4-substituted phenyl-pyrimidine-2-amine compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention discloses a 4-substituted phenyl-pyrimidine-2-amine compound as well as a preparation method, a pharmaceutical composition and application thereof. The invention provides a compound shown as a formula I or a pharmaceutically acceptable salt thereof, and the compound has JAKs, especially Tyk2 inhibitory activity, so that the compound can be used for treating or preventing JAKs-mediated inflammation, autoimmunity, infectious diseases and tumor-related diseases, especially Tyk2-mediated inflammation, autoimmunity, infectious diseases and tumor-related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to a 4-substituted phenyl-pyrimidin-2-amine compound, a preparation method thereof, a pharmaceutical composition and an application. Background Art

[0002] Tyk2 kinase (tyrosine kinase 2) is a member of the Janus kinase (JAKs) family, mainly involved in cytokine signal transduction, and is associated with receptors such as IL-12 and IL-23, which play key roles in immune responses, especially inflammatory and autoimmune responses. Tyk2 consists of a catalytic active domain (JH1), a pseudokinase domain (JH2), an SH2 (Src homology2, JH3-JH4) domain, and a FERM domain (JH5-7). The FERM and SH2 domains jointly participate in regulating the interaction between Tyk2 and the receptor, the pseudokinase domain plays a regulatory role in kinase activity, and the kinase catalytic active domain is responsible for transmitting phosphorylation signals to activate subsequent signal pathways (Frontiers in Endocrinology, Vol. 8, Article 71, April 2017).

[0003] Tyk2 kinase plays a key regulatory role in multiple important cytokine signaling pathways, including those related to cytokines such as IL-12, IL-23, and type I interferon (IFN, interferon) (Int. J. Mol. Sci. 2023, 24 (4), 3391). IL-12 is a cytokine secreted by dendritic cells and macrophages. It can activate Tyk2 and Jak2, which interacts with it, and then enter the cell nucleus through STAT3 activation to promote the expression of IFN-γ and Th1 type immune response-related genes. IL-23 usually works synergistically with IL-17 and participates in the differentiation and maintenance of Th17 cells. After the IL-23 receptor is activated, it will also induce the production of STAT3, which in turn induces the production of downstream IL-17 and the expression of genes related to autoimmunity and inflammatory processes (Frontiers in Immunology, Vol. 12, Article 637829, 2021; Therapeutics, Vol. 397, P754-766, 2021). Tyk2 kinase also plays a core role in related immune responses mediated by type I interferon. Through the activation of type I interferon receptor (IFNAR), Tyk2 and its interacting Jak1 can mediate a variety of inflammatory and immune responses by phosphorylating STAT1 / 2. Studies have also shown that it can play a key role in antiviral immunity by phosphorylating STAT3 (Cell. Mol. Life Sci, 2017, DOI 10.1007 / s00018-016-2435-3), demonstrating its therapeutic potential in some common infectious diseases such as Mycobacterium tuberculosis or COVID-19 infection in recent years (Cell 185, P3086-3103, August 18, 2022). In addition, in recent years, people have found that Tyk2 also plays an important role in the IL-10 cytokine family-related pathways and is closely related to tumor immune surveillance (Cancers 2020, 12, 150; doi: 10.3390 / cancers12010150). Tyk2 small molecule inhibitors inhibit the production of inflammatory factors and regulate the activation and differentiation of immune cells by targeting and blocking the key signal transduction links in the above-mentioned pathways, making them a hot research and development topic for new treatments for inflammatory, autoimmune, infectious and tumor-related diseases.

[0004] Currently, the allosteric inhibitor deucravacitinib (BMS-986165) targeting the Tyk2 JH2 pseudokinase domain has been approved for marketing in 2022 for the treatment of moderate to severe plaque psoriasis in adults, and several companies such as Nimbus (NDI-034858), Alumis (ESK-001), and Ventyx (VTX-958) have followed. Nevertheless, inhibitors targeting its JH1 catalytic active domain still have corresponding therapeutic value. The Tyk2 inhibitor ropsacitinib (PF-06826647) and the Jak1 / Tyk2 bifunctional inhibitor brepocitinib (PF-06700841) developed by Pfizer have both entered clinical phase 3 studies, and companies such as Oncostellae (OST-122) are also actively exploring their applications in indications such as ulcerative colitis. Searching for new Jak inhibitors, especially those with strong inhibitory activity against Tyk2, is expected to provide a compound with potentially better druggability in this field, which is currently the overall effort direction in this field. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a Jak inhibitor with a new structure, especially an inhibitor with strong inhibitory activity against Tyk2. The present invention aims to provide a 4-substituted phenyl-pyrimidin-2-amine compound, its preparation method, pharmaceutical composition, and application. This type of 4-substituted phenyl-pyrimidin-2-amine compound has good application prospects in the treatment or prevention of JAKs-mediated, especially Tyk2-mediated diseases.

