ H ₁₈ N ₇ O[M+H] ⁺ 360.1573,found:360.1564.

Example 43

3- (4- (5-fluoro-2- (indol-5-ylamino) pyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile

Steps 1, 2,3, 4 are the same as steps 1, 2,3, 4 of example 38.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.10(s,1H),8.47(d,J＝2.0Hz,1H),8.41(d,J＝2.9Hz,1H),8.09(s,1H),7.40(d,J＝2.1Hz,1H),7.23(dd,J＝8.3,2.2Hz,1H),6.47(d,J＝8.3Hz,1H),5.19(s,1H),4.53(t,J＝6.4Hz,2H),3.39(td,J＝8.4,2.1Hz,2H),3.13(t,J＝6.4Hz,2H),2.91(t,J＝8.4Hz,2H). ¹³ C NMR(101MHz,DMSO)δ167.59,156.96,146.51,139.91,137.64,137.02,132.68,132.38,118.89,117.35,116.38,115.70,50.46,47.56,28.31,18.97.HRMS-ESI:calcd for C ₁₈ H ₁₇ FN ₆ [M+H] ⁺ 350.1529,found:350.1529.

Example 44

1- (5- ((4- (1- (2- (cyanoethyl) -1H-pyrazol-4-yl) -5-fluoropyrimidin-2-yl) amino) indoline-1-carbonyl) cyclopropane-1-carbonitrile

Steps 1, 2,3, 4 are the same as steps 1, 2,3, 4 of example 38.

Step 5: the compound of formula five was reacted with 1-cyano-1-cyclopropanecarboxylic acid as in example 38, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.63(s,1H),8.53(t,J＝2.8Hz,2H),8.15(s,1H),7.85(d,J＝8.7Hz,1H),7.74(d,J＝2.2Hz,1H),7.59(dd,J＝8.7,2.3Hz,1H),4.55(t,J＝6.4Hz,2H),4.38(d,J＝7.3Hz,2H),3.27(t,J＝8.0Hz,2H),3.15(t,J＝6.4Hz,2H),1.67(d,J＝5.8Hz,4H). ¹³ CNMR(101MHz,DMSO)δ161.07,156.89,146.51,137.94,132.81,120.31,118.88,117.28,116.36,116.30,115.59,47.57,18.95,15.96,15.13.HRMS-ESI:calcd for C ₂₂ H ₂₀ FN ₈ O[M+H] ⁺ 443.1744,found:443.1740.

Example 45

3- (4- (2- ((1- (2- (1, 1-dioxothiomorpholino) acetyl) indol-5-yl) amino) -5-fluoropyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile

Steps 1, 2, 3, 4 are the same as steps 1, 2, 3, 4 of example 38.

Step 5: the compound of formula 5 is reacted with thiomorpholinoacetic acid-1 ',1' -dioxide, monohydrate according to example 38, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.57(s,1H),8.53(d,J＝1.9Hz,1H),8.51(d,J＝2.9Hz,1H),8.15(s,1H),8.01(d,J＝8.7Hz,1H),7.68(s,1H),7.56(dd,J＝8.8,2.3Hz,1H),4.56(t,J＝6.4Hz,2H),4.11(t,J＝8.4Hz,2H),3.56(s,2H),3.20–3.11(m,12H). ¹³ C NMR(101MHz,DMSO)δ167.59,156.96,150.00,147.52,146.62,146.50,146.28,139.87,137.64,137.02,132.76,132.68,132.38,118.89,117.35,116.38,115.70,59.07,51.17,50.47,47.56,47.24,28.31,18.97.HRMS-ESI:calcd for C ₂₄ H ₂₅ FN ₈ NaO ₃ S[M+Na] ⁺ 547.1652,found:547.1662.

Example 46

5- ((4- (1- (2-cyanoethyl) -1H-pyrazol-4-yl) -5-fluoropyrimidin-2-yl) amino) -N- (4- (trifluoromethyl) phenyl) indoline-1-carboxamide

Steps 1, 2, 3, 4 are the same as steps 1, 2, 3, 4 of example 38.

