WO2021078021A1

WO2021078021A1 - Small molecular compound

Info

Publication number: WO2021078021A1
Application number: PCT/CN2020/120131
Authority: WO
Inventors: 邢莉; 李冠群; 王晓磊; 蔡雨婷; 姜翔; 潘翔; 朱文浩; 汪杨; 王增全
Original assignee: 嘉兴特科罗生物科技有限公司
Priority date: 2019-10-24
Filing date: 2020-10-10
Publication date: 2021-04-29
Also published as: CN110862376A

Abstract

Provided in the present invention is a small molecular compound, which is characterized in being a compound represented by the following structural formula or a stereoisomer, geometric isomer, tautomer, racemate, hydrate, solvate or metabolite thereof and a pharmaceutically acceptable salt or prodrug shown in formula (I): X1 and X2 are selected from carbon or nitrogen; Z is carbon or nitrogen; n1 is 0 or 1; n2 and n3 are the same or different, and are 0 or any natural number; the cyclic group represented by G is a saturated heterocyclic ring; any one or several hydrogen atoms on the saturated heterocyclic ring are substituted by R; and R is selected from hydrogen, halogen, alkyl, substituted alkyl, amino, amine, substituted amine, carboxy, amide, substituted amide, ester, substituted carbonyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted sulfone, and substituted sulfoxide. The small molecular compound of the present invention may be used to treat, prevent and alleviate autoimmune diseases and/or immune-related inflammatory skin diseases.

Description

A small molecule compound

Technical field

The present invention relates to the field of small molecule compounds, in particular, to a small molecule compound and derivatives that can be used to treat, prevent and alleviate autoimmune diseases and or immune-related inflammatory skin diseases.

Background technique

JAK (Janus Kinase)-STAT (Signal Transducer and Activator of Transcription proteins) signal transduction pathway is the main pathway of intracellular transmission of signals stimulated by the combination of inflammatory cytokines and receptors. JAKs are a family of intracellular non-receptor tyrosine protein kinases (Tyrosine Kinase), including four members: JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). JAKs are mainly expressed in hematopoietic cells, leukocytes and intestinal epithelial cells, and are responsible for mediating the signal transmission of various cytokines involved in inflammation. When the cytokine binds to the cell surface receptor, JAK is activated by autophosphorylation, and the activated JAK is then activated by phosphorylation of the intracellular part of the receptor and recruits members of the STAT protein family. JAK activates STAT through phosphorylation. The activated STAT can form a dimer, break away from the receptor and enter the cell nucleus to regulate gene transcription, thereby affecting the biological function of the cell. JAK-STAT signal transmission, through gene mutation, express or increase the local concentration of cytokine, has been recognized in various inflammatory diseases and various cancers.

A large amount of evidence proves that JAKs have important effects on immune and inflammatory diseases, cancer and many diseases. For example, transgenic mice lacking JAK1 cannot respond to IFN stimulation, suggesting that JAK1 is mainly related to the differentiation of Th1 cells in the immune system. The high activity of JAK2 caused by gene fusion is related to leukemia, especially the type of clonal proliferation of eosinophils; the high activity of JAK2 caused by JAK2-V617F and Polycythemia Vera, Essential Thrombocythemia , Myelofirbosis (Myelofirbosis) and other myeloproliferative disorders (Myeloproliferative disorders) are related, because this hyperactive mutation makes hematopoietic stem cells more sensitive to the stimulation of growth factors. JAK3 is mainly expressed in blood system cells, especially T cells and NK cells, as well as epidermal cells. In neutrophils, JAK3 is responsible for mediating the chemotaxis of neutrophils induced by IL-8 stimulation. The inactivating mutation of JAK3 leads to autosomal inherited severe combined immunodeficiency (SCID), and its activating mutation (mostly occurring in the JH1 and JH2 regions) can lead to lymphoid and NK cell lineage leukemia or megakaryocyte leukemia. In the intestinal epithelium, JAK3 combines with the villus protein on the cytoskeleton, which plays an important role in the normal differentiation, damage repair and homeostasis maintenance of the intestinal epithelium. In view of the role of JAK3 in the differentiation and development of immune cells, inhibiting JAK3 can achieve immunosuppressive functions. Pfizer's JAK3 inhibitor Tofacitinib (Xeljanz) was approved by the FDA in 2012 to treat rheumatoid arthritis. Tyk2 is expressed in a variety of tissues, especially the bone marrow, appendix, lymph nodes and spleen, which are immune-related organs and tissues. Tyk2 knock-out gene (Tyk2-/-) mice have a normal phenotype, but cannot be induced to experimental arthritis; A variety of immune cells isolated from Tyk2-/- mice have decreased response to inflammatory stimuli. In particular, Tyk2-/- macrophages lack production of nitric oxide after being stimulated by LPS. Further molecular mechanism studies have found that Tyk2-/- and Tyk2-/- and IFN-/- mice lack LPS-induced endotoxin shock response, while STAT1-/- mice are highly sensitive to this response, suggesting that Tyk2 plays an indispensable role in the body's inflammatory response. In terms of signal transduction to cytokines, studies have found that Tyk2 is necessary for the intracellular signal transmission of Type I IFN (IFNα & IFNβ), IL-6, IL-10, IL-12, and IL-23. These cells Factors except IL-10 can stimulate inflammation and play an important role in the pathogenesis of autoimmune diseases. Tyk2 loss-of-function gene mutations in humans can cause high IgE syndrome (Hyperimmuoglobulin E syndrome), which is a Th2 cell-driven disease state; this may be because Tyk2-mediated immune responses are mostly achieved by Th1 and Th17 cells. It is an autoimmune response, which inhibits the differentiation of Th2 cells to a certain extent. When Tyk2 is missing, the differentiation of T cells is unbalanced, turning from Th1/Th17 to Th2. It can be seen that inhibition of Tyk2 may be a new direction for immunosuppressive drug development, especially for autoimmune diseases driven by the IL17/IL23 axis.

After the combination of inflammatory cytokines and cell surface receptors, it promotes intracellular signal transduction, and finally signal transduction enters the nucleus, achieving specific biological functions by affecting the expression of downstream genes. Therefore, the development of autoimmune drugs against targets on intracellular signal transduction pathways should achieve better specificity and stronger drug effects, and of course, it should be correspondingly safer. The research progress of JAK-STAT signal transduction pathway which is common to inflammatory cytokines provides the basis for such a conception. During the pathogenesis of psoriasis, several cytokines such as IL21 and IL-23 derived from monocytes and macrophages and DCs play a key role in the differentiation of Th17 cells, and the accumulation of a large number of Th17 cells in the epidermis is psoriasis. One of the characteristics is that blocking the signal transduction induced by inflammatory cytokines in the differentiation process of Th17 cells and the signal transduction induced by inflammatory factors in keratinocytes and other immune cells is expected to obtain efficient and safe autoimmune inhibitors.

In summary, it is necessary to develop efficient and selective JAK inhibitors, especially inhibitors for Tyk2 and Jak1. Tyk2 is extremely important for signaling pathways mediated by Type I interfenons (IFN-α, IFN-β), IL-6, IL-10, IL-12, IL-23 and other cytokines. Tyk2 through different combinations with other members of the JAK family, such as Tyk2/Jak1, Tyk2/Jak2, Tyk2/Jak1/Jak2, directly affects the natural killing of cells, B cells and T cells related to inflammatory diseases and autoimmune diseases. Differentiation and functional changes. At present, many pharmaceutical companies have conducted research and development of new drugs for members of the JAK family, but most of them are focused on inhibiting JAK1 and JAK3. In particular, there are few reports on inhibitors against Tyk2.

Summary of the invention

The present invention aims to develop suitable high-efficiency and specific JAK kinase inhibitors, especially Tyk2 inhibitors, and/or JAK1 inhibitors, Tyk2/Jak2, and/or Jak1/Tyk2 dual inhibitors for the treatment, prevention and relief of self Small molecule compounds and derivatives for immune diseases and or immune-related inflammatory skin diseases, the first indication is psoriasis as an example.

The small molecule compound provided by the present invention is characterized in that it is a compound represented by the following structural formula or its stereoisomers, geometric isomers, tautomers, racemates, hydrates, solvates, Metabolites and pharmaceutically acceptable salts or prodrugs:

Wherein, the aforementioned X ₁ and X _{2 are} selected from carbon or nitrogen;

That is, in the present invention, the left structure of the small molecule compound can be three types of compounds as shown in the following structures:

The above Z is carbon or nitrogen;

The above n1 is 0, 1;

When n1 is 1, Z is preferably N;

The above n2 and n3 are the same or different, and are 0 or any natural number;

The cyclic group represented by G above is a saturated heterocyclic ring;

That is, the G ring can be any alkyl heterocycle, such as three-membered, four-membered, five-membered, six-membered, seven-membered aza, oxa, and sulfur heterocycles. Generally speaking, the number of aza, oxa, and thia on the ring does not exceed three. It can appear in the following form:

When R is multiple substitution, each R is the same or different;

The above-mentioned R is selected from hydrogen, halogen, alkyl, substituted alkyl, amino, amino, substituted amine, carboxy, amido -CONH ₂ , substituted amido, ester (-C(O)OR _z , R _z is alkyl, aryl, etc.), substituted carbonyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted The heteroaryl group, substituted sulfone group, substituted sulfoxide group.

The above-mentioned alkyl groups are generally branched or branched chain alkyl groups with no more than 6 carbon atoms;

The above-mentioned substituted alkyl group means that one or more of the hydrogen atoms on the carbon chain of the alkyl group is substituted by other groups, and the other groups referred to herein may be cycloalkyl groups (in order to be similar to

Any hydrogen atom on the cycloalkyl ring can also be substituted by halogen, cyano, alkyl, hydroxyl, carboxyl and other groups), heterocycloalkyl (ie, in the aforementioned cycloalkyl On the basis of, at least one carbon atom on the alkyl ring is replaced by oxygen, sulfur, and nitrogen), halogen (F, Cl, Br, I), carboxyl, cyano (-CN), sulfonic acid (-SO) _4,), a sulfonyl group (-SO ₂ R _{_a,} R _a is hydrogen, an alkyl group, an aryl group, etc.), an alkynyl group (-C≡CH, -C≡CR _{_b,} R _b is alkyl, aryl, etc.) , Amido group (-C(O)NR _x R _y , R _x R _y is alkyl, aryl, etc.), ester group (-C(O)OR _z , R _z is alkyl, aryl, etc.), aryl Groups, heteroaryl groups, etc.;

As several special schemes, the above-mentioned substituted alkyl groups can be several types of compounds shown in the following structures:

That is, the substituted alkyl group can be

form;

Wherein, the aforementioned n is 1, 2, 3...a natural number; preferably within 6.

The above R ¹ is an alkyl group, such as a branched or straight chain alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.;

One or more hydrogen atoms on the alkyl group can also be cycloalkyl, cyano, halogen, haloalkane (chloromethyl, dichloromethane, trichloromethyl, chloroethyl, chloropropan, Bromomethyl, dibromomethyl, tribromomethyl, bromoethyl, bromopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethane, fluoropropanyl and similar halogenated alkyl groups ) Is substituted, taking the substituted methyl as an example, to form the structure shown in the following molecular formula:

R ¹¹ and R ^{12 are the} same or different, and are respectively selected from cyano, halogen, and alkyl halide;

Or R ¹ is a cycloalkyl group, such as: cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc., one or more hydrogen atoms on the cycloalkylalkyl ring may be an alkyl group, a cyano group, Substituted by halogen and alkyl halide, the specific structure can be a compound shown in the following structural formula:

n1 is 0,1,2,3,4,5;

R ¹³ is that one or more hydrogen atoms on the alkyl ring are substituted or unsubstituted by halogen or cyano;

Or R ¹ is a heterocycloalkyl group, such as a four-membered, five-membered, six-membered heterocyclic ring of aza, oxa, or thia. One or more hydrogen atoms on the ring of the heterocycloalkyl group may be an alkyl group , Cyano, halogen, haloalkane, the specific structure can be a compound shown in the following structural formula:

B ₁ , B ₂ , B ₃ , B ₄ , B ₅ , and B ₆ are carbon, oxygen, sulfur, and nitrogen;

R ¹⁴ is that one or more hydrogen atoms on the alkyl ring are substituted or unsubstituted by halogen or cyano.

In addition, the above R can also be

That is, the methyl group has three substituents, which are substituted by R ² , R ³ and -C(O)-R ¹ ;

Among them, the above R ² and R ³ are the same or different alkyl groups (for example, generally refer to alkyl groups with no more than 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.) ).

In addition, the above-mentioned substituted alkyl group may also be

That is, two hydrogens on the methyl group form an alkyl ring through a bridge bond, and the other hydrogen is replaced ^{by -C(O)-R 1;}

Wherein, the above m is 0,1,2,3,4,5, that is, cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc., one or more hydrogens on the cycloalkyl alkyl ring Atoms may be ^{substituted or unsubstituted by R 4} alkyl, cyano, halogen, haloalkane.

The above-mentioned substituted amine group means that one or more of the hydrogen atoms on the amine group is substituted by other groups, and the other groups referred to here can be alkyl groups, cycloalkyl groups, carboxyl groups, cyano groups, and sulfonic acid groups. , Amide, ester, etc. groups;

As several special schemes, the above-mentioned substituted amine groups can be several types of compounds as shown in the following structures:

Wherein, the above-mentioned R ₁ is hydrogen or an alkyl group (for example, generally refers to an alkyl group with carbon atoms not greater than 6 such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.);

The above R ₂ is alkyl (same as above), substituted alkyl (same as above), cycloalkyl (cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc.), substituted cycloalkyl (i.e. , One or more of the hydrogen atoms on the cycloalkyl ring are substituted by halogen, cyano, or alkynyl, such as:

The structure shown in the form, R ¹⁵ is halogen, cyano, alkynyl, etc.), heterocycloalkyl (at least one carbon atom on the 3- to 7-membered ring is replaced by nitrogen, sulfur or oxygen), substituted heterocycle Alkyl (one or more of the hydrogen atoms on the heterocycloalkyl ring are substituted by halogen, cyano, or alkynyl), sulfone (

R ¹⁶ is an alkyl group, a halogen group, an aryl group, etc.), a sulfoxide group (

R ¹⁷ is alkyl, halogen, aryl, etc.), substituted carbonyl (

R ¹⁷ is an alkyl group, a substituted alkyl group, an aryl group, etc.).

In addition, the above-mentioned substituted amine group can also be

form;

Wherein, the above R ₃ is hydrogen or alkyl;

The above R _{4 is the} same as R ₂ .

As a special example, the above-mentioned substituted amide group can be several types of compounds as shown in the following structures:

Wherein, the above R ₅ is hydrogen or alkyl;

The above R _{6 is the} same as R ₂ .

As a special example, the above-mentioned substituted carbonyl group can be several types of compounds as shown in the following structures:

The above R is

Wherein, the above-mentioned R _{7 is the} same as R ₂ .

