A small molecule compound

Abstract

This invention provides a small molecule compound characterized by a structure represented by the following general molecular formula: wherein X1 and X2 are selected from carbon or nitrogen; G1 is an aromatic carbon ring or heterocycle; any or several hydrogen atoms on the G1 ring are substituted by R1; and R1 is selected from nitrogen-containing groups. The small molecule compound of this invention can serve as a highly efficient and specific JAK kinase inhibitor, particularly a Tyk2 inhibitor, and / or a JAK1 inhibitor, and / or a JAK1 / Tyk2 or Tyk2 / JAK1, Tyk2 / Jak2 dual inhibitor.

Description

Technical Field

[0001] This invention relates to the field of small molecule compounds, specifically to a small molecule compound that can be used to treat, prevent and alleviate autoimmune diseases such as rheumatoid arthritis, ulcerative colitis, or related inflammatory skin diseases such as psoriasis, eczema, vitiligo, etc. Background Technology

[0002] Protein kinases catalyze the phosphorylation of amino acids at specific sites in proteins. Based on amino acid phosphorylation, they can be classified into tyrosine kinases, serine kinases, and arginine kinases. JAK is a family of intracellular non-receptor tyrosine kinases, including four members: JAK1, JAK2, JAK3, and Tyk2. JAKs are mainly expressed in hematopoietic cells, leukocytes, and intestinal epithelial cells, and are responsible for mediating the signal transduction of various cytokines involved in inflammatory responses. When cytokines bind to cell surface receptors, JAKs are activated through autophosphorylation. Activated JAKs then activate the intracellular portion of the receptor by phosphorylation and recruit members of the STAT protein family. Subsequently, STATs are activated by JAK phosphorylation to form dimers, which detach from the receptor and enter the cell nucleus to regulate gene transcription, thereby affecting the cell's biological functions. The JAK (Janus Kinase)-STAT (Signal Transducer and Activator of Transcription Proteins) signaling pathway is the main pathway for the intracellular transmission of signals triggered by the binding of inflammatory cytokines and receptors. Numerous studies have demonstrated the significant association between the JAK-STAT signaling pathway and numerous diseases, particularly autoimmune diseases such as rheumatoid arthritis, intestinal diseases, and allergic diseases. Therefore, these protein kinases have become crucial drug development targets for disease intervention. Currently, many pharmaceutical companies are developing new drugs targeting members of the JAK family, but most focus on inhibiting JAK1 and JAK3, with very few reports on inhibitors targeting Tyk2.

[0003] The JAK-STAT pathway can be activated by more than 50 different cytokines. Pro-inflammatory cytokines (IL6, TNF-α, IL12, IL23), anti-inflammatory cytokines (IL4, IL10), hematopoietic growth factors (g-CSF, EPO, TPO), and metabolic cytokines (leptin, GH) can activate this signaling pathway, thereby regulating cell proliferation, differentiation, and activation, as well as the transcriptional regulation of various genes involved in human metabolic homeostasis. The JAK / STAT cascade is a convergence point for many extracellular regulatory signals, making it a central communication node in the cell. Studies have shown that cytokine-mediated signal transduction systems activate JAK family members JAK1, JAK2, JAK3, and TYK2 tyrosine kinases, phosphorylate cytokine receptors, recruit STAT (signal transducer and activator of transcription proteins), and ultimately lead to intracellular gene expression. The pairing between JAK members is directly related to upstream cytokines. Depending on the specific cytokine stimulation, upstream cytokine signals may exhibit different pairings, such as JAK1 / JAK2, JAK1 / JAK3, JAK1 / TYK2, JAK2 / TYK2, and JAK2 / JAK2, with JAK1 pairing being the most common. TYK2 is crucial for the signal transduction of type I interferons (IFN-alpha, IFN-beta), IL-6, and IL-23. Immune cell differentiation and function associated with inflammatory and autoimmune diseases are significantly related to TYK2. Typically, TYK2 and its family members, upon activation by the signal transduction system, may appear in pairings such as TYK2 / JAK1, TYK2 / JAK2, and TYK2 / JAK1 / JAK2. TYK2 plays a vital role in mediating the signal transduction pathways of IL-12, IL-17, and IL-23. Biological antibody drugs targeting IL17 and IL23 have achieved good therapeutic effects on diseases such as psoriasis. It is conceivable that by using highly efficient small molecules to inhibit JAK kinase activity, especially TYK2 kinase activity, it is possible to block the signaling pathway mediated by inflammatory factors, control inflammation, effectively treat autoimmune diseases and / or inflammatory skin diseases, and reduce side effects. Summary of the Invention

[0004] The present invention aims to develop highly effective and specific JAK kinase inhibitors, particularly Tyk2 inhibitors, and / or JAK1 inhibitors, and / or JAK1 / Tyk2 or Tyk2 / JAK1 and / or Tyk2 / Jak2 dual inhibitors, suitable for the treatment of autoimmune diseases such as rheumatoid arthritis, ulcerative colitis, and inflammatory skin diseases such as eczema and psoriasis.

[0005] This invention provides a small molecule compound, characterized in that it is a compound or its stereoisomers, geometric isomers, tautomers, racemates, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs as shown in the following structural formulas:

[0006]

[0007] Among them, X1 and X2 are selected from carbon or nitrogen;

[0008] The aforementioned G1 is a six-membered or more-membered carbon ring or heterocycle with aromaticity;

[0009] In the G1 ring mentioned above, any one or several hydrogen atoms are replaced by R1;

[0010] The R1 mentioned above is selected from hydrogen, halogen, alkyl, substituted alkyl, amino, amino, substituted amino, carboxyl, amide, substituted amide, ester, substituted carbonyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl.

[0011] Furthermore, the present invention provides a small molecule compound characterized in that:

[0012] The structure of G1 above is shown in the following general formula:

[0013]

[0014] Among them, A1, A2, A3, A4, and A5 are selected from carbon, nitrogen, oxygen, or sulfur;

[0015] like:

[0016]

[0017] or

[0018] The structure of G1 above is shown in the following general formula:

[0019]

[0020] Among them, A1, A2, A3, A4, and A5 are selected from carbon, nitrogen, oxygen, or sulfur;

[0021] The bonds A1 to A2, A2 to A3, A3 to A4, and A4 to A5 are connected in parallel with five-membered aromatic carbon rings / heterocyclic rings and six-membered aromatic carbon rings / heterocyclic rings.

[0022] like:

[0023]

[0024] Similar structures.

[0025] Furthermore, the present invention provides a small molecule compound characterized in that:

[0026] The structure of G1 above is shown in the following general formula:

[0027]

[0028] Among them, B1, B2, B3, and B4 are selected from carbon, nitrogen, oxygen, or sulfur.

[0029] The bonds B1 to B2, B2 to B3, and B3 to B4 are connected to five-membered aromatic carbon rings / heterocyclic rings or six-membered aromatic carbon rings / heterocyclic rings. For example:

[0030]

[0031] Similar structures.

[0032] or

[0033]

[0034] Among them, B1, B2, B3, and B4 are selected from carbon, nitrogen, oxygen, or sulfur.

[0035] The bonds B1 to B2, B2 to B3, and B3 to B4 are connected in parallel with five-membered aromatic carbon rings / heterocyclic rings or six-membered aromatic carbon rings / heterocyclic rings; for example:

[0036]

[0037] Furthermore, the present invention provides a small molecule compound characterized in that:

[0038] R1 is

[0039] Where n is 0 and a natural number;

[0040] The R 11 Selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyl, and ether groups;

[0041] The R 12 Selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyl, and ether groups.

[0042] Furthermore, the small molecule compound provided by the present invention also has the following characteristic: that is, R1 above is And the products that react with the amide group.

[0043] Here, substances that can react with amide groups are preferably halogenated compounds such as halogenated hydrocarbons, acyl halides, and sulfonyl halides.

[0044] Furthermore, the small molecule compound provided by the present invention also has the following characteristic: that is, R1 above is

[0045] Among them, the above R 13 Selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyl, ether, aryl, substituted aryl, heteroaryl, substituted heteroaryl;

[0046] The above R 14 Selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyl, ether, aryl, substituted aryl, heteroaryl, substituted heteroaryl.

[0047] Furthermore, the small molecule compound provided by the present invention also has the following characteristics: that is, R1 is NH2, and the product is reacted with the NH2 group.

[0048] Furthermore, the small molecule compound provided by the present invention also has the following characteristic: that is, R1 above is

[0049] Among them, the above R 15 Selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyl, ether, aryl, substituted aryl, heteroaryl, substituted heteroaryl;

[0050] The above R 16 Selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyl, ether, aryl, substituted aryl, heteroaryl, substituted heteroaryl.

[0051] Furthermore, the small molecule compound provided by the present invention also has the following characteristic: that is, R1 above is

[0052] Among them, the above R 17 Selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, hydroxyl, ether, aryl, substituted aryl, heteroaryl, substituted heteroaryl;

[0053] The above R 18 Selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, hydroxyl, ether, aryl, substituted aryl, heteroaryl, substituted heteroaryl.

[0054] Furthermore, a small molecule compound is characterized as being a compound or its stereoisomers, geometric isomers, tautomers, racemates, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs represented by the following structural formulas:

[0055]

[0056] The R2 mentioned above is selected from alkyl, substituted alkyl, ester, substituted carbonyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, sulfone, substituted sulfone, sulfoxide, and substituted sulfoxide.

[0057] In this invention, the alkyl group is generally a branched alkyl group or a branched alkyl group having no more than 6 carbon atoms.

[0058] The aforementioned substituted alkyl refers to the alkyl group in which one or more hydrogen atoms on the carbon chain are replaced by other groups, which may be cycloalkyl (similar to...) Substitution can be performed in the form of halogen, cyano, alkyl, hydroxyl, carboxyl, etc., and any hydrogen atom on the cycloalkyl ring can also be replaced by halogen, cyano, alkyl, hydroxyl, carboxyl, etc. heterocyclic alkyl (i.e., based on the aforementioned cycloalkyl, at least one carbon atom on its alkyl ring is replaced by oxygen, sulfur, nitrogen), halogen (F, Cl, Br, I), carboxyl, cyano (-CN), sulfonic acid (-SO) 4, ), sulfonyl (-SO2R) a R a (e.g., hydrogen, alkyl, aryl, etc.) alkenyl (-C=CR) b R b (Hydrogen, alkyl, aryl, etc.) and alkynyl (-C≡CH, -C≡CR) b R b (e.g., hydrogen, alkyl, aryl, etc.) amide group (-C(O)NR) x R y R x R y (alkyl, aryl, etc.), ester group (-C(O)OR) z R z (alkyl, aryl, etc.), aryl, heteroaryl, ether ( n is a natural number from 1, 2, 3, ..., R c Groups such as hydrogen, alkyl, aryl, etc.

[0059] The aforementioned substituted amino group refers to one or more hydrogen atoms on the amino group being replaced by other groups. These other groups can be alkyl, cycloalkyl, carboxyl, cyano, sulfonic acid, amide, ester, etc.

[0060] The aforementioned substituted cycloalkyl refers to a cycloalkyl group in which one or more hydrogen atoms are replaced by other groups. These other groups can be alkyl groups, substituted alkyl groups (as above), halogens (F, Cl, Br, I), carboxyl groups, cyano groups (-CN), or sulfonic acid groups (-SO). 4, ), sulfonyl (-SO2R) aR a (Hydrogen, alkyl, aryl, etc.) and alkynyl (-C≡CH, -C≡CR) b R b (alkyl, aryl, etc.), amide group (-C(O)NR) x R y R x R y (alkyl, aryl, etc.), ester group (-C(O)OR) z R z These are alkyl, aryl, heteroaryl, and other groups.

[0061] The aforementioned substituted heterocyclic alkyl refers to a cyclic alkyl in which one or more carbon atoms on the ring are replaced by oxygen, sulfur, or nitrogen.

[0062] The aforementioned aryl group refers to six-membered or higher aromatic rings such as benzene and naphthalene, or benzo[a]aromatic rings.

[0063] The aforementioned substituted aryl group refers to a five-membered or higher aromatic ring, such as benzene, naphthalene, or fluorene, or a benzo[a]aromatic ring, in which one or more hydrogen atoms on the ring are replaced by other groups. These other groups can be alkyl groups, substituted alkyl groups (as above), halogens (F, Cl, Br, I), carboxyl groups, cyano groups (-CN), or sulfonic acid groups (-SO). 4, ), sulfonyl (-SO2R) a R a (Hydrogen, alkyl, aryl, etc.) and alkynyl (-C≡CH, -C≡CR) b R b (alkyl, aryl, etc.), amide group (-C(O)NR) x R y R x R y (alkyl, aryl, etc.), ester group (-C(O)OR) z R z These are alkyl, aryl, heteroaryl, and other groups.

[0064] The aforementioned heteroaryl groups refer to five-membered or higher aromatic heterocycles or benzo[a]aromatic heterocycles, such as thiophene, pyrrole, pyridine, furan, imidazole, benzimidazole, and quinoline.

[0065] The aforementioned substituted heteroaryl groups refer to five-membered or higher aromatic heterocycles or benzo[a]aromatic heterocycles, such as thiophene, pyrrole, pyridine, furan, imidazole, benzimidazole, and quinoline, where one or more hydrogen atoms on the ring are replaced by other groups. These other groups can be alkyl groups, substituted alkyl groups (as above), halogens (F, Cl, Br, I), carboxyl groups, cyano groups (-CN), or sulfonic acid groups (-SO). 4, ), sulfonyl (-SO2R) a R a(Hydrogen, alkyl, aryl, etc.) and alkynyl (-C≡CH, -C≡CR) b R b (alkyl, aryl, etc.), amide group (-C(O)NR) x R y R x R y (alkyl, aryl, etc.), ester group (-C(O)OR) z R z These are alkyl, aryl, heteroaryl, and other groups.

[0066] The above amide group has the structure shown as -CONH2;

[0067] The aforementioned substituted amide group is formed when one or more hydrogen atoms in the above structure are replaced by other groups. These other groups can be alkyl groups, substituted alkyl groups (as above), halogens (F, Cl, Br, I), carboxyl groups, cyano groups (-CN), or sulfonic acid groups (-SO). 4, ), sulfonyl (-SO2R) a R a (Hydrogen, alkyl, aryl, etc.) and alkynyl (-C≡CH, -C≡CR) b R b (alkyl, aryl, etc.), amide group (-C(O)NR) x R y R x R y (alkyl, aryl, etc.), ester group (-C(O)OR) z R z These are alkyl, aryl, heteroaryl, and other groups.

[0068] The above ester group is -C(O)OR z R z It can be alkyl, aryl, etc.

[0069] The substituted carbonyl groups mentioned above belong to several classes of compounds with the following structures:

[0070] The above R is

[0071] Wherein, R7 above is an alkyl group (same as above), a substituted alkyl group (same as above), a cycloalkyl group (cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc.), or a substituted cycloalkyl group (i.e., one or more hydrogen atoms on the cycloalkyl ring are replaced by halogen, cyano, or alkynyl groups, such as: The structure shown is in the form of R 15Halogen, cyano, alkynyl, etc.), heterocyclic alkyl (at least one carbon atom on the 3- to 7-membered ring is replaced by nitrogen, sulfur, or oxygen), substituted heterocyclic alkyl (one or more hydrogen atoms on the heterocyclic alkyl ring are replaced by halogen, cyano, or alkynyl), sulfone ( R 16 (alkyl, halogen, aryl, etc.), sulfoxide ( R 17 Alkyl, halogen, aryl, etc.), substituted carbonyl groups ( R 17 (e.g., alkyl, substituted alkyl, aryl, etc.)

[0072] The above sulfone group is Among them, R 16 Alkyl, substituted alkyl (same as above), halogen, aryl, substituted aryl (same as above), ether, cycloalkyl, substituted cycloalkyl (same as above), etc.

[0073] The above-mentioned sulfoxide group is R 17 It can be alkyl, halogen, aryl, etc.

[0074] Furthermore, the small molecule compound provided by this invention also has the characteristic of being used to treat, prevent, and alleviate inflammatory skin diseases related to autoimmunity. It can be available in various dosage forms, including oral, topical, and injectable forms.

[0075] The function and effects of this invention:

[0076] Based on the protein structure of JAK kinase, particularly Tyk2, this invention involves the targeted and rational design of small molecule drug formulations. The synthesized compounds are first subjected to JAK kinase biochemical activity assays, and SAR (structure-activity relationship) is established based on IC50. Potent inhibitors with IC50 values ​​below 200 nM are then subjected to cellular testing to determine the selectivity of the compounds. Specific activity experimental data reveal that the compounds involved in this invention possess excellent inhibitory capabilities against cellular activity.

[0077] The inhibitors provided by this invention can also be used for other autoimmune-related skin diseases such as alopecia areata, vitiligo, lupus erythematosus with predominantly cutaneous manifestations, lichen planus, lichen luster, lichen sclerosus, panniculitis, atopic dermatitis, etc.

[0078] The Tyk2 inhibitors, and / or JAK1 inhibitors, and / or JAK1 / Tyk2 dual inhibitors obtained in this invention, suitable for oral or intravenous administration, can still be used to treat psoriasis and other autoimmune diseases such as RA, IBD, MS, etc. Detailed Implementation

[0079] Example 1: General method for synthesizing compound TDM-180712

[0080]

[0081] Step 1: Example 112b

[0082] The original compound 112a, namely methyl 1H-indole-3-carboxylic acid methyl ester (554 mg, 3.16 mmol), and sodium hydride (183 mg, 4.59 mmol, 60% wt.) were added to a three-necked flask, and the system was purged with nitrogen three times under water pump conditions. Anhydrous DMF (50 mL) was added via syringe while stirring under ice bath conditions, and the mixture was then stirred for 30 min. A DMF (10 mL) solution of compound B0, namely 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (600 mg, 2.87 mmol), was slowly injected into the reaction mixture. The resulting reaction mixture was refluxed at 100 °C for 4 hours. After the reaction was complete, it was poured into water (30 mL) and extracted with ethyl acetate (60 mL x 3). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 0 / 100) to give a white solid compound 112b, namely methyl 1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indole-3-carboxylic acid (0.6 g, yield 60%).

[0083] LCMS[M+1] + =349.

[0084] Step 2: Example 112c

[0085] A solution of methyl 1-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indole-3-carboxylic acid (600 mg, 1.72 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL) was added to a solution of lithium hydroxide (10 mL, 1 M). The reaction mixture was reacted at 40 °C for 3 hours. The mixture was concentrated under reduced pressure to remove the organic solvent, neutralized with HCl (2 N) to pH approximately 5, and the precipitated solid was collected by filtration. Ethanol was added to the solid and concentrated by rotary evaporation to remove residual water. A green solid compound 112c, 1-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indole-3-carboxylic acid (0.5 g, yield 87%), was obtained. LCMS [M+1] + =335.1.

[0086] Step 3: Example 112 (TDM-180712)

[0087] N-(cyanomethyl)-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indole-3-carboxamide

[0088] Compound 112c, namely N-(cyanomethyl)-1-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indole-3-carboxamide (100 mg, 0.3 mmol) and DIPEA (155 mg, 1.2 mmol) in DMF (8 mL), was supplemented with compound 112d, namely 2-aminoacetonitrile hydrochloride (55 mg, 0.6 mmol) and HATU (126 mg, 0.33 mmol). The mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction solution was poured into water, and the precipitated solid was collected by filtration. The solid was slurried with EtOAc / MeOH (approximately 4:1) to give a grayish-white solid compound 112, namely N-(cyanomethyl)-1-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indole-3-carboxamide (95.3 mg, yield 85%).

[0089] LCMS[M+1] + =373.1

[0090] 1 H NMR (400MHz, DMSO-d6)) δ9.74(s,1H),8.96(s,1H),8.80(s,1H),8.57(d,J=5.6Hz,1H),8.24(d,J=8.0Hz,1 H),7.94(s,1H),7.56(s,1H),7.31-7.45(m,2H),7.04(d,J=5.6Hz,1H),4.39(d,J=5.6Hz,2H),3.84(s,3H).