Step 5: after the compound of formula 5 reacts with 2eq NaH under the protection of anhydrous DMF nitrogen at 0 ℃ for 30min, 4-trifluoromethyl phenylisocyanate is added dropwise. And adding water for quenching after the reaction is finished, extracting with dichloromethane, concentrating an organic phase to be dry, and separating a mixed sample by a silica gel column to obtain the CLJ-48 compound.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.50(s,1H),8.81(s,1H),8.52(dd,J＝8.2,2.4Hz,2H),8.15(d,J＝1.2Hz,1H),7.83(d,J＝8.5Hz,3H),7.65(d,J＝9.2Hz,3H),7.53(d,J＝8.8Hz,1H),4.56(t,J＝6.4Hz,2H),4.17(t,J＝8.5Hz,2H),3.22(t,J＝8.5Hz,2H),3.15(t,J＝6.4Hz,2H). ¹³ C NMR(101MHz,DMSO)δ157.06,152.48,147.47,146.49,144.26,139.91,138.13,135.96,131.89,126.13,126.09,122.68,119.94,118.89,117.73,116.43,116.38,116.00,115.32,47.92,47.56,28.09,18.96.HRMS-ESI:calcd for C ₂₆ H ₂₀ F ₄ N ₈ NaO[M+Na] ⁺ 559.1594,found:559.1588.

Example 47

3- (4- (5-fluoro-2- ((3-fluoro-4- (2- (methyl (pyridin-2-yl) amino) ethoxy) phenyl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile

Steps 1 and 2 are the same as steps 1 and 2 of example 38.

Step 3: the compound of formula 3 is reacted with N- (2- (4-amino-2-fluorophenoxy) ethyl) -N-methylpyridin-2-amine as in example 38, step 3.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.68(s,1H),8.58(d,J＝2.8Hz,2H),8.20(s,1H),8.18–8.11(m,1H),7.76(dd,J＝14.2,2.6Hz,1H),7.60–7.50(m,2H),7.19(t,J＝9.4Hz,1H),6.72(d,J＝8.6Hz,1H),6.67–6.59(m,1H),4.60(t,J＝6.4Hz,2H),4.24(t,J＝5.8Hz,2H),3.98(t,J＝5.8Hz,2H),3.20(t,J＝6.4Hz,2H),3.15(s,3H). ¹³ C NMR(101MHz,DMSO)δ158.50,156.75,156.73,152.96,150.56,150.12,148.02,147.64,146.74,146.62,146.46,146.22,141.12,141.01,139.85,139.81,137.79,135.21,135.11,132.80,132.71,118.84,116.29,116.23,115.88,114.73,114.70,112.00,107.40,107.17,106.21,67.67,49.07,47.59,37.54,18.94.HRMS-ESI:calcd for C ₂₄ H ₂₃ F ₂ N ₈ O[M+H] ⁺ 477.1963,found:477.1961.

Example 48

3- (4- (5-fluoro-2- ((4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile

Steps 1 and 2 are the same as steps 1 and 2 of example 38.

Step 3: the compound of formula 3 is reacted with 4- [2- (pyrrolidin-1-yl) ethoxy ] aniline according to example 38 step 3.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.40(s,1H),8.51(d,J＝2.0Hz,1H),8.47(d,J＝3.0Hz,1H),8.14(s,1H),7.64(d,J＝9.1Hz,2H),6.90(d,J＝9.0Hz,2H),4.54(t,J＝6.4Hz,2H),4.03(t,J＝6.0Hz,2H),3.14(t,J＝6.4Hz,2H),2.77(t,J＝6.0Hz,2H),2.52(p,J＝3.1Hz,4H),1.68(p,J＝3.1Hz,4H). ¹³ C NMR(101MHz,DMSO)δ157.14,153.80,150.30,142.85,139.85,134.33,120.63,118.86,115.82,115.41,114.90,67.68,55.04,54.47,47.55,23.60,18.95.HRMS-ESI:calcd for C ₂₂ H ₂₅ FN ₇ O[M+H] ⁺ 422.2105,found:422.2103.