[0006] The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof,

[0007]

[0008] Wherein:

[0009] Ring A is a C6-C 10 Aromatic ring or a 5- to 10-membered heteroaromatic ring; the heteroatoms in the 5- to 10-membered heteroaromatic ring are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3;

[0010] m is 0, 1, 2, 3, 4, or 5;

[0011] R 1 Independently is halogen, C1-C6 alkyl, C1-C6 alkyl substituted by one, two, or three R 1-1 Substituted C1-C6 alkoxy, C1-C6 alkoxy substituted by one, two, or three R 1-2 Substituted, -NR 1-3 R1-4 、 -C(O)R 1-5 、 nitro or -SO2R 1-6 ;

[0012] R 1-1 is independently hydroxy or -SO2R 1-1-1 ;

[0013] R 1-1-1 is hydrogen, hydroxy, -NR a R b or C1-C6 alkyl;

[0014] R 1-2 is independently hydroxy;

[0015] R 1-3 is hydrogen or C1-C6 alkyl;

[0016] R 1-4 is -SO2R 1-4-1 、 hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted by one, two or three R 1-4-2 or -C(O)R 1 -4-3 ;

[0017] R 1-4-1 is -OH or C1-C6 alkyl;

[0018] R 1-4-2 is independently -NR 1-4-2a R 1-4-2b ;

[0019] R 1-4-2a and R 1-4-2b are independently hydrogen, C1-C6 alkyl or -C(O)OR 1-4-2c ;

[0020] R 1-4-2c is C1-C6 alkyl;

[0021] R 1-4-3 is C1-C6 alkyl;

[0022] R 1-5 is -OH, -NR 1-5-1 R 1-5-2 or C1-C6 alkoxy;

[0023] R 1-5-1 and R 1-5-2 are independently hydrogen or C1-C6 alkyl;

[0024] R 1-6 is -OH, -NR a R b or C1-C6 alkyl;

[0025] R 2 is hydrogen or -(CH2) m1 -C(=O)-R 2-1 ;

[0026] R 2-1 is hydroxy, -NR a R b , guanidino, C1-C6 alkoxy or C1-C6 alkoxy substituted with one, two or three R 2-1-1 , and m1 is 1, 2, 3 or 4;

[0027] R 2-1-1 is independently C1-C6 alkyl;

[0028] R 3 is CN-(CH2) n -, where n is 0 or 1;

[0029] R 4 and R 5 are independently hydrogen, halogen, hydroxy or -NR a R b ;

[0030] R a and R b are independently hydrogen or C1-C6 alkyl.

[0031] In certain preferred embodiments of the present invention, some groups in the compound of formula I or its pharmaceutically acceptable salt are defined as follows. For groups not mentioned, they are the same as those described in any embodiment of the present invention (abbreviated as "in a certain embodiment of the present invention"). The C6-C 10 aryl ring is a benzene ring or a naphthalene ring, such as a benzene ring.

[0032] In a certain embodiment of the present invention, the 5-10 membered heteroaryl ring is independently a 5-6 membered monocyclic heteroaryl ring or a 9-10 membered bicyclic heteroaryl ring.

[0033] In a certain embodiment of the present invention, the heteroatoms in the 5-10 membered heteroaryl ring are independently selected from N, and the number of heteroatoms is 1, 2 or 3, such as a pyrazole ring (such as ), a pyridine ring (such as ) or a benzopyrrole ring (such as ).

[0034] In a certain embodiment of the present invention, each of the halogens is independently F, Cl, Br or I. For example, F, Cl or Br, and further for example, F.

[0035] In one embodiment of the present invention, each of the C1-C6 alkyl groups and the C1-C6 alkyl groups in the substituted C1-C6 alkyl groups is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl or ethyl.

[0036] In one embodiment of the present invention, each of the C1-C6 alkoxy groups and the C1-C6 alkoxy groups in the substituted C1-C6 alkoxy groups is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example, ethoxy.

[0037] In one embodiment of the present invention, m is 1 or 2.