The substituted cycloalkyl mentioned in the present invention means that one or more hydrogen atoms on the ring of the cyclic group are substituted by other groups, and the other groups referred to herein can be alkyl groups, substituted alkyl groups (same as above) , halo (F, Cl, Br, I ), carboxy, cyano (-CN), a sulfonic acid group (-SO _4,), a sulfonyl group (-SO ₂ R _{_a,} R _a is hydrogen, alkyl, aryl, Etc.), alkynyl (-C≡CH, -C≡CR _b , R _b is alkyl, aryl, etc.), amide group (-C(O)NR _x R _y , R _x R _y is alkyl, aryl Groups, etc.), ester groups (-C(O)OR _z , R _z is alkyl, aryl, etc.), aryl, heteroaryl, etc. groups.

The substituted heterocycloalkyl mentioned in the present invention refers to the above-mentioned substituted cycloalkyl in which one or more carbon atoms on the ring are replaced by oxygen, sulfur, and nitrogen.

The aryl group mentioned in the present invention refers to a six-membered or above aromatic ring such as benzene and naphthalene or a benzo aromatic ring.

The substituted aryl groups mentioned in the present invention refer to five-membered or above aromatic rings or benzo aromatic rings such as benzene, naphthalene, and fluorene. One or more hydrogen atoms on the ring are replaced by other groups. Other groups referred to can be alkyl, substituted alkyl (same as above), halogen (F, Cl, Br, I), carboxyl, cyano (-CN), sulfonic acid (-SO _4, ), sulfonyl (-SO ₂ R _{_a,} R _a is hydrogen, an alkyl group, an aryl group, etc.), an alkynyl group (-C≡CH, -C≡CR _{_b,} R _b is an alkyl group, an aryl group, etc.), an amide group (-C (O)NR _x R _y , R _x R _y is alkyl, aryl, etc.), ester group (-C(O)OR _z , R _z is alkyl, aryl, etc.), aryl, heteroaryl, etc. And other groups.

The heteroaryl mentioned in the present invention refers to thiophene, pyrrole, pyridine, furan, imidazole, benzimidazole, quinoline and other five-membered or above aromatic heterocyclic rings or benzo aromatic heterocyclic rings.

The substituted heteroaryl mentioned in the present invention refers to thiophene, pyrrole, pyridine, furan, imidazole, benzimidazole, quinoline and other five-membered or above aromatic heterocycles or benzo aromatic heterocycles, one on the ring Or multiple hydrogen atoms are substituted by other groups. The other groups referred to here can be alkyl, substituted alkyl (same as above), halogen (F, Cl, Br, I), carboxyl, cyano (- the CN), a sulfonic acid group (-SO _4,), a sulfonyl group (-SO ₂ R _{_a,} R _a is hydrogen, an alkyl group, an aryl group, etc.), an alkynyl group (-C≡CH, -C≡CR _b, R _b is an alkyl group, an aryl group, etc.), an amide group (-C(O)NR _x R _y , R _x R _y is an alkyl group, an aryl group, etc.), an ester group (-C(O)OR _z , R _z is Alkyl, aryl, etc.), aryl, heteroaryl, etc. groups.

The sulfone group mentioned in the present invention is in the form shown in the following structure:

R ¹⁶ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, halogen, aryl, substituted aryl, etc.;

The sulfoxide group mentioned in the present invention is in the form shown in the following structure:

R ¹⁷ is an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a halogen, an aryl group, a substituted aryl group, and the like.

Furthermore, a small molecule compound provided by the present invention also has the characteristics: that is, it is a compound represented by the following structural formula or its stereoisomers, geometric isomers, tautomers, racemates, Hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs:

That is, when n1 is 0.

That is, when n1 is 1, and Z is N.

Wherein, R'is hydrogen, alkyl, substituted alkyl, ester, or substituted carbonyl.

Among them, at least one of B1 and B2 is nitrogen, sulfur or oxygen.

Among them, B1 is one of nitrogen or carbon;

R" is selected from hydrogen, halogen, alkyl, substituted alkyl, amino, amine, substituted amine, carboxy, amide, substituted amide, ester, substituted carbonyl, cycloalkyl, substituted ring Alkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl.

Further, a small molecule compound provided by the present invention also has the following characteristics: namely,

The above R is

Wherein, the m is 0 or any natural number;

The above-mentioned R ₁ is an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocycloalkyl group, and a substituted heterocycloalkyl group.

The above R is

Wherein, the above-mentioned R ₂ is an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocycloalkyl group, and a substituted heterocycloalkyl group.

Furthermore, a small molecule compound provided by the present invention also has the characteristic that any two hydrogen atoms on the cyclic group represented by G form a bridge bond.

For example: G can be represented by the following structure:

Further, a small molecule compound provided by the present invention also has the characteristics of being used for the treatment, prevention and alleviation of autoimmune diseases and inflammatory skin diseases related to autoimmunity. It can be oral, external, injection and other dosage forms.

Furthermore, a small molecule compound provided by the present invention has the following characteristics: that is, it is a composition; the mass percentage content of the small molecule compound in the composition is 10-6% to 100%. The form can be various types of preparations, such as gels, ointments, tablets and other dosage forms.

The function and effect of the present invention:

According to the protein structure of JAK kinase, especially the protein structure of JAK1 and Tyk2, the present invention is rationally designed. The synthesized compound is first tested for the kinase biochemical activity of JAK, and SAR (structure-activity relationship) is established according to IC50. The potent inhibitors below 200nM are then subjected to cytological testing to determine the selectivity of the compound. With reference to the specific activity experimental data, it can be found that the several types of compounds involved in the present invention have good cell activity inhibitory ability.

The inhibitors provided by the present invention can also be used for other autoimmune-related skin diseases such as alopecia areata, vitiligo, lupus erythematosus, lichen planus, lichen glaze, atrophic lichen sclerosus, panniculitis, atopic dermatitis. ,and many more.

The JAK inhibitors, Tyk2 inhibitors, and/or JAK1 inhibitors, and/or JAK1/Tyk2 dual inhibitors obtained in the present invention suitable for oral or intravenous administration can still be used to treat psoriasis and other autoimmunity Sexual diseases such as RA, IBD, MS, etc.

Detailed ways

Example 1. The reaction equation for the synthesis of compound TDM-180656 is as follows:

Step 1: Example 56c

The compound 56a (1.2g, 8.0mmol), compound 56b (2.97g, 9.6mmol), Pd(dppf)Cl ₂ (585mg, 0.8mmol), sodium carbonate (2.0g, 19.2mmol), 1,4-dioxide Six rings (30 mL) and water (5 mL) were added to the three-necked flask. The system is pumped to replace nitrogen three times under the condition of water pump. The reaction solution was reacted at 90°C for 2 hours and then cooled. After the completion of the reaction, the crude product was purified by column chromatography after concentration under reduced pressure (eluent: petroleum ether/EtOAc=1/1) to obtain compound 56c, which is compound 4-(2-chloropyrimidin-4-yl), as a colorless oily liquid )-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.9g, yield 80%).

LCMS[M-55] ⁺ = 240.0

¹ H NMR (400MHz, Chloroform-d) δ8.57 (d, J = 5.2Hz, 1H), 7.26 (d, J = 5.2Hz, 1H), 7.81 (s, 1H), 7.02 (s, 1H), 4.20(d,J=2.4Hz,2H), 2.60(br s,2H), 1.50(s,9H).

Step 2: Example 56e

Compound 56c (2.1g, 7.1mmol), compound 56d (0.97g, 9.94mmol), Pd ₂ (dba) ₃ (330mg, 0.36mmol), x-phos (330mg, 0.72mmol), cesium carbonate (4.6g, 14.2mmol) was added to a three-necked flask. Pumping and replacing argon three times under the condition of system oil pump Then, 1,4-dioxane (30 mL, anhydrous) was injected into the system. The reaction solution was reacted at 100°C for 3.5 hours and then cooled. After the reaction, it was filtered through Celite, the filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 9/1) to obtain the yellow solid compound 56e, 4-(2- ((1-Methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.2g, yield 48 %).

LCMS[M+1] ⁺ =357.1

¹ H NMR(400MHz,Chloroform-d)δ8.36(d,J=5.6Hz,1H),7.81(s,1H),7.55(s,1H),6.90(s,1H),6.82(s,1H) ), 6.74 (d, J = 5.6 Hz, 1H), 4.17 (d, J = 2.4 Hz, 2H), 3.93 (s, 3H), 3.66 (t, J = 5.6 Hz, 2H), 2.61 (s, 2H) ), 1.52(s, 9H).

Step 3: Example 56f(V836-48)

Compound 56e (1 g, 2.8 mmol), methanol (30 mL), and Pd/C (200 mg, 10% wt.) were added to the reaction flask. Under the condition of the system water pump, the hydrogen is pumped and replaced three times. The reaction solution was stirred at 45°C for 16 hours. After the reaction, it was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the dark yellow oily compound 56f, which is 4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl ) Tert-butyl piperidine-1-carboxylate (1.0 g, yield 89%).

LCMS[M+1] ⁺ =359.1

Step 4: Example 56g

Compound 56f (1 g, 2.8 mmol) and a 1,4-dioxane solution (8 mL, 4M) of hydrochloric acid were stirred in dichloromethane (8 mL) at room temperature for 8 hours. After the reaction, the yellow solid compound 56g (0.9g crude product) was obtained after concentration under reduced pressure, namely N-(1-methyl-1H-pyrazol-4-yl)-4-(piperidin-4-yl)pyrimidine- 2-amine.

LCMS[M+1] ⁺ = 259.1.

Step 5: Example 56 (TDM-180656)

A mixture of compound 56g (50mg, 0.19mmol) and triethylamine (97mg, 0.95mmol) in N,N-dimethylformamide (3mL) was stirred at room temperature for 5 minutes. Add ethyl sulfonyl chloride (49 mg, 0.39 mmol) under ice cooling. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, it was poured into water (10 mL), and extracted with ethyl acetate (20 mL*3). The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, the crude product was slurried with a mixed solvent (petroleum ether/ethyl acetate = 3/1), filtered, and the filter cake was washed with petroleum ether and dried to obtain a white color. The solid compound 56 is 4-(1-(ethylsulfonyl)piperidin-4-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (29.3mg, yield Rate 44%).

LCMS[M+1] ⁺ =351.1

¹ H NMR(400MHz,Chloroform-d)δ8.32(d,J=5.0Hz,1H),7.84(s,1H),7.51(s,1H),6.87(s,1H),6.55(d,J =5.0Hz,1H),3.86-4.03(m,5H),2.88-3.08(m,4H),2.61-2.73(m,1H),1.98-2.09(m,2H),1.83-1.97(m,2H) ),1.42(t,J=7.2Hz,3H).

Compounds of the same series with similar structure:

The white solid compound TDM-180657 is N-(1-methyl-1H-pyrazol-4-yl)-4-(1-(propylsulfonyl)piperidin-4-yl)pyrimidin-2-amine (40.3 mg, yield 58%).

TDM-180909 yellow solid compound 309 is N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidine-4- Base) ethanesulfonamide (2.2mg, yield: 0.7%)

Example 2: The reaction equation for the synthesis of compound TDM-180658 is as follows:

Add compound 56g (80mg, 0.31mmol), triethylamine (313mg, 3.1mmol) and N,N-dimethylformamide (5mL) into the reaction flask, and stir for about 6 minutes. Then compound 58a, propionic acid (46 mg, 0.62 mmol) and HATU (177 mg, 0.47 mmol) were added. The mixture was stirred at room temperature for 5 hours. After the reaction was completed, it was poured into water (2 mL), and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: methanol/ethyl acetate = 1/20) to obtain a yellow solid compound 58 which is 1-( 4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-1-yl)propan-1-one (73.4mg, yield 34%) .

LCMS[M+1] ⁺ =315.1

¹ H NMR(400MHz,Chloroform-d)δ8.31(d,J=5.2Hz,1H),7.82(s,1H),7.52(s,1H),6.86(s,1H),6.54(d,J =5.2Hz,1H), 4.80(d,J=13.6Hz,1H),4.01(d,J=13.6Hz,1H),3.92 (s,3H),3.11-3.21(m,2H),2.64-2.83 (m,2H),2.41(q,J=7.6Hz,2H),1.92-2.05(m,2H),1.64-1.79(m,2H),1.20(t,J=7.6Hz,3H).

The same series of compounds with similar structures are as follows:

Among them, TDM-180659 light green oily compound 59 is 1-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-1-yl) Butan-1-one (55.2 mg, yield 43%).

TDM-180660 Light yellow solid compound 60 is 3-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-1-yl)-3 -Oxopropionitrile (55.2 mg, 45% yield).

TDM-180661 White solid compound 61 is 3,3,3-trifluoro-1-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piper Pyridin-1-yl)propan-1-one (55 mg, yield 38%).

TDM-180663 Light gray solid compound 63 is cyclopropyl (4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-1-yl)methyl Ketone (46.7 mg, 37% yield).

TDM-180664 Light green oily compound 64 (2,2-difluorocyclopropyl) (4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl ) Piperidin-1-yl) ketone (62.5 mg, yield 44%).

Example 3. General synthesis method of synthetic compound TDM-180662

Step 1: Example 62b

Using compound 56g as raw material, the synthesis procedure is similar to that of compound 58. Obtain the light yellow solid compound 62b that is compound 2-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-1-yl)-2- Oxoethyl acetate (90 mg, 32% yield).

LCMS[M+1] ⁺ =359.1

¹ H NMR(400MHz,Chloroform-d)δ8.32(d,J=4.8Hz,1H),7.82(s,1H),7.51(s,1H),6.89(s,1H),6.54(d,J =4.8Hz,1H),4.65-4.85(m,3H),3.92(s,3H),3.74-3.85(m,1H),3.13-3.27(m,1H),2.70-2.86(m,2H), 2.22(s,3H),1.94-2.06(m,2H).

Step 2: Example 62 (TDM-180662)

To a solution of compound 62b (90 mg, 0.25 mmol) in tetrahydrofuran (5 mL) was added aqueous lithium hydroxide solution (1.5 mL, 1M). The mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate (15 mL*7). The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: methanol/ethyl acetate = 1/20 to obtain compound 62, which is 2-hydroxy- 1-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-1-yl)ethanone (47.7mg, yield 60%) .

LCMS[M+1] ⁺ ＝317.1

¹ H NMR(400MHz,Chloroform-d)δ8.32(d,J=5.2Hz,1H),7.80(s,1H),7.50(s,1H),6.86(s,1H),6.54(d,J =5.2Hz, 1H), 4.69-4.79 (m, 1H), 4.15-4.29 (m, 2H), 3.92 (s, 3H), 3.60-3.79 (m, 3H), 3.08-3.19 (m, 1H), 2.76-2.92 (m, 3H), 1.98-2.08 (m, 2H), 1.71-1.84 (m, 2H).

Example 4. The reaction equation for the synthesis of compound TDM-180682 is as follows:

Step 1: Example 82c

The original compound 82a, namely 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (674mg, 3.07mmol) and n-butanol (40mL) were added to the single-necked flask, and then Compound 82b, 1-tert-butoxycarbonylpiperazine (735 mg, 6.45 mol) and trifluoroacetic acid (735 mg, 6.45 mol) were added to a single-necked flask. After reacting at 50°C for 16 hours, the reaction solution was concentrated under reduced pressure. Purification by column (dichloromethane/methanol=98.5/1.5) to obtain a white solid compound 82c, namely 4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piper Tert-Butyl oxazine-1-carboxylate (660 mg, yield 52.6%). LCMS [M+1] ⁺ = 360.1.