[0091] Example 2: General method for synthesizing compound 125 (TDM-180725)

[0092]

[0093] Step 1: Example 125b

[0094] (1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indole-3-yl)tert-butyl carbamate

[0095] To an argon-protected, stirrered three-necked flask, compound 125a (0.25 g, 0.75 mmol), a mixture of DIPEA (193 mg, 1.5 mmol) and THF (10 mL), was added, followed by the addition of t-BuOH (15 mL) and DPPA (309 mg, 1.13 mmol). The mixture was heated to 105 °C and refluxed for 18 hours. The remaining feed was determined by LCMS, and another batch of DIPEA (193 mg) and DPPA (309 mg) was added. The resulting mixture was stirred at 105 °C under Ar for 20 hours. The reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 0 / 100) to give a yellow solid, compound 125b (80 mg, yield <12.5%).

[0096] [Note: The reaction has poor reproducibility.]

[0097] LCMS[M+1] + =406.2

[0098] Step 2: Example 125c

[0099] HCl / 1,4-dioxane (3 mL, 4 M) was added to a DCM (6 mL) solution of compound 125b (80 mg, 0.2 mmol). The mixture was stirred at room temperature for 26 hours. The reaction mixture was concentrated under reduced pressure to give compound 125c (60 mg crude) as a yellow solid. The crude product was used directly for the next step without purification.

[0100] LCMS[M+1] + =306.1

[0101] Step 3: Example 125 (TDM-180725)

[0102] 2-Cyano-N-(1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-3-yl)acetamide

[0103] To a solution of compound 125c (60 mg, 0.2 mmol) in DIPEA (129 mg, 1.0 mmol) and DMF (10 mL), HATU (114 mg, 0.3 mmol) and compound 125d (51 mg, 0.6 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours, then poured into H2O and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (EtOAc / MeOH = 20). The crude product was pulped with EtOAc / PE (approximately 3:1), filtered, and the solid was collected and dried under vacuum. This yielded an orange solid, compound 125 (9.5 mg; <10% yield).

[0104] LCMS[M+1] + =373.1.

[0105] 1H NMR(400MHz,Chloroform-d)δ10.56(s,1H),9.59(brs,1H),8.87(brs,1H),8.43(d,J=5.6Hz,1H),7 .86-8.00(m,2H),7.53(s,1H),7.27-7.43(m,2H),7.00(d,J=5.6Hz,1H),4.06(s,2H),3.85(s,3H).

[0106] Example 3: General method for synthesizing compound 122 (TDM-180722)

[0107]

[0108] Step 1: Example 122c

[0109] At room temperature, 1,4-dioxane (20 mL) and water (3 mL) were added to a mixture of compound 122a (200 mg, 0.96 mmol), i.e., 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine, compound 122b (287 mg, 0.96 mmol), i.e., 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborane, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (70.2 mg, 0.096 mmol), and sodium carbonate (210 mg, 1.92 mmol). The mixture was then degassed under vacuum and heated to 105 °C and stirred for 3 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated under reduced pressure. The compound was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 25:75) to give a red solid compound 122c (242 mg, yield 56.8%), namely N-(1-methyl-1H-pyrazol-4-yl)-4-(4-nitrophenyl)pyrimidine-2-amine. LCMS [M+1] + =297.

[0110] Step 2: Example 122d

[0111] Pd / C was added to a methanol (30 mL) suspension of compound 122c (100 mg, 0.34 mmol) at room temperature. The mixture was then degassed under vacuum, heated to 45 °C under hydrogen atmosphere, and stirred for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a white solid compound 112d (57 mg, 63% yield), namely 4-(4-aminophenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2-amine. LCMS [M+1] + =267.

[0112] Step 3: Example 122 (TDM-180722)

[0113] Triethylamine (22.7 mg, 0.225 mmol) was added to a solution of compound 122d (40 mg, 0.15 mmol) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was stirred for 5 minutes, and then benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (117 mg, 0.225 mmol) and compound 122e (19.1 mg, 0.225 mmol) i.e. 2-cyanoacetic acid were added to the mixture, and the mixture was stirred at room temperature for 6 hours. The mixture was extracted with ethyl acetate (50 ml × 3), the organic layer was washed with saturated brine (30 ml × 6), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (ethyl acetate:methanol = 20:1) and HPLC to give a yellow solid compound 122, TDM-180722 (13.3 mg, yield 13.3%), namely 2-cyano-N-(4-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)acetamide. LCMS [M+1] + =334

[0114] 1H NMR (400MHz, DMSO-d6) δ10.56(s,1H),9.49(s,1H),8.45(d,J=5.2Hz,1H),8.14(d,J=8.7Hz,2H), 7.93(s,1H),7.73(d,J=8.7Hz,2H),7.56(s,1H),7.25(d,J=5.3Hz,1H),3.97(s,2H),3.84(s,3H).

[0115] Compounds prepared by similar methods are as follows:

[0116]

[0117]

[0118] TDM-180754 is a yellow solid compound 154, namely 3,3,3-trifluoro-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propionamide (6.6 mg, yield: 9.3%).

[0119] TDM-180755 is a grayish-white solid compound, namely N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)cyclopropane formamide (30.5 mg, yield: 48.5%).

[0120] TDM-180757 is a yellow solid compound 157, namely 2,2-difluoro-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)cyclopropane-1-carboxamide (32.5 mg, yield: 46.7%).

[0121] TDM-180759 is a yellow solid compound 159, namely 2-methoxy-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)acetamide (46 mg, yield: 51.7%).

[0122] TDM-180799 is a pale yellow solid compound, namely 3-methoxy-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propionamide (8 mg, yield: 12%).

[0123] TDM-180802 is a yellow solid compound 202, namely 1-methyl-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)cyclopropane-1-carboxamide (30.4 mg, yield: 46.4%).

[0124] TDM-180803 is a yellow solid compound 203, namely 1-fluoro-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)cyclopropane-1-carboxamide (43.4 mg, yield: 65.4%).

[0125] TDM-180813 is a yellow solid compound 213, namely N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)cyclobutane methane (22.8 mg, 34.8% yield).

[0126] TDM-180804 is a gray solid compound, 204, namely 2-cyclopropyl-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)acetamide (7.4 mg, yield: 11.3%).

[0127] TDM-180805 is a yellow solid compound, 205, namely 2,2-difluoro-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)acetamide (10.8 mg, yield: 16.7%).

[0128] Example 4: General method for synthesizing compound 191 (TDM-180791)

[0129]

[0130] Step 1: Example 191c

[0131] At room temperature, N,N-diisopropylethylamine (116.3 mg, 0.9 mmol) was added to a solution of compound 191a (80 mg, 0.3 mmol), i.e., 4-(4-aminophenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine, in N,N-dimethylformamide (10 mL). The mixture was stirred for 5 minutes, and then 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (171 mg, 0.45 mmol) and compound 191b (53 mg, 0.45 mmol), i.e., 2-acetoxyacetic acid, were added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to remove the solvent. Methanol and petroleum ether were added to the residue, and the mixture was filtered to collect a brown solid compound 191, namely 2-((4-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)amino)-2-oxoethyl acetate (128 mg, crude product). LCMS [M+1] + =367.

[0132] Step 2: Example 191 (TDM-180791)

[0133] A solution of sodium hydroxide (100 mg) in water (10 mL) was added to a mixed solution of compound 191c (128 mg, 0.349 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL). The mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure to remove methanol and tetrahydrofuran. The precipitate was collected by filtration, and ethyl acetate and petroleum ether were added to the solid. A white solid, compound 191, TDM-180791, i.e., 2-hydroxy-N-(4-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)acetamide (60 mg, yield 46.9%), was collected by filtration. LCMS [M+1]+ = 325.1.

[0134] 1H NMR (400MHz, DMSO-d6) δ9.91(s,1H),9.43(s,1H),8.44(d,J=5.2Hz,1H),8.11(d,J=8.7Hz,2H),7.96–7. 86(m,3H),7.55(s,1H),7.24(d,J=5.2Hz,1H),5.70(t,J=6.0Hz,1H),4.04(d,J=6.0Hz,2H),3.83(s,3H).

[0135] Example 5: General method for synthesizing compound 213 (TDM-180813)

[0136]

[0137] Step 1: Example 213

[0138] Triethylamine (38 mg, 0.376 mmol) was added to a solution of compound 213a (50 mg, 0.188 mmol), i.e., 4-(4-aminophenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine, in N,N-dimethylformamide (10 mL) at room temperature, followed by compound 213b (26.7 mg, 0.226 mmol), i.e., cyclobutanecarbonyl chloride. The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was purified by preparation to give a yellow solid compound 213, TDM-180813, i.e., N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)cyclobutanemethyl (22.8 mg, 34.8% yield). LCMS [M+1] + =349.1

[0139] 1 H NMR (400MHz, DMSO-d6) δ9.98(s,1H),9.49(s,1H),8.43(d,J=5.3Hz,1H),8.11(d,J=8.8Hz,2H),7.92(s,1H),7.79(d,J =8.7Hz,2H),7.56(s,1H),7.24(d,J=5.3Hz,1H),3.84(s,3H),3.33–3.19(m,1H),2.34–2.08(m,4H),2.02–1.77(m,2H).

[0140] Example 6: General method for synthesizing compound 167 (TDM-180767)

[0141]

[0142] Step 1: Example 167 (TDM-180767)

[0143] At room temperature, compound 167b (39.6 mg, 0.282 mmol), i.e., cyclopropanesulfonyl chloride, was added to a pyridine (5 mL) solution of compound 167a (50 mg, 0.188 mmol), i.e., 4-(4-aminophenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine. The mixture was heated to 40 °C and stirred for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to remove excess pyridine. The residue was dissolved in hydrochloric acid (2 M), then neutralized with sodium hydroxide solution, and the precipitate was collected by filtration. Ethyl acetate and petroleum ether were added to the precipitate, and the mixture was filtered to collect a pale yellow solid, compound 167, TDM-180767 (49.2 mg, 70.8% yield), i.e., N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)cyclopropanesulfonyl chloride. LCMS [M+1] + =371.

[0144] 1H NMR (400MHz, DMSO-d6) δ10.10(s,1H),9.45(s,1H),8.44(d,J=5.1Hz,1H),8.12(d,J=8.6Hz,2H),7.92(s,1H),7.55(s, 1H),7.39(d,J=8.6Hz,2H),7.22(d,J=5.2Hz,1H),3.83(s,3H),2.73(ddd,J=12.6,7.6,5.1Hz,1H),1.05–0.91(m,4H).

[0145] Compounds prepared by similar methods are as follows:

[0146]

[0147]

[0148] TDM-180768 is a pale yellow solid compound, namely N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethanesulfonamide (12.7 mg, yield: 18.8%).

[0149] TDM-180893 is a yellow solid compound 293 (22.8 mg, yield 16%), namely N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propane-1-sulfonamide.

[0150] TDM-180844 is a light green solid compound 244 (17.9 mg, yield 12%), namely N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)prop-2-ene-1-sulfonamide.

[0151] TDM-180832 is a yellow solid compound 232, namely N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)butane-1-sulfonamide (19.6 mg, 13.3% yield).

[0152] TDM-180896 is a yellow solid compound 296 (50.6 mg, yield 23%), namely 3-fluoro-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propane-1-sulfonamide.

[0153] TDM-1808503,3,3-trifluoro-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propyl-1-sulfonamide, yellow solid compound (2.2 mg, yield 2.3%).

[0154] TDM-180834 is a yellow solid compound (Example 234, 36.6 mg, yield 40.42%), 2-ethoxy-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)ethyl-1-sulfonamide.

[0155] TDM-180820 is a light yellow solid compound 220, namely N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)-1-phenylmethanesulfonamide (16.8 mg, yield: 10.6%).

[0156] Example 7: General method for synthesizing compound 294 (TDM-180894)

[0157]

[0158] Step 1: Example 294c

[0159] At room temperature, compound 294a (232 mg, 1.134 mmol), i.e., 4-bromoaniline, was added to a solution of compound 294b (150 mg, 0.872 mmol), i.e., pyridine of 2-phenylethane-1-sulfonyl chloride (5 mL). The mixture was heated to 40 °C and stirred for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (100% dichloromethane) to give compound 294c, i.e., N-(4-bromophenyl)-2-phenylethane-1-sulfonamide (200 mg, 67.4% yield), as a white solid. LCMS [M+1] + =340&342

[0160] Step 2: Example 294c

[0161] Dioxane (18 mL) was added to a mixture of compound 294c (150 mg, 0.441 mmol), compound 294d (134.4 mg, 0.529 mmol) (i.e., pinacol diborate), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (48.4 mg, 0.066 mmol), and potassium acetate (86.4 mg, 0.822 mmol). The mixture was degassed under vacuum, purged several times with N2, and then heated to 100 °C and stirred for 2 hours. This mixture was used directly for the next reaction without purification. LCMS [M+1] + =388

[0162] Step 3: Example 294 (TDM-180894)

[0163] Compound 294f (92 mg, 0.441 mmol), namely 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (48.4 mg, 0.066 mmol), cesium carbonate (287 mg, 0.882 mmol), and water (3 mL) were added to the mixture from step 2. The mixture was degassed under vacuum, purged several times with nitrogen, and then heated to 100 °C and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the purified residue was obtained by silica gel chromatography (dichloromethane:10% methanol = 50:50) and preparative purification to give a yellow solid compound 294, TDM-180894, namely N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)-2-phenylethane-1-sulfonamide (25.7 mg, 13.5% yield). LCMS [M+1] + =435.2

[0164] 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),9.45(s,1H),8.44(d,J=5.2Hz,1H),8.13(d,J=8.6Hz,2H),7.92(s,1H ),7.55(s,1H),7.39(d,J=8.7Hz,2H),7.28–7.12(m,6H),3.83(s,3H),3.51–3.41(m,2H),3.08–2.96(m,2H).

[0165] Example 7: General method for synthesizing compound 135 (TDM-180735)

[0166]

[0167] Step 1: Example 135c

[0168] Compound 135a (1.0 g, 5.37 mmol) was dissolved in 1,4-dioxane (20 mL), and compound 135b (2.73 g, 10.75 mmol), KOAc (1.58 g, 16.12 mmol), and PdCl2 (dppf) (0.39 g, 0.54 mmol) were added. The mixture was purged with nitrogen three times, and then stirred at 80 °C for 17 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with ethyl acetate (20 mL × 3). The mixture was concentrated, and the concentrate was purified by silica gel chromatography (ethyl acetate: petroleum ether = 0-20%) to give a white solid compound 135c, namely 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)aniline (1.776 g, yield 94.6%). LCMS [M+1] + =234.1.

[0169] Step 2: Example 135e

[0170] Compound 135d (1.05 g, 5.01 mmol) was dissolved in 1,4-dioxane (20 mL) and water (4 mL). Compound 135c (1.17 g, 5.01 mmol), Na₂CO₃ (1.06 g, 10.02 mmol), and PdCl₂ (dppf) (0.37 g, 0.50 mmol) were added. The mixture was purged with nitrogen three times, and then stirred at 95 °C for 3 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with ethyl acetate (20 mL × 3). The mixture was concentrated, and the concentrate was purified by silica gel chromatography (ethyl acetate: petroleum ether = 0-80%) to give a yellow solid compound 135e, namely 4-(4-amino-2-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (263 mg, yield 18.8%). LCMS [M+1] + =281.4.

[0171] Step 3: Example 135 (TDM-180735)

[0172] To a solution of compound 135e (140 mg, 0.50 mmol) in dichloromethane (30 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (143.6 mg, 0.75 mmol), triethylamine (75.7 mg, 0.75 mmol), 1-hydroxybenzotriazole (101.1 mg, 0.75 mmol), and compound 135f (51.0 mg, 0.6 mmol) were added, and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated, and the concentrate was purified by silica gel chromatography (ethyl acetate: petroleum ether = 50-100%) and preparative HPLC to give a yellow solid compound 135, namely 2-cyano-N-(3-methyl-4-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)acetamide (45.4 mg, 18.3% yield). LCMS: [M+1] + =348.1.

[0173] 1 H NMR (400MHz, DMSO) δ10.41 (s, 1H), 9.46 (s, 1H), 8.44 (d, J = 5.1Hz, 1H), 7.85 (s, 1H) ,7.66–7.37(m,4H),6.84(d,J=5.1Hz,1H),3.93(s,3H),3.79(s,3H),2.41(s,3H).

[0174] Compounds prepared by similar methods are as follows:

[0175]

[0176]

[0177] TDM-180740 is a yellow solid compound 136, namely 3,3,3-trifluoro-N-(3-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propionamide (32.8 mg, yield: 27.6%).

[0178] Example 8: General method for synthesizing compound 131 (TDM-180731)

[0179]

[0180] Step 1: Example 131

[0181] Sodium borohydride (564 mg, 14.9 mmol) was added to a mixed solution of compound 131a (1.2 g, 5.97 mmol) in tetrahydrofuran (50 mL) and ethanol (5 mL). The mixture was stirred at room temperature for 4 hours under nitrogen protection. Dilute hydrochloric acid (0.5 N) and water were added to the mixture, and the mixture was concentrated under reduced pressure to remove excess tetrahydrofuran and ethanol. The residue was extracted with ethyl acetate (50 mL × 3), and the organic layer was washed with saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give compound 131b (925 mg, 76.3% yield), a yellow oil, which is (4-bromo-3-methylphenyl)methanol.

[0182] Step 2: Example 131c

[0183] Triethylamine (923 mg, 9.12 mmol) was added to a solution of compound 131b (925 mg, 4.56 mmol) in dichloromethane (20 mL). The mixture was cooled to 0 °C and methanesulfonyl chloride (627 mg, 5.47 mmol) was added. The mixture was allowed to warm naturally to room temperature and then stirred for 1.5 hours. Sodium bicarbonate solution was added to the mixture and it was extracted with dichloromethane (50 mL × 3). The organic layer was washed with saturated brine (50 mL) and then with anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give a yellow oily compound 131c (1.24 g, 97.4% yield), namely 4-bromo-3-methylbenzyl methanesulfonate.

[0184] Step 3: Example 131e

[0185] Compound 131d (600 mg, 4.44 mmol), i.e., thiomorpholine 1,1-dioxide, and triethylamine (420 mg, 4.15 mmol), were added to a solution of compound 131c (1.24 g, 4.44 mmol) in N,N-dimethylformamide (40 mL). The mixture was stirred at room temperature for 18 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to remove N,N-dimethylformamide. Water was added to the residue and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with saturated brine (30 mL × 4) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. Petroleum ether and ethyl acetate were added to the residue, and the precipitate was collected by filtration to give a white solid, compound 131e (587 mg, yield 41.5%), i.e., 4-(4-bromo-3-methylbenzyl)thiomorpholine 1,1-dioxide. LCMS [M+1] + =319.

[0186] Step 4: Example 131g

[0187] Potassium acetate (115 mg, 0.47 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (35.8 mg, 0.049 mmol) were added to a mixture of compound 131e (150 mg, 0.47 mmol) and compound 131h (143.2 mg, 0.564 mmol), i.e., 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane). 1,4-Dioxane was added to the mixture and degassed under vacuum. The mixture was then heated to 95 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, the mixture was used directly for the next reaction. LCMS [M+1] + =366.