[0038] In one embodiment of the present invention, the R 1 is independently a C1-C6 alkyl group, a C1-C6 alkyl group substituted with one, two or three R 1-1 groups, -NR 1-3 R 1-4 or nitro; preferably, the R 1 is independently a C1-C6 alkyl group substituted with one, two or three R 1-1 groups or -NR 1-3 R 1 -4 .

[0039] In one embodiment of the present invention, the R 1-1 is independently -SO2R 1-1-1 .

[0040] In one embodiment of the present invention, the R 1-1-1 is hydroxy or -NR a R b ; preferably hydroxy.

[0041] In one embodiment of the present invention, the R 1-3 is hydrogen.

[0042] In one embodiment of the present invention, the R 1-4 is -SO2R 1-4-1 , hydrogen or a C1-C6 alkyl group substituted with one, two or three R 1-4-2 groups; preferably -SO2R 1-4-1 or hydrogen; more preferably -SO2R 1-4-1 .

[0043] In one embodiment of the present invention, the R 1-4-1 is a C1-C6 alkyl group.

[0044] In one embodiment of the present invention, the R 1-4-2a and R 1-4-2b are independently hydrogen or -C(O)OR 1-4-2c。

[0045] In one embodiment of the present invention, the R 2 is hydrogen.

[0046] In one embodiment of the present invention, the R 2-1 is hydroxy, guanidino or C1-C6 alkoxy, preferably C1-C6 alkoxy.

[0047] In one embodiment of the present invention, m1 is 1.

[0048] In one embodiment of the present invention, n is 0.

[0049] In one embodiment of the present invention, the R 4 and R 5 are independently hydrogen or halogen.

[0050] In one embodiment of the present invention, the compound represented by Formula I is the compound represented by Formula I-1,

[0051]

[0052] wherein the definitions of ring A, R 1 , R 2 , R 3 , R 4 and R 5 are as described in any one of the present invention;

[0053] R 6 is -NR 1-3 R 1-4 or C1-C6 alkyl substituted by one, two or three R 1-1 ; R 1-4 is -SO2R 1-4-1 ; the definitions of R 1-3 and R 1-1 are as described in any one of the present invention;

[0054] m2 is m-1, and m is 1, 2, 3, 4 or 5.

[0055] In one embodiment of the present invention, in Formula I-1, R 1 is independently -NR 1-3 R 1-4 or nitro; preferably -NR 1-3 R 1-4 .

[0056] In one embodiment of the present invention, R 6 is -NH-SO2R 1-4-1 or -CH2-SO2R 1-1-1 .

[0057] In a certain embodiment of the present invention, the compound represented by Formula I is the compound represented by Formula I-2,

[0058]

[0059] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and m2 are defined as described in any one of the present invention.

[0060] In a certain embodiment of the present invention, the compound represented by Formula I is the compound represented by Formula I-3,

[0061]

[0062] wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are defined as described in any one of the present invention.

[0063] In a certain embodiment of the present invention, is

[0064] In a certain embodiment of the present invention, R 2 is hydrogen, In a certain embodiment of the present invention, R 3 is In a certain embodiment of the present invention, R 4 is hydrogen or fluorine.

[0065] In a certain embodiment of the present invention, R 5 is hydrogen.

[0066] In a certain embodiment of the present invention, the compound represented by Formula I is any of the following compounds:

[0067]

[0068]

[0069] The present invention also provides a method for preparing the compound represented by Formula I, which includes any of the following methods: Method 1: Reacting compound C with compound D to prepare the compound of Formula I;

[0070]

[0071] R xis F, Cl, Br, I, OTf, OTs or OMe;

[0072] Method 2: The compound of formula I is prepared by reacting compound F with compound G;

[0073]

[0074] wherein Y is F, Cl, Br, I, OTf or OTs;

[0075] Method 3: The compound of formula I is obtained by deprotection reaction of compound I';

[0076]

[0077] wherein R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' have the same definitions as those of R 1 , R 2 , R 3 , R 4 and R 5 in any one of the present invention respectively, and at least one possible activating functional group is protected with a protecting group;

[0078] Method 4: The compound of formula I is obtained by hydrolysis reaction of compound II-1;

[0079]

[0080] In Method 4, R 2-1’ is C1-C6 alkoxy, and R 2 is -(CH2) m1 -C(=O)OH;

[0081] Method 5: The compound of formula I is obtained by reacting compound II-2 with Cl-SO2R 1-4-1 ;

[0082]