Step 2: Example 82d

The compound 82c (660mg, 1.84mmol), dioxane hydrochloride solution (15mL) and ethyl acetate (20mL) were added to a single-necked flask and reacted at 20°C for 2 hours. After the reaction solution was concentrated, compound 82d was obtained. N-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)pyrimidin-2-amine (660 mg, crude product). LCMS [M+1] ⁺ = 260.1.

Step 3: Example 82 (TDM-180682)

The compound 82d (100mg, 0.385mmol), triethylamine (156mg, 1.54mmol) and N,N-dimethylformamide (10mL) were added to a single-neck flask, and after stirring for 5 min, compound 82e was ethyl sulfonate The acid chloride (74 mg, 0.577 mmol) was added to a single-necked flask and stirred at room temperature for 16 h. The reaction solution was washed with water and extracted with ethyl acetate (50mL*3). The organic phases were combined, and then washed with water (50mL*3) and saturated brine (50mL*3) respectively. The organic phase was separated, and the organic phase was dried and concentrated. Purification by column (ethyl acetate/methanol=20/1) to obtain a white solid compound 82, namely 4-(4-(ethylsulfonyl)piperazin-1-yl)-N-(1-methyl-1H-pyridine) Azol-4-yl)pyrimidin-2-amine (45 mg, yield 33%). LCMS [M+1] ⁺ =352.2.

¹ H NMR (400MHz, MeOD) δ 7.88 (d, J = 6.2Hz, 1H), 7.74 (s, 1H), 7.50 (s, 1H), 6.19 (d, J = 6.2Hz, 1H), 3.85 ( s, 3H), 3.79-3.73 (m, 4H), 3.38-3.33 (m, 5H), 3.06 (q, J = 7.4 Hz, 2H), 1.33 (t, J = 7.4 Hz, 4H).

Example 5: The reaction equation for synthesizing compound TDM-180683 is as follows:

Step 1: Example 83 (TDM-180683)

The compound 82d (100mg, 0.385mmol), N,N-diisopropylethylamine (200mg, 1.55mmol) and N,N-dimethylformamide (10mL) were added to the single-necked flask and stirred for 5min. , Compound 83b, 2,2-difluorocyclopropane carboxylic acid (71 mg, 0.5783 mmol) and HATU (221 mg, 0.583 mmol) were added to a single-necked flask, and stirred at room temperature for 16 hours. The reaction solution was washed with water and extracted with ethyl acetate (50mL*3). The organic phases were combined, and then washed with water (50mL*3) and saturated brine (50mL*3) respectively. The organic phase was separated, and the organic phase was dried and concentrated. Purification by column (ethyl acetate/methanol=20/1) to obtain a light yellow solid compound 83 (2,2-difluorocyclopropyl) (4-(2-((1-methyl-1H-pyrazole- 4-yl)amino)pyrimidin-4-yl)piperazin-1-yl)methanone (17 mg, yield 12%). LCMS [M+1] ⁺ = 364.2.

¹ H NMR (400MHz, MeOD) δ 7.89 (d, J = 6.2Hz, 1H), 7.76 (s, 1H), 7.51 (s, 1H), 6.20 (d, J = 6.3 Hz, 1H), 3.88- 3.59 (m, 11H), 3.00 (ddd, J=12.9, 11.2, 7.8 Hz, 1H), 2.03 (dtd, J=13.0, 7.8, 5.3 Hz, 1H), 1.86-1.73 (m, 1H).

The same series of compounds with similar structures are as follows:

White solid compound 84 is 3,3,3-trifluoro-1-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperazine-1 -Yl)-1-acetone (8 mg, yield: 5%).

Example 6. The reaction equation for synthesizing compound TDM-180685 is as follows:

Step 1: Example 85c

The original compound 82a, namely 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (627mg, 3.00mmol) and N,N-dimethylformamide (40mL) Add to a single-neck flask, and then add compound 85b, 4,7-diazaspiro[2-4]octane-4-carboxylic acid tert-butyl ester (636mg, 3.0mmol) and cesium carbonate (1.95g, 6.0mmol) Add it to a single-necked flask and react at 90°C for 16 hours. The reaction solution was washed with water and extracted with ethyl acetate (100mL*3). The organic phases were combined, washed with water and saturated brine, dried and concentrated, and purified by column (ethyl acetate/methanol=20/1) to obtain a pale yellow solid Compound 85c is 7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,7-diazaspiro[2-4]octane-4 -Tert-butyl carboxylate (820 mg, yield 71%). LCMS [M+1] ⁺ = 386.1.

Step 2: Example 85d

The compound 85c (820mg, 2.13mmol), dioxane hydrochloride solution (15mL) and ethyl acetate (30mL) were added to a single-necked flask and reacted at 20°C for 2 hours. After the reaction solution was concentrated, compound 85d was obtained. N-(1-methyl-1H-pyrazol-4-yl)-4-(4,7-diazaspiro[2.5]oct-7-yl)pyrimidin-2-amine (800 mg, crude). LCMS [M+1] ⁺ = 286.1.

Step 3: Example 85 (TDM-180685)

The compound 85d (100mg, 0.351mmol), triethylamine (143.3mg, 1.40mmol) and N,N-dimethylformamide (10 mL) were added to a single-necked flask, and after stirring for 5 min, compound 85e was ethyl Sulfonyl chloride (67 mg, 0.526 mmol) was added to a single-necked flask and stirred at room temperature for 16 h. The reaction solution was washed with water and extracted with ethyl acetate (50mL*3). The organic phases were combined, and then washed with water (50mL*3) and saturated brine (50mL*3) respectively. The organic phase was separated, and the organic phase was dried and concentrated. Purification by column (ethyl acetate/methanol=20/1) to obtain a white solid compound 85, namely 4-(4-(ethylsulfonyl)-4,7-diazaspiro[2.5]oct-7-yl)- N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (1.8 mg, yield 1.3%). LCMS[M+1] ⁺ =378.1.

¹ H NMR (400MHz, MeOD) δ 7.85 (d, J = 6.2Hz, 1H), 7.70 (s, 1H), 7.48 (s, 1H), 6.12 (d, J = 6.2Hz, 1H), 3.93- 3.75(m,5H),3.61(dd,J=11.2,5.7Hz,4H),3.06(q,J=7.3Hz,2H),1.29–1.19(m,3H),1.08(s,2H),0.91 (d, J=7.3 Hz, 2H).

Example 7. The reaction equation for synthesizing compound TDM-180686 is as follows:

Step 1: Example 86 (TDM-180686)

The compound 85d (100mg, 0.351mmol), triethylamine (143mg, 1.40mmol) and N,N-dimethylformamide (10mL) were added to the single-neck flask, and after stirring for 5min, the compound 86b was 2, 2-Difluorocyclopropane carboxylic acid (64 mg, 0.526 mmol) and HATU (200 mg, 0.526 mmol) were added to a single-necked flask and stirred at room temperature for 16 hours. The reaction solution was washed with water and extracted with ethyl acetate (50mL*3). The organic phases were combined, and then washed with water (50mL*3) and saturated brine (50mL*3) respectively. The organic phase was separated, and the organic phase was dried and concentrated. After column purification (ethyl acetate/methanol=20/1), a white solid compound 86 (2,2-difluorocyclopropyl) (7-(2-((1- Methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,7-diazaspiro[2.5]oct-4-yl)methanone (40 mg, yield 29%). LCMS [M+1] ⁺ = 390.1.

¹ H NMR (400MHz, MeOD) δ 7.87 (d, J = 6.2 Hz, 1H), 7.71 (s, 1H), 7.49 (s, 1H), 6.14 (d, J = 6.2 Hz, 1H), 4.22 ( s, 1H), 4.03 (d, J = 7.8 Hz, 1H), 3.85 (s, 3H), 3.74–3.56 (m, 2H), 3.44 (dd, J = 21.2, 11.0 Hz, 2H), 3.26–3.08 (m, 1H), 2.14 (td, J = 13.2, 7.6 Hz, 1H), 1.79 (dd, J = 14.6, 8.8 Hz, 1H), 1.44-1.21 (m, 2H), 1.09-0.89 (m, 2H ).

The same series of compounds with similar structures are as follows:

TDM-180687 White solid compound 87 is 3-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,7-diazaspiro[ 2.5]oct-4-yl)-3-oxopropionitrile (30 mg, yield: 12%).

TDM-180688 White solid compound 88 is 3,3,3-trifluoro-1-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)- 4,7-diazaspiro[2.5]oct-4-yl)propan-1-one (5 mg, yield: 4%).

Example 8. The reaction equation for synthesizing compound TDM-180695 is as follows:

Step 1: Example 95c

The original compound 82a, namely 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (627mg, 3.00mmol) and N,N-dimethylformamide (20mL) Add to the single-neck flask, and then add compound 95b (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (600mg, 3.0mol) and cesium carbonate (1.95g, 6.0mmol) into the single-neck flask , Reaction at 90°C for 16 hours. The reaction solution was washed with water and extracted with ethyl acetate (100mL*3). The organic phases were combined, washed with water and saturated brine, dried and concentrated, and purified by column (ethyl acetate/methanol=20/1) to obtain a pale yellow solid Compound 95c is (S)-2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl Ester (750 mg, 57% yield). LCMS [M+1] ⁺ = 374.1.

Step 2: Example 95d

The compound 95c (750mg, 2.01mmol), dioxane hydrochloride solution (30mL) and ethyl acetate (50mL) were added to a single-necked flask and reacted at 20°C for 2 hours. The reaction solution was concentrated to obtain the compound 95d is (S)-4-(3-methylpiperazin-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (770mg, crude). LCMS [M+1] ⁺ = 274.1.

Step 3: Example 95 (TDM-180690)

The compound 95d (100mg, 0.366mmol), triethylamine (148mg, 1.46mmol) and N,N-dimethylformamide (10mL) were added to the single-necked flask, and after stirring for 5min, the compound 95e was 2, 2-Difluorocyclopropane carboxylic acid (67 mg, 0.549 mmol) and HATU (208 mg, 0.549 mmol) were added to a single-necked flask and stirred at room temperature for 16 h. The reaction solution was washed with water and extracted with ethyl acetate (50mL*3). The organic phases were combined, and then washed with water (50mL*3) and saturated brine (50mL*3) respectively. The organic phase was separated, and the organic phase was dried and concentrated. Purification by column (ethyl acetate/methanol=20/1) to obtain a white solid compound 95 (2,2-difluorocyclopropyl)((S)-2-methyl-4-(2-((1- Methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperazin-1-yl)methanone (51 mg, 37% yield). LCMS[M+1] ⁺ =378.1.

¹ H NMR(400MHz,MeOD)δ7.77(d,J=31.2Hz,2H), 7.58(s,1H), 6.60(d,J=7.0Hz,1H), 4.78–4.39(m,2H), 4.40–4.00(m, 2H), 3.92(s, 3H), 3.80–3.42(m, 2H), 3.17–2.83(m, 1H), 2.05(d, J=13.0Hz, 1H), 1.86–1.70( m,1H),1.34–1.02(m,3H).

Example 9. The reaction equation for synthesizing compound TDM-180696 is as follows:

Step 1: Example 96 (TDM-180696)

The compound 95d (100mg, 0.366mmol), triethylamine (148mg, 1.46mmol) and N,N-dimethylformamide (10mL) were added to a single-necked flask, and after stirring for 5min, compound 96b, namely cyanoacetic acid (47mg, 0.549mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (105mg, 0.549mmol) were added to a single-necked flask and stirred at room temperature for 16h. The reaction solution was washed with water and extracted with ethyl acetate (50mL*3). The organic phases were combined, and then washed with water (50mL*3) and saturated brine (50mL*3) respectively. The organic phase was separated, and the organic phase was dried and concentrated. Purification by column (ethyl acetate/methanol=20/1) to obtain a white solid compound 96 (S)-3-(2-methyl-4-(2-((1-methyl-1H-pyrazole-4 -Yl)amino)pyrimidin-4-yl)piperazin-1-yl)-3-oxopropionitrile (24 mg, yield 19%). LCMS [M+1] ⁺ = 341.1.

¹ H NMR(400MHz, MeOD)δ7.77(d,J=30.6Hz,2H), 7.57(s,1H), 6.59(d,J=7.3Hz,1H), 4.81–4.66(m,1H), 4.42(d,J=12.3Hz,1H), 4.26–4.02(m,1H), 3.97–3.70(m,4H), 3.69–3.40(m,2H), 3.39–3.32(m,1H), 3.28– 3.01 (m, 1H), 1.23 (dd, J=38.4, 7.1 Hz, 3H).

The same series of compounds with similar structures are as follows:

TDM-180729 white solid compound 129, namely (S)-3,3,3-trifluoro-1-(2-methyl-4-(2-((1-methyl-1H-pyrazole-4- (Yl)amino)pyrimidin-4-yl)piperazin-1-yl)propan-1-one (10mg, yield 8%)

Example 9. The reaction equation for synthesizing compound TDM-180689 is as follows:

Step 1: Example 89c

To compound 89a (500mg, 2.39mmol) namely 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine and compound 89b (480mg, 2.39mmol) at room temperature, namely ( R) To the mixture of tert-butyl-2-methylpiperazine-1-carboxylate was added cesium carbonate (1.557g, 4.78mmol) and N,N-dimethylformamide (25ml). The mixture was then heated to 90°C and stirred at 90°C for 16 hours. The mixture was extracted with ethyl acetate (100ml×3). The organic layer was washed with saturated brine (60 ml×6), dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. It was purified by a silica gel column (ethyl acetate: methanol = 20:1) to obtain a white solid compound 89c, namely (R)-2-methyl-4-(2-((1-methyl-1H-pyrazole- 4-yl)amino)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (408.4 mg, yield 45.8%). LCMS [M+1] ⁺ =374.

Step 2: Example 89d

Compound 89c (408.4 mg, 1.09 mmol) and hydrochloric acid/1,4-dioxane (6 ml) were added to ethyl acetate (12 ml) at room temperature, and then the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to obtain a white solid compound 89d, namely (R)-N-(1-methyl-1H-pyrazol-4-yl)-4-(3-methylpiperazin-1-yl)pyrimidine-2 -Amine (435.6 mg). LCMS [M+1] ⁺ =274.

Step 5: Example 89f (TDM-180689)

Compound 89d (100mg, 0.366mmol) and triethylamine (0.5ml) were added to N,N-dimethylformamide (10mL), the mixture was stirred for 5 minutes, and then 2-(7-oxybenzene) was added to the mixture Triazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (208.62mg, 0.549mmol) and compound 89e (67mg, 0.549mmol) that is 2,2-difluorocyclopropane- 1-carboxylic acid and stirred at room temperature for 16 hours. The mixture was extracted with ethyl acetate (100 mL×3), and the organic layer was washed with saturated brine (60 mL×6), dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. It was first passed through a silica gel column (ethyl acetate: methanol = 20:1) and then preparatively purified to obtain a white solid compound 89 (2,2-difluorocyclopropyl)((R)-2-methyl-4- (2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperazin-1-yl)methanone (17 mg, 12.3% yield). LCMS [M+1] ⁺ =378.