[0188] Step 5: Example 131 (TDM-180731)

[0189] Compound 131h (98 mg, 0.47 mmol), namely 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (34 mg, 0.047 mmol), sodium carbonate (99.6 mg, 0.94 mmol), and water (1.2 mL) were added to the mixture (V834-123). The mixture was degassed under vacuum, heated to 105 °C under nitrogen protection, and stirred for 16 hours. After the reaction was complete, water was added to the mixture and extracted with ethyl acetate (40 mL × 3). The organic layer was washed with saturated brine (30 mL). The mixture was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The compound was purified by silica gel column chromatography (ethyl acetate:methanol = 20:1) to give a yellow solid compound 131, TDM-180731 (32 mg, yield 16.6%), namely 4-(3-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiomorpholine 1,1-dioxide. LCMS [M+1] + =413.

[0190] 1H NMR (400MHz, CDCl3) δ8.43(d,J=5.1Hz,1H),7.83(s,1H),7.52(s,1H),7.44(d,J=8.1Hz,1H),7.24(s,2 H),7.04(s,1H),6.78(d,J=5.1Hz,1H),3.89(s,3H),3.68(s,2H),3.06(d,J=21.7Hz,8H),2.44(s,3H).

[0191] Example 9: General method for synthesizing compound 183 (TDM-180783)

[0192]

[0193] Step 1: Example 183c

[0194] Compound 183a (1.0 g, 5.37 mmol), compound 183b (2.73 g, 10.75 mmol), potassium acetate (1.58 g, 16.12 mmol), and PdCl2 (dppf) (0.39 g, 0.54 mmol) were added to 1,4-dioxane (20 mL), purged three times with nitrogen, and then heated to 90 °C and stirred for 4 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (15 mL × 2). The filtrate was concentrated, and the concentrate was purified by silica gel chromatography (ethyl acetate: petroleum ether = 0-80%) to obtain a yellow solid compound 183c, namely (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)aniline (1.21 g, 96.6% yield). LCMS [M+1] + =234.1.

[0195] Step 2: Example 183e

[0196] Compound 183d (200 mg, 0.95 mmol), compound 183c (266.9 mg, 1.14 mmol), cesium carbonate (621.6 mg, 1.91 mmol), and PdCl2 (dppf) (69.8 mg, 0.10 mmol) were added to a mixture of 1,4-dioxane (10 mL) and water (1 mL). The mixture was purged with nitrogen three times, and then heated to 85 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (15 mL × 2). The filtrate was concentrated, and the concentrate was purified by silica gel chromatography (ethyl acetate: petroleum ether = 0-80%) to obtain the crude product. The crude product was purified by preparative HPLC to obtain a pale yellow solid compound 183e, namely 4-(4-amino-3-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (128 mg, 48.4% yield). LCMS[M+1] + =281.1.

[0197] Step 3: Example 183 (TDM-180783)

[0198] To a solution of compound 183e (50 mg, 0.179 mmol) in N,N-dimethylformamide (5 mL), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (102.1 mg, 0.269 mmol), triethylamine (27.2 mg, 0.269 mmol), and compound 183f (27.4 mg, 0.21 mmol) were added. The reaction mixture was stirred at 30 °C for 2 hours. After solvent removal, the solution was purified by preparative HPLC to obtain a yellow solid compound 183, namely 3,3,3-trifluoro-N-(2-methyl-4-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propionamide (19.2 mg, 27.3% yield). LCMS [M+1] + =391.1. 1 HNMR (400MHz, DMSO) δ9.79(s,1H),9.52(s,1H),8.46(d,J=5.2Hz,1H),8.03(s,1H),7.98(d,J=8.4Hz,1H),7.93(s ,1H),7.67(d,J=8.4Hz,1H),7.55(s,1H),7.27(d,J=5.3Hz,1H),3.83(s,3H),3.62(q,J=11.2Hz,2H),2.32(s,3H).

[0199] Compounds prepared by similar methods are as follows:

[0200]

[0201] TDM-180784 is a yellow solid compound, namely N-(cyanomethyl)-2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (18.1 mg, yield: 27.8%).

[0202] Example 10: General method for synthesizing compound 121 (TDM-180721)

[0203]

[0204] Step 1: Example 121b

[0205] (4-Bromo-3-methylphenyl)hydrazine hydrochloride

[0206] The original compound 121a (3 g, 16.1 mmol) was suspended in HCl (25.5 mL, 6 N) and cooled to 0 °C. A solution of sodium nitrite (1.2 g, 17.4 mmol) in water (12 mL) was added to the mixture (addition continued for about 5 min). The mixture was stirred at 0 °C for 15 min. Then, anhydrous stannous chloride (10.8 g, 47.9 mmol) in HCl (7.5 mL, 12 N) was added to the mixture. The resulting mixture was stirred at 0 °C for 2 h. The mixture was filtered, and the filter cake was washed with cold water to give a brown solid compound 121b, namely (4-bromo-3-methylphenyl)hydrazine hydrochloride (1.89 g, yield 58.4%).

[0207] LCMS[M+1] + =202.

[0208] Step 2: Example 121d

[0209] (Z)-1-Cyclopropyl-3-(dimethylamino)prop-2-en-1-one

[0210] A mixture of compound 121c (5.5 g, 65 mmol) and DMF·DMA (15 g, 126 mmol) was heated to 115 °C and reacted for 16 hours. The reaction mixture was concentrated under reduced pressure to give crude compound 121d (900 mg, yield <15%), which was used directly in the next reaction without purification. LCMS [M+1] + =140.2

[0211] Step 3: Example 121e

[0212] 1-(4-bromo-3-methylphenyl)-5-cyclopropyl-1H-pyrazole

[0213] Compound 121b (200 mg, 0.84 mmol), compound 121d (233 mg, 1.68 mmol), and EtOH (6 mL) were added to a microwave tube. The sealed microwave tube was reacted at 150 °C for 45 minutes. The different batches of the reaction were combined, the mixture was concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 0 / 10) to give a yellow oily compound 112e, namely 1-(4-bromo-3-methylphenyl)-5-cyclopropyl-1H-pyrazole (750 mg, 80% yield).

[0214] LCMS[M+1] + =279.

[0215] 1H NMR(400MHz,Chloroform-d)δ7.46-7.67(m,3H),7.32-7.38(m,1H),5.99(d,J=2 .4Hz,1H),2.48(s,3H),1.78-1.86(m,1H),0.98-1.05(m,2H),0.76-0.82(m,2H).

[0216] Step 4: Example 121g

[0217] 5-Cyclopropyl-1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)-1H-pyrazole was added to a three-necked flask along with compound 121e (200 mg, 0.72 mmol), compound 121f (274 mg, 1.08 mmol), PdCl(dppf) (158 mg, 0.22 mmol), KOAc (211 mg, 2.16 mmol), and 1,4-dioxane (20 mL). The mixture was evacuated by a water pump and purged with nitrogen three times. The reaction mixture was reacted at 95 °C for 3 hours. Compound 121 g (theoretically 234 mg) was obtained as the reaction mixture. The reaction mixture was used directly in the next step.

[0218] LCMS[M+1] + =325.2

[0219] Step 5: Example 121 (TDM-180721)

[0220] 4-(4-(5-cyclopropyl-1H-pyrazol-1-yl)-2-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

[0221] 4-(4-(5-cyclopropyl-1H-pyrazol-1-yl)-2-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine was added to compound 121 g (234 mg, 0.72 mmol) with compound B0 (118 mg, 0.56 mmol), PdCl2 (dppf) (82 mg, 0.11 mmol), K2CO3 (193 mg, 1.4 mmol), 1,4-oxohexane (10 mL), and H2O (5 mL). The mixture was evacuated three times by a water pump and replaced with nitrogen. The reaction mixture was reacted at 95 °C for 3 hours. The mixture was concentrated, purified by column chromatography (petroleum ether / ethyl acetate = 0 / 100), and purified again under basic conditions to give compound 121 (83.2 mg, 34% yield) as a light green solid.

[0222] LCMS[M+1] + =372.1.

[0223] ¹H NMR (400MHz, Chloroform-d) δ 8.48 (d, J = 5.2Hz, ¹H), 7.88 (s, ¹H), 7.50–7.67 (m, 5H), 7.01 (br s, ¹H), 6.85 (d, J = 5.2Hz, ¹H), 6.02 (d, J = 1.2Hz, ¹H), 3.91 (s, 3H), 2.53 (s, 3H), 1.87–1.96 (m, ¹H), 1.01–1.10 (m, 2H), 0.80–0.87 (m, 2H). Example 11: General method for the synthesis of compound 163 (TDM-180763)

[0224]

[0225] Step 1: Example 163c

[0226] A mixture of compounds 163a (5.5 g, 65.4 mmol) and 163b (15.6 g, 130.8 mmol) was stirred at 115 °C for 19 hours. After cooling to room temperature, water (50 mL) was added, and the mixture was extracted with EtOAc (20 mL × 4). The organic layers were combined and washed with water (30 mL × 2), dried over MgSO4, filtered, and evaporated to give a yellow oily compound 163c, namely (Z)-1-cyclopropyl-3-(dimethylamino)prop-2-en-1-one (1.23 g, 13.5% yield). LCMS [M+1] + =140.1.

[0227] Step 2: Example 163e

[0228] A solution of compound 163d (400 mg, 1.79 mmol) and compound 163c (498 mg, 3.58 mmol) in EtOH (12 mL) was reacted at 150 °C with microwave stirring for 45 min. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (rapid chromatography) with ethyl acetate:petroleum ether = 0%–10% to give a yellow solid compound 163e, namely 1-(4-bromophenyl)-5-cyclopropyl-1H-pyrazole (416 mg, 88.3% yield). LCMS [M+1] + =264.1.

[0229] Step 3: Example 163g

[0230] The solution of compound 163e (200 mg, 0.76 mmol), compound 163f (289.7 mg, 1.14 mmol), KOAc (223.6 mg, 2.28 mmol), and PdCl2 (dppf) (55.6 mg, 0.08 mmol) in 20 mL of 1,4-dioxane was stirred at room temperature, purged three times with nitrogen, and then heated to 90 °C and stirred for 3 hours. After the reaction was complete, the solution was used directly for the next step without further treatment.

[0231] Step 4: Example 163 (TDM-180763)

[0232] Compound 163h (122.3 mg, 0.58 mmol), compound 163g (235.1 mg, 0.76 mmol), K2CO3 (201.3 mg, 1.46 mmol), and PdCl2 (dppf) (85.4 mg, 0.12 mmol) were dissolved in a mixture of 1,4-dioxane (20 mL) and water (5 mL). The mixture was purged with nitrogen three times, and then heated to 95 °C and stirred for 17 hours. After cooling to room temperature, the mixture was filtered, the filter cake was washed with ethyl acetate, and the organic phase was collected and concentrated. The concentrate was purified by preparative HPLC to give a light green solid compound 163, namely 4-(4-(5-cyclopropyl-1H-pyrazol-1-yl)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (29.1 mg, 13.8% yield). LCMS: [M+1] + =358.2.

[0233] 1 H NMR (400MHz, DMSO) δ9.54(s,1H),8.52(d,J=5.1Hz,1H),8.30(d,J=8.6Hz,2H),7.93(s,1H),7.85(d,J=8.7Hz,2H),7.60(t,J=4 .5Hz,2H),7.35(d,J=5.2Hz,1H),6.19(d,J=1.3Hz,1H),3.84(s,3H),2.08–1.90(m,1H),1.12–0.94(m,2H),0.88–0.67(m,2H).

[0234] Example 12: General method for synthesizing compound 182 (TDM-180782)

[0235]

[0236] Step 1: Example 182b

[0237] The mixture of compound 182a (2.75 g, 32.7 mmol) and N,N-dimethylformamide dimethyl acetal (7.8 g, 65.4 mmol) was heated to 115 °C and stirred for 19 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 4). The organic layers were combined and washed with water (20 mL × 2), dried over MgSO4, filtered, and concentrated to give a yellow oily liquid compound 182b, namely (Z)-1-cyclopropyl-3-(dimethylamino)prop-2-en-1-one (0.4 g, 8.8% yield). LCMS [M+1] + =140.1.

[0238] Step 2: Example 182d

[0239] Compound 182c (0.5 g, 2.69 mmol) was dissolved in 6 mol / L hydrochloric acid (4 mL), cooled to 0 °C, and sodium nitrite aqueous solution (0.2 g sodium nitrite, 2 mL aqueous solution) was slowly added. The reaction mixture was stirred at 0 °C for 15 minutes, and then stannous chloride dihydrate (1.8 g, dissolved in 1.2 mL of 12 mol / L hydrochloric acid) was added. Stirring was continued at 0 °C for 2 hours. The mixture was filtered, and the filter cake was washed with cold water (10 mL × 2). The filter cake was then slurried with dichloromethane (2 mL) and petroleum ether (5 mL) for 15 minutes, filtered, and dried to give a brown solid compound 182d, namely (4-bromo-2-methylphenyl)hydrazine hydrochloride (290 mg, 45.4% yield). LCMS [M+1] + =201.1,203.1.

[0240] Step 3: Example 182e

[0241] Compound 182d (200 mg, 0.84 mmol) and compound 182c (234.4 mg, 1.68 mmol) were dissolved in ethanol (6 mL) and reacted by microwave heating to 150 °C for 45 min. After cooling to room temperature and removing the solvent, the concentrate was purified by silica gel chromatography (ethyl acetate: petroleum ether = 0%–10%) to give a yellow solid compound 182e, namely 1-(4-bromo-2-methylphenyl)-5-cyclopropyl-1H-pyrazole (160 mg, 47.4% yield). LCMS [M+1] + =277.1,279.1.

[0242] Step 4: Example 182g

[0243] Compound 182e (60 mg, 0.22 mmol) and compound 182f (82.5 mg, 0.32 mmol), potassium acetate (63.7 mg, 0.65 mmol), and PdCl2 (dppf) (15.8 mg, 0.02 mmol) were dissolved in 1,4-dioxane (10 mL) and stirred at room temperature. The mixture was purged with nitrogen three times, then heated to 90 °C and stirred for 5 hours. After cooling, the reaction solution was used directly for the next step. LCMS [M+1] + =325.1.

[0244] Step 5: Example 182 (TDM-180782)

[0245] Compound 182h (35 mg, 0.17 mmol), compound 182g (70.3 mg, 0.22 mmol), potassium carbonate (57.6 mg, 0.42 mmol), and PdCl2 (dppf) (24.4 mg, 0.03 mmol) were added to a mixture of 1,4-dioxane (12 mL) and water (2 mL). The mixture was purged with nitrogen three times and heated to 95 °C with stirring for 17 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (10 mL × 2). The organic phase was collected, concentrated, and the concentrate was subjected to preparative HPLC to give a yellow solid compound 182, namely 4-(4-(5-cyclopropyl-1H-pyrazol-1-yl)-3-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (7.3 mg, 11.7% yield). LCMS [M+1] + =372.1.

[0246] 1 H NMR (400MHz, DMSO) δ9.57(s,1H),8.53(d,J=5.1Hz,1H),8.19(d,J=1.5Hz,1H),8.11(d,J=8.2Hz,1H),7.94(s,1H),7.54(dd,J=22.3,5.0Hz,3 H),7.36(d,J=5.2Hz,1H),6.07(d,J=1.7Hz,1H),3.83(s,3H),2.13(s,3H),1.51(td,J=8.3,4.2Hz,1H),0.94–0.78(m,2H),0.74–0.61(m,2H).

[0247] Example 13: General method for synthesizing compound 206 (TDM-180806)

[0248]

[0249] Step 1: Example 206c

[0250] To a mixture of compound 206a (1 g, 4.785 mmol), i.e. 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine and compound 206b (1.05 g, 4.785 mmol), i.e. 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine-2-amine, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (350 mg, 0.479 mmol) and sodium carbonate (1.01 g, 9.57 mmol) were added. Water (7 mL) and dioxane (42 mL) were added to the mixture. The mixture was then purged several times with nitrogen under vacuum. The mixture was heated to 100 °C and stirred for 2.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by silica gel chromatography (dichloromethane: 10% methanol / dichloromethane = 50:50) to give a gray solid compound 206c, namely 4-(6-amino-pyridin-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (824 mg, 64.4% yield). LCMS [M+1] + =268

[0251] Step 2: Example 206e

[0252] At room temperature, N,N-diisopropylethylamine (217.5 mg, 1.683 mmol) was added to a solution of compound 206c (150 mg, 0.561 mmol) in N,N-dimethylformamide (15 mL). The mixture was stirred for 5 minutes, followed by the addition of 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (320 mg, 0.842 mmol) and compound 206d (99.4 mg, 0.842 mmol), i.e., 2-acetoxyacetic acid. The reaction mixture was heated to 90 °C and stirred for 18 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane:10% methanol in dichloromethane solution = 75:25) to give a yellow solid compound 206e, namely 2-((5-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)amino)-2-oxoethyl acetate (165 mg, 80.1% yield). LCMS [M+1] + =368.

[0253] Step 3: Example 206 (TDM-180806)

[0254] A solution of sodium hydroxide (108 mg) in water (10 mL) was added to a solution of compound 206e (165 mg, 0.45 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to remove methanol and tetrahydrofuran, the precipitate was collected by filtration, and the solid was purified by silica gel chromatography (ethyl acetate:methanol = 20:1) to give a pale yellow solid compound 206, TDM-180806, namely 2-hydroxy-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)acetamide (4.5 mg, yield 3.1%). LCMS [M+1] + =326.1.

[0255] 1H NMR (400MHz, DMSO-d6) δ9.98 (s, 1H), 9.54 (s, 1H), 9.09 (d, J = 2.0Hz, 1H), 8.52 (dd, J = 20.9, 6.7Hz, 2H), 8.27 (d, J = 8. 7Hz,1H),7.94(s,1H),7.54(s,1H),7.33(d,J=5.2Hz,1H),5.76(t,J=6.0Hz,1H),4.10(d,J=5.9Hz,2H),3.83(s,3H).

[0256] Compounds prepared by similar methods are as follows:

[0257]

[0258]

[0259]

[0260] TDM-180822 is a yellow solid compound 222, namely 2,2-difluoro-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)cyclopropane-1-carboxamide (19.5 mg, yield: 14%).

[0261] TDM-1808332-Cryptyl-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)acetamide Example 233, white solid compound (18 mg, yield 18%).

[0262] TDM-180830 is a yellow solid compound 230, namely 3,3,3-trifluoro-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)propionamide (9.5 mg, yield: 6.7%).

[0263] TDM-180819N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)cyclopropylformamide, yellow solid compound (11.9 mg, yield 11.8%).

[0264] TDM-180831 is a yellow solid compound 231, namely 2-methoxy-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)acetamide (35.8 mg, yield: 28%).

[0265] TDM-180814 is a yellow solid compound 214, namely 3-methoxy-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)propionamide (18.2 mg, yield: 13.7%).

[0266] TDM-180853 is a yellow solid compound 253, namely 1-methyl-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)cyclopropane-1-carboxamide (3.2 mg, yield: 2.5%).

[0267] TDM-180821 is a yellow solid compound 221, namely 1-fluoro-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)cyclopropane-1-carboxamide (54.9 mg, yield: 41.4%).

[0268] TDM-180823 is a yellow solid compound 223, namely N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)cyclobutanemethane (28.3 mg, yield: 43.1%).

[0269] TDM-180818 is a yellow solid compound, 2-cyclopropyl-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)acetamide (Example 218, 14.8 mg, yield 22.7%).

[0270] TDM-180849 is a pale yellow solid compound (Example 249, 17.6 mg, yield 13.6%), namely 2,2-difluoro-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)acetamide.