Example 49

3- (4- (5-fluoro-2- ((4- (2-morpholinoethyl) phenyl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile

Steps 1 and 2 are the same as steps 1 and 2 of example 38.

Step 3: the compound of formula 3 is reacted with 4- (2-morpholin-4-ethyl) -aniline as in example 38, step 3.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.52(s,1H),8.53(d,J＝1.9Hz,1H),8.50(d,J＝3.0Hz,1H),8.15(s,1H),7.70–7.63(m,2H),7.16(d,J＝8.4Hz,2H),4.55(t,J＝6.4Hz,2H),3.58(t,J＝4.7Hz,4H),3.15(t,J＝6.4Hz,2H),2.71–2.65(m,2H),2.47(s,2H),2.42(s,4H). ¹³ C NMR(101MHz,DMSO)δ157.02,150.03,147.55,146.63,146.50,146.27,139.91,139.03,133.54,132.75,132.67,129.13,118.97,118.86,116.41,116.35,66.66,60.79,53.76,47.56,32.32,18.95.HRMS-ESI:calcd for C ₂₂ H ₂₅ FN ₇ O[M+H] ⁺ 422.2105,found:422.2098.

Example 50

N- (4- ((4- (1- (2-cyanoethyl) -1H-pyrazol-4-yl) -5-fluoropyrimidin-2-yl) amino) -2-fluorophenyl) -3-morpholinopropionamide

Steps 1 and 2 are the same as steps 1 and 2 of example 38.

Step 3: after reacting the compound of formula 3 with 3-fluoro-4-nitroaniline according to example 1, step 3, the nitro group is reduced with palladium carbon hydrogen, and then reacted with 3- (morpholin-4-yl) propionic acid according to example 1, step 5 to obtain CLJ-52.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.11(s,1H),9.79(s,1H),8.58–8.52(m,2H),8.16(s,1H),7.86(t,J＝9.0Hz,1H),7.78(dd,J＝13.9,2.4Hz,1H),7.51(dd,J＝8.9,2.4Hz,1H),4.56(t,J＝6.4Hz,2H),3.62(t,J＝4.5Hz,4H),3.16(t,J＝6.4Hz,2H),2.64(d,J＝6.5Hz,2H),2.53(t,J＝4.7Hz,2H),2.47(s,4H). ¹³ C NMR(101MHz,DMSO)δ170.61,156.62,154.96,152.56,150.25,147.76,146.84,146.71,146.50,146.27,139.88,138.34,138.24,132.86,132.78,124.31,120.06,119.94,118.84,116.23,116.17,114.24,105.72,105.48,66.58,54.47,53.29,47.60,33.27,18.94.HRMS-ESI:calcd for C ₂₃ H ₂₅ F ₂ N ₈ O ₂ [M+H] ⁺ 483.2069,found:483.2065.

Example 51

3- (4- (5-fluoro-2- ((2- ((4- (trifluoromethyl) phenyl) sulfonyl) isoindolin-5-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile

Steps 1 and 2 are the same as steps 1 and 2 of example 38.

Step 3: the compound of formula 3 was reacted with 5-aminoisoindole-2-carboxylic acid tert-butyl ester as per example 38, step 3.

Steps 4 and 5 are the same as steps 4 and 5 of example 24.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.69(s,1H),8.52(t,J＝3.3Hz,2H),8.16(s,1H),8.12(d,J＝8.1Hz,2H),8.00(d,J＝8.3Hz,2H),7.79(s,1H),7.56(d,J＝7.7Hz,1H),7.18(d,J＝8.3Hz,1H),4.67(s,2H),4.61–4.49(m,4H),3.15(t,J＝6.3Hz,2H).HRMS-ESI:calcd for C ₂₅ H ₂₀ F ₄ N ₇ O ₂ S[M+H] ⁺ 558.1335,found:558.1335.