1H NMR(400MHz,CDCl3)δ11.88(d,J=18.6Hz,1H),7.88(d,J=53.5Hz,1H),7.72(s,1H),7.55(s,1H),6.12(s ,1H),5.09-4.24(m,5H),3.91(s,3H),3.76-3.06(m,3H),2.50(s,1H),2.31-2.02(m,1H),1.72(dd,J = 28.0, 21.2 Hz, 1H), 1.26 (dd, J = 23.6, 19.1 Hz, 4H).

TDM-180703 White solid compound 103 is (R)-3-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piper (Azin-1-yl)-3-oxopropionitrile (42.6mg, yield: 34.2%)

TDM-180732 White solid compound 132 namely (R)-3,3,3-trifluoro-1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl) Amino)pyrimidin-4-yl)piperazin-1-yl)propan-1-one (7mg, yield: 10%)

Example 10: The reaction equation for synthesizing compound TDM-180701 is as follows:

Step 1: Example 101c

The original compound 82a, namely 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (627mg, 3.00mmol) and N,N-dimethylformamide (20mL) Add to the single-necked flask, and then add compound 701b (S)-2-ethylpiperazine-1-carboxylic acid tert-butyl ester (632mg, 3.0mol) and cesium carbonate (1.95g, 6.0mmol) into the single-necked flask , Reaction at 90°C for 16 hours. The reaction solution was washed with water and extracted with ethyl acetate (100mL*3). The organic phases were combined, washed with water and saturated brine, dried and concentrated, and purified by column (ethyl acetate/methanol=20/1) to obtain a pale yellow solid Compound 701c is (S)-2-ethyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl Ester (670mg, 58% yield). LCMS [M+1] ⁺ = 388.1.

Step 2: Example 101d

The compound 101c (670mg, 1.73mmol), dioxane hydrochloride solution (15mL) and ethyl acetate (30mL) were added to a single-necked flask and reacted at 20°C for 2 hours. The reaction solution was concentrated to obtain the compound 101d is (S)-4-(3-ethylpiperazin-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (760mg, crude). LCMS [M+1] ⁺ = 288.1.

Step 3: Example 101 (TDM-180701)

The compound 101d (100mg, 0.348mmol), triethylamine (142mg, 1.39mmol) and N,N-dimethylformamide (10mL) were added to a single-necked flask, and after stirring for 5min, compound 101e was 2, 2-Difluorocyclopropanecarboxylic acid (64mg, 0.522mmol) and HATU (198mg, 0.522mmol) were added to a single-necked flask, and stirred at room temperature for 16h. The reaction solution was washed with water and extracted with ethyl acetate (50mL*3). The organic phases were combined, and then washed with water (50mL*3) and saturated brine (50mL*3) respectively. The organic phase was separated, and the organic phase was dried and concentrated. Purification by column (ethyl acetate/methanol=20/1) to obtain a white solid compound 101 (2,2-difluorocyclopropyl)((S)-2-ethyl-4-(2-((1- Methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperazin-1-yl)methanone (35 mg, yield 26%). LCMS [M+1] ⁺ = 392.2.

¹ H NMR(400MHz, MeOD)δ7.77(d,J=30.8Hz,2H), 7.58(s,1H), 6.60(d,J=7.3Hz,1H), 4.77–4.30(m,2H), 4.31–3.99(m,2H), 3.92(s,3H), 3.72–3.36(m,2H), 3.22–2.86(m,2H), 2.20–1.93(m,1H), 1.81(dd,J=11.7 ,6.8Hz,1H),1.61(d,J=30.0Hz,2H),1.00-0.73(m,3H).

The same series of compounds with similar structures are as follows:

TDM-180702 white solid compound 102 is (S)-3-(2-ethyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piper Azin-1-yl)-3-oxopropionitrile (21 mg, yield: 17%).

TDM-180730 White solid compound 130, namely (S)-1-(2-ethyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl) Piperazin-1-yl)-3,3,3-trifluoropropan-1-one (5mg, yield 7%)

Embodiment 11. The reaction equation for synthesizing compound TDM-180690 is as follows:

Step 1: Example 90c

The original compound 82a, namely 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (627mg, 3.00mmol) and N,N-dimethylformamide (20mL) Add to the single-necked flask, and then add compound 90b (R)-2-ethylpiperazine-1-carboxylic acid tert-butyl ester (632mg, 3.0mmol) and cesium carbonate (1.95g, 6.0mmol) into the single-necked flask , Reaction at 90°C for 16 hours. The reaction solution was washed with water and extracted with ethyl acetate (100mL*3). The organic phases were combined, washed with water and saturated brine, dried and concentrated, and purified by column (ethyl acetate/methanol=20/1) to obtain a pale yellow solid Compound 90c is (R)-2-ethyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl Ester (740 mg, yield 55%). LCMS [M+1] ⁺ = 388.1.

Step 2: Example 90d

The compound 90c (740 mg, 1.91 mmol), dioxane hydrochloride solution (20 mL) and ethyl acetate (40 mL) were added to a single-necked flask and reacted at 20°C for 2 hours. The reaction solution was concentrated to obtain the compound 90d is (R)-4-(3-ethylpiperazin-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (810mg, crude). LCMS [M+1] ⁺ = 288.1.

Step 3: Example 90 (TDM-180690)

The compound 90d (100mg, 0.348mmol), triethylamine (142mg, 1.39mmol) and N,N-dimethylformamide (10mL) were added to the single-necked flask, and after stirring for 5min, the compound 90e was 2, 2-Difluorocyclopropane carboxylic acid (64 mg, 0.522 mmol) and HATU (198 mg, 0.522 mmol) were added to a single-necked flask and stirred at room temperature for 16 hours. The reaction solution was washed with water and extracted with ethyl acetate (50mL*3). The organic phases were combined, and then washed with water (50mL*3) and saturated brine (50mL*3) respectively. The organic phase was separated, and the organic phase was dried and concentrated. Purification by column (ethyl acetate/methanol=20/1) to obtain a white solid compound 90 (2,2-difluorocyclopropyl)((R)-2-ethyl-4-(2-((1- Methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperazin-1-yl)methanone (26 mg, yield 8%). LCMS [M+1] ⁺ = 392.1.

¹ H NMR(400MHz,MeOD)δ7.77(d,J=33.0Hz,2H), 7.57(s,1H), 6.60(d,J=7.2Hz,1H), 4.75–3.96(m,4H), 3.92(s,3H), 3.48(s,1H), 3.20–2.86(m,2H), 2.15–1.96(m,1H), 1.89–1.77(m,1H), 1.61(d,J=30.5Hz, 2H), 0.89 (dd, J=22.5, 14.8 Hz, 3H).

The same series of compounds with similar structures are as follows:

TDM-180691 white solid compound 91 is (R)-3-(2-ethyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piper Azin-1-yl)-3-oxopropionitrile (15 mg, yield: 6%).

TDM-180692 White solid compound 92 is (R)-1-(2-ethyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piper (Azin-1-yl)-3,3,3-trifluoropropan-1-one (15 mg, yield: 11%).

Example 12: The reaction equation for synthesizing compound TDM-180733 is as follows:

Step 1: Example 133b

Tert-Butyl 2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperazine-1-carboxylate

A mixture of the original compound B0 (250 mg, 1.2 mmol), compound 133a (368 mg, 1.84 mmol), Cs2CO3 (782 mg, 2.4 mmol) in DMSO (15 mL) was stirred at 100°C for 16 hours. The reaction mixture was poured into water (20 mL). Then the mixture was extracted with EtOAc (40 mL×3). The combined organic layer was washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. Column chromatography (petroleum ether/ethyl acetate=0/100, 5% methanol in ethyl acetate) was purified to obtain white solid compound 133b (300 mg, yield 67%). LCMS[M+1] ⁺ ＝374.2.

Step 2: Example 133c

N-(1-methyl-1H-pyrazol-4-yl)-4-(3-methylpiperazin-1-yl)pyrimidin-2-amine

To a solution of compound 133b (300 mg, 0.89 mmol) in DCM (6 mL) was added HCl/1,4-oxane (3 mL, 4M). The reaction was stirred at 30°C for 2 hours. The reaction mixture was concentrated under reduced pressure, sucked dry, and used directly in the next step. A white solid compound 133c (280 mg crude product, should be HCl salt) was obtained. LCMS[M+1] ⁺ ＝274.2.

Step 3: Example 133e

2-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperazin-1-yl) benzyl acetate

A mixture of compound 133c (130 mg, 0.48 mmol), compound 133d (220 mg, 0.96 mmol), Cs2CO3 (390 mg, 1.2 mmol) and DMF (10 mL) was stirred at 40°C for 2 hours. The mixture was poured into H2O (40 mL), and extracted with EtOAc (30 mL×3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (petroleum ether/ethyl acetate=0/100, 5% methanol in ethyl acetate) gave a colorless oily substance 133e (130mg, yield 64%). LCMS[M+1] ⁺ = 422.1.

Step 4: Example 133f

2-(2-Methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperazin-1-yl)acetic acid

To a solution of compound 133e (130 mg, 0.31 mmol) in MeOH (6 mL) was added LiOH (6 mL, 1M) aqueous solution. The resulting mixture was stirred at 30°C for 4 hours. The reaction mixture was concentrated and neutralized to pH about 5 with HCl (2N). Attempt to extract the product with DCM, ethyl acetate, 10% MeOH in DCM, but failed. The aqueous phase was lyophilized to obtain a crude white solid. DMF (10 mL) was added to the solid, filtered, and the filtrate was used directly in the next condensation step without further purification. [Assume 100 mg of product is obtained]. LCMS[M+1] ⁺ =332.1.

Step 5: Example 133 (TDM-180733)

1-(3,3-Difluoropyrrolidin-1-yl)-2-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine- 4-yl)piperazine-piperazin-1-yl)ethan-1-one

To DIPEA (200 mg, 1.5 mmol) and DMF (10 mL) of compound 133f (100 mg, 0.3 mmol) were added HATU (171 mg, 0.45 mmol) and compound 133g (129 mg, 0.9 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was poured into H2O, extracted with EtOAc (30mL×3), the combined organic layer was washed with H2O and brine, dried over Na2SO4, filtered, concentrated, and purified by preliminary column chromatography (DCM/MeOH=10/1), then Basic preparation and purification, and column chromatography (EtOAc/MeOH=20:1) purification again. A white solid compound 133 (29.8 mg; yield 24%) was obtained.

LCMS[M+1] ⁺ = 421.1.

1H NMR(400MHz,Chloroform-d)δ7.90(d,J=5.6Hz,1H),7.66(s,1H),7.53(s,1H),6.01(d,J=5.6Hz,1H),3.71 -4.18 (m, 9H), 3.48-3.62 (m, 1H), 3.28-3.40 (m, 1H), 2.87-3.15 (m, 3H), 2.63-2.76 (m, 1H), 2.37-2.60 (m, 4H), 1.16 (d, J=6.4Hz, 3H).

Example 13, The reaction equation for the synthesis of compound TDM-180745 is as follows:

Step 1: Example 145c

At room temperature, to compound 145a (600mg, 2.86mmol) that is 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine in dimethyl sulfoxide (30mL) Compound 145b (573 mg, 2.86 mmol), tert-butyl 2-methylpiperazine-1-carboxylate and cesium carbonate (1.86 g, 5.72 mmol) were added. The mixture was then heated to 100°C and stirred for 16 hours. Water was added to the mixture and extracted with ethyl acetate (50 mL×3). The organic layer was washed with saturated brine (30 mL×6) and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. It was purified by a silica gel column (petroleum ether: ethyl acetate = 0: 100) to obtain a pale yellow solid compound 145c (571 mg, yield 53.5%), namely 2-methyl-4-(2-((1-methyl) 1-H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester. LCMS[M+1] ⁺ =374.

Step 2: Example 145d

To a solution of compound 145c (571 mg, 1.53 mmol) in dichloromethane (16 mL) was added HCl-1,4-dioxane (8 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction, the mixture was concentrated under reduced pressure to obtain a white solid compound 145d (665 mg), namely N-(1-methyl-1H-pyrazol-4-yl)-4-(3-methylpiperazin-1-yl) Pyrimidine-2-amine. LCMS[M+1] ⁺ =274.

Step 3: Example 145 (TDM-180745)

At room temperature, to a solution of compound 145d (120 mg, 0.44 mmol) in N,N-dimethylformamide (10 mL) was added triethylamine (177.8 mg, 1.76 mmol). The mixture was stirred for 5 minutes, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (126.5 mg, 0.66 mmol), 1-hydroxybenzotriazole ( 89 mg, 0.66 mmol) and compound 145e (65.4 mg, 0.66 mmol), namely 3-cyanopropionic acid, were stirred at room temperature for 16 hours. At the end of the reaction, the mixture was concentrated under reduced pressure to remove N,N-dimethylformamide, and the residue was prepared and purified by HPLC to obtain white solid compound 145, TDM-180745, (20.9 mg, yield 13.4%), namely 4-(2 -Methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperazin-1-yl)-4-oxobutyronitrile. LCMS[M+1] ⁺ =355.

1H NMR(400MHz,DMSO-d6)δ8.85(s,1H),7.92(d,J=6.0Hz,1H),7.74(s,1H),7.43(s, 1H),6.16(s,1H) ,4.19(dd,J=38.6,25.4Hz,3H),3.78(s,3H),3.25-3.02(m,2H),3.03-2.86(m,2H),2.76-2.58(m,4H),1.10 (dd,J=40.3,6.1Hz,3H).

Example 14. The reaction equation for synthesizing compound TDM-180708 is as follows:

Step 1: Example 108c

In a three-necked flask, add compound 108a, 2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (2.13g, 10.0mmol), pump the system oil pump to replace argon three times, and inject dry tetrahydrofuran ( 40mL) and then the system was cooled to -78°C. Slowly inject LiHMDS (12mL, 1M). Then stir at this temperature for 30 min. Subsequently, compound 108b, N-phenylbis(trifluoromethanesulfonyl)imide (4.28 g, 12.0 mmol) in tetrahydrofuran (30 mL) was slowly injected. After the addition was completed, the system was warmed to room temperature and stirred for 2.5 hours. After the reaction was completed, saturated NH ₄ Cl (~30 mL) was quenched. Extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry and concentrate, and purify by column (ethyl acetate/petroleum ether=0-10%; _{color developed by KMnO 4} ) to obtain the colorless oily liquid compound 108c, which is 2-methyl -4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3.3g, yield>100%). LCMS[M-55] ⁺ =290.

Step 2: Example 108e

Add compound 108c (2.2g<6.4mmol) into a three-necked flask, compound 108d is 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di (1,3,2-dioxaborane) (1.94g, _{7.7mmol), PdCl 2} (ddpf) (234mg, 0.32mmol) and potassium acetate (1.25g, 12.8mmol), then add 1,4-two Oxyhexanol (35mL). The system is pumped and replaced with nitrogen three times. The reaction was stirred at 80°C for 2 hours. The reaction solution is directly used in the next step without further post-treatment and purification.