[0271] Example 12: General method for synthesizing compound 253 (TDM-180853)

[0272]

[0273] Step 1: Example 253

[0274] At 0°C, compound 253b (56.2 mg, 0.561 mmol), i.e., 1-methylcyclopropanecarboxylic acid and phosphorus oxychloride (100 mg, 0.374 mmol), was added to a pyridine solution of compound 253a (100 mg, 0.374 mmol), i.e., 4-(6-amino-pyridin-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine. The reaction mixture was stirred at 0°C for one hour. The reaction solution was then concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane:10% methanol in dichloromethane = 70:30) and preparative analysis to give a yellow solid compound 253, TDM-180853, namely 1-methyl-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)cyclopropane-1-carboxamide (3.2 mg, yield: 2.5%). LCMS [M+1] + =350.2

[0275] 1 H NMR (400MHz, DMSO-d6) δ9.82(s,1H),9.54(s,1H),9.10(d,J=2.1Hz,1H),8.49(d,J=5.1Hz,2H),8.19(d,J=8.8Hz,1H),7 .93(s,1H),7.53(s,1H),7.33(d,J=5.2Hz,1H),3.83(s,3H),1.45(s,3H),1.17(q,J=3.7Hz,2H),0.70(q,J=3.9Hz,2H).

[0276] Example 13: General method for synthesizing compound 223 (TDM-180823)

[0277]

[0278] Step 1: Example 223

[0279] Triethylamine (38 mg, 0.376 mmol) was added to a solution of compound 223a (50 mg, 0.188 mmol), i.e., 4-(6-amino-pyridin-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)pyrimidin-2-amine, in N,N-dimethylformamide (10 mL) at room temperature, followed by compound 223b (26.7 mg, 0.226 mmol), i.e., cyclobutane carbamate. The mixture was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) to give a yellow solid compound 223, TDM-180823, i.e., N-(5-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)cyclobutane methane (28.3 mg, yield: 43.1%). LCMS [M+1] + =350.1

[0280] 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H),9.54(s,1H),9.07(d,J=1.9Hz,1H),8.49(t,J=7.1Hz,2H),8.28(d,J=8.8Hz,1H),7 .93(s,1H),7.54(s,1H),7.32(d,J=5.2Hz,1H),3.83(s,3H),3.41(p,J=8.3Hz,1H),2.37–2.03(m,4H),2.03–1.74(m,2H).

[0281] Example 14: General method for synthesizing compound 295 (TDM-180895)

[0282]

[0283] Step 1: Example 295

[0284] To a pyridine (10 mL) solution of compound 295a (150 mg, 0.561 mmol), i.e., 4-dimethylaminopyridine (13.7 mg, 0.112 mmol) and compound 295b (220 mg, 1.122 mmol), i.e., 3,3,3-trifluoropropane-1-sulfonyl chloride, were added. The mixture was heated to 115 °C and stirred for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane: 10% methanol in dichloromethane = 60:40) to give a yellow solid. Methanol and dichloromethane were added to this solid, and the yellow solid compound 295, TDM-180895, i.e., 3,3,3-trifluoro-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)propane-1-sulfonamide (49.1 mg, yield 20.5%), was collected by filtration. LCMS [M+1] + =428.2

[0285] 1 H NMR (400MHz, DMSO-d6) δ9.52 (s, 1H), 8.92 (s, 1H), 8.48 (d, J = 4.9Hz, 2H), 7.91 (s, 1H) ),7.54(s,1H),7.28(t,J=12.6Hz,2H),3.83(s,3H),3.70(s,2H),2.88–2.67(m,2H).

[0286] Compounds prepared by similar methods are as follows:

[0287]

[0288]

[0289] TDM-180877 is a yellow solid compound 277, namely 2-ethoxy-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)ethanesulfonamide (3.2 mg, yield: 2.1%).

[0290] TDM-180875 is a white solid compound 275, namely N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-sulfonamide (3.2 mg, 2.6% yield).

[0291] TDM-180897 is a yellow solid compound 297, namely N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)-1-phenylmethanesulfonamide (6.9 mg, 4.4% yield).

[0292] Example 15: General method for synthesizing compound 229 (TDM-180829)

[0293]

[0294] Step 1: Example 229c

[0295] N-(5-bromopyridin-2-yl)ethanesulfonamide

[0296] Compound 229b (625 mg, 4.88 mmol) was added to a pyridine (10 mL) solution of compound 229a (422 mg, 2.44 mmol). The reaction was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and an aqueous solution of HCl (~0.5 M) was added. The precipitate was collected by filtration. The orange solid was neutralized to pH approximately 8 with saturated Na₂CO₃ solution, extracted with EtOAc (30 mL x 4), and the combined organic layers were washed with brine (30 mL x 1), dried over Na₂SO₄, filtered, and the concentrated crude product was slurried with DCM / PE (~1:4). This yielded a pale yellow solid, compound 229c (380 mg, 59% yield).

[0297] LCMS[M+1] + =267.0

[0298] Step 2: Example 229e

[0299] N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridin-2-yl)ethanesulfonamide was added to a three-necked flask along with compound 229c (200 mg, 0.76 mmol), compound 229d (228 mg, 0.9 mmol), PdCl2 (dppf) (83 mg, 0.11 mmol), KOAc (223 mg, 2.28 mmol), and 1,4-dioxane (20 mL). The mixture was purged with water three times, and the mixture was heated to 105 °C for 2 hours. The mixture was concentrated and purified by column chromatography (0-100% EtOAc / PE) to give a colorless oily product, compound 229e (80 mg, 33% yield).

[0300] LCMS[M+1] + =313.1

[0301] Step 3: Example 229 (TDM-180829)

[0302] N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)ethanesulfonamide was added to compound 229e (80 mg, 0.26 mmol) with BO (44 mg, 0.21 mmol), PdCl2 (dppf) (18 mg, 0.03 mmol), Na2CO3 (56 mg, 0.53 mmol), 1,4-dioxane (10 mL), and H2O (2 mL). The mixture was purged with water three times, and the reaction was heated to 105 °C and stirred for 2 hours. The mixture was concentrated and purified by column chromatography (Petroleum ether / EtOAc = 0 / 100, then 10% MeOH in DCM / EtOAc (1:1). The resulting solid was purified by DCM / PE The mixture was pulped. A light green solid compound 229 was obtained (4.5 mg, <10% yield).

[0303] LCMS[M+1] + =360.1

[0304] 1H NMR(400MHz,DMSO-d6)δ10.96(br s,1H),9.51(s,1H),8.97(s,1H),8.39-8.52(m,2H),7.92(s,1H),7.55(s,1H),7.28(d,J= 5.2Hz,1H),7.16(d,J=8.8Hz,1H),3.84(s,3H),3.43-3.56(m,2H),1.25(t,J=7.6Hz,3H).

[0305] Example 16: General method for synthesizing compound 301 (TDM-180901)

[0306]

[0307] Step 1: Example 301c

[0308] Compound 301b (558 mg, 4.0 mmol) was added to a mixture of compound 301a (340 mg, 2.00 mmol) and pyridine (10 mL). The reaction was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, H2O (~10 mL) was added, the precipitate was collected by filtration, washed with saturated NaHCO3 solution and H2O, and dried. An orange solid, compound 301c (260 mg, yield 46%), was given.

[0309] LCMS[M+1] + =279

[0310] Step 2: Example 301e

[0311] N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridin-2-yl)propane-1-sulfonamide was added to a three-necked flask along with compound 301c (260 mg, 0.93 mmol), compound 301d (228 mg, 0.9 mmol), PdCl2 (dppf) (68 mg, 0.09 mmol), KOAc (274 mg, 2.79 mmol), and 1,4-dioxane (20 mL) and 1,4-dioxane (20 mL). The mixture was purged with water 3 times, and the mixture was heated to 105 °C for 2 hours. The mixture was concentrated and purified by column chromatography (0-100% EtOAc / PE). A pale yellow solid, compound 301e (100 mg, yield <30%), was given. LCMS [M+1] + =327

[0312] Step 3: Example 301 (TDM-180901)

[0313] N-(5-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)propane-1-sulfonamide was added to compound 301e (156 mg, 0.48 mmol) with BO (100 mg, 0.48 mmol), PdCl2 (dppf) (60 mg), Cs2CO3 (312 mg, 0.96 mmol), 1,4-dioxane (12 mL), and H2O (2 mL). The mixture was purged with water 3 times, and the mixture was heated to 108 °C for 2 hours. The mixture was concentrated and purified by column chromatography (DCM / MeOH = 10 / 1). The residue was slurried with DCM / PE (~1:1). A pale yellow solid, compound 301 (7.9 mg, yield <10%), was obtained.

[0314] LCMS[M+1] + =374.2

[0315] 1¹H NMR (400MHz, DMSO-d⁶) δ 11.13 (brs, ¹H), 9.49 (s, ¹H), 8.96 (s, ¹H), 8.35–8.53 (m, 2H), 7.92 (s, ¹H), 7.55 (s, ¹H), 7.28 (d, J = 5.2 Hz, ¹H), 7.12 (d, J = 8.8 Hz, ¹H), 3.84 (s, 3H), 3.39–3.52 (m, 2H), 1.67–1.80 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H). Example 18: General method for synthesizing compound 303 (TDM-180903)

[0316]

[0317] Step 1: Example 303

[0318] Compounds 303a (186 mg, 1.08 mmol) and 303b (174 mg, 1.08 mmol) were added to pyridine (4 mL), and the mixture was heated to 50 °C and stirred for 3 hours. After solvent removal, the mixture was purified by silica gel chromatography (ethyl acetate: petroleum ether = 0-20%) to obtain a yellow solid compound 303c, namely N-(5-bromopyridin-2-yl)-3-fluoropropane-1-sulfonamide (28 mg, 8.7%). LCMS [M+1] + =299.1,301.1.

[0319] Step 2: Example 303e

[0320] Compound 303c (40 mg, 0.134 mmol), compound 303d (68 mg, 0.268 mmol), potassium acetate (39.4 mg, 0.402 mmol), and PdCl2 (dppf) (22 mg, 0.03 mmol) were added to a 5 mL solution of 1,4-dioxane. The mixture was purged with nitrogen three times, then heated to 90 °C and stirred for 17 hours. After cooling to room temperature, the reaction solution was used directly for the next step. LCMS [M+1] + =263.1.

[0321] Step 2: Example 303 (TDM-180903)

[0322] Compound 303f (30.9 mg, 0.147 mmol), compound 303e (35 mg, 0.134 mmol), sodium carbonate (28 mg, 0.268 mmol), and PdCl2 (dppf) (20 mg, 0.027 mmol) were dissolved in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL). The mixture was purged with nitrogen three times, then heated to 95 °C and stirred for 4 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL × 2). The filtrate was concentrated, and the concentrate was purified by silica gel chromatography (methanol:dichloromethane = 0-3%) to obtain a crude product. Further purification by preparative HPLC yielded a yellow solid compound 303, namely 3-fluoro-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)propane-1-sulfonamide (8.8 mg, 16.8% yield). LCMS[M+1] + =392.2.

[0323] 1 H NMR (400MHz, DMSO) δ9.51(s,1H),8.95(s,1H),8.46(t,J=5.7Hz,2H),7.91(s,1H),7.54(s,1H),7.29(d,J=5.2Hz,1H ),7.18(d,J=6.9Hz,1H),4.61(t,J=5.9Hz,1H),4.49(t,J=5.9Hz,1H),3.83(s,3H),3.58(s,2H),2.22–1.99(m,2H).

[0324] Example 19: General method for synthesizing compound 160 (TDM-180760)

[0325]

[0326] Step 1: Example 160b

[0327] 4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzaldehyde

[0328] Compound BO (300 mg, 1.44 mmol), PdCl2 (dppf) (73 mg, 0.10 mmol), Na2CO3 (458 mg, 4.32 mmol), 1,4-dioxane (25 mL), and H2O (4 mL) were added to compound 160a (400 mg, 1.73 mmol). Nitrogen gas was purged three times by a water pump, and the reaction mixture was reacted at 100 °C for 2 hours. The reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 0 / 100) to give a yellow solid, compound 160b (370 mg, 79% yield). LCMS [M+1] + =280.1.

[0329] Step 2: Example 160 (TDM-180760)

[0330] N-(1-Methyl-1H-pyrazol-4-yl)-4-(4-(((2,2,2-trifluoroethyl)amino)methyl)phenyl)pyrimidin-2-amine

[0331] A mixture of compound 160b (80 mg, 0.07 mmol), compound 160c (115 mg, 1.16 mmol), and HOAc (8 drops) in ClCH2CH2Cl (15 mL) was stirred at 35 °C for 1 hour. Then, NaB(OAc)3H (307 mg, 1.45 mmol) was added. The resulting mixture was stirred at 35 °C for 20 hours. The mixture was neutralized with saturated NaHCO3. Extraction was performed using DCM (30 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was slurried with ethyl acetate / petroleum ether (1:2). The solid was collected by filtration and dried under vacuum to give a pale green solid, compound 160 (65.1 mg, 62% yield).

[0332] LCMS[M+1] + =363.1.

[0333] 1 H NMR (400MHz, DMSO-d6) δ9.48(s,1H),8.48(d,J=5.2Hz,1H),8.11(d,J=8.0Hz,2H),7.93(s,1H),7.56(br s,1H),7.51(d,J=8.0Hz,2H),7.28(d,J=5.2Hz,1H),3.89(d,J=6.0Hz,2H),3.84(s,3H),3.18-3.31(m,2H),2.97-3.10(m,1H).

[0334] Compounds prepared by similar methods are as follows:

[0335]

[0336]

[0337] TDM-180761 is a white solid compound 161, namely 2-((4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)amino)acetonitrile (4.7 mg, yield <10%).

[0338] TDM-180787 Orange solid compound 187 (33 mg, yield 38%) N-(1-methyl-1H-pyrazol-4-yl)-4-(4-(morpholinomethyl)phenyl)pyrimidine-2-amine.

[0339] TDM-180788 is a grayish-white solid compound, 188 (28.6 mg, yield 31%), N-(1-methyl-1H-pyrazol-4-yl)-4-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidine-2-amine.

[0340] TDM-180789 is a light green solid compound, 189 (30.8 mg, yield 31%), 1-(4-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)piperazin-1-yl)ethyl-1-one.

[0341] Example 20: General method for synthesizing compound 134 (TDM-180734)

[0342]

[0343] Step 1: Example 134c

[0344] Triethylamine (303.54 mg, 3 mmol) and compound 134b (297 mg, 2.2 mmol), thiomorpholine 1,1-dioxide, were added to a tetrahydrofuran (20 mL) solution of compound 134a (500 mg, 2 mmol), i.e., p-bromobenzyl bromide. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and ethyl acetate and petroleum ether were added to the residue. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 134c (518 mg, 85% yield), i.e., 4-(4-bromobenzyl)thiomorpholine 1,1-dioxide, as a white solid.

[0345] Step 2: Example 134e

[0346] Potassium acetate (120 mg, 1.225 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (35.8 mg, 0.049 mmol) were added to a mixture of compounds 134c (150 mg, 0.49 mmol) and 134d (149 mg, 0.588 mmol). 1,4-Dioxane (14 mL) was added to the mixture, and the mixture was degassed under vacuum. The mixture was then heated to 95 °C and stirred for 2 hours under nitrogen protection. After the reaction was complete, the mixture was used directly for the next reaction. LCMS [M+1] + =352.

[0347] Step 3: Example 134 (TDM-180734)

[0348] Compound 134f (102.4 mg, 0.49 mmol), namely 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (31.9 mg, 0.047 mmol), cesium carbonate (319 mg, 0.98 mmol), and water (2 mL) were added to the mixture (V834-132). The mixture was degassed under vacuum, heated to 105 °C, and stirred for 3 hours under nitrogen protection. After the reaction was complete, water was added to the mixture and extracted with ethyl acetate (50 mL × 3). The organic layer was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The filtrate was then concentrated under reduced pressure. The compound was purified by silica gel column chromatography (ethyl acetate:methanol = 20:1) to give a yellow solid compound 134, TDM-180734 (55 mg, yield 28.2%), namely 4-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)thiomorpholine 1,1-dioxide. LCMS [M+1] + =399.

[0349] 1H NMR (400MHz, CDCl3) δ8.37(d,J=5.2Hz,1H),7.95(d,J=8.2Hz,2H),7.79(s,1H),7.51(s,1H),7.38(d,J= 8.2Hz,2H),7.01(d,J=5.2Hz,1H),6.94(s,1H),3.85(s,3H),3.66(s,2H),2.98(dt,J=10.0,4.0Hz,8H).

[0350] Example 21: General method for synthesizing compound 119 (TDM-180719)

[0351]

[0352] Step 1: Example 119c

[0353] At room temperature, 1,4-dioxane (20 mL) and water (3 mL) were added to a mixture of compound 119a (209 mg, 1 mmol), i.e., methyl 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine, compound 119b (314.4 mg, 1.2 mmol), i.e., methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzoate, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (73.1 mg, 0.1 mmol), and cesium carbonate (651.6 mg, 2 mmol). The mixture was then degassed under vacuum and heated to 105 °C and stirred for 3 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated under reduced pressure. The compound was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:70) to give a yellow solid, compound 119c (381 mg, yield 71.6%), namely methyl 4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate. LCMS [M+1] + =310.

[0354] Step 2: Example 119d

[0355] At room temperature, a solution of sodium hydroxide (240 mg, 6 mmol) in water (10 mL) was added to a mixed solution of compound 119c (185 mg, 0.6 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL). The mixture was then stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to remove excess methanol and tetrahydrofuran, and then the solution was neutralized with hydrochloric acid (2 M). The precipitate was collected by filtration. Ethanol was added to the precipitate, and the mixture was concentrated under reduced pressure to remove residual water, giving a yellow solid compound 119d (173 mg, 97.7% yield), namely 4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid. LCMS [M+1] + =296.

[0356] Step 3: Example 119 (TDM-180719)

[0357] Compound 119d (80 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (10 ml) at room temperature, followed by the addition of N,N-diisopropylethylamine (139 mg, 1.08 mmol). The mixture was stirred for 5 minutes, and then 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (153.9 mg, 0.405 mmol) and compound 119e (37.5 mg, 0.405 mmol), i.e. 2-aminoacetonitrile, were added to the mixture, which was stirred at room temperature for 16 hours. Water (40 mL) was added to the mixture, and the precipitate was collected by filtration. Ethanol was added to the precipitate, and the mixture was concentrated under reduced pressure to remove residual water. Ethyl acetate and petroleum ether were added to the residue, and the mixture was then collected by filtration to give a grayish-white solid compound 119, TDM-180719 (37.2 mg, yield 41.3%), namely N-(cyanomethyl)-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide. LCMS [M+1] + =334

[0358] ¹H NMR (400 MHz, DMSO-d⁶) δ 9.58 (s, ¹H), 9.35 (t, J = 5.2 Hz, ¹H), 8.54 (d, J = 5.0 Hz, ¹H), 8.27 (d, J = 8.2 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.94 (s, ¹H), 7.56 (s, ¹H), 7.36 (d, J = 5.1 Hz, ¹H), 4.36 (d, J = 5.3 Hz, 2H), 3.84 (s, 3H). Compounds prepared by similar methods are as follows:

[0359]

[0360]

[0361] TDM-180748 is a yellow solid compound 148, namely 4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)benzamide (28.5 mg, yield: 60.6%).

[0362] TDM-180749 is a yellow solid compound 149, namely (1,1-sulfur dioxide)(4-(2-((3-methyl-3H-1l4,3,4-thiadiazol-1-yl)amino)pyrimidin-4-yl)phenyl)methyl ketone (31.4 mg, yield: 60.9%).

[0363] TDM-180758 is a yellow solid compound, namely N-(2,2-difluorocyclopropyl)-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (10.6 mg, yield: 16.9%).

[0364] TDM-180852 is a yellow solid compound, namely N-cyclopropyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (59.3 mg, yield: 74.8%).

[0365] Example 22: General method for synthesizing compound 156 (TDM-180756)

[0366]

[0367] Step 1: Example 156c

[0368] Compound 156a (500 mg, 2.31 mmol) was dissolved in 1,4-dioxane (20 mL), followed by compound 156b (705.3 mg, 2.78 mmol), KOAc (453.6 mg, 4.63 mmol), and PdCl2 (dppf) (169.4 mg, 0.23 mmol). The mixture was purged with nitrogen three times, and then stirred at 90 °C for 3 hours. After cooling to room temperature, the mixture was filtered and concentrated. The concentrate was used directly as feedstock for the next reaction step. LCMS [M+1] + =264.1.