Example 52

3- (4- (2- ((1- (1- (6- (1H-pyrazol-1-yl) nicotinyl) indol-5-yl) amino) -5-fluoropyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile

Steps 1, 2, 3, 4 are the same as steps 1, 2, 3, 4 of example 38.

Step 5: the compound of formula 5 is reacted with 6- (1H-pyrazol-1-yl) nicotinic acid according to example 38, step 5.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.64(s,1H),8.74(s,1H),8.69(d,J＝2.6Hz,1H),8.53(d,J＝3.3Hz,2H),8.24(s,1H),8.15(s,1H),8.03(s,1H),8.01(s,1H),7.90(s,1H),7.75(s,1H),7.63(s,1H),6.66–6.61(m,1H),4.55(t,J＝6.4Hz,2H),4.13(t,J＝8.1Hz,2H),3.21–3.07(m,4H).HRMS-ESI:calcd for C ₂₇ H ₂₁ FN ₁₀ NaO[M+Na] ⁺ 543.1782,found:543.1776.

Example 53

3- (4- (2- (((4- ((1, 1-thiomorpholino)) methyl) phenyl) amino) -5-fluoropyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile

Steps 1 and 2 are the same as steps 1 and 2 of example 38.

Step 3: the compound of formula 3 is reacted with 4- (4-aminobenzyl) thiomorpholine 1, 1-dioxide as in example 38 step 3.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.62(s,1H),8.53(dd,J＝10.1,2.4Hz,2H),8.17(s,1H),7.75(d,J＝8.3Hz,2H),7.27(d,J＝8.3Hz,2H),4.55(t,J＝6.4Hz,2H),3.61(s,2H),3.15(t,J＝6.4Hz,2H),3.10(t,J＝5.1Hz,4H),2.87(dd,J＝7.2,3.5Hz,4H).

¹³ C NMR(101MHz,DMSO)δ156.93,156.91,150.11,147.63,146.66,146.53,146.28,140.26,139.96,139.91,132.79,132.70,130.65,129.65,118.86,118.72,116.39,116.33,59.89,50.83,50.45,47.57,18.96.HRMS-ESI:calcd for C ₂₁ H ₂₃ FN ₇ O ₂ S[M+H] ⁺ 456.1618,found:456.1617.

Example 54

3- (4- (5-fluoro-2- ((1-methyl-1H-indol-5-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile

Steps 1 and 2 are the same as steps 1 and 2 of example 38.

Step 3: the compound of formula 3 is reacted with 1-methyl-1H-indol-5-amine as in example 38, step 3.

¹ H NMR(400MHz,Chloroform-d)δ8.27–8.21(m,2H),8.16(s,1H),7.87(s,1H),7.35–7.28(m,2H),7.13(s,1H),7.05(d,J＝3.0Hz,1H),6.46(d,J＝3.0Hz,1H),4.44(t,J＝6.7Hz,2H),3.79(s,3H),2.99(t,J＝6.6Hz,2H). ¹³ C NMR(101MHz,CDCl ₃ )δ157.39,150.29,147.79,146.76,146.63,145.66,145.42,141.21,141.16,133.81,131.80,131.54,131.46,129.53,128.68,117.53,116.62,112.50,109.32,100.86,47.87,32.98,19.19.HRMS-ESI:calcd for C ₁₉ H ₁₆ FN ₇ NaO[M+Na] ⁺ 384.1349,found:384.1346.

Example 55

3- (4- (5-fluoro-2- ((1- ((trifluoromethyl) sulfonyl) -1H-indol-5-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile

Steps 1 and 2 are the same as steps 1 and 2 of example 38.