LCMS[M-55] ⁺ = 268.1.

Step 3: Example 108g

In a three-necked flask containing compound 108e (1.84g, 5.7mmol), add compound 108f that is 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (1g, 4.8 mmol), PdCl ₂ (dppf) (263 mg, 0.36 mmol), sodium carbonate (1.0 g, 9.6 mmol), 1,4-dioxane (30 mL) and water (8 mL). The system water pump is pumped to replace the nitrogen three times. The reaction was stirred at 100°C for 2.5 hours. The reaction solution was concentrated under reduced pressure and purified by column (petroleum ether/ethyl acetate=4/1) to obtain 108 g of a pale yellow solid compound, namely 2-methyl-4-(2-((1-methyl-1H-pyrazole -4-yl)amino)pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (650 mg, yield 36%).

LCMS[M+H] ⁺ = 371.1

Step 4: Example 108h

108 g (650 mg, 1.76 mmol) of compound, methanol (20 mL), and Pd/C (150 mg, 10% wt.) were added to the reaction flask. Under the condition of the system water pump, the hydrogen is pumped and replaced three times. The reaction solution was stirred at 45°C for 48 hours. After the reaction, it was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the dark yellow oily compound 108h, which is 2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino) (Pyrimidine-4-yl)piperidine-1-carboxylic acid tert-butyl ester (600 mg, yield 92%).

LCMS[M+1] ⁺ = 373.2

Step 5: Example 108i (V836-122)

Compound 108h (600 mg, 1.6 mmol) and a 1,4-dioxane solution (4 mL, 4M) of hydrochloric acid were stirred in dichloromethane (10 mL) at room temperature for 2 hours. After the reaction is over, the light green solid compound 108i is obtained after concentration under reduced pressure, namely N-(1-methyl-1H-pyrazol-4-yl)-4-(2-methylpiperidin-4-yl)pyrimidine-2 -Amine (0.62 g crude product). LCMS[M+1] ⁺ ＝273.1

Step 6: Example 108 (TDM-180708) (V836-105)

A mixture of compound 108i (80 mg, 0.29 mmol) and triethylamine (438 mg, 4.35 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 5 minutes. Ethyl sulfonyl chloride (222 mg, 1.76 mmol) was added under ice cooling. The reaction solution was stirred at room temperature for 8 hours. After the reaction was completed, it was poured into water (10 mL), and extracted with ethyl acetate (20 mL*4). The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate=0-100%) to obtain a white solid compound 108, 4 -(1-(ethylsulfonyl)-2-methylpiperidin-4-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (25.5mg, yield Rate 26%).

LCMS[M+1] ⁺ = 365.1

1H NMR(400MHz,Chloroform-d)δ8.31(d,J=5.2Hz,1H),7.87(s,1H),7.51(s,1H),7.01(br s,1H),6.57(d,J =5.2Hz,1H),3.84-3.97(m,4H),3.58-3.68(m,1H),3.16-3.26(m,1H),2.99-3.09(m,2H),2.80-2.92(m,1H) ), 1.82-2.10 (m, 4H), 1.35-1.47 (m, 6H).

The same series of compounds with similar structures are as follows:

TDM-180709 White solid compound 109 is (2,2-difluorocyclopropyl)(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine- 4-yl)piperidin-1-yl)methanone (48.3mg, yield 25%)

Embodiment 15. The reaction equation for synthesizing compound TDM-180694 is as follows:

Step 1: Example 94 (TDM-180694)

The compound 93d (150 mg, 0.508 mmol) and N,N-diisopropylethylamine (262 mg, 2.032 mmol) were stirred in DMF (3 mL) for 5 minutes. Compound 94a (71 mg, 0.583 mmol) and EDCl, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (146 mg, 0.762 mmol) were added to the reaction solution. The resulting reaction solution was stirred at room temperature for 3 hours. Then, the reaction solution was poured into 10 mL of water, and extracted with ethyl acetate (20 mL×3). The organic layers were combined and washed with water (20 mL). The organic layer was separated, dried over Mg ₂ SO ₄ and concentrated under reduced pressure. Purified by Prep-HPLC, a yellow solid compound 94 (2,2-difluorocyclopropyl)((R)-3-((2-((1-methyl-1H-pyrazol-4-yl) was obtained Amino)pyrimidin-4-yl)amino)pyrrolidin-1-yl)methanone (8.9 mg, yield 4.8%). LCMS [M+1] ⁺ = 364.2.

¹ H NMR (400MHz, MeOD) δ 7.82 (d, J = 7.8 Hz, 1H), 7.73 (t, J = 5.3 Hz, 1H), 7.52 (dd, J = 9.5, 4.2 Hz, 1H), 5.91 ( dd, J = 6.0, 2.1 Hz, 1H), 4.60 (d, J = 32.9 Hz, 1H), 3.84 (t, J = 2.2 Hz, 3H), 3.65–3.53 (m, 1H), 3.15–3.08 (m ,1H),2.91–2.69(m,1H),2.55–2.23(m,4H),2.04–1.96(m,1H),1.87–1.62(m,2H),1.09(t,J=7.2Hz,1H ).

The same series of compounds with similar structures are as follows:

TDM-180697 Light yellow solid compound 97 (R)-3-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)pyrrolidine -1-yl)-3-oxopropionitrile (7.1mg, yield: 4.3%)

Embodiment 16. The reaction equation for synthesizing compound TDM-180723 is as follows:

Step 1: Example 123c

At room temperature, compound 123b (300mg, 1.8mmol), 3-amino-3-methylpyrrolidine-1-carboxylic acid tert-butyl ester and Example 123a (266mg, 1.8mmol), namely 2,4-dichloropyrimidine N,N-diisopropylethylamine (700 mg, 6.86 mmol) was added to the dimethyl sulfoxide (20 mL) solution of dimethyl sulfoxide, and then the mixture was heated to 100°C and stirred at 100°C for 2 hours. After the reaction, the mixture was diluted with water and extracted with ethyl acetate (3×100 mL). The organic layer was washed with water (3×100 mL) and brine (3×100 mL), and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane/methanol=10/1) to obtain compound 123c as a yellow oil, namely 3-((2-chloropyrimidin-4-yl)amino)-3-methylpyrrolidine-1 -Tert-butyl carboxylate (300 mg, yield 55%). LCMS[M+1] ⁺ =313.

Step 2: Example 123e

At room temperature, to compound 123c (250mg, 0.8mmol) and compound 123d (85mg, 0.88mmol) that is 1-methyl-1H-pyrazole-4-amine in n-butanol (10mL) was added trifluoroacetic acid ( 182mg, 1.6mmol). The mixture was then heated to 100°C and stirred at 100°C for 2 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=100/0 to 0/100 and ethyl acetate/methanol=20/1) to obtain brown solid compound 123e, namely 3-methyl- 3-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (330mg, yield 92%) . LCMS[M+1] ⁺ ＝374.2.

Step 3: Example123f

At room temperature, to a mixture of compound 123e (330 mg, 1.86 mmol) in ethyl acetate (20 mL) was added a dioxane hydrochloride solution (10 mL). The mixture was then stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure to obtain a yellow solid compound 123f, namely N2-(1-methyl-1H-pyrazol-4-yl)-N4-(3-methylpyrrolidine- 3-yl)pyrimidine-2,4-diamine (300 mg, crude product). LCMS[M+1] ⁺ ＝274.2.

Step 4: Example123 (TDM-180723)

To a solution of compound 123f (50 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was added triethylamine (74 mg, 0.73 mmol) and stirred at room temperature for 5 minutes. To this solution was added compound 123g (34mg, 0.27mmol) namely 2,2-difluorocyclopropane-1-carboxylic acid and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide ( 53mg, 0.27mmol). The mixture was then stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with water (3×50 mL) and brine (3×50 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (ethyl acetate/methanol=20/1) and preparative HPLC to obtain light green oily compound 123, TDM-180723, that is (2,2-difluorocyclopropyl)(3-methyl- 3-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)pyrrolidin-1-yl)methanone (1.9mg, yield 2.3%) . LCMS[M+1] ⁺ =378.1.

The same series of compounds with similar structures are as follows:

TDM-180724 White solid compound 124, namely 3-(3-methyl-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)pyrrole Alk-1-yl)-3-oxopropionitrile (10mg, yield 8%)

Embodiment 17. The reaction equation for synthesizing compound TDM-180715 is as follows:

Step 1: Example 115c

At room temperature, to compound 115b (750mg, 4.75mmol), 4-amino-4-methylpiperidine-1-carboxylic acid tert-butyl ester and compound 115a (1.01g, 4.75mmol), which is 2,4-dichloropyrimidine N,N-diisopropylethylamine (7 mL) was added to the dimethyl sulfoxide (14 mL) solution, and then the mixture was heated to 100°C and stirred at 100°C for 6 hours. After the reaction, the mixture was diluted with water and extracted with ethyl acetate (3×100 mL). The organic layer was washed with water (3×100 mL) and brine (3×100 mL), and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=100/0 to 100/40) to obtain yellow solid compound 115c, that is, tert-butyl 4-((2-chloropyrimidin-4-yl)amino)-4 -Methylpiperidine-1-carboxylate (570 mg, yield 37%). LCMS[M+1] ⁺ ＝327.1

Step 2: Example 115e

At room temperature to compound 115c (570mg, 1.74mmol) and compound 115d (169mg, 1.74mmol) that is 1-methyl-1H-pyrazole-4-amine in n-butanol (10ml) mixed solution was added trifluoroacetic acid ( 397mg, 3.49mmol). The mixture was then heated to 90°C and stirred at 90°C for 2h. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=100/0 to 0/100) to give a yellow solid compound 115e, namely 4-methyl-4-((2-((1 -Methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)tert-butyl piperidine-1-carboxylate (720 mg, yield 83%). LCMS[M+1] ⁺ ＝388.2.

Step 3: Example115f

At room temperature, to a solution of compound 115e (720 mg, 1.86 mmol) in ethyl acetate (20 mL) was added a dioxane hydrochloride solution (10 mL). The mixture was then stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure to obtain a yellow solid compound 115f, namely N2-(1-methyl-1H-pyrazol-4-yl)-N 4-(4-methylpiperidine -4-yl)pyrimidine-2,4-diamine (640 mg, crude product). LCMS[M+1] ⁺ ＝288.2.

Step 4: Example115 (TDM-180715)

To a solution of compound 115f (100 mg, 0.35 mmol) in N,N-dimethylformamide (5 mL) was added triethylamine (141 mg, 1.39 mmol) and stirred at room temperature for 5 minutes, and then the compound was added to the solution 115g (64mg, 0.52mmol) namely 2,2-difluorocyclopropane-1-carboxylic acid and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (100mg, 0.52mmol), The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with water (3×50 mL) and brine (3×50 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/methanol=20/1) to obtain white solid compound 115, TDM-180715, that is (2,2-difluorocyclopropyl)(4-methyl-4- ((2-((1-Methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)methanone (19 mg, yield 14%). LCMS[M+1] ⁺ =392.2.

¹ H NMR(400MHz,DMSO-d ₆ )δ6.82(s,1H), 6.77(d,J=6.0Hz,1H), 6.59(s,1H), 5.06(d,J=6.0Hz,1H) ,3.29–3.10(m,1H),3.00–2.89(m,4H),2.56(dd,J=22.0,10.8Hz,1H), 2.26(dt,J=25.5,11.1Hz,1H),2.11–1.95 (m, 1H), 1.67 (dd, J = 73.2, 13.8 Hz, 1H), 1.47 (d, J = 13.9 Hz, 1H), 1.14-1.01 (m, 1H), 0.88-0.80 (m, 1H), 0.61(d,J=11.4Hz,3H). The same series of compounds with similar structures are as follows:

TDM-180716 White solid compound 116, namely 3-(4-methyl-4-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)piper (Pyridin-1-yl)-3-oxopropionitrile (6mg, yield 5%)

Example 18: The reaction equation for synthesizing compound TDM-180693 is as follows:

Step 1: Example 93c

The compound 93a (1.048 g, 5.0 mmol), compound 93b (1.397 g, 7.5 mmol), Cs ₂ CO ₃ (2.444 mg, 7.5 mmol) and dimethyl sulfoxide (30 mL) were added to a single-necked flask. After stirring the reaction at 110°C for 16 hours, the mixture was diluted with water and extracted with ethyl acetate (20 mL×4). The combined organic layer was washed with water (2×20 mL). The organic layer was separated, dried over Mg ₂ SO 4, and concentrated under reduced pressure. Purified by silica gel column (petroleum ether/ethyl acetate = 1/4) to obtain a white solid compound 93c (R)-3-((2-((1-methyl-1H-pyrazol-4-yl)amino )Pyrimidin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (954 mg, yield 53.1%). LCMS [M+1] ⁺ = 360.1.

Step 2: Example 93d

The compound 93c (954mg, 2.658mmol) was dissolved in ethyl acetate (15mL) and methanol (5mL), and then a 1,4-dioxane solution (5mL) of hydrogen chloride was added to the reaction solution at room temperature Stir for 16 hours. Then the reaction solution was concentrated under reduced pressure to obtain a yellow solid compound 93d, namely (R)-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(pyrrolidin-3-yl)pyrimidine-2, 4-Diamine (800mg, crude product). LCMS [M+1] ⁺ = 260.1.

Step 3: Example 93 (TDM-180693)

A solution of the compound 93d (150 mg, 0.508 mmol) and triethylamine (205 mg, 2.032 mmol) in DMF (3 mL) was stirred at room temperature for 5 minutes. Compound 93e (71.5 mg, 0.558 mmol) was added to the reaction solution, and stirring was continued for 3 hours at room temperature. The reaction solution was poured into 10 mL of water, and then extracted with ethyl acetate (15 mL×4). The organic layers were combined and washed with water (20 mL). The organic layer was separated, dried over Mg ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/methanol=20/1) to obtain yellow solid compound 93 (R)-N ⁴ -(1-(ethylsulfonyl)pyrrolidin-3-yl)-N ^2- (1-Methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (44 mg, yield 24.7%). LCMS [M+1] ⁺ =352.2.

¹ H NMR (400MHz, MeOD) δ 7.80 (s, 1H), 7.73 (d, J = 5.9 Hz, 1H), 7.51 (s, 1H), 5.91 (d, J = 6.0 Hz, 1H), 4.54 ( s, 1H), 3.85 (s, 3H), 3.74 (dd, J = 10.2, 6.0 Hz, 1H), 3.59-3.44 (m, 3H), 3.16-3.01 (m, 3H), 2.40-2.27 (m, 1H), 2.02 (dd, J = 13.0, 7.2 Hz, 1H), 1.32 (t, J = 7.4 Hz, 4H).