[0369] Step 2: Example 156e

[0370] Compound 156d (404.8 mg, 1.93 mmol) was dissolved in 1,4-dioxane (20 mL) and water (5 mL). Compound 156c, CS2CO3 (1.57 g, 4.83 mmol), and PdCl2 (dppf) (141.3 mg, 0.19 mmol) were added. The mixture was purged with nitrogen three times, and then stirred at 95 °C for 17 hours. The mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (20 mL × 3). The aqueous phase was collected, acidified with hydrochloric acid (1 mol / L), concentrated, and dissolved in DMF (20 mL). The mixture was filtered to obtain a filtrate. The solvent was concentrated to give a yellow solid compound 156e, namely 5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridinecarboxylic acid (380 mg, yield 66.3%). LCMS [M+1] + =297.1.

[0371] Step 3: Example 156 (TDM-180756)

[0372] To a DMF (10 mL) solution of compound 156e (80 mg, 0.27 mmol), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (154.1 mg, 0.41 mmol), triethylamine (40.9 mg, 0.41 mmol), and compound 156f (40.2 mg, 0.41 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated, and the concentrate was purified by silica gel chromatography (ethyl acetate: petroleum ether = 50-100%) to give a pale yellow solid compound 156, namely 5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)pyridinecarboxamide (7.0 mg, 6.9% yield). LCMS: [M+1] + =378.1.

[0373] 1 H NMR (400MHz, DMSO) δ9.67(s,1H),9.47(t,J=6.6Hz,1H),9.38(s,1H),8.71(d,J=7.4Hz,1H),8.59(d,J=5.0Hz,1H) ,8.24(d,J=8.1Hz,1H),7.94(s,1H),7.57(s,1H),7.47(d,J=5.1Hz,1H),4.12(dd,J=9.6,6.7Hz,2H),3.84(s,3H).

[0374] Compounds prepared by similar methods are as follows:

[0375]

[0376]

[0377] TDM-180762 is a yellow solid compound 162, namely N-(cyanomethyl)-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridinecarboxamide (21.0 mg, yield: 23.3%).

[0378] TDM-180764 is a yellow solid compound 164, namely (1,1-sulfur dioxide)(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)methyl ketone (7.5 mg, yield: 6.7%).

[0379] TDM-180781 is a pale yellow solid compound, namely N-(2,2-difluorocyclopropyl)-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridinecarboxamide (2.3 mg, 2.3% yield).

[0380] TDM-180826 is a pale yellow solid compound 226, namely N-cyclopropyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridinecarboxamide (28.1 mg, yield: 31.1%).

[0381] Example 23: General method for synthesizing compound 120 (TDM-180720)

[0382]

[0383] Step 1: Example 120c

[0384] Compound 120a (1.0 g, 4.365 mmol) was dissolved in 1,4-dioxane (30 mL), and compound 120b (2.22 g, 8.73 mmol), KOAc (1.5 g, 15.277 mmol), and PdCl2 (dppf) (0.32 g, 0.436 mmol) were added. The mixture was purged with nitrogen three times, and then the reaction solution was stirred at 95 °C for 16 hours. Cool to room temperature, add water (60 mL), extract with ethyl acetate (30 mL × 3), combine the organic layers and wash with water (30 mL × 2), dry to MgSO4, filter and concentrate. The concentrate is purified by silica gel chromatography (ethyl acetate: petroleum ether = 0-10%) to give a white solid compound 120c, namely methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzoate (1.113 g, yield 92.4%). LCMS [M+1] + =277.1.

[0385] Step 2: Example 120e

[0386] Compound 120d (0.21 g, 1.0 mmol) was dissolved in 1,4-dioxane (20 mL) and water (3 mL), and compound 120c (0.33 g, 1.2 mmol), CS2CO3 (0.65 g, 2.0 mmol), and PdCl2(dppf) (0.07 g, 0.1 mmol) were added. The mixture was purged with nitrogen three times, and then the reaction solution was stirred at 85 °C for 16 hours. The reaction solution was cooled to room temperature, then water (60 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with water (30 mL × 2), dried over MgSO4, filtered, and the solvent was concentrated. The solution was purified by silica gel chromatography (ethyl acetate: petroleum ether = 0-50%) to obtain a white solid compound 120e, namely methyl 3-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (198 mg, yield 61.2%). LCMS [M+1] + =323.1.

[0387] Step 3: Example 120f

[0388] Sodium hydroxide (244.9 mg, 6.12 mmol) was added to a mixture of 198 mg (0.61 mmol) of the compound 120e in methanol (5 mL), tetrahydrofuran (5 mL), and water (3 mL). The mixture was stirred at room temperature for 4 hours. After concentration to remove the solvent, water (15 mL) was added, and the mixture was acidified with hydrochloric acid (1 mol / L), extracted with ethyl acetate (15 mL × 3), the organic layers were combined and washed with water (20 mL × 2), and dried over MgSO4. The mixture was filtered and concentrated to give a yellow solid, compound 120f, namely 3-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (168 mg, 89.0% yield). LCMS: [M+1] + =310.1.

[0389] Step 4: Example 120 (TDM-180720)

[0390] To a DMF (5 mL) solution of compound 120f (80 mg, 0.26 mmol), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (147.9 mg, 0.39 mmol), triethylamine (78.5 mg, 0.78 mmol), and compound 120g (26.3 mg, 0.28 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (15 mL) and stirred for 30 minutes. The mixture was filtered, and the filter cake was slurried with ethyl acetate (10 mL) for 30 minutes. The filter cake was then filtered and dried to give a white solid, compound 120, namely N-(cyanomethyl)-3-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (31.4 mg, 34.8% yield). LCMS: [M+1] + =348.1.

[0391] 1 H NMR (400MHz, DMSO) δ9.56 (s, 1H), 9.28 (t, J = 5.4Hz, 1H), 8.51 (d, J = 4.9Hz, 1H), 7.96–7.73 (m, 3H), 7.59 (d,J=7.9Hz,1H),7.49(s,1H),6.89(d,J=5.0Hz,1H),4.34(d,J=5.4Hz,2H),3.79(s,3H),2.45(s,3H).

[0392] Compounds prepared by similar methods are as follows:

[0393]

[0394] TDM-180736 is a yellow solid compound 136, namely 3-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)benzamide (44.5 mg, yield: 42.3%).

[0395] Example 24: General method for synthesizing compound 179 (TDM-180779)

[0396]

[0397] Step 1: Example 179c

[0398] Compound 179a (500 mg, 2.18 mmol), compound 179b (665.1 mg, 2.62 mmol), potassium acetate (427.8 mg, 4.36 mmol), and PdCl2 (dppf) (159.7 mg, 0.22 mmol) were dissolved in 1,4-dioxane (10 mL), purged three times with nitrogen, and then heated to 85 °C and stirred for 6 hours. After cooling to room temperature, the reaction solution was used directly for the next step. LCMS [M+1] + =277.1.

[0399] Step 2: Example 179e

[0400] Compound 179d (380.8 mg, 1.81 mmol), compound 179c (601.8 mg, 2.18 mmol), Na₂CO₃ (385.1 mg, 3.63 mmol), and PdCl₂ (dppf) (132.9 mg, 0.18 mmol) were added to a mixture of 1,4-dioxane (20 mL) and water (5 mL). The mixture was purged with nitrogen three times, and then stirred at 85 °C for 16 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with ethyl acetate (15 mL × 2). The filtrate was concentrated, and the concentrate was purified by silica gel chromatography (ethyl acetate: petroleum ether = 0-80%) to give a yellow solid, compound 179e, namely methyl 2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (420 mg, 78.0% yield). LCMS [M+1] + =297.1.

[0401] Step 3: Example 179f

[0402] Compound 179e (420 mg, 1.3 mmol) was added to a mixture of tetrahydrofuran (10 mL), methanol (10 mL), and water (5 mL), followed by sodium hydroxide (519.5 mg, 12.99 mmol). The reaction mixture was then stirred at 40 °C for 2 hours. After cooling to room temperature, the solvent was removed, water (15 mL) was added, and the mixture was acidified with hydrochloric acid (1 mol / L). The mixture was filtered, and the filter cake was dissolved in N,N-dimethylformamide (10 mL). The solution was concentrated to give a yellow solid, compound 179f, namely 2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (387 mg, 96.2% yield). LCMS [M+1] + =310.2.

[0403] Step 4: Example 179 (TDM-180779)

[0404] To a solution of compound 179f (80 mg, 0.26 mmol) in N,N-dimethylformamide (5 mL), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (147.5 mg, 0.39 mmol), triethylamine (78.4 mg, 0.78 mmol), and compound 179 g (35.9 mg, 0.39 mmol) were added. The reaction mixture was then stirred at 40 °C for 16 hours. After solvent removal, the crude product was purified by silica gel chromatography (MeOH / DCM = 0%–2%). The crude product was slurried with methanol (5 mL) for 5 minutes, filtered, and the filter cake was dried to give a yellow solid compound 179, namely N-(cyanomethyl)-2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (48.2 mg, 53.5% yield). LCMS[M+1] + =348.1. 1 H NMR(400MHz, DMSO)δ9.56(s,1H),9.11(t,J=5.6Hz,1H),8.51(d,J=5.2Hz,1H),8.12–7.97(m,2H),7.92 (s,1H),7.54(d,J=8.1Hz,2H),7.32(d,J=5.2Hz,1H),4.33(d,J=5.6Hz,2H),3.83(s,3H),2.46(s,3H).

[0405] Compounds prepared by similar methods are as follows:

[0406]

[0407] TDM-180780 is a yellow solid compound 180, namely 2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)benzamide (49.3 mg, yield: 48.5%).

[0408] Example 25: General method for synthesizing compound 267 (TDM-180867)

[0409]

[0410] Step 1: Example 267b

[0411] Cesium carbonate (13.5 g, 40.5 mmol) and methyl iodoformate (3.8 mL, 61 mmol) were added to a solution of compound 267a (5 g, 4.07 mmol), i.e., 4-bromo-2-nitrobenzoic acid, in N,N-dimethylformamide (50 mL). The mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure to remove some solvent. Water was added to the residue and the mixture was extracted with ethyl acetate (160 mL × 2), washed with saturated brine (60 mL × 3), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was then purified by silica gel chromatography (petroleum ether: ethyl acetate = 91:9) to give compound 267b, i.e., methyl 4-bromo-2-nitrobenzoate (4.98 g, 94.2% yield), as a white solid.

[0412] Step 2: Example 267c

[0413] A solution of compound 267b (2.5 g, 9.614 mmol) in tetrahydrofuran (15 mL) was cooled to -60 °C, and vinyl magnesium bromide (1.0 M, in tetrahydrofuran, 34 mL, 34 mmol, 3.5 equivalence) was added dropwise to the solution under a nitrogen atmosphere. The reaction mixture was stirred at -40 °C for 2 hours. The reaction mixture was then treated with a saturated aqueous solution of ammonium chloride (30 mL), and the resulting mixture was extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with water (60 mL) and brine (60 mL), dried over anhydrous sodium sulfate, and then purified by silica gel chromatography (petroleum ether: ethyl acetate = 97:3) to give compound 267c, a white solid, namely methyl 4-bromo-1H-indole-7-carboxylic acid (850 mg, 30% yield). LCMS [M+1] + =254&256

[0414] Step 3: Example 267d

[0415] At room temperature, a solution of lithium hydroxide in water (12 mL) was added to a mixed solution of methanol (6 mL) and tetrahydrofuran (6 mL) of compound 267c (800 mg, 3.149 mmol). The mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue and neutralized with dilute hydrochloric acid, and then extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, ethyl acetate and petroleum ether were added to the residue, and the mixture was filtered to collect a white solid, compound 267d, i.e., 4-bromo-1H-indole-7-carboxylic acid (360 mg, 44.8% yield). LCMS [M+1] + =240&242

[0416] Step 4: Example 267e

[0417] At room temperature, triethylamine (522.7 mg, 5.165 mmol) was added to a 20 mL solution of compound 267d (310 mg, 1.291 mmol) in toluene. The mixture was purged with nitrogen several times under vacuum, and then diphenyl azidophosphate (461.9 mg, 1.678 mmol) was added. The reaction mixture was heated to 80 °C and stirred for 0.5 h. Tert-butanol (191.4 mg, 2.582 mmol) was then added to the mixture, and the mixture was heated to 100 °C and stirred for 16 h. The mixture was concentrated under reduced pressure to remove toluene, and the residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 84:16) to give a pale yellow solid, 267e, namely (4-bromo-1H-indol-7-yl)carbamate tert-butyl ester (158 mg, 39.3% yield). LCMS [M+1] + =255&257

[0418] Step 5: Example 267g

[0419] Dioxane (12 mL) was added to a mixture of compound 67e (155 mg, 0.5 mmol), compound 267f (190 mg, 0.75 mmol) i.e., pinacol diborate, tris(dibenzylacetone)dipalladium (91.6 mg, 0.1 mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (83.3 mg, 0.2 mmol), and potassium acetate (147 mg, 1.5 mmol). The mixture was purged with nitrogen several times under vacuum, then heated to 100 °C and stirred for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 94:6) to give 267 g of a dark red solid compound, namely 125 mg of crude (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-indol-7-yl)carbamate tert-butyl ester. LCMS [M+1] + =359

[0420] Step 6: Example 267i

[0421] To a mixed solution of compound 267 g (125 mg, 0.349 mmol), compound 267 h (73 mg, 0.349 mmol) i.e. 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine, cesium carbonate (227 mg, 0.698 mmol), dioxane (12 mL), and water (2 mL), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (51 mg, 0.07 mmol) was added. The mixture was purged with nitrogen several times under vacuum, and then heated to 100 °C and stirred for 2.5 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 20:80) to give a yellow solid compound 267i, namely tert-butyl(4-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)carbamate (72 mg, 50.9% yield). LCMS [M+1] + =406

[0422] Step 7: Example 267j

[0423] To a solution of compound 267i (72 mg, 0.178 mmol) in dichloromethane (4 mL), 1 mL of 1,4-dioxane hydrochloride was added. The mixture was stirred at room temperature for 1.5 hours, and then concentrated under reduced pressure to give an orange solid, compound 267i, namely 4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indole-7-amine hydrochloride (81 mg actual). LCMS [M+1] + =306.

[0424] Step 8: Example 267 (TDM-180867)

[0425] To a solution of compound 267i (30 mg, 0.098 mmol) in N,N-dimethylformamide (5 mL), N,N-diisopropylethylamine (50.7 mg, 0.392 mmol) was added at room temperature. The mixture was stirred for 5 minutes, followed by the addition of 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (55.9 mg, 0.147 mmol) and compound 267j (9.2 mg, 0.108 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the purified residue was obtained by silica gel chromatography (dichloromethane:10% methanol in dichloromethane solution = 30:70) and preparative purification to give a yellow solid compound 267, TDM-180867, namely 2-cyano-N-(4-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)acetamide (12.8 mg, 35.1% yield). LCMS [M+1] + =373.1

[0426] 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),10.22(s,1H),9.57(s,1H),8.44(d,J=5.3Hz,1H),7. 95(s,1H),7.70(d,J=7.0Hz,1H),7.59–7.48(m,3H),7.27(s,2H),4.02(s,2H),3.81(s,3H).

[0427] Compounds prepared by similar methods are as follows:

[0428]

[0429]

[0430] TDM-180868 is a yellow solid compound 268, namely 2,2-difluoro-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)cyclopropane-1-carboxamide (13.3 mg, yield: 33.1%).

[0431] TDM-180869 is a yellow solid compound, 269, namely N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)cyclopropanecarboxamide (27.6 mg, yield: 56.4%).

[0432] TDM-180870 is a yellow solid compound, 270, namely 3,3,3-trifluoro-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)propionamide (21.4 mg, yield: 39.3%).

[0433] Example 26: General method for synthesizing compound 298 (TDM-180898)

[0434]

[0435] Step 1: Example 298cN-(3-bromo-2-methyl-6-nitrophenyl)-2,2,2-trifluoroacetamide

[0436] Compound 298b (16 ml, 113.5 mmol) was added to a solution of compound 298a (8 g, 43 mmol) in dichloromethane (80 ml) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, followed by the addition of solid potassium nitrate (5.43 g, 53.7 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was monitored by LCMS until the starting material was completely reacted. The reaction mixture was concentrated to dryness under vacuum. The residue was added with water and extracted twice with dichloromethane (2 x 200 ml). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was column chromatography to give a yellow solid compound (Example 298c, 4.0972 g, yield 28.57%). LCMS [M+H]+ = 327, 329.

[0437] Step 2: Example 298d

[0438] 3-Bromo-2-methyl-6-nitroaniline

[0439] Potassium carbonate (5.2 g, 37.5 mmol) was added to a methanol (100 mL) solution of compound 298c (4.1 g, 12.5 mmol). The reaction mixture was heated to 60 °C and stirred overnight. The reaction mixture was monitored by TLC until the reactants were completely reacted. After the reaction was cooled to room temperature, it was slowly introduced into water and extracted three times with dichloromethane (100 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried to obtain a yellow solid compound (Example 298d, 2.6111 g, yield 90.4%). LCMS [M+H]+ = 231, 233.

[0440] Step 3: Example 298e4-bromo-7-nitro-1H-indazole

[0441] Compound 298d (2.6111 g, 11.3 mmol) was dissolved in acetic acid (100 mL) solution. The solution was cooled to 0 °C and 15 mL of an aqueous solution of sodium nitrite (1.56 g, 22.6 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 4 hours. TLC showed that the starting material reacted completely. The reaction solution was slowly poured into ice water and neutralized to neutral with solid sodium carbonate. The aqueous phase was extracted three times with ethyl acetate (3 x 150 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, dried to dryness, and the crude product was column chromatography to give a yellow solid compound (Example 298e, 1.5475 g, yield 56.4%). LCMS [M+H]+ = 242, 244.

[0442] Step 4: Example 298g of 7-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1H-indazole was added to a 250ml three-necked flask. Compound 298e (1.15g, 4.75mmol), compound 298f (1.8g, 7.127mmol), tris(dibenzylideneacetone)dipalladium (870mg, 0.95mmol), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (905mg, 1.9mmol), potassium acetate (1.4g, 14.25mmol), and 1,4-dioxane (25mL) were added. The reaction mixture was purged with nitrogen several times, and then heated to 100°C and stirred for two hours. The reaction of the starting material was monitored by LCMS until it was completely dried under vacuum. The crude product was passed through a column to obtain a yellow solid compound (Example 298g, 937.9mg, yield 68.3%). LCMS [M+H]+ = 290.

[0443] Step 5: Example 298i

[0444] N-(1-Methyl-1H-pyrazol-4-yl)-4-(7-nitro-1H-indazol-4-yl)pyrimidin-2-amine

[0445] In a 250 mL three-necked flask, 298 g (900 mg, 3.11 mmol) of compound 298 h (650 mg, 3.11 mmol), tris(dibenzylacetone)dipalladium (569.5 mg, 0.622 mmol), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (593 mg, 1.244 mmol), cesium carbonate (2.533 g, 7.775 mmol), 1,4-dioxane (24 mL), and water (4 mL) were added. The reaction mixture was purged with nitrogen several times, and then heated to 100 °C with stirring for two hours. The reaction mixture was monitored by LC-MS to ensure complete reaction. The reaction mixture was dried under vacuum, and the crude product was purified by column chromatography to give a yellow solid compound (Example 298i, 450 mg, yield 43.1%). LC-MS [M+H]+ = 337.