Step 3: the compound of formula 3 is reacted with 1- ((trifluoromethyl) sulfonyl) -1H-indol-5-amine as in example 38 step 3.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.86(s,1H),8.57(t,J＝2.8Hz,2H),8.27(d,J＝2.0Hz,1H),8.21(s,1H),7.85–7.75(m,2H),7.72(d,J＝3.8Hz,1H),7.18(d,J＝3.8Hz,1H),4.56(t,J＝6.4Hz,2H),3.16(t,J＝6.4Hz,2H). ¹³ C NMR(101MHz,DMSO)δ156.87,156.84,150.25,147.76,146.75,146.63,146.53,146.30,140.06,140.00,138.91,132.83,132.75,131.60,129.86,127.73,121.29,118.87,118.34,118.06,116.33,116.27,113.68,113.62,111.11,47.60,18.97.HRMS-ESI:calcd for C ₁₉ H ₁₄ F ₄ N ₇ O ₂ S[M+H] ⁺ 480.0866,found:480.0865.

Example 56

3- (4- (2- ((1- (cyclopropanecarbonyl) -1H-indol-5-yl) amino) -5-fluoropyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile

Steps 1 and 2 are the same as steps 1 and 2 of example 38.

Step 3: the compound of formula 3 was reacted with 1-Boc-5-aminoindole as in example 38, step 3 to give 5- ((4- (1- (2- (cyanoethyl) -1H-pyrazol-4-yl) -5-fluoropyrimidin-2-yl) amino) t-butyl-1H-indole-1-carboxylic acid ester.

Step 4: the 3- (4- (2- (((1H-indol-5-yl) amino) -5-fluoropyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile is obtained by dissolving 4- (1- (2- (cyanoethyl) -1H-pyrazol-4-yl) -5-fluoropyrimidin-2-yl) amino) tert-butyl-1H-indole-1-carboxylate in a mixed solvent of methanol/water (V/V=1/3), adding 3eq potassium carbonate, refluxing, drying methanol in a reaction system after the reaction is finished, extracting ethyl acetate, and concentrating an organic phase to dryness.

Step 5:3- (4- (2- (((1H-indol-5-yl) amino) -5-fluoropyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile is reacted with cyclopropanecarbonyl chloride according to example 53 step 5, to give CLJ-58.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.53(s,1H),8.81(d,J＝1.8Hz,1H),8.58(d,J＝2.6Hz,1H),8.45(s,1H),7.99(d,J＝2.0Hz,1H),7.54–7.32(m,3H),6.44(d,J＝3.1Hz,1H),4.47(t,J＝6.5Hz,2H),3.17–3.08(m,1H),3.03(t,J＝6.5Hz,2H),1.32–1.18(m,4H). ¹³ C NMR(101MHz,CDCl ₃ )δ173.16,157.40,145.92,143.52,143.48,132.93,132.08,129.47,129.37,128.33,125.18,120.09,117.07,112.40,111.29,102.88,29.84,14.26,12.35,12.16.HRMS-ESI:calcd for C ₂₂ H ₁₈ FN ₇ NaO[M+Na] ⁺ 438.1455,found:438.1457.

Example 57

3- (4- (5-fluoro-2- ((1- ((4- (trifluoromethyl) phenyl) sulfonyl) -1H-indol-5-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile

Steps 1, 2, 3, 4 are the same as steps 1, 2, 3, 4 of example 56.

Step 5:3- (4- (2- (((1H-indol-5-yl) amino) -5-fluoropyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile is reacted with p-trifluoromethanesulfonyl chloride according to example 56 step 5 to give CLJ-59. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.53(s,1H),8.95(d,J＝1.6Hz,1H),8.59(d,J＝2.5Hz,1H),8.44(s,1H),8.35(d,J＝8.3Hz,2H),8.10(d,J＝8.4Hz,2H),7.97(d,J＝2.0Hz,1H),7.49(d,J＝8.9Hz,1H),7.39(dd,J＝9.5,2.6Hz,2H),6.44(d,J＝3.1Hz,1H),4.46(t,J＝6.5Hz,2H),3.02(t,J＝6.5Hz,2H). ¹³ C NMR(101MHz,DMSO)δ157.52,147.75,145.39,139.90,135.13,133.27,132.28,129.73,129.28,128.65,128.17,127.80,126.81,124.84,120.07,119.35,116.14,111.14,110.04,101.73,51.02,22.58.HRMS-ESI:calcd for C ₂₅ H ₁₈ F ₄ N ₇ O ₂ S[M+H] ⁺ 556.1179,found:556.1176.