Example 19: The reaction equation for synthesizing compound TDM-180706 is as follows:

Step 1: Example 106c

The compound 106a (1.5 g, 7.16 mmol), compound 106b (2.0 g, 10.74 mmol), Cs ₂ CO ₃ (3.5 g, 10.74 mmol) and dimethyl sulfoxide (40 mL) were added to a single-necked flask. After stirring the reaction at 110°C for 18 hours, the mixture was diluted with water and extracted with ethyl acetate (30 mL×4). The combined organic layer was washed with water (2×40 mL). The organic layer was separated, dried over Mg ₂ SO 4, and concentrated under reduced pressure. Purified by silica gel column (petroleum ether/ethyl acetate = 1/4) to obtain a white solid compound 106c (S)-3-((2-((1-methyl-1H-pyrazol-4-yl)amino )Pyrimidin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (1.2 g, yield 46.7%). LCMS [M+1] ⁺ = 360.1.

Step 2: Example 106d

The compound 106c (980 mg, 2.73 mmol) was dissolved in methanol (10 mL), and then a 1,4-dioxane solution (3.5 mL) of hydrogen chloride was added to the reaction solution and stirred at room temperature for 16 hours. Then the reaction solution was concentrated under reduced pressure to obtain a yellow solid compound 106d, namely (S)-N ² -(1-methyl-1H-pyrazol-4-yl)-N ⁴ -(pyrrolidin-3-yl)pyrimidine- 2,4-Diamine (830mg, crude product). LCMS [M+1] ⁺ = 260.1.

Step 3: Example 106 (TDM-180906)

A DMF (5 mL) solution of the compound 106d (100 mg, 0.386 mmol) and triethylamine (58.5 mg, 0.579 mmol) was stirred at room temperature for 5 minutes. To the reaction solution was added compound 106e (56.5mg, 0.463mmol) EDCl that is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (111mg, 0.579mmol) and HOBT that is 1 -Hydroxybenzotriazole (78.2mg, 0.579mmol), and continue to stir at room temperature for 16 hours. The reaction solution was poured into 10 mL of water (15 mL), and then extracted with ethyl acetate (15 mL×4). The organic layers were combined and washed with water (20 mL). The organic layer was separated, dried over Mg ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/methanol=20/1) to obtain yellow solid compound 106 (S)-N ⁴ -(1-(ethylsulfonyl)pyrrolidin-3-yl)-N ^2- (1-Methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (32.2 mg, yield 23.0%). LCMS [M+1] ⁺ = 364.1.

1H NMR(400MHz,MeOD)δ7.95–7.64(m,2H), 7.52(dd,J=9.5,4.2Hz,1H), 5.91(td,J=6.0,2.2Hz,1H), 4.60(d, J = 33.5Hz, 1H), 3.84 (t, J = 2.3Hz, 3H), 3.69–3.41(m, 2H), 3.38–3.32(m, 2H), 2.92–2.71(m, 1H), 2.47–2.23 (m,1H),2.21–1.95(m,2H),1.85–1.67(m,1H),1.33(t,J=22.2Hz,1H).

The same series of compounds with similar structures are as follows:

TDM-180707 Light yellow solid compound 107 (S)-3-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)pyrrolidine -1-yl)-3-oxopropionitrile (12.1mg, yield: 9.6%)

Example 20: The reaction equation for synthesizing compound TDM-180750 is as follows:

Step 1: Example150b

The compound 150a (0.52 g, 2.0 mmol) was dissolved in tetrahydrofuran (10 mL), dioxane hydrochloride (10.0 mL, 40.0 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Concentrate, add tetrahydrofuran (10 mL), and concentrate to obtain a white solid compound 150b, methyl 4-methylpiperidine-4-carboxylate (304 mg, yield 95.5%). LCMS [M+1] ⁺ = 158.1.

Step 2: Example150d

The compound 150c (93.6 mg, 0.45 mmol) was dissolved in dimethyl sulfoxide (5 mL), the compound 150b (105.3 mg, 0.67 mmol) and CS ₂ CO ₃ (436.5 mg, 1.34 mmol) were added, and then Stir at 110°C for 3 hours. The reaction solution was cooled to room temperature, poured into water (10 mL), and extracted with ethyl acetate (20 mL×3). The organic layers were combined and dried over MgSO _{4. The} solvent was concentrated to obtain a white solid compound 150d, 4-methyl-1-( Methyl 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidine-4-carboxylate (221 mg, crude). LCMS [M+1] ⁺ = 331.1.

Step 3: Example150e

Sodium hydroxide (267.6 mg, 6.69 mmol) was added to the mixture of compound 150d (221 mg, 0.67 mmol) in tetrahydrofuran (10 mL) and water (2 mL), and then stirred at 40° C. for 19 hours. After concentrating to remove the solvent, add water (15mL), acidify with hydrochloric acid (1mol/L), filter to obtain a filter cake, dissolve the filter cake in DMF (10mL), and spin off the solvent to obtain an off-white solid compound 150e, which is 4-methyl-1 -(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidine-4-carboxylic acid (206 mg, 97.0% yield, crude product). LCMS: [M+1] ⁺ = 317.1.

Step 4: Example 150 (TDM-180750)

Add 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate to the DMF (10mL) solution of the compound 150e (80mg, 0.25mmol) (144.2 mg, 0.38 mmol), triethylamine (38.3 mg, 0.38 mmol) and compound 150f (37.6 mg, 0.38 mmol) were stirred at room temperature for 16 hours. The solvent was concentrated, and the residue was purified by preparative HPLC to obtain the off-white solid compound 150, namely 1-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl )-N-(2,2,2-trifluoroethyl)cyclohexanecarboxamide (11.1 mg, 12.4% yield). LCMS: [M+1] ⁺ = 398.2.

¹ H NMR(400MHz,DMSO)δ9.88(s,1H), 8.41(t,J=6.2Hz,1H),7.84(s,2H),7.54(s,1H),6.62(d,J=7.6 Hz, 1H), 3.96 (d, J = 6.6 Hz, 4H), 3.85 (s, 3H), 3.35 (d, J = 10.4 Hz, 2H), 2.14 (d, J = 14.2 Hz, 2H), 1.48 ( t, J = 10.3 Hz, 2H), 1.19 (s, 3H).

The same series of compounds with similar structures are as follows:

TDM-180751 white solid compound 151 is N-(cyanomethyl)-4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-4- Base) piperidine-4-carboxamide (12.5mg, yield: 10.9%)

TDM-180793 white solid compound 193 that is N-cyclopropyl-4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piper Pyridine-4-carboxamide (25.7 mg, 43.8% yield).

Example 21. The reaction equation for synthesizing compound TDM-180809 is as follows:

Step 1: Example 209c

Tert-butyl (4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-4-yl)carbamate

To the dimethyl sulfoxide (50ml) solution of compound 209a (2g, 9.57mmol), cesium carbonate (4.68g, 14.35mmol) and compound 209b (3.07g, 14.35mmol) were added, and the solution was heated to 110°C and stirred for three hours , TLC (PE:EA=1:1), LCMS[M+1] ⁺ =388, it is detected that the reaction is complete. Post-treatment: the solution was cooled to room temperature and slowly poured into stirring ice water, the aqueous phase was extracted with ethyl acetate (3*100ml), the organic phases were combined and washed with water (3*100ml), washed with saturated brine once, and dried over anhydrous sodium sulfate It was concentrated to dryness to obtain the yellow oily target compound (Example 209c, 3.6g, yield 97.3%), LCMS[M+1]+=388.

Step 2: Example 209d

4-(4-Amino-4-methylpiperidin-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

To the ethyl acetate (200ml) solution of compound 209c (4.1g, 10.58mmol) was slowly added dropwise hydrochloric acid/1,4-dioxane (60ml, 4mol/L, 240mmol) solution, stirred at room temperature overnight, reaction monitoring LCMS [M+H] ⁺ =288, the reaction is complete. Post-treatment: the solution was directly evaporated to dryness, the solvent N,N-dimethylformamide (100ml) was added, and the base was adjusted with solid sodium carbonate while stirring at room temperature, stirred for 30 minutes, filtered, and the filter cake used solvent N,N -Wash with dimethylformamide (3*20ml), and spin-dry the filtrate to obtain a white solid compound (Example 209d, 3.03g, yield 99.6%), LCMS[M+1]+=288.

Step 3: Example 209

2,2-Difluoro-N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-4-yl )Cyclopropane-1-carboxamide

To compound 209d (80mg, 0.28mmol) in N, N-dimethylformamide (5ml) was added triethylamine (42mg, 0.42mmol), 2-(7-benzotriazole oxide)-N, N,N',N'-tetramethylurea hexafluorophosphate (158.5 mg, 0.42 mmol) and compound 209e (50.9 mg, 0.42 mmol). The solution was stirred at room temperature for two hours. LCMS showed that the reaction of the starting materials was complete, and the product was LCMS [M+H] ⁺ =392. Post-processing: the solution is spin-dried directly and sent for preparation. The eluate was concentrated to remove the solvent, and the aqueous phase was lyophilized to obtain a white solid compound (Example 209, 43.8 mg, yield 40.3%), LCMS [M+H] ⁺ =392.

¹ H NMR (400MHz, DMSO) δ 8.07 (s, 1H), 7.83 (s, 2H), 7.53 (s, 1H), 6.63 (d, J = 7.6 Hz, 1H), 3.84 (s, 3H), 3.42(d,J=11.6Hz,2H),2.70–2.62(m,1H),2.24(d,J=13.9Hz,2H),1.84(dd,J=13.6,7.0Hz,2H),1.53(t ,J=10.6Hz,2H),1.32(s,3H).

The same series of compounds with similar structures are as follows:

TDM-180811 White solid compound 211 is 3,3,3-trifluoro-N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine- 4-yl)piperidin-4-yl)propionamide (24.6 mg, 37.1% yield).

TDM-180812 White solid compound 212 is N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidine-4- Yl)cyclopropane (39.1 mg, yield: 39.3%).

TDM-1808152-Methoxy-N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidine-4- Yl)acetamide, yellow solid (41.5 mg, yield 41.5%).

TDM-180816, 1-Fluoro-N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidine-4- Yl)cyclopropane-1-carboxamide, a white solid compound (77 mg, yield 74.2%).

TDM-1808172-Cyclopropyl-N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidine-4- Yl)acetamide, yellow solid compound (34.9 mg, yield 33.98%).

TDM-180824 White solid compound 224 is 2-cyano-N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl) Piperidin-4-yl)acetamide (24.6 mg, yield: 20.1%).

TDM-180842 White solid compound 242 is 2,2-difluoro-N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-4- Yl)piperidin-4-yl)acetamide (27.2 mg, yield: 26.8%).

Example 21. The reaction equation for the synthesis of compound TDM-180825 is as follows:

Step 1: Example225c

To the N,N-dimethylformamide (5mL) solution of the compound 225a (80mg, 0.28mmol) was added 2-(7-benzotriazole oxide)-N,N,N',N'- Tetramethylurea hexafluorophosphate (158.9 mg, 0.42 mmol), triethylamine (42.2 mg, 0.42 mmol) and compound 225b (49.3 mg, 0.42 mmol). The reaction solution was stirred at room temperature for 3 hours. After removing the solvent, it was purified by silica gel chromatography (methanol: dichloromethane=0-5%) to obtain a white solid compound 225c, namely 2-((4-methyl-1-(2-((1-methyl-1H- Pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-4-yl)amino)-2-oxoethyl acetate (107.6 mg, crude). LCMS [M+1] ⁺ = 388.1.

Step 2: Example 225 (TDM-180825)

_{LiOH·H 2} O (11.8 mg, 0.28 mmol) was added to the mixture of compound 225c (107.6 mg, 0.28 mmol, crude product) in tetrahydrofuran (6 mL), methanol (1 mL) and water (2 mL), and stirred at room temperature 1 hour. After removing the solvent, the white solid compound 225 was obtained by preparative HPLC purification, namely 2-hydroxy-N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino) Pyrimidine-4-yl)piperidin-4-yl)acetamide (23.9 mg, 24.7% yield). LCMS [M+1] ⁺ = 346.2.

¹ H NMR (400MHz, DMSO) δ 7.83 (s, 2H), 7.53 (s, 1H), 7.23 (s, 1H), 6.63 (d, J = 7.6 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 2H), 3.41 (t, J = 11.2 Hz, 2H), 2.32 (d, J = 13.6 Hz, 2H), 1.61-1.46 (m, 2H), 1.34 (s, 3H).

Example 23. The reaction equation for synthesizing compound TDM-180835 is as follows:

Step 1: Example 235 (TDM-180835)

To a solution of compound 235a (80mg, 0.28mmol) in N,N-dimethylformamide (5mL) was added 4-dimethylaminopyridine (7.0mg, 0.06mmol), sodium hydroxide (16.7mg, 0.42mmol) and Compound 235b (79.6 mg, 0.42 mmol). The reaction solution was stirred at room temperature for 3 hours. The solvent was removed, and the concentrate was purified by preparative HPLC to obtain a white solid compound 235, namely N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-4 -Yl)piperidin-4-yl)-1-phenylmethanesulfonamide (44.3 mg, 25.6% yield). LCMS [M+1] ⁺ = 442.2.

¹ H NMR(400MHz,DMSO)δ7.82(s,2H),7.53(s,1H),7.43-7.33(m,5H),6.99(s,1H),6.57(d,J=7.5Hz,1H ), 4.36(s,2H),3.84(s,3H),3.63-3.47(m,4H),1.99(d,J=14.2Hz,2H),1.58(t,J=9.8Hz,2H),1.39 (s,3H).

The same series of compounds with similar structures are as follows:

TDM-180837 White solid compound 237 is N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidine-4- Yl)cyclopropane sulfonamide (18.9 mg, yield: 17.4%).

TDM-180838 White solid compound 238 is N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidine-4- Yl)prop-2-ene-1-sulfonamide (17.8 mg, yield: 16.4%).

TDM-180839 White solid compound 239 is 3,3,3-trifluoro-N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine- 4-yl)piperidin-4-yl)propane-1-sulfonamide (30.7 mg, yield: 24.7%).

Example 24. The reaction equation for synthesizing compound TDM-180862 is as follows:

Step 1: Example 262c

Benzyl 4-(cyanomethylene)piperidine-1-carboxylate

Under the _{conditions of N 2} and 0° C., to a mixture of NaH (480 mg, 12 mmol) in THF (30 mL) was added compound 262b (1.95 g, 11 mmol) in THF (20 mL). The mixture was stirred for 0.5 hour, and a solution of compound 262a (2.33 g, 10 mmol) in THF (10 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated NH ₄ Cl (~30 mL) solution, extracted with EtOAc (40 mL x 3), the combined organic layer was _{dried over Na 2} SO ₄ , filtered, concentrated, and purified by column chromatography (0-100% PE/EtOAc). Compound 262c (500 mg, yield <20%) was obtained as a colorless oil.

LCMS[M+1] ⁺ = 257.1

Step 2: Example 262c

4-amino-4-(cyanomethyl)piperidine-1-carboxylic acid benzyl ester

Compound 262c (500 mg, 1.95 mmol) was added to the sealed tube, and NH ₃ /MeOH (7N, 7 mL) was added. The mixture was heated to 100°C and stirred for 20 hours. The mixture was concentrated and purified by column chromatography (0-100% B in DCM [B: 10% MeOH/DCM (0.1% Et ₃ N)]. A colorless oily compound 262d (250 mg, yield 52%) was obtained.