[0446] Step 6: Example 298j 4-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indazole-7-amine) was added to a methanol (100 ml) / tetrahydrofuran (20 ml) solution of compound 298i (400 mg, 1.19 mmol) under nitrogen atmosphere, with Pd / C (10%, 16 mg). The reaction solution was purged several times with hydrogen balloons, and the reaction was stirred at 40 °C for 3 hours. LCMS monitoring showed that the starting material reacted completely. The mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated and dried to obtain a yellow solid (Example 298j, 300 mg, yield 82.42%). LCMS [M+H]+ = 307.

[0447] Step 7: Example 298 (TDM-180898)

[0448] 2-Cyano-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indazole-7-yl)acetamide

[0449] To a solution of compound 298j (50 mg, 0.163 mmol) in N,N-dimethylformamide (5 mL), N,N-diisopropylethylamine (31.6 mg, 0.245 mmol), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (93.1 mg, 0.245 mmol), and compound 298k (15.3 mg, 0.179 mmol) were added. The reaction mixture was heated to 90 °C and stirred for 3 hours. LCMS was used to monitor the reaction until most of the starting material had reacted. The reaction mixture was concentrated to dryness under vacuum, and the crude product was passed through a column chromatography to obtain a yellow solid compound (Example 298, 10.2 mg, yield 16.77%). LCMS [M+H]+ = 374.

[0450] 1H NMR (400MHz, DMSO) δ12.92(s,1H),10.43(s,1H),9.57(s,1H),8.49(d,J=5.3Hz,1H),7.93(s,1H), 7.88(d,J=7.8Hz,1H),7.73(s,1H),7.55(s,1H),7.37(d,J=4.7Hz,1H),4.07(s,2H),3.83(s,3H).

[0451] Compounds prepared by similar methods are as follows:

[0452]

[0453] TDM-180884N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indazol-7-yl)cyclopropanemethane, a yellow solid compound (5 mg, yield 14%).

[0454] TDM-1808992, 2-Difluoro-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indazole-7-yl)cyclopropane-1-carboxamide, Example 299, yellow solid compound (7.8 mg, yield 11.82%) TDM-1809003, 3,3-Trifluoro-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indazole-7-yl)propionamide, yellow solid compound (14.1 mg, yield 5.78%)

[0455] Example 29: General method for synthesizing compound 276 (TDM-180876)

[0456]

[0457] Step 1: Example 276c

[0458] tert-butyl (4-bromo-3-nitrophenyl) carbamate

[0459] 4-Dimethylaminopyridine (840 mg, 6.84 mmol), triethylamine (2 g, 20.28 mmol), and compound 276b (3.3 g, 15.2 mmol) were added to a tetrahydrofuran (20 ml) solution of compound 276a (2.2 g, 10.14 mmol) at 0 °C.

[0460] The reaction mixture was heated to 60°C and stirred overnight. The reaction mixture was monitored by TLC until the starting material was fully reacted. The reaction mixture was concentrated to dryness. The solid residue was extracted three times with water (20 ml) and ethyl acetate (3 x 20 ml). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was column chromatography to give a yellow oil (Example 276c, 2.6278 g, yield 81.86%), LCMS [M+1]+ = 261, 263.

[0461] Step 2: Example 276e

[0462] tert-butyl (7-bromo-1H-indole-4-yl)carbamate

[0463] Compound 276d (1.0 M in THF, 83 mL, 82.8 mmol) was slowly added to a tetrahydrofuran (100 mL) solution of compound 276c (2.6278 g, 8.28 mmol) at -40 °C, and the mixture was stirred at -40 °C for 4 h. LCMS monitoring showed that the product had MS values ​​of [Mt-Bu+H]+ = 255, 257. After the reaction was complete, the mixture was quenched with a saturated ammonium chloride (150 mL) aqueous solution and stirred at room temperature for 1 h. Ethyl acetate was then added for extraction, the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to dryness. The crude product was column chromatography to give a yellow solid compound (Example 276e, 989.7 mg, yield 38.4%), with LCMS values ​​of [Mt-Bu+H]+ = 255, 257.

[0464] Step 3: Example 276g

[0465] (1H-indol-4-yl)tert-butyl carbamate

[0466] Compound 276e (989.7 mg, 3.18 mmol), compound 276f (1211 mg, 4.77 mmol), tris(dibenzylacetone)dipalladium (582.4 mg, 0.636 mmol), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (606 mg, 1.272 mmol), potassium acetate (935 mg, 9.54 mmol), and 1,4-dioxane (25 mL) were added to a 250 mL three-necked flask. The mixture was purged with nitrogen several times and heated to 100 °C for two hours. The reaction mixture was monitored by LC-MS until complete. The reaction solution was concentrated to dryness, and the solid residue was passed through a column chromatography to give a yellow solid (Example 276 g, 250 mg, yield 21.9%). LC-MS [M+H] + =177.

[0467] Step 4: Example 276i

[0468] In a 250 mL three-necked flask, 276 g (286 mg, 0.8 mmol) of compound 276 h (500 mg, 2.4 mmol), tris(dibenzylacetone)palladium (146.5 mg, 0.16 mmol), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (152.5 mg, 0.32 mmol), cesium carbonate (651.64 mg, 2 mmol), 1,4-dioxane (24 mL), and water (4 mL) were added to (1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-4-yl)carbamate. After several nitrogen purgings, the temperature was raised to 100°C and heated for two hours. The reaction of the raw materials was monitored by LCMS until the reaction was complete. The reaction solution was concentrated and dried. The solid residue was passed through a column to obtain a yellow solid (Example 276i, 151.6mg, yield 46.8%). LCMS [M+H]+=406.

[0469] Step 5: Example 276j

[0470] A solution of 1,4-dioxane (3.0 mL, 4 mol / L, 12 mmol) in hydrochloric acid was slowly added dropwise to a solution of compound 276i (151.6 mg, 0.374 mmol) in dichloromethane (15 mL). The reaction mixture was stirred at room temperature for one hour, and the reaction was monitored by TLC until complete. The solid was directly dried to obtain a solid. The solid was dissolved in N,N-dimethylformamide (10 mL), adjusted to neutral with solid sodium carbonate, and the solid was removed by filtration. The filtrate was dried to obtain a yellow solid (Example 276j, 110 mg, yield 96.5%). LCMS [M+H]+ = 306.

[0471] Step 6: Example 276 (TDM-180876)

[0472] To a solution of N,N-dimethylformamide (5 mL) containing N-(1-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-4-yl)cyclopropane methyl compound 276j (20 mg, 0.053 mmol), N,N-diisopropylethylamine (24 mg, 0.1855 mmol), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (30 mg, 0.0795 mmol), and compound 276k (5 mg, 0.058 mmol) were added. The reaction mixture was stirred overnight at room temperature. LCMS was used to monitor the reaction progress. The product LCMS [M+H]+ = 374. The reaction solution was directly concentrated and dried to prepare the solution. The eluent was removed by vacuum distillation at 45°C, and the aqueous phase was freeze-dried to give a yellow solid (Example 276, 8.1 mg, yield 47.6%). LCMS[M+H]+=374. 1 H NMR (400MHz, DMSO) δ9.98 (s, 1H), 9.65 (s, 1H), 8.44 (d, J = 5.7Hz, 1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.78 (d, J = 7.8Hz, 1H),7.54(s,1H),7.22(s,1H),7.11(d,J=4.1Hz,2H),3.85(d,J=15.6Hz,3H),2.06(s,1H),0.84(t,J=6.2Hz,4H).

[0473] Compounds prepared by similar methods are as follows:

[0474]

[0475] TDM-180881 is a yellow solid compound 281, namely 2-cyano-N-(1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-4-yl)acetamide (5.1 mg, yield: 11.8%).

[0476] TDM-180882 is a yellow solid compound 282, namely 3,3,3-trifluoro-N-(1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-4-yl)propionamide (5.6 mg, yield: 15.1%).

[0477] TDM-180885 is a yellow solid compound, 285, namely 2,2-difluoro-N-(1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-4-yl)cyclopropane-1-carboxamide (39 mg, yield: 81.41%).

[0478] TDM-180911 is a white solid compound, 311, namely 2-cyclopropyl-N-(1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-4-yl)acetamide (45.7 mg, yield: 53.14%).

[0479] Example 30: General method for synthesizing compound 292 (TDM-180892)

[0480]

[0481] Step 1: Example 292c

[0482] 5-(4,4,5,5-Tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)pyrazine-2-amino

[0483] Compound 292a (300 mg, 1.72 mmol), compound 292b (656.74 mg, 2.59 mmol), tris(dibenzylacetone)dipalladium (315.7 mg, 0.34 mmol), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (328.7 mg, 0.69 mmol), potassium acetate (422.38 mg, 4.31 mmol), and 1,4-dioxane (24 mL) were added to a 250 mL three-necked flask. The reaction solution was purged with nitrogen several times, heated to 100 °C for two hours, and LCMS monitoring showed that the starting materials had reacted completely. The reaction solution was not further purified and was used directly for the next reaction. LCMS (m / z): 140 (MH+ corresponds to boric acid).

[0484] Step 2: Example 292e4-(5-aminopyrazin-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2-amino

[0485] Compound 292c (381 mg, 1.724 mmol), compound 292d (360 mg, 1.724 mmol), tris(dibenzylacetone)dipalladium (158 mg, 0.1724 mmol), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (164 mg, 0.3448 mmol), cesium carbonate (1.4 g, 4.31 mmol), 1,4-dioxane (24 mL), and water (4 mL) were added to a 250 mL three-necked flask. The reaction mixture was purged with nitrogen several times, stirred, and heated to 100 °C for one hour. The reaction mixture was monitored for complete reaction by LC-MS. The reaction mixture was directly dried and then passed through a column with DCM:MeOH as the eluent at a ratio of 50:1 to give a yellow solid compound (Example 292e, 140 mg, yield 30.3%). LC-MS [M+H] + =269.

[0486] Step 3: Example 292 (TDM-180892)

[0487] 2,2-Difluoro-N-(5-(2-(((1-methyl-1H-pyrazole-4-yl)amino)pyrimidin-4-yl)pyrazin-2-yl)cyclopropane-1-carboxamide was added to an anhydrous pyridine (5 ml) solution of compound 292e (87 mg, 0.32 mmol) at 0 °C, followed by the addition of phosphorus oxychloride (74.5 mg, 0.49 mmol). The reaction mixture was kept at 0 °C and stirred for three hours. LCMS monitoring showed that most of the starting material remained, and a small portion of the product was present. LCMS[M+H]+=373. The reaction solution was concentrated to dryness, water was added, and it was extracted three times with DCM:MeOH = 10:1 (3*30ml). After drying with anhydrous sodium sulfate, it was filtered, dried, and column filtered to obtain a yellow solid compound (Example 292, 5.2mg, yield 5.83%). LCMS [M+H]+ = 373.

[0488] 1 H NMR (400MHz, DMSO) δ11.59(s,1H),9.61(s,1H),9.42(d,J=1.3Hz,1H),9.29(s,1H),8.58(d,J=5.0Hz,1H),7.96(s ,1H),7.57(s,1H),7.50(d,J=5.0Hz,1H),3.84(s,3H),3.06(dd,J=22.7,9.6Hz,1H),2.11(dd,J=19.0,8.9Hz,2H).

[0489] Compounds prepared by similar methods are as follows:

[0490]

[0491] TDM-180905 3,3,3-Trifluoro-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyrazin-2-yl)propionamide, Example 305, yellow solid compound (2.3 mg, yield 2.7%)

[0492] Example 31: General method for synthesizing compound 286 (TDM-180886)

[0493]

[0494] Step 1: Example 286c

[0495] N 2-(1-methyl-1H-pyrazol-4-yl)-[4,5'-bipyrimidine]-2,2'-diamine

[0496] Compound 286a (500 mg, 2.392 mmol), i.e., 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine, compound 286b (529 mg, 2.392 mmol), i.e., 5-(4,4,5,5-tetramethyl-1,3,2-dioxanepentane-2-yl)pyrimidin-2-amine, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (174 mg, 0.239 mmol), and cesium carbonate (1.59 g, 4.784 mmol) were added to a three-necked flask. Water (4 mL) and dioxane (24 mL) were added to the mixture, and then the mixture was degassed under vacuum and purged several times with nitrogen. The mixture was heated to 100 °C and stirred for 2 hours. The mixture was then concentrated under reduced pressure and purified by silica gel chromatography (dichloromethane:10% methanol in dichloromethane = 50:50) to give a yellow solid compound 286c, i.e., N. 2 -(1-Methyl-1H-pyrazol-4-yl)-[4,5'-bipyrimidine]-2,2'-diamine (418 mg, 65.2% yield). LCMS [M+1] + =269

[0497] Step 2: Example 286 (TDM-180886)

[0498] At 0 °C, compound 286d (34 mg, 0.282 mmol), i.e., 2,2-difluorocyclopropane-1-carboxylic acid, and phosphorus oxychloride (85.06 mg, 0.558 mmol) were added to a pyridine (5 mL) solution of compound 286c (50 mg, 0.186 mmol). The mixture was stirred for 3 hours, then concentrated under reduced pressure. The solution was purified by silica gel chromatography (dichloromethane:10% methanol = 50:50) and by preparative purification of the residue to give a yellow solid compound 286, TDM-180886, i.e., 2,2-difluoro-N-(2-((1-methyl-1H-pyrazol-4-yl)amino)-[4,5'-bipyrimidin]-2'-yl)cyclopropane-1-carboxamide (7.1 mg, 10.3% yield). LCMS [M+1] + =373.1

[0499] 1H NMR (400MHz, DMSO-d6) δ11.39(s,1H),9.60(s,1H),9.36(s,2H),8.53(d,J=5.1Hz,1H),7.94(s,1H),7.54(s, 1H), 7.39 (d, J=5.2Hz, 1H), 3.83 (s, 3H), 3.21 (dd, J=22.1, 10.1Hz, 1H), 2.03 (ddd, J=15.8, 12.5, 5.8Hz, 2H).

[0500] Compounds prepared by similar methods are as follows:

[0501]

[0502] TDM-180887 is a yellow solid compound 287, namely 3,3,3-trifluoro-N-(2-((1-methyl-1H-pyrazol-4-yl)amino)-[4,5'-bipyrimidin]-2'-yl)propionamide (8.7 mg, yield: 12.4%).

[0503] TDM-180902 is a yellow solid compound 302 (52.9 mg, ~80% purity, 42% yield).

[0504] 2-Cyano-N-(2-((1-methyl-1H-pyrazol-4-yl)amino)-[4,5'-bipyrimidine]-2'-yl)acetamide TDM-180904 Yellow solid compound 304 (25.3 mg, yield 20%).

[0505] N-(2-((1-methyl-1H-pyrazol-4-yl)amino)-[4,5'-bipyrimidin]-2'-yl)cyclopropaneformamide Example 31: General method for synthesizing compound 288 (TDM-180888)

[0506]

[0507] Step 1: Example 288b

[0508] Compound 288a (0.3 g, 2.68 mmol) was dissolved in acetonitrile (15 mL), and N-bromosuccinimide (0.48 g, 2.68 mmol) was added. The mixture was stirred at room temperature for 3 hours. After removing the solvent, the solution was purified by silica gel chromatography (ethyl acetate: petroleum ether = 40:60) to give a white solid compound 288b, namely 5-bromo-3-fluoropyridine-2-amine (0.436 g, 85.1% yield). LCMS [M+1] + =191.1.

[0509] Step 2: Example 288d

[0510] Compound 288b (0.436 g, 2.27 mmol), compound 288c (1.152 g, 4.54 mmol), potassium acetate (0.668 g, 6.81 mmol), and PdCl2 (dppf) (0.166 g, 0.23 mmol) were dissolved in 1,4-dioxane (10 mL) and purged three times with nitrogen. The mixture was heated to 90 °C and stirred for 17 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with ethyl acetate (15 mL × 2). The filtrate was concentrated, and the concentrate was purified by silica gel chromatography (ethyl acetate: petroleum ether = 0-50%) to obtain a yellow solid compound 288d, namely 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)pyridine-2-amine (0.84 g, crude). LCMS [M+1] + =156.1.

[0511] Step 3: Example 288f

[0512] Compound 288e (396.1 mg, 1.89 mmol), compound 288d (540 mg, 2.27 mmol), sodium carbonate (300.5 mg, 2.83 mmol), and PdCl2 (dppf) (276.6 mg, 0.38 mmol) were added to a mixture of 1,4-dioxane (30 mL) and water (3 mL). The mixture was purged with nitrogen three times, and then heated to 105 °C and stirred for 4 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (20 mL × 2). The filtrate was concentrated, and the concentrate was purified by silica gel chromatography (methanol:dichloromethane = 0-3%) to obtain a brown solid compound 288f, namely 4-(6-amino-5-fluoropyridin-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (0.48 g, 88.9% yield). LCMS [M+1] + =286.1.

[0513] Step 4: Example 288 (TDM-180888)

[0514] Compound 288 (25.7 mg, 0.21 mmol) was added to a pyridine (5 mL) solution of 50 mg (0.18 mmol) of compound 288f, and POCl3 (40.3 mg, 0.26 mmol) was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. After solvent removal, the concentrate was purified by silica gel chromatography (methanol:dichloromethane = 0-6%) to obtain a crude product, which was then purified by preparative HPLC to obtain compound 288, namely 2,2-difluoro-N-(3-fluoro-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)cyclopropanecarboxamide (3.4 mg, 4.7% yield). LCMS [M+1] + =390.1.

[0515] 1 H NMR (400MHz, DMSO) δ11.00(s,1H),9.60(s,1H),9.02(s,1H),8.54(d,J=5.2Hz,1H),8.42(dd,J=11.1,1.8Hz,1H),7.9 2(s,1H),7.55(s,1H),7.41(d,J=5.2Hz,1H),3.83(s,3H),2.97(dt,J=13.5,9.9Hz,1H),2.04(dd,J=18.9,9.1Hz,2H).

[0516] Compounds prepared by similar methods are as follows:

[0517]

[0518] TDM-180889 is a yellow solid compound 289, namely 3,3,3-trifluoro-N-(3-fluoro-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)propionamide (7.6 mg, yield: 9.2%).

[0519] TDM-180890 is a yellow solid compound 290, namely 2-cyano-N-(3-fluoro-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)acetamide (2.2 mg, yield: 3.0%).

[0520] TDM-180891 is a yellow solid compound 291, namely N-(3-fluoro-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)cyclopropanecarboxamide (3.5 mg, yield: 4.7%).

[0521] Example 32: General method for synthesizing compound 306 (TDM-180906)

[0522]

[0523] Step 1: Example 306c

[0524] Dioxane (40 mL) was added to a mixture of compound 306a (1 g, 5.346 mmol), i.e., 5-bromo-3-methylpyridin-2-amine; compound 306b (2.036 g, 8.02 mmol), i.e., pinacol diborate; 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (390 mg, 0.535 mmol); and potassium acetate (1.407 g, 10.692 mmol). The mixture was degassed under vacuum, purged several times with nitrogen, and heated to 100 °C with stirring overnight. This mixture was used directly for the next reaction without purification. LCMS [M+1] + =235&153

[0525] Step 2: Example 306c

[0526] Compound 306d (1.117 g, 5.346 mmol), i.e., 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (390 mg, 0.535 mmol), cesium carbonate (3.474 g, 10.692 mmol), and water (7 mL) were added to the mixture from the previous step. The mixture was then degassed under vacuum, purged several times with nitrogen, and heated to 100 °C and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane:10% methanol in dichloromethane = 60:40) to give a grayish-white solid compound 306e, i.e., 4-(6-amino-5-methylpyridin-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (240 mg, 16% yield). LCMS [M+1] + =282

[0527] Step 3: Example 306 (TDM-180906)

[0528] At room temperature, N,N-diisopropylethylamine (137.6 mg, 1.065 mmol) was added to a solution of compound 306e (100 mg, 0.355 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred for 5 minutes, and then 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (202 mg, 0.107 mmol) and compound 306f (65 mg, 0.533 mmol), i.e., 2,2-difluorocyclopropane-1-carboxylic acid, were added. The mixture was heated to 90 °C and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane:10% methanol = 50:50) and preparative (HCOOH) to give a yellow solid compound 306, TDM-180906, namely 2,2-difluoro-N-(3-methyl-5-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)cyclopropane-1-carboxamide (12 mg, 8.8% yield). LCMS [M+1] + =386.2

[0529] 1 H NMR (400MHz, DMSO-d6) δ10.68(s,1H),9.57(s,1H),9.00(d,J=2.0Hz,1H),8.52(d,J=5.1Hz,1H),8.37(d,J=1.7Hz,1H),7.93( s,1H),7.55(s,1H),7.35(d,J=5.2Hz,1H),3.83(s,3H),2.95(ddd,J=13.8,10.7,8.2Hz,1H),2.26(s,3H),2.09–1.93(m,2H).