Test example 1, pharmacological Activity test

In vitro kinase activity determination experimental method

In a reaction tube, buffer (8 mM) MOPS, pH 7.0,0.2mM EDTA,10mM MnCl, was added sequentially ₂ ) The kinase to be tested, the substrate for the kinase to be tested, 10mM magnesium acetate and gamma 33P-ATP solution, and various concentrations of the compound are then added MgATP to the reaction to initiate the enzymatic reaction process, and incubated at room temperature for 40 minutes. The reaction was finally stopped with 5. Mu.l of 3% phosphate buffer and 10. Mu.l of the reaction solution was titrated onto a Filtermat A membrane, washed three times with 75mM phosphate solution for 5 min each, once with methanol, finally the Filtermat A membrane was dried and scintillation counted, the scintillation count value reflecting the substrate was phosphorylatedThe extent to which kinase activity can be characterized. 100nM indicates inhibition of the enzyme at a level of 100nM, data were measured by Eurofins. The measurement results are shown in Table 1:

table 1. Results of enzyme activity at 100nM for the JAK kinase family for the test compounds.

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Claims

A 2, 4-disubstituted pyrimidine derivative or a pharmaceutically acceptable salt thereof, characterized by the following structural formula:
2.2,4-disubstituted pyrimidine derivatives or pharmaceutically acceptable salts thereof, characterized by the following structure:
3. a pharmaceutical composition comprising the 2, 4-disubstituted pyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2 as an active ingredient, and a pharmaceutically acceptable auxiliary ingredient.
4. Use of a 2, 4-disubstituted pyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2 or a pharmaceutical composition according to claim 3 in the preparation of a JAK kinase inhibitor.
5. The use according to claim 4, wherein the JAK kinase inhibitor is a JAK1 kinase inhibitor, a JAK2 kinase inhibitor, a JAK3 kinase inhibitor or a TYK2 kinase inhibitor.
6. Use of a 2, 4-disubstituted pyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2 or a pharmaceutical composition according to claim 3 in the manufacture of a medicament for the treatment and/or prevention of a tumor.
7. The use according to claim 6, wherein the tumor is selected from the group consisting of solid tumors and hematological tumors.
8. The use according to claim 7, wherein the solid tumor is selected from the group consisting of: lymphoma, ovarian, breast, bladder, kidney, esophagus, neck, pancreas, colorectal, stomach, non-small cell lung, thyroid, brain, epidermal transitional hyperplasia, psoriasis, or prostate cancer, and combinations thereof;

The hematological neoplasm is selected from: acute myelogenous leukemia, chronic myelogenous leukemia, myeloma, acute lymphoblastic leukemia, acute myelogenous leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic neutrophilic leukemia, acute undifferentiated leukemia, myelodysplastic syndrome, myelodysplastic disorder, myelofibrosis, multiple myeloma or spinal sarcoma, and combinations thereof.
9. The use according to claim 8, wherein the lymphoma is selected from the group consisting of: b-cell lymphoma, chronic lymphocytic lymphoma or lymphoplasmacytic lymphoma.
10. Use of a 2, 4-disubstituted pyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2 or a pharmaceutical composition according to claim 3 in the manufacture of a medicament for the treatment and/or prophylaxis of autoimmune diseases.
11. The use according to claim 10, wherein the immune disorder is selected from the group consisting of: psoriasis, inflammatory bowel disease, sjogren's syndrome, behcet's disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, polymyositis, dermatomyositis, peri-arteritis nodosa, mixed connective tissue disease, scleroderma, deep lupus erythematosus, chronic thyroiditis, graves 'disease, autoimmune gastritis, type I and type II diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, graft versus host disease, addison's disease, abnormal immune response, arthritis, or dermatitis.