LCMS[M+1] ⁺ ＝274.2

Step 3: Example 262e

4-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)piperidine-1-carboxylic acid benzyl ester

To a solution of compound 262d (380 mg, 1.39 mmol) in THF (20 mL) was added DIPEA (359 mg, _{2.78 mmol) and (Boc) 2} O (458 mg, 2.1 mmol). The reaction was stirred at 50°C for 20 hours. The mixture was concentrated and purified by column chromatography (0-80% EtOAc/PE). A white solid compound 262e (490 mg, yield 93%) was obtained.

LCMS[M-Boc+1] ⁺ ＝274.2

Step 4: Example 262f

(4-(Cyanomethyl)piperidin-4-yl) tert-butyl carbamate

To a THF (30 mL) solution of compound 262e (490 mg, 1.31 mmol) was added Pd(OH) ₂ /C (80 mg, 20% wt.). The obtained mixture was pumped to replace hydrogen 3 times, and stirred at room temperature for 4 hours. The mixture was filtered through Celite, and the filtrate was concentrated and dried under vacuum. A brown solid compound 262f (280 mg, yield 89%) was obtained.

LCMS[M+1] ⁺ = 240.2

Step 5: Example 262g

(4-(Cyanomethyl)-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-4-yl)tert-butyl carbamate ester

To a mixture of B0 (219 mg, 1.05 mmol) in DMSO (15 mL) was added compound 262f (250 mg, 1.05 mmol) and DIPEA (405 mg, 3.13 mmol). The reaction was stirred at 100°C for 18 hours. The mixture was poured into H ₂ O (~25 mL), extracted with EtOAc (30 mL x 3), the combined organic layer was _{washed 6 times with H 2} O and brine, then _{dried over Na 2} SO ₄ , filtered, concentrated, column layer Analytical purification (0-100% EtOAc/PE, 5% MeOH/EtOAc). 262 g (320 mg, yield 74%) of a white solid compound was obtained.

LCMS[M+1] ⁺ = 413.2

Step 6: Example 262h

2-(4-amino-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-4-yl)acetonitrile to compound 262g (300mg, HCl/1,4-dioxane (4 mL) was added to a solution of 0.73 mmol) in DCM (12 mL). The mixture was stirred at room temperature for 3 hours. Concentrate under reduced pressure, and use the crude product directly in the next step. A pale yellow solid compound 262h (280 mg, crude product) was obtained.

LCMS[M+1] ⁺ =313.2

Step 7: Example 262

N-(4-(cyanomethyl)-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-4-yl)cyclopropane A

To DIPEA (129 mg, 1.0 mmol) and DMF (6 mL) of compound 262h (60 mg, 0.2 mmol) were added HATU (110 mg, 0.29 mmol) and compound 262i (35 mg, 0.4 mmol). The reaction was stirred at room temperature for 3h. Concentrate, purify by column chromatography (DCM/MeOH=10/1), then prepare (TFA conditions) and purify again, and freeze-dry. A white solid compound 262 (26.8 mg; yield 35%) was obtained.

LCMS[M+1] ⁺ ＝381

1H NMR(400MHz,DMSO-d ₆ )δ10.25(brs,1H),8.29(s,1H),7.74-7.96(m,2H),7.53(s,1H),6.63(d,J=7.2Hz ,1H),3.85(s,3H),3.23-3.78(m,4H),3.10(s,2H),2.22-2.38(m,2H),1.70-1.80(m,1H),1.54-1.69(m ,2H),0.58-0.77(m,4H).

The same series of compounds with similar structures are as follows:

White solid compound TDM-180863 namely N-(4-(cyanomethyl)-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidine -4-yl)-2,2-difluorocyclopropane-1-carboxamide (25.7mg, yield: 38.6%)

White solid compound TDM-180864 is 2-cyano-N-(4-(cyanomethyl)-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-4 -Yl)piperidin-4-yl)acetamide (15.5mg, yield: 25.5%)

White solid compound TDM-180865, namely N-(4-(cyanomethyl)-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidine -4-yl)-3,3,3-trifluoropropionamide (36.4mg, yield: 53.9%)

Example 25. The reaction equation for synthesizing compound TDM-180874 is as follows:

Step 1: Example274b

To a methanol (30 mL) solution of the compound 274a (813 mg, 3.0 mmol) was added water (4 mL) and potassium hydroxide (1.68 g, 30 mmol). The mixture was heated to 70°C and reacted for 19 hours. Cooled to room temperature, acidified with hydrochloric acid (1mol/L), and extracted with ethyl acetate (20mL×3). The combined organic layer was washed with water (20mL), dried with Na ₂ SO ₄ , filtered and concentrated to obtain a white solid Compound 274b is 1-(tert-butoxycarbonyl)-4-ethylpiperidine-4-carboxylic acid (0.76 g, 98.5% yield). LCMS [M+1] ⁺ = 258.1.

Step 2: Example274c

To the toluene (10 mL) solution of the compound 274b (257.3 mg, 1.0 mmol) was added triethylamine (404 mg, 4.0 mmol), replaced with nitrogen three times, and then added diphenyl azide phosphate (357.7 mg, 1.3 mmol), The temperature was raised to 100°C and stirred for 2 hours, then benzyl alcohol (216.2 mg, 2.0 mmol) was added, and the reaction was continued to stir at 100°C for 3 hours. After cooling to room temperature and removing the solvent, add ethyl acetate (20mL), wash with water, dry, filter and concentrate. The concentrate is purified by silica gel chromatography (ethyl acetate: petroleum ether=0-30%) to obtain compound 274c as a colorless oily liquid Namely 3-(cyanomethyl)-3-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazole-1- Yl)azetidine-3-pyridine-1-carboxylic acid (0.38 g, crude). LCMS [M+1] ⁺ = 263.1.

Step 3: Example274d

The compound 274c (0.38 g, 1.0 mmol) was dissolved in a 1,4-dioxane (10 mL, 40.0 mmol) solution of hydrogen chloride, and reacted at room temperature for 3 hours. Concentrate to obtain the crude product, which is directly used in the next reaction. LCMS [M+1] ⁺ = 263.1.

Step 4: Example274f

To the compound 274e (174.7 mg, 0.83 mmol) and compound 274d (262.1 mg, 1.0 mmol) were dissolved in dimethyl sulfoxide (5 mL), and N,N-diisopropylethylamine (323.8 mg, 2.5 mmol), the reaction solution was heated to 110°C for 18 hours. Cool to room temperature and pour into water (20 mL). It was extracted with ethyl acetate (20 mL×3), the organic phase was collected, dried, filtered, concentrated, and purified by silica gel chromatography (MeOH:DCM=0-3%) to obtain a white solid compound 274f, which is benzyl (4-ethyl- 1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-4-yl)carbamate (110 mg, 30.1% yield). LCMS [M+1] ⁺ = 436.1.

Step 5: Example274g

The compound 274f (110 mg, 0.25 mmol) was dissolved in THF (10 mL), Pd(OH) ₂ /C (11 mg) was added, hydrogen was replaced three times, and the reaction solution was reacted under H ₂ atmosphere for 18 hours. The reaction solution was filtered through Celite and concentrated to obtain 274g of a yellow solid compound compound, namely 4-(4-amino-4-ethylpiperidin-1-yl)-N-(1-methyl-1H-pyrazole-4- Yl)pyrimidin-2-amine (69 mg, 92% yield). LCMS [M+1] ⁺ = 302.1.

Step 6: Example 274 (TDM-180874)

To a solution of 274g (69mg, 0.23mmol) of the compound in N,N-dimethylformamide (5mL), add 2-(7-oxybenzotriazole)-N,N,N',N' -Tetramethylurea hexafluorophosphate (130.7mg, 0.34mmol), N,N-diisopropylethylamine (44.5mg, 0.34mmol) and compound 274g (29.6mg, 0.34mmol). Stir at room temperature for 3 hours. After removal of the solvent, purification by preparative HPLC gave a white solid compound 274, namely N-(4-ethyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-4- (Yl)piperidin-4-yl)cyclopropanecarboxamide (35.4 mg, 41.7% yield). LCMS [M+1] ⁺ = 370.2.

¹ H NMR (400MHz, DMSO) δ 7.83 (s, 2H), 7.67 (s, 1H), 7.54 (s, 1H), 6.62 (d, J = 7.6 Hz, 1H), 4.47 (s, 1H), 3.99 (s, 1H), 3.84 (s, 3H), 3.28 (d, J = 18.8 Hz, 2H), 2.30 (d, J = 13.2 Hz, 2H), 1.79-1.58 (m, 3H), 1.41 (t ,J=10.8Hz,2H),0.76(t,J=7.4Hz,3H),0.62(d,J=7.5Hz,4H).

The same series of compounds with similar structures are as follows:

The white solid compound TDM-180878 is N-(4-ethyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-4-yl )-3,3,3-Trifluoropropionamide (78.2mg, yield: 70.4%).

The white solid compound TDM-180879 is N-(4-ethyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-4-yl )-2,2-Difluorocyclopropanecarboxamide (32.9 mg, yield: 38.6%).

The white solid compound TDM-180883 is 2-cyano-N-(4-ethyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piper (Pyridin-4-yl)acetamide (5.1 mg, yield: 5.2%).

Example 26. General method for synthesizing compound TDM-180704

Step 1: Example 104b

The compound 104a (30 mg, 0.117 mmol), methyl iodide (20 mg, 0.141 mmol), potassium hydroxide (19.7 mg, 0.351 mmol) and tetrahydrofuran (5 mL) were added to a single-mouth bottle. After stirring and reacting at 66°C for 4 hours, the reaction solution was filtered and the filtrate was concentrated to obtain the off-white solid compound 104b, namely N-(1-methyl-1H-pyrazol-4-yl)-4-(4-(formaldehyde). (Amino)-1H-pyrazol-1-yl)pyrimidin-2-amine (30.5 mg, crude). LCMS[M+1] ⁺ ＝271.1

Step 2: Example 104 (TDM-180704)

The compound 104b (30mg, 0.106mmol), triethylamine (16mg, 0.159mmol), compound 104c (16.3mg, 0.133mmol), HATU is 2-(7-oxybenzotriazole)-N, N ,N',N'-Tetramethylurea hexafluorophosphate (63.4mg, 0.167mmol) and dichloromethane (5mL) were added to a 50mL single-necked flask and stirred at room temperature for 1.5 hours. Then the reaction solution was washed with water (10 mL×2), and the organic layer was separated, dried over Mg ₂ SO ₄ and concentrated under reduced pressure. Purified by preparing a silica gel plate (100% ethyl acetate), the off-white solid compound 104 is obtained, namely 2,2-difluoro-N-methyl-N-(1-((1-methyl-1H-pyrazole-4 -Yl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)cyclopropanecarboxamide (22.5 mg, yield 51.4%). LCMS [M+1] ⁺ = 375.1.

¹ H NMR(400MHz,CDCl3)δ8.78(s,1H), 8.45-8.30(m,2H), 7.95(s,1H), 7.82(s,1H), 7.68(s,1H), 7.25-7.23 (m,1H),3.98(s,3H),3.58(s,3H),2.57–2.38(m,1H),2.23(td,J=14.0,7.7Hz,1H),1.81(tdd,J=12.3 ,7.9,4.8Hz,1H).

Embodiment 27. General method for synthesizing compound TDM-180698

Step 1: Example 98c

The compound 98a (100 mg, 0.391 mmol), compound 98b (73 mg, 0.469 mmol), potassium hydroxide (66 mg, 1.173 mmol) and tetrahydrofuran (20 mL) were added to a single-neck bottle. After stirring and reacting at 66°C for 16 hours, the reaction solution was filtered, the filtrate was concentrated, and the concentrate was purified by preparing a silica gel plate (100% ethyl acetate) to obtain the off-white solid compound 98c, which is 4-(4-(ethylamino)- 1H-pyrazol-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (90.5 mg, yield 81.5%). LCMS[M+1] ⁺ = 285.1

Step 2: Example 98 (TDM-180698)

The compound 98c (30mg, 0.106mmol), triethylamine (16mg, 0.159mmol), compound 98d (16.2mg, 0.127mmol), EDCl is 1-(3-dimethylaminopropyl)-3-ethyl Carbodiimide hydrochloride (30.5 mg, 0.159 mmol) and dichloromethane (10 mL) were added to a 50 mL single-neck flask and stirred at room temperature for 16 hours. Then the reaction solution was washed with water (10 mL×2), and the organic layer was separated, dried over Mg ₂ SO ₄ and concentrated under reduced pressure. Purified by preparing a silica gel plate (100% ethyl acetate) to obtain a white solid compound 98 that is N-ethyl-2,2-difluoro-N-(1-((1-methyl-1H-pyrazole-4 -Yl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)cyclopropanamide (9.6 mg, yield 23.3%). LCMS [M+1] ⁺ = 389.1.

1H NMR(400MHz,CDCl3)δ8.76(s,1H), 8.40(d,J=5.4Hz,1H),7.91(s,1H),7.84(s,1H),7.73(s,1H),7.58 (s, 1H), 7.17 (d, J = 5.4 Hz, 1H), 4.05 (q, J = 7.0 Hz, 2H), 3.94 (s, 3H), 2.52-2.41 (m, 1H), 2.23 (td, J = 14.0, 7.6 Hz, 1H), 1.86–1.75 (m, 2H), 1.30 (t, J = 6.1 Hz, 4H).

The compounds prepared by similar methods are as follows:

White solid compound TDM-180705, namely N-ethyl-3,3,3-trifluoro-N-(1-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl )-1H-pyrazol-4-yl)propionamide (17.4mg, yield: 41.7%)

Embodiment 28. General method for synthesizing compound TDM-180699

Step 1: Example 99c

Compound 99a is 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (824mg, 4.0mmol), compound 99b is 4-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (2.35g, 8.0mmol), Pd(dppf)Cl ₂ (292mg, 0.4mol), sodium carbonate (292mg, 0.4mmol), 1,4-dioxane (42mL) and water (7mL) were added to the three-necked flask. The system is pumped to replace nitrogen three times under the condition of water pump. The reaction solution was reacted at 95°C for 24 hours and then cooled. After the reaction was completed, the crude product was purified by column chromatography (eluent: ethyl acetate/methanol=1/20) after concentration under reduced pressure to obtain the off-white solid compound 99c, namely N-(1-methyl-1H-pyrazole- 4-yl)-4-(1H-pyrazol-4-yl)pyrimidin-2-amine (0.8 g, yield 83%). LCMS[M+1] ⁺ ＝242.1

Step 2: Example 99e

Compound 99c (600mg, 2.48mmol), cesium carbonate (3.23g, 9.92mmol) and compound 99d, namely methyl 2,4-dibromobutyrate (710mg, 2.73mmol) were added to dimethylformamide (15mL), The mixture was stirred at 45°C for 2 hours. After the reaction is complete, pour it into water (30 mL), and extract with ethyl acetate (40 mL x 4). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (eluent: ethyl acetate) to obtain an off-white solid compound 99e, which is 1-(4-(2-) ((1-Methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)cyclopropanecarboxylic acid methyl ester (420 mg, yield 50%).