[0530] Compounds prepared by similar methods are as follows:

[0531]

[0532] Example 32: General method for synthesizing compound 307 (TDM-180907)

[0533]

[0534] Step 1: Example 307 (TDM-180907)

[0535] At 0 °C, compound 307b (31.8 mg, 0.373 mmol), namely cyanoacetic acid and phosphorus oxychloride (76.4 mg, 0.498 mmol), was added to a pyridine (5 mL) solution of compound 307a (70 mg, 0.249 mmol), namely 4-(6-amino-5-methylpyridin-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine, and the mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure, and the residue was dissolved in a dichloromethane solution containing 10% methanol. Water was added, and the aqueous phase was extracted with a dichloromethane solution containing 10% methanol (50 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Ethyl acetate and petroleum ether were added to the residue, and the mixture was filtered to collect a yellow solid compound 307, TDM-180907, namely 2-cyano-N-(3-methyl-5-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)acetamide (15.2 mg, 17.5% yield). LCMS [M+1] + =349.2

[0536] 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),9.57(s,1H),8.99(d,J=1.9Hz,1H),8.52(d,J=5.1Hz,1H),8.38(d ,J=1.8Hz,1H),7.93(s,1H),7.55(s,1H),7.35(d,J=5.2Hz,1H),4.03(s,2H),3.83(s,3H),2.29(s,3H).

[0537] TDM-180908

[0538]

[0539] Yellow solid compound 308, namely 3,3,3-trifluoro-N-(3-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)propionamide (27.4 mg, yield: 28.1%).

[0540] 1H NMR (400MHz, DMSO-d6) δ10.60(s,1H),9.57(s,1H),9.01(d,J=1.7Hz,1H),8.52(d,J=5.1Hz,1H),8.38(d,J=1.6Hz, 1H),7.93(s,1H),7.55(s,1H),7.35(d,J=5.2Hz,1H),3.83(s,3H),3.62(q,J=11.2Hz,2H),2.27(s,3H).TDM-180910

[0541]

[0542] Yellow solid compound 310 is N-(3-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)cyclopropanemethane (11.4 mg, yield: 8%).

[0543] 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),9.55(s,1H),8.98(d,J=2.0Hz,1H),8.50(d,J=5.1Hz,1H),8.33(d,J=1.8Hz,1 H),7.93(s,1H),7.55(s,1H),7.34(d,J=5.2Hz,1H),3.83(s,3H),2.24(s,3H),2.00–1.84(m,1H),0.88–0.76(m,4H).

[0544] Example 33: General method for synthesizing compound 177 (TDM-180777)

[0545]

[0546] Step 1: Example 177c

[0547] Potassium acetate (588 mg, 6 mmol) and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (175.4 mg, 0.24 mmol) were added to a mixture of compound 177a (415 mg, 2.4 mmol), i.e., 4-bromopyridin-2-amine, and compound 177b (792.3 mg, 3.12 mmol), i.e., pinacol diboronate. Then, dioxane (50 mL) was added to the mixture. The mixture was purged with nitrogen several times under vacuum, heated to 90 °C, and reacted for 8 hours. The reaction solution was used directly for the next step. LCMS [M+1] + =221.

[0548] Step 2: Example 177e

[0549] Compound 177d (415 mg, 2 mmol), i.e., 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (175.4 mg, 0.24 mmol), sodium carbonate (424 mg, 4 mmol), and water (6 mL) were added to the reaction mixture from the previous step. The mixture was purged with nitrogen several times under vacuum, then heated to 110 °C and stirred for 18 hours. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (dichloromethane:methanol = 20:1) to give a dark green solid compound 177e, i.e., 4-(2-aminopyridin-4-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (90 mg, yield 16.8%). LCMS [M+1] + =268.

[0550] Step 3: Example 177 (TDM-180777)

[0551] 2-methoxy-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)acetamide

[0552] At room temperature, N,N-diisopropylethylamine (72.4 mg, 0.374 mmol) was added to a solution of compound 177e (50 mg, 0.187 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred for 5 minutes, and then 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (141.1 mg, 0.374 mmol) and compound 177f (33.7 mg, 0.374 mmol), i.e., 2-methoxyacetic acid, were added. The mixture was heated to 40 °C and stirred for 16 hours. The mixture was concentrated under reduced pressure to remove the solvent. Water was added to the residue, and the mixture was extracted with dichloromethane (3 × 60 mL). The combined organic phases were washed with saturated brine and dried over sodium sulfate. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (dichloromethane: 10% methanol in dichloromethane solution = 30:70) and preparative purification to give an orange solid compound 177, TDM-180777, namely 2-methoxy-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)acetamide (8.9 mg, yield 14%). LCMS [M+1] + =340.1.

[0553] 1H NMR (400MHz, DMSO-d6) δ10.25(s,1H),9.73(s,1H),9.10(s,1H),8.59(d,J=5.0Hz,1H),8.50(d,J=5. 2Hz,1H),8.28(s,1H),7.80(s,1H),7.49(s,1H),7.38(s,1H),4.14(s,2H),3.91(s,3H),3.41(s,3H).

[0554] Compounds prepared by similar methods are as follows:

[0555]

[0556]

[0557] TDM-180773N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)cyclopropanemethane, yellow solid compound 773 (5.9 mg; <10% yield). [This product has very poor solubility; attempts were made to purify it again by preparative HPLC, but its solubility in DMF was also poor.]

[0558] TDM-180774 is a yellow solid compound 174 (2.5 mg, 3.2% yield).

[0559] 2-Cyano-N-(4-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)acetamide TDM-180790 Orange solid compound 190, namely 3,3,3-trifluoro-N-(4-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)propionamide (6.9 mg, yield: 4.9%)

[0560] TDM-180792 is a yellow solid compound, 192, namely 2,2-difluoro-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)cyclopropane-1-carboxamide (25.4 mg, yield: 14.6%).

[0561] Example 34: General method for synthesizing compound 243 (TDM-180843)

[0562]

[0563] Step 1: Example 243 (TDM-180843)

[0564] To a mixture of N-(4-(4-aminophenyl)pyrimidin-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)propane-1-sulfonamide, 100 mg (0.38 mmol) of compound 243a in 6 mL of DMF, NaOH (61 mg, 1.52 mmol) was added. The reaction was stirred at room temperature for 0.5 h. Then, DMAP (~5 mg) and compound 243b (162 mg, 1.14 mmol) were added. The reaction was stirred at room temperature for 1 h. After the reaction was complete, the mixture was quenched with H2O (~10 mL), extracted with EtOAc (~20 mL x 3), the combined organic layers were washed with saturated LiCl (~20 mL x 3) aqueous solution, dried over Na2SO4, filtered, concentrated, and purified (TFA system), then lyophilized. The resulting light green solid was compound 243 (21.8 mg, 15% yield).

[0565] LCMS[M+1] + =373.1

[0566] 1 H NMR (400MHz, DMSO-d6) δ8.46(d,J=5.6Hz,1H),7.92(s,1H),7.85(d,J=8.8Hz,2H),7.54(d,J=5.6Hz,1H),7. 48(s,1H),6.68(d,J=8.8Hz,2H),3.89-3.98(m,2H),3.86(s,3H),1.79-1.94(m,2H),1.03(t,J=7.2Hz,3H).

[0567] Compounds prepared by similar methods are as follows:

[0568]

[0569]

[0570] TDM-180845 is a light green solid compound, 245 (47.2 mg, yield 30%).

[0571] N-(4-(4-aminophenyl)pyrimidin-2-yl)-3-fluoro-N-(1-methyl-1H-pyrazol-4-yl)propane-1-sulfonamide TDM-180848 is a pale yellow solid compound (33.1 mg, yield 21.3%).

[0572] N-(4-(4-aminophenyl)pyrimidin-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-sulfonamide TDM-180851 is a yellow solid compound 251, TDM-180851, namely N-(4-(4-aminophenyl)pyrimidin-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)-2-phenylethane-1-sulfonamide (compound 251, 74.1 mg, 45.4% yield).

[0573] Example 35: General method for synthesizing compound 246 (TDM-180846)

[0574]

[0575] Step 1: Example 246 (TDM-180846)

[0576] To a mixture of N-(4-(6-aminopyridin-3-yl)pyrimidin-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)propane-1-sulfonamide, 72 mg (1.8 mmol) of NaH was added to a DMF mixture of 80 mg (0.3 mmol). The mixture was stirred at room temperature for 0.5 h. Then, 128 mg (0.9 mmol) of compound 246b was added. The reaction was stirred at room temperature for 3 min. The mixture was quenched with HCl (1N HCl) until pH was about 6, concentrated to remove the solvent, and MeOH was added to the residue. The mixture was filtered (twice), purified by filtrate preparation (TFA system), and lyophilized. Compound 246 (33.7 mg, 30% yield) was given as a white solid.

[0577] LCMS[M+1] + =374.1

[0578] 1 H NMR(400MHz,DMSO-d6)δ8.62-8.72(m,2H),8.28-8.36(m,1H),7.94(s,1H),7.86(br s,1H),7.71(d,J=5.6Hz,1H),7.50(s,1H),6.91(d,J=9.2Hz,1H),3.80-3.97(m,5H),1.76-1.93(m,1H),1.03(t,J=7.6Hz,3H).

[0579] Compounds prepared by similar methods are as follows:

[0580]

[0581]

[0582] TDM-180847 is a pale yellow solid compound, 247 (24.5 mg, yield 21%).

[0583] N-(4-(6-aminopyridin-3-yl)pyrimidin-2-yl)-3-fluoro-N-(1-methyl-1H-pyrazol-4-yl)propane-1-sulfonamide TDM-180856 is a white solid compound (Example 256, 14.2 mg, yield 11%).

[0584] N-(4-(6-aminopyridin-3-yl)pyrimidin-2-yl)-3,3,3-trifluoro-N-(1-methyl-1H-pyrazol-4-yl)propane-1-sulfonamide

[0585] TDM-180857 is a white solid compound, 257 (7.9 mg, yield <10%).

[0586] N-(4-(6-aminopyridin-3-yl)pyrimidin-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-sulfonamide

[0587] Example 36: General method for synthesizing compound 276 (TDM-180876)

[0588]

[0589] Step 1: Example 276c

[0590] tert-butyl (4-bromo-3-nitrophenyl) carbamate

[0591] At 0 °C, 4-dimethylaminopyridine (840 mg, 6.84 mmol), triethylamine (2 g, 20.28 mmol), and compound 276b (3.3 g, 15.2 mmol) were added to a tetrahydrofuran (20 mL) solution of compound 276a (2.2 g, 10.14 mmol). The reaction mixture was heated to 60 °C and stirred overnight. The reaction mixture was monitored by TLC until the starting material was completely reacted. The reaction mixture was concentrated to dryness, and the solid residue was extracted three times with water (20 mL) and ethyl acetate (3 x 20 mL). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was column chromatography to give a yellow oil (Example 276c, 2.6278 g, yield 81.86%), LCMS [M+1]+ = 261, 263.

[0592] Step 2: Example 276e

[0593] tert-butyl (7-bromo-1H-indole-4-yl)carbamate

[0594] Compound 276d (1.0 M in THF, 83 mL, 82.8 mmol) was slowly added to a tetrahydrofuran (100 mL) solution of compound 276c (2.6278 g, 8.28 mmol) at -40 °C, and the mixture was stirred at -40 °C for 4 h. LCMS monitoring showed that the product had MS values ​​of [Mt-Bu+H]+ = 255, 257. After the reaction was complete, the mixture was quenched with a saturated ammonium chloride (150 mL) aqueous solution and stirred at room temperature for 1 h. Ethyl acetate was then added for extraction, the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to dryness. The crude product was column chromatography to give a yellow solid compound (Example 276e, 989.7 mg, yield 38.4%), with LCMS values ​​of [Mt-Bu+H]+ = 255, 257.

[0595] Step 3: Example 276g

[0596] (1H-indol-4-yl)tert-butyl carbamate

[0597] Compound 276e (989.7 mg, 3.18 mmol), compound 276f (1211 mg, 4.77 mmol), tris(dibenzylacetone)dipalladium (582.4 mg, 0.636 mmol), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (606 mg, 1.272 mmol), potassium acetate (935 mg, 9.54 mmol), and 1,4-dioxane (25 mL) were added to a 250 mL three-necked flask. The mixture was purged with nitrogen several times and heated to 100 °C for two hours. The reaction mixture was monitored by LC-MS until complete. The reaction solution was concentrated to dryness, and the solid residue was passed through a column chromatography to give a yellow solid (Example 276 g, 250 mg, yield 21.9%). LC-MS [M+H] + =177.

[0598] Step 4: Example 276i

[0599] (1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indole-4-yl)tert-butyl carbamate

[0600] In a 250 mL three-necked flask, 276 g (286 mg, 0.8 mmol) of compound 276 h (500 mg, 2.4 mmol), tris(dibenzylacetone)palladium (146.5 mg, 0.16 mmol), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (152.5 mg, 0.32 mmol), cesium carbonate (651.64 mg, 2 mmol), 1,4-dioxane (24 mL), and water (4 mL) were added. After several nitrogen purgings, the mixture was heated to 100 °C for two hours. The reaction was monitored by LCMS until the reactants were fully reacted. The reaction mixture was concentrated to dryness, and the solid residue was passed through a column chromatography to give a yellow solid (Example 276i, 151.6 mg, yield 46.8%). LCMS [M+H]+ = 406.

[0601] Step 5: Example 276j1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indole-4-amine

[0602] A solution of 1,4-dioxane (3.0 ml, 4 mol / L, 12 mmol) in hydrochloric acid was slowly added dropwise to a solution of compound 276i (151.6 mg, 0.374 mmol) in dichloromethane (15 ml). The reaction mixture was stirred at room temperature for one hour, and the reaction was monitored by TLC until complete. The solid was directly dried to obtain a solid. The solid was dissolved in N,N-dimethylformamide (10 ml), adjusted to neutral with solid sodium carbonate, and the solid was removed by filtration. The filtrate was dried to obtain a yellow solid (Example 276j, 110 mg, yield 96.5%). LCMS [M+H]+ = 306.

[0603] Step 6: Example 276

[0604] To a solution of N,N-dimethylformamide (5 mL) containing N-(1-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-4-yl)cyclopropane methyl compound 276j (20 mg, 0.053 mmol), N,N-diisopropylethylamine (24 mg, 0.1855 mmol), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (30 mg, 0.0795 mmol), and compound 276k (5 mg, 0.058 mmol) were added. The reaction mixture was stirred overnight at room temperature. LCMS was used to monitor the reaction progress. The product LCMS [M+H]+ = 374. The reaction solution was directly concentrated and dried to prepare the solution. The eluent was removed by vacuum distillation at 45°C, and the aqueous phase was freeze-dried to give a yellow solid (Example 276, 8.1 mg, yield 47.6%). LCMS[M+H]+=374. 1H NMR (400MHz, DMSO) δ9.98 (s, 1H), 9.65 (s, 1H), 8.44 (d, J = 5.7Hz, 1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.78 (d, J = 7.8Hz, 1H),7.54(s,1H),7.22(s,1H),7.11(d,J=4.1Hz,2H),3.85(d,J=15.6Hz,3H),2.06(s,1H),0.84(t,J=6.2Hz,4H).

[0605]

[0606]

[0607] TDM-180881 is a yellow solid compound 281, namely 2-cyano-N-(1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-4-yl)acetamide (5.1 mg, yield: 11.8%).

[0608] TDM-180882 is a yellow solid compound 282, namely 3,3,3-trifluoro-N-(1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-4-yl)propionamide (5.6 mg, yield: 15.1%).

[0609] TDM-180885 is a yellow solid compound, 285, namely 2,2-difluoro-N-(1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-4-yl)cyclopropane-1-carboxamide (39 mg, yield: 81.41%).

[0610] TDM-180911 is a white solid compound, 311, namely 2-cyclopropyl-N-(1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-4-yl)acetamide (45.7 mg, yield: 53.14%).

[0611] TDM-180920 is a yellow solid compound, 320, namely 2-cyclopropyl-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)acetamide (28.9 mg, yield: 45.5%).

[0612] TDM-180917 is a yellow solid compound 317, namely 2-cyclopropyl-N-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indazole-7-yl)acetamide (5.9 mg, yield: 5.7%).

[0613] Example 37: General method for synthesizing compound 326 (TDM-180926)

[0614]

[0615] Step 1: Example 326g

[0616] (7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indol-4-yl)tert-butyl carbamate was added to a three-necked flask with compound 276e (2100 mg, 6.75 mmol), compound 326f (2570 mg, 10 mmol), Pd2(dba)3 (500 mg, 0.54 mmol), X-phos (500 mg, 1.1 mmol), KOAc (1980 mg, 20 mmol), and 1,4-dioxane (60 mL). A vacuum was applied using a water pump to displace Ar. The mixture was heated to 100 °C and stirred for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (0-100% EtOAc / PE). 326 g (1.5 g, 50% yield) of a purple solid product was given, along with a brown solid byproduct 326 g-B (300 mg).

[0617] Example 326g LCMS[M+H]+=303.2(Mt-Bu+H) +

[0618] Example 326g-B LCMS[M+H]+=177.1(Mt-Bu+H) +

[0619] 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),8.97(s,1H),7.47(d,J=1.6Hz,1H),7.35(d,J=7.2 Hz,1H),7.07(d,J=8.0Hz,1H),6.97(d,J=8.0Hz,1H),6.74(d,J=2.4Hz,1H),1.46(s,9H).

[0620] Step 2: Example 326i

[0621] (4-(4-((tert-butoxycarbonyl)amino)-1H-indol-7-yl)pyrimidin-2-yl)(1-methyl-1H-pyrazol-4-yl)carbamate tert-butyl ester was added to 326 g (1430 mg, 1.1 mmol) of compound 326h (1122 mg, 3.63 mmol), PdCl2 (dppf) (100 mg), Cs2CO3 (2367 mg, 7.26 mmol), 1,4-dioxane (40 mL), and H2O (8 mL). The resulting mixture was evacuated by a water pump and replaced with N2, then heated to 100 °C and stirred for 2 hours. The mixture was concentrated, and the residue was purified by column chromatography (0-100% EtOAc / PE, EtOAc containing 50% DCM). The crude product was then slurried with EtOAc / PE at a ratio of 1:4 to give compound 326i (1300 mg, 71% yield) as a pale yellow solid.

[0622] LCMS[M+H] + =506.3

[0623] 1 H NMR (400MHz, DMSO-d6) δ11.72(s,1H),9.46(s,1H),8.62(d,J=5.2Hz,1H),7.95(d,J=8.4Hz,1H),7.87(d,J=5.6Hz,1H),7.84(brs ,1H),7.71(d,J=8.4Hz,1H),7.33-7.38(m,1H),7.47(d,J=0.4Hz,1H),7.01-7.04(m,1H),3.85(s,3H),1.54(s,9H),1.47(s,9H).