LCMS[M+1] ⁺ =340.1

1H NMR(400MHz,DMSO-d ₆ ))δ9.36(s,1H),8.59(s,1H),8.35(d,J=5.2Hz,1H),8.15(s,1H),7.94(s, 1H),7.51(s,1H),7.00(d,J=5.2Hz,1H),4.23-4.47(m,2H),3.83(s,3H),3.64(s,3H),1.72-1.81(m ,4H).

Step 3: Example 99f

To a solution of compound 99e (400 mg, 1.18 mmol) in methanol (5 mL) was added an aqueous solution of lithium hydroxide (1M, 5 mL). The reaction solution was reacted at room temperature for 2 hours. After the reaction is completed, it is spin-dried under reduced pressure, acidified with hydrochloric acid (2M) to pH 4 to precipitate a solid precipitate, filtered, and the filter cake is dried to obtain the green solid compound 99f, which is 1-(4-(2-((1-methyl-1H- Pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)cyclopropanecarboxylic acid (320 mg, yield 84%).

LCMS[M+1] ⁺ = 326.1

1H NMR (400MHz, DMSO-d ₆ ) δ 13.14 (br s, 1H), 9.35 (s, 1H), 8.56 (s, 1H), 8.34 (d, J = 5.2 Hz, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.51 (s, 1H), 7.00 (d, J = 5.2 Hz, 1H), 3.83 (s, 3H), 1.61-1.76 (m, 4H).

Step 4: Example 99 (TDM-180699)

Compound 74h 99f (80mg, 0.25mmol) and N,N'-diisopropylethylamine (57mg, 0.44mmol) were added to dimethylformamide (5mL) and stirred for 5 minutes. Subsequently, 99 g of compound 3,3-difluoroazetidine hydrochloride (43 mg, 0.34 mmol) and HATU (100 mg, 0.26 mmol) were added. The resulting mixture was stirred at room temperature for 4 hours, poured into water (30 mL), and extracted with ethyl acetate (30 mL*3). The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was purified and separated by column chromatography (ethyl acetate/petroleum ether=0-100%) to obtain a white solid compound 99 (3,3- Difluoropyrrolidin-1-yl)(1-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazole-1- (Yl)cyclopropyl)methanone (97.2 mg, yield 84%).

LCMS[M+1] ⁺ = 401.1

1H NMR (400MHz, Chloroform-d) δ 8.39 (d, J = 5.2 Hz, 1H), 8.18 (s, 1H), 8.09 (s, 1H), 7.81 (s, 1H), 7.59 (s, 1H) ,6.94(s,1H),6.83(d,J=5.2Hz,1H),4.23-4.47(m,2H),3.95(s,3H),3.69-3.86(m,2H),1.94-1.99(m ,2H),1.57-1.65(m,2H).

Off-white solid compound TDM-180700 (3,3-difluoropyrrolidin-1-yl)(1-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine- 4-yl)-1H-pyrazol-1-yl)cyclopropyl)methanone (85mg, yield 79%)

Experiment to identify the inhibitory effect of compound on JAK kinase activity

Janus kinases (JAK) include JAK1, JAK2, JAK3 and Tyk2, which transduce cytokine-mediated signals through the JAK-STAT pathway. The size of the kinase is 120-140kDa, and there are 7 identified homology regions, JH1-JH7. JH1 is an important region of JAK enzyme activity and contains typical tyrosine kinase characteristics. The phosphorylation of tyrosine leads to a change in the conformation of JAK protein, thereby promoting substrate binding. The JAK-STAT system consists of three main parts: receptors that pass through the cell membrane, Janus kinases connected to the receptors, and signal transduction and transcription activators (STAT) that transmit signals to the nucleus and DNA. When the cytokine binds to the receptor, JAK phosphorylates the receptor and attracts the STAT protein. The STAT protein is also phosphorylated and binds to each other to form a dimer. The dimer enters the nucleus and binds to DNA, leading to gene transcription.

PerkinElmer's EZ Reader can be used to detect the phosphorylation of peptide substrates catalyzed by kinases. The device is based on micro-control fluid separation technology, which can directly detect fluorescently labeled substrates and products. The separation step is controlled by the pressure and electric field strength in the microfluidic chip. achieve. Kinase experiments are generally controlled at a product conversion rate of 20-30%. This biological test method is used to identify the inhibitory effects of compounds on JAK kinase activity.

1. Experimental materials

S1.1 Test compound

The compound powder was dissolved in DMSO and stored in a refrigerator at -20°C sealed. The internalized substance Ref1 is used as the positive control for JAK1, JAK2 and Tyk2 tests, and Ref2 is used for the positive control for JAK3 tests.

2. Reagent preparation

S2.1. 1M HEPES buffer: Weigh 0.5M HEPES free acid and 0.5M HEPES sodium salt, add ultrapure water to dissolve, constant volume, filter, and store in a refrigerator at 4 degrees.

S2.2, 40mM ATP solution: Dissolve in 50mM HEPES buffer, configure to 40mM, aliquot, and store in a refrigerator at -20 degrees Celsius.

S2.3. 0.5% Tween 20: Dilute 100% Tween 20 with ultrapure water and store in a refrigerator at 4 degrees.

S2.4. 35% bovine serum albumin: prepare a 35% bovine serum albumin solution in ultrapure water, pack it, and store it in a refrigerator at -20 degrees.

S2.5, 1M dithiothreitol solution: Use ultrapure water to prepare a 1M solution of dithiothreitol, pack it, and store it in a refrigerator at -20 degrees.

S2.6, 0.5mM Jaktide Peptide substrate solution: Dissolve it to 0.5mM with 50mM HEPES, aliquot and store in a refrigerator at -20 degrees.

S2.7, 0.5mM IRStide Peptide substrate solution: Dissolve it to 0.5mM with 50mM HEPES, aliquot and store in a refrigerator at -20 degrees.

S2.8. Assay Buffer: 20mM HEPES buffer, pH 7.4, 10mM magnesium chloride, 0.01% bovine serum albumin BSA, 0.0005% Tween-20, 1mM dithiothreitol solution.

S2.9. Stop Buffer: 180mM HEPES buffer, 20mM ethylenediaminetetraacetic acid, 0.2% Coating Reagent 3.

S2.10. Separation Buffer: 100mM HEPES buffer, 10mM ethylenediaminetetraacetic acid, 0.0005% Tween 20, 0.1% Coating Reagent 3,1% dimethyl sulfoxide.

3. Experimental method

S3.1. Preparation of compound board

The compound was dissolved to 10 mM with dimethyl sulfoxide, a certain volume was diluted to 0.6 mM, and 10 μl of 0.6 mM dilution was added to a 384 microtiter plate, and then diluted in a 3-fold gradient, with a total of 8 concentration points.

S3.2, compound arrangement

Positive control (HPE1): Ref1, final concentration: 10μM

Positive control (HPE1): Ref2, final concentration: 10μM

Negative control (ZPE): DMSO, the final concentration is 1.6%

Compound: The highest final concentration is 10μM, 3 times dilution, 8 concentration points, 2 replicates.

4. Experimental operation steps

S4.1. Use ECHO to add 250nl compound to each well of the experiment plate, and centrifuge at 1000 rpm for 1 minute;

S4.2. Add 5μl of experimental buffer, shake for a few seconds to fully dissolve the compound;

S4.3. Add 5μl 3× substrate solution, add 5μl 3× kinase solution, and centrifuge at 800 rpm for 1 minute;

S4.4. The final concentrations of JAK1, JAK2, JAK3 and Tyk2 kinases in the reaction system are 20, 1, 1, and 1 nM, respectively

S4.5. Incubate at room temperature, each kinase needs a different time, and different batches of kinases have time differences

S4.6. When the reaction reaches 20%-30%, add 15μl stop solution to stop, and centrifuge at 1000 rpm for 2 minutes.

S4.7. Place it on the EZ Reader to read the board.

S4.8. EZ Reader reading is calculated from the peak height,% product conversion rate = product/(product+substrate)*100

5. Data processing: IC50 calculation

The graphing software Xlfit was used to make the concentration curve of the test compound and calculate the IC50 value.

The IC50 values of the compounds shown in the above examples obtained by this experimental method are listed in the following table.

The following table lists the IC50 values of the compounds shown in the above examples. "A" means ≥10μM; "B" means ≥1μM and <10μM; "C" means ≥0.1μM and <1μM; "D" means <0.1μM.

TDMNo.TDMNo.	Tyk2/μMTyk2/μM	JAK1/μMJAK1/μM	JAK2/μMJAK2/μM	JAK3/μMJAK3/μM
TDM-180656TDM-180656	AA	AA	AA	AA
TDM-180657TDM-180657	AA	AA	AA	AA
TDM-180658TDM-180658	AA	AA	AA	AA
TDM-180659TDM-180659	AA	AA	AA	AA
TDM-180660TDM-180660	AA	AA	AA	AA
TDM-180661TDM-180661	AA	AA	AA	AA
TDM-180662TDM-180662	AA	AA	AA	AA
TDM-180663TDM-180663	AA	AA	AA	AA
TDM-180664TDM-180664	AA	AA	AA	AA
TDM-180682TDM-180682	AA	AA	AA	AA
TDM-180683TDM-180683	AA	AA	BB	AA
TDM-180684TDM-180684	BB	AA	AA	AA
TDM-180685TDM-180685	BB	AA	BB	AA
TDM-180686TDM-180686	BB	BB	BB	AA
TDM-180687TDM-180687	BB	BB	BB	AA
TDM-180688TDM-180688	BB	BB	BB	AA
TDM-180689TDM-180689	BB	BB	BB	AA
TDM-180690TDM-180690	BB	BB	BB	AA
TDM-180691TDM-180691	AA	BB	AA	AA
TDM-180692TDM-180692	BB	BB	BB	AA
TDM-180693TDM-180693	AA	AA	AA	AA
TDM-180694TDM-180694	AA	AA	AA	AA
TDM-180695TDM-180695	CC	BB	BB	AA
TDM-180696TDM-180696	BB	BB	AA	AA
TDM-180697TDM-180697	AA	AA	AA	AA
TDM-180701TDM-180701	BB	BB	BB	AA
TDM-180702TDM-180702	BB	BB	AA	AA
TDM-180703TDM-180703	AA	AA	AA	AA
TDM-180706TDM-180706	AA	AA	AA	AA
TDM-180707TDM-180707	AA	AA	AA	AA
TDM-180708TDM-180708	AA	AA	AA	AA
TDM-180709TDM-180709	BB	BB	AA	AA

TDM-180715TDM-180715	AA	AA	AA	AA
TDM-180716TDM-180716	AA	AA	AA	AA
TDM-180723TDM-180723	AA	AA	AA	AA
TDM-180724TDM-180724	AA	AA	AA	AA
TDM-180729TDM-180729	CC	BB	BB	AA
TDM-180730TDM-180730	BB	BB	BB	AA
TDM-180732TDM-180732	BB	BB	BB	AA
TDM-180733TDM-180733	AA	BB	AA	AA
TDM-180745TDM-180745	BB	BB	BB	AA
TDM-180750TDM-180750	CC	CC	BB	BB
TDM-180751TDM-180751	CC	CC	CC	CC
TDM-180793TDM-180793	BB	BB	To	To
TDM-180809TDM-180809	CC	DD	CC	BB
TDM-180811TDM-180811	BB	BB	To	To
TDM-180812TDM-180812	CC	CC	BB	AA
TDM-180815TDM-180815	BB	BB	To	To
TDM-180816TDM-180816	CC	CC	CC	BB
TDM-180817TDM-180817	BB	BB	To	To
TDM-180824TDM-180824	BB	BB	To	To
TDM-180825TDM-180825	BB	BB	To	To
TDM-180835TDM-180835	BB	BB	To	To
TDM-180837TDM-180837	BB	BB	To	To
TDM-180838TDM-180838	BB	BB	To	To
TDM-180839TDM-180839	BB	CC	BB	AA
TDM-180842TDM-180842	BB	BB	BB	AA
TDM-180862TDM-180862	BB	BB	To	To
TDM-180863TDM-180863	CC	CC	To	To
TDM-180864TDM-180864	BB	BB	To	To
TDM-180865TDM-180865	BB	BB	To	To
TDM-180874TDM-180874	BB	BB	To	To
TDM-180878TDM-180878	AA	BB	To	To
TDM-180879TDM-180879	CC	CC	To	To
TDM-180883TDM-180883	AA	BB	To	To
TDM-180909TDM-180909	BB	BB	To	To

Claims

A small molecule compound characterized by being a compound represented by the following structural formula or its stereoisomers, geometric isomers, tautomers, racemates, hydrates, solvates, metabolites and pharmaceuticals Acceptable salts or prodrugs:

Wherein, the X 1 and X 2 are selected from carbon or nitrogen;

The Z is carbon or nitrogen;

The n1 is 0, 1;

The n2 and n3 are the same or different, and are 0 or any natural number;

The cyclic group represented by G is a saturated heterocyclic ring;

The R is selected from hydrogen, halogen, alkyl, substituted alkyl, amino, amine, substituted amine, carboxy, amide, substituted amide, ester, substituted carbonyl, cycloalkyl, substituted Cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, sulfone, sulfoxide.
A small molecule compound according to claim 1, characterized in that it is a compound represented by the following structural formula or its stereoisomers, geometric isomers, tautomers, racemates, hydrates, Solvates, metabolites and pharmaceutically acceptable salts or prodrugs:
A small molecule compound according to claim 1, characterized in that it is a compound represented by the following structural formula or its stereoisomers, geometric isomers, tautomers, racemates, hydrates, Solvates, metabolites and pharmaceutically acceptable salts or prodrugs:

Wherein, R'is hydrogen, alkyl, substituted alkyl, ester, or substituted carbonyl.
A small molecule compound according to claim 1, characterized in that it is a compound represented by the following structural formula or its stereoisomers, geometric isomers, tautomers, racemates, hydrates, Solvates, metabolites and pharmaceutically acceptable salts or prodrugs:

Among them, at least one of B 1 and B 2 is nitrogen, sulfur or oxygen.
A small molecule compound according to claim 1, characterized in that it is a compound represented by the following structural formula or its stereoisomers, geometric isomers, tautomers, racemates, hydrates, Solvates, metabolites and pharmaceutically acceptable salts or prodrugs:

Wherein, B 1 is one of nitrogen or carbon;

R" is selected from hydrogen, halogen, alkyl, substituted alkyl, amino, amine, substituted amine, carboxy, amide, substituted amide, ester, substituted carbonyl, cycloalkyl, substituted ring Alkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl.
The small molecule compound of claim 1, wherein:

The R is

Wherein, the m is 0 or any natural number;

The R 1 is an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocycloalkyl group, and a substituted heterocycloalkyl group.
The small molecule compound of claim 1, wherein:

The R is

Wherein, the R 2 is an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocycloalkyl group, and a substituted heterocycloalkyl group.
The small molecule compound of claim 1, wherein:

Any two hydrogen atoms on the cyclic group represented by G form a bridge bond.
The application of a small molecule compound according to any one of claims 1-8, characterized in that:

It is used to treat, prevent and alleviate autoimmune diseases and inflammatory skin diseases related to autoimmunity.
The application of a small molecule compound according to claim 9, characterized in that:

Is a composition;

The mass percentage content of the small molecule compound in the composition is 10-6 % to 100%.