[0624] Step 3: Example 326j

[0625] 7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indole-4-amine was added to a DCM solution of compound 326i (250 mg, 0.5 mmol) in 6 mL of HCl / 1,4-dioxane (4 mL, 4 M in 1,4-dioxane). The mixture was stirred at room temperature for 2 days. The mixture was concentrated, the residue was diluted with DMF (6 mL), neutralized with Na2CO3 (~3 g), filtered, and the filtrate was collected and used directly for the next step. 130 mg of product (100% yield in 6 mL DMF) was obtained.

[0626] LCMS[M+H] + =306.2

[0627] Step 4: Example 326

[0628] N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indole-4-yl)cyclopropaneformamide

[0629] To a DMF (10 mL) solution of compound 326j (60 mg, 0.20 mmol), DI PEA (77.6 mg, 0.60 mmol), compound 326k (25.8 mg, 0.30 mmol), and HATU (114.1 mg, 0.30 mmol) were added. The mixture was heated to 45 °C and stirred for 16 hours. The mixture was concentrated under reduced pressure, purified by preparative purification (FA), and freeze-dried to give compound 326 (19 mg, 25% yield) as a yellow solid.

[0630] LCMS[M+1] + =374.2

[0631] 1 H NMR (400MHz, DMSO-d6) δ11.92(s,1H),10.06(s,1H),9.63(s,1H),8.43(d,J=5.5Hz,1H),8.00(s,1H),7.91(s,2H),7.54(s,1H) ,7.49(s,1H),7.42(d,J=5.5Hz,1H),7.06–6.96(m,1H),3.85(s,3H),2.24–2.11(m,1H),0.91–0.87(m,2H),0.87–0.82(m,2H).

[0632]

[0633]

[0634] TDM-180923 is a yellow solid compound 323, namely 2-cyano-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-4-yl)acetamide (15.5 mg, yield: 14.1%).

[0635] TDM-180924 is a yellow solid compound 324, namely 3,3,3-trifluoro-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-4-yl)propionamide (7.8 mg, yield: 6.4%).

[0636] TDM-180926 is a yellow solid compound 326, namely N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-4-yl)cyclopropanemethane (19.0 mg, yield: 25%).

[0637] TDM-180929 is a yellow solid compound 329, namely 2,2-difluoro-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-4-yl)cyclopropane-1-carboxamide (11.2 mg; yield: 14%).

[0638] TDM-180933 is a yellow solid compound, namely 2-cyclopropyl-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-4-yl)acetamide (30.3 mg, yield: 39%).

[0639] Example 38: General method for synthesizing compound 313 (TDM-180913)

[0640]

[0641] Step 1: Example 313c

[0642] Compounds 313a (192 mg, 1.0 mmol) and 313b (190.6 mg, 1.0 mmol) were added to pyridine (4 mL) and stirred at room temperature for 3 hours. After solvent removal, the mixture was purified by silica gel chromatography (ethyl acetate: petroleum ether = 0-15%) to obtain a yellow solid compound 313c, namely N-(5-bromo-3-fluoropyridin-2-yl)-1-phenylmethanesulfonamide (180 mg, 52.2%). LCMS [M+1] + =345.1,347.1.

[0643] Step 2: Example 313e

[0644] Compound 313c (180 mg, 0.52 mmol), compound 313d (263.9 mg, 1.04 mmol), potassium acetate (152.9 mg, 1.56 mmol), and PdCl2 (dppf) (73 mg, 0.1 mmol) were added to a 1,4-dioxane (10 mL) solution. The mixture was purged with nitrogen three times, then heated to 90 °C and stirred for 17 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL × 2). The filtrate was concentrated, and the concentrate was purified by silica gel chromatography (ethyl acetate: petroleum ether = 0-20%) to obtain a yellow solid compound 313e, namely N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyridin-2-yl)-1-phenylmethanesulfonamide (138.0 mg, 85.3% yield). LCMS [M+1] + =311.1.

[0645] Step 3: Example 313 (TDM-180913)

[0646] Compound 313f (104 mg, 0.496 mmol), compound 303e (138 mg, 0.452 mmol), sodium carbonate (95.4 mg, 0.90 mmol), and PdCl2 (dppf) (66.2 mg, 0.090 mmol) were dissolved in a mixture of 1,4-dioxane (10 mL) and water (1 mL). The mixture was purged with nitrogen three times, and then heated to 95 °C and stirred for 4 hours. Cool to room temperature, filter, wash the filter cake with ethyl acetate (15 mL × 2), concentrate the filtrate, and purify the concentrate by silica gel chromatography (methanol:dichloromethane = 0-3%) to obtain the crude product. Disperse the crude product in methanol (1 mL), slurry, and dry to obtain a yellow solid compound 313, namely N-(3-fluoro-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)-1-phenylmethanesulfonamide (2.2 mg, 1.1% yield). LCMS [M+1] + =440.1.

[0647] 1 H NMR (400MHz, DMSO) δ11.07 (s, 1H), 9.56 (s, 1H), 9.03 (s, 1H), 8.53 (d, J = 4.5Hz, 1H), 8. 36(d,J=10.9Hz,1H),7.92(s,1H),7.57(s,1H),7.36(s,6H),4.99(s,2H),3.84(s,3H).

[0648]

[0649]

[0650] TDM-180914 is a yellow solid compound 314, namely N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyrazin-2-yl)cyclopropane (3 mg, yield: 2.7%).

[0651] Example 39: General method for synthesizing compound 321 (TDM-180921)

[0652]

[0653] Step 1: Example 321c

[0654] (2'-amino-[4,5'-bipyrimidin]-2-yl)(1-methyl-1H-pyrazol-4-yl)carbamate tert-butyl ester was added to compound 321b (581 mg, 2.63 mmol) along with compound 321a (500 mg, 2.39 mmol), PdCl2 (dppf) (60 mg), Cs2CO3 (1556 mg, 4.78 mmol), 1,4-dioxane (20 mL), and H2O (4 mL). The resulting mixture was evacuated by a water pump and purged with nitrogen three times. The reaction was heated to 105 °C and stirred for 2 hours. The mixture was concentrated and purified by column chromatography (DCM / MeOH = 10 / 1) to give a colorless oily compound 321c (420 mg, 48% yield).

[0655] LCMS[M+H] + =369.

[0656] Step 2: Example 321e

[0657] (1-Methyl-1H-pyrazol-4-yl)(2'-((phenylmethyl)sulfonylamino)-[4,5'-bipyrimidin]-2-yl)tert-butyl carbamate

[0658] Sodium hydroxide (14 mg, 0.353 mmol) was added to a solution of tert-butyl carbamate (2'-amino-[4,5'-bipyrimidin]-2-yl)(1-methyl-1H-pyrazol-4-yl)carbamate in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 1 hour. Then, compound 321d (67.3 mg, 0.353 mmol) benzylsulfonyl chloride was added to the mixture and stirred for 1.5 hours. After the reaction was complete, the mixture was added to water (20 mL), and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane: 10% methanol in dichloromethane solution = 70:30) to give a pale yellow solid compound 321e, namely tert-butyl(1-methyl-1H-pyrazol-4-yl)(2'-((phenylmethyl)sulfinylamino)-[4,5'-bipyrimidin]-2-yl)carbamate (87 mg, yield 61.4%). LCMS [M+1] + =523.2.

[0659] Step 3: Example 321 (TDM-180921)

[0660] N-(2-((1-methyl-1H-pyrazol-4-yl)amino)-[4,5'-bipyrimidin]-2'-yl)-1-phenylmethanesulfonamide

[0661] To a solution of compound 321e (87 mg, 0.166 mmol) in dichloromethane (10 mL), 1,4-dioxane hydrochloride (0.4 mL, 1.665 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and N,N-dimethylformamide (10 mL) and potassium carbonate (460 mg, 3.33 mmol) were added to the residue. The mixture was stirred at room temperature for 4 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by formic acid to give a pale yellow solid, compound 321, TDM-180921, namely N-(2-((1-methyl-1H-pyrazol-4-yl)amino)-[4,5'-bipyridine]-2'-yl)-1-phenylmethanesulfonamide (4 mg, yield 5.7%). TLCMS[M+1] + =423.1.

[0662] 1 H NMR(400MHz,DMSO-d6)δ11.61(s,1H),9.56(s,1H),9.31(s,2H),8.52(d,J=5.0Hz,1H), 7.95(s,1H),7.55(s,1H),7.31(ddd,J=9.6,8.2,4.0Hz,6H),4.92(s,2H),3.84(s,3H).

[0663]

[0664] TDM-180919 is a yellow solid compound 327, namely N-(2-((1-methyl-1H-pyrazol-4-yl)amino)-[4,5'-bipyrimidine]-2'-yl)ethanesulfonamide (3.9 mg, yield: 12%).

[0665] General method for synthesizing compound 286-2 (TDM-180886-2)

[0666]

[0667] Step 1: Example 286-2

[0668] 2,2-Difluoro-N-(2-((1-methyl-1H-pyrazol-4-yl)amino)-[4,5'-bipyrimidin]-2'-yl)cyclopropane-1-carboxamide

[0669] At 0 °C, compound 286-2a (350 mg, 1.314 mmol), i.e. N, was subjected to [treatment / treatment]. 2 Compound 286-2b (192.5 mg, 1.577 mmol), namely 2,2-difluorocyclopropane-1-carboxylic acid and phosphorus oxychloride (403 mg, 2.628 mmol), was added to a pyridine solution of (1-methyl-1H-pyrazol-4-yl)-[4,5'-bipyrimidine]-2,2'-diamine and stirred for 1.5 hours. The mixture was concentrated under reduced pressure, water was added to the residue, the solution was neutralized with an aqueous sodium bicarbonate solution, and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane:10% methanol in dichloromethane = 50:50) and formic acid to give a yellow solid compound 286-2, TDM-180886-2, namely 2,2-difluoro-N-(2-((1-methyl-1H-pyrazol-4-yl)amino-[4,5'-bipyrimidin]-2'-yl)cyclopropane-1-carboxamide (76.7 mg, yield 15.1%). LCMS [M+1] + =373.1.

[0670] 1 H NMR (400MHz, DMSO-d6) δ11.39(s,1H),9.60(s,1H),9.36(s,2H),8.53(d,J=5.0Hz,1H),7.94(s,1H),7.54(s, 1H), 7.39 (d, J=5.2Hz, 1H), 3.83 (s, 3H), 3.21 (dd, J=22.3, 10.4Hz, 1H), 2.03 (ddd, J=16.2, 12.4, 5.9Hz, 2H).

[0671] Example 41: General method for synthesizing compound 334 (TDM-180934)

[0672]

[0673] Step 1: Example 334

[0674] At room temperature, N,N-diisopropylethylamine (72.9 mg, 0.564 mmol) was added to a solution of compound 334a (50 mg, 0.188 mmol), i.e., 4-(4-aminophenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine, in N,N-dimethylformamide (5 mL). The mixture was stirred for 5 minutes, and then 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (93 mg, 0.244 mmol) and compound 334b ​​(30 mg, 0.244 mmol), i.e., (S)-2,2-difluorocyclopropane-1-carboxylic acid, were added. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to remove some solvent, water was added to the residue, and the solution was extracted with ethyl acetate (40 mL x 3). The organic layer was washed with saturated brine (50 mL x 5) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by formic acid to give a yellow solid compound 334, TDM-180934 (43.4 mg, yield 61.8%), namely (S)-2,2-difluoro-N-(4-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)cyclopropane-1-carboxamide. LCMS[M+1]+=371.2

[0675] 1 H NMR (400MHz, DMSO-d6) δ10.67(s,1H),9.45(s,1H),8.44(d,J=5.2Hz,1H),8.23–8.05(m,2H),7.92(s,1H),7.76(d,J= 8.7Hz,2H),7.55(s,1H),7.24(d,J=5.3Hz,1H),3.83(s,3H),2.86(ddd,J=13.6,10.8,8.0Hz,1H),2.13–1.89(m,2H).

[0676]

[0677] TDM-180936 is a yellow solid compound 336, namely (R)-2,2-difluoro-N-(4-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)cyclopropane-1-carboxamide (37.7 mg, yield 53%).

[0678] Example 42: General method for synthesizing compound 335 (TDM-180935)

[0679]

[0680] Step 1: Example 335

[0681] At room temperature, N,N-diisopropylethylamine (72.9 mg, 0.564 mmol) was added to a solution of compound 335a (80 mg, 0.299 mmol), i.e., 4-(6-aminopyridin-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine, in N,N-dimethylformamide (5 mL). The mixture was stirred for 5 minutes, and then 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (170 mg, 0.449 mmol) and compound 335b (54 mg, 0.449 mmol), i.e., (S)-2,2-difluorocyclopropane-1-carboxylic acid, were added. The mixture was heated to 90 °C and stirred for 16 hours. The mixture was concentrated under reduced pressure to remove some solvent, water was added to the residue, and the solution was then extracted with ethyl acetate (60 mL * 3). The organic layer was washed with saturated brine (50 mL x 5) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by formic acid to give a yellow solid compound 335, TDM-180935 (21.6 mg, yield 19.5%), namely (S)-2,2-difluoro-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)cyclopropane-1-carboxamide. LCMS[M+1]+=372.1

[0682] 1 H NMR (400MHz, DMSO-d6) δ11.29(s,1H),9.54(s,1H),9.11(d,J=2.0Hz,1H),8.51(dd,J=14.3,6.9Hz,2H),8.22(d,J=8.7Hz,1H ),7.93(s,1H),7.54(s,1H),7.34(d,J=5.2Hz,1H),3.83(s,3H),3.04(dd,J=22.4,9.9Hz,1H),2.05(dt,J=11.8,8.0Hz,2H).

[0683]

[0684] TDM-180939 is a yellow solid compound 339, namely (R)-2,2-difluoro-N-(5-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2-yl)cyclopropane-1-carboxamide (26.0 mg, yield 32%).

[0685] Experiment to identify the inhibitory effect of compounds on JAK kinase

[0686] Janus kinases (JAKs) include JAK1, JAK2, JAK3, and Tyk2, which transduce cytokine-mediated signals via the JAK-STAT pathway. The kinases are 120-140 kDa in size and have seven defined homologous regions, JH1-JH7. JH1 is a crucial region for enzyme activity, containing typical tyrosine kinase characteristics. Phosphorylation of tyrosine residues leads to a conformational change in the JAK protein, thereby promoting substrate binding. The JAK-STAT system comprises three main parts: a receptor that crosses the cell membrane, a Janus kinase attached to the receptor, and a signal transducer and activator of transcription (STAT) that transmits signals to the nucleus and DNA. When a cytokine binds to its receptor, JAK phosphorylates the receptor, attracting STAT proteins. The STAT proteins are also phosphorylated and bind to each other to form a dimer. The dimer enters the nucleus and binds to DNA, leading to gene transcription.

[0687] PerkinElmer's EZ Reader can be used to detect phosphorylation of peptide substrates catalyzed by kinases. This device, based on microfluidic separation technology, can directly detect fluorescently labeled substrates and products. The separation step is achieved within a microfluidic chip by controlling pressure and electric field strength. Kinase assays are typically performed with a product conversion rate of 20-30%. This biological assay method is used to identify the inhibitory effect of compounds on JAK.

[0688] 1. Experimental Materials

[0689] S1.1 Test Compound

[0690] The compound powder was dissolved in DMSO and stored in a sealed container at -20°C. Internal compound Ref1 served as a positive control for the JAK1, JAK2, and Tyk2 tests, and Ref2 served as a positive control for the JAK3 test.

[0691] 2. Reagent preparation

[0692] S2.1, 1M HEPES buffer: Weigh 0.5M HEPES free acid and 0.5M HEPES sodium salt, dissolve in ultrapure water, bring to volume, filter, and store at 4 degrees Celsius.

[0693] S2.2, 40mM ATP solution: Dissolve in 50mM HEPES buffer to prepare 40mM, aliquot, and freeze at -20°C.

[0694] S2.3, 0.5% Tween 20: Dilute 100% Tween 20 with ultrapure water and store at 4 degrees Celsius.

[0695] S2.4, 35% bovine serum albumin: Prepare a 35% bovine serum albumin solution with ultrapure water, dispense into smaller containers, and store at -20 degrees Celsius.

[0696] S2.5, 1M dithiothreitol solution: Prepare a 1M solution of dithiothreitol with ultrapure water, dispense into portions, and store at -20 degrees Celsius.

[0697] S2.6, 0.5mM Jaktide Peptide substrate solution: Dissolve to 0.5mM with 50mM HEPES, aliquot, and store at -20°C.

[0698] S2.7, 0.5mM IRStide Peptide substrate solution: Dissolve to 0.5mM with 50mM HEPES, aliquot, and store at -20°C.

[0699] 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.

[0700] S2.9, Stop Buffer: 180mM HEPES buffer, 20mM ethylenediaminetetraacetic acid, 0.2% Coating Reagent 3.

[0701] S2.10 Separation Buffer: 100mM HEPES buffer, 10mM ethylenediaminetetraacetic acid, 0.0005% Tween 20, 0.1% Coating Reagent 3, 1% dimethyl sulfoxide.

[0702] 3. Experimental Methods

[0703] S3.1 Preparation of compound plates

[0704] The compound was dissolved in dimethyl sulfoxide to 10 mM, and a certain volume was taken to dilute to 0.6 mM. 10 μL of the 0.6 mM dilution was added to a 384 microplate, and then serially diluted 3-fold to obtain a total of 8 concentration points.

[0705] S3.2, Compound Arrangement

[0706]

[0707] Positive control (HPE1): Ref1, final concentration: 10 μM

[0708] Positive control (HPE1): Ref2, final concentration: 10 μM

[0709] Negative control (ZPE): DMSO, final concentration 1.6%.

[0710] Compounds: highest final concentration of 10 μM, 3-fold dilution, 8 concentration points, 2 replicates.

[0711] 4. Experimental Procedure

[0712] S4.1. Add 250 nmol of ECHO compound to each well of the experimental plate and centrifuge at 1000 rpm for 1 minute;

[0713] S4.2. Add 5 μl of experimental buffer and shake for a few seconds to fully dissolve the compound;

[0714] S4.3. Add 5 μl of 3× substrate solution and 5 μl of 3× kinase solution, and centrifuge at 800 rpm for 1 minute;

[0715] S4.4. The final concentrations of JAK1, JAK2, JAK3, and Tyk2 kinases in the reaction system were 20, 1, 1, and 1 nM, respectively.

[0716] S4.5. Incubate at room temperature. Each kinase requires a different time, and there may be time differences between different batches of kinase.

[0717] S4.6. When the reaction reaches 20%-30%, add 15μl of stop solution to terminate the reaction, and centrifuge at 1000 rpm for 2 minutes.

[0718] S4.7. Place it on the EZ Reader to read the board.

[0719] S4.8.EZ Reader readings are calculated from peak height. % Product Conversion Rate = Product / (Product + Substrate) * 100

[0720] 5. Data Processing: IC50 Calculation

[0721] Concentration curves of the test compounds were generated using the graphing software XLfit, and the IC50 values ​​were calculated.

[0722] The IC50 values ​​of the compounds shown in the above embodiments were obtained using this experimental method and are listed in the table below.

[0723] The table below lists the IC50 values ​​of the compounds shown in the above examples. "A" indicates ≥10 μM; "B" indicates ≥1 μM.

[0724] Simultaneously <10μM; "C" indicates ≥0.1μM and <1μM; "D" indicates <0.1μM.

[0725]

[0726]

[0727]

[0728]

[0729]

Claims

1. A small molecule compound, characterized in that, for the preparation of a JAK1 / Tyk2 dual inhibitor.

2. Use of the small molecule compound according to claim 1 for the preparation of a medicament for the treatment, prevention and alleviation of inflammatory skin diseases associated with autoimmunity.

3. Use of the small molecule compound according to claim 1 for the preparation of a medicament for use as a JAK1 / Tyk2 dual inhibitor. ​

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