[0083] In Method 5, R 1 is independently -NR 1-3 R 1-4 , R 1-4 is -SO2R 1-4-1 or hydrogen, and at least one R 1 is -NR 1-3 -SO2R 1 -4-1 , and the remaining R 1 are -NHR 1-3 ;

[0084] Method 6: Compound II-3 reacts with Na2SO3 to obtain the compound of formula I;

[0085]

[0086] In Method 6, in formula II-3, at least one R 7 is a C1-C6 alkyl group substituted by 1, 2 or 3 halogens, and the remaining Rs 7 are defined the same as R 1 ; correspondingly, in formula I, at least one R 1 is a C1-C6 alkyl group substituted by 1, 2 or 3 -SO2OH;

[0087] Method 7: Compound II-4 reacts with a reducing agent to obtain the compound of formula I;

[0088]

[0089] In Method 7, in formula II-4, at least one R 8 is nitro, and the remaining Rs 8 are defined the same as R 1 ; correspondingly, in formula I, at least one R 1 is amino;

[0090] In Methods 1 to 7, unless otherwise specified, ring A, R 1 , R 2 , R 3 , R 4 , R 5 and m are defined as described in any one of the present invention.

[0091] In a certain embodiment of the present invention, the R x is Cl.

[0092] In a certain embodiment of the present invention, the Y is Cl, Br or I.

[0093] In a certain embodiment of the present invention, Method 1 includes the following Steps 1 and 2:

[0094] Step 1, Compound A and Compound B undergo a Suzuki coupling reaction to prepare Compound C;

[0095] Step 2, Compound C and Compound D react to prepare the compound of formula I;

[0096]

[0097] wherein, X is -B(OH)2 or R X , ring A, R 1 , R 2, R 3 , R 4 , R 5 and the definitions of m are as described in any one of the present invention.

[0098] In one embodiment of the present invention, Method 2 includes the following Steps 1 and 2:

[0099] Step 1, a Suzuki coupling reaction occurs between compound A and compound E to prepare compound F;

[0100] Step 2, compound F reacts with compound G to prepare the compound of formula I;

[0101]

[0102] wherein X is -B(OH)2 or Y, ring A, R 1 , R 2 , R 3 , R 4 , R 5 and the definitions of m are as described in any one of the present invention.

[0103] In one embodiment of the present invention, in Step 1 of Method 1, the Suzuki coupling reaction is carried out under the action of a metal catalyst and a base.

[0104] In one embodiment of the present invention, in Step 1 of Method 1, the metal catalyst is a palladium catalyst, such as Pd(PPh3)2Cl2, Pd(PPh3)4, PdCl2 or Pd(OAc)2.

[0105] In one embodiment of the present invention, in Step 1 of Method 1, the base is an alkali metal carbonate, such as Na2CO3, Cs2CO3, K2CO3 or Li2CO3.

[0106] In one embodiment of the present invention, in Step 2 of Method 1, the reaction is carried out under the action of a metal catalyst, an organic phosphine ligand and a base.

[0107] In one embodiment of the present invention, in Step 2 of Method 1, the organic phosphine reagent is SPhos, XPhos or XantPhos.

[0108] In one embodiment of the present invention, in Step 2 of Method 1, the base is an alkali metal carbonate, such as Na2CO3, Cs2CO3, K2CO3 or Li2CO3.

[0109] In one embodiment of the present invention, in Step 1 of Method 2, the Suzuki coupling reaction is carried out under the action of a metal catalyst and a base.

[0110] In a certain embodiment of the present invention, in step 1 of method 2, the metal catalyst is a palladium catalyst, such as Pd(PPh3)2Cl2, Pd(PPh3)4, PdCl2 or Pd(OAc)2.

[0111] In a certain embodiment of the present invention, in step 1 of method 2, the base is an alkali metal carbonate, such as Na2CO3, Cs2CO3, K2CO3 or Li2CO3.

[0112] In a certain embodiment of the present invention, in step 2 of method 2, the reaction is carried out under the action of an organic phosphine reagent and a base.

[0113] In a certain embodiment of the present invention, in step 2 of method 2, the organic phosphine reagent is SPhos, XPhos or XantPhos.

[0114] In a certain embodiment of the present invention, in step 2 of method 2, the base is an alkali metal alkoxide or an alkali metal carbonate, such as sodium tert-butoxide, Cs2CO3, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium methoxide or TMSOK, etc.

[0115] The present invention also provides the following compounds:

[0116]

[0117] Wherein, R X is F, Cl, Br, I, OTf, OTs or OMe; preferably Cl;

[0118] R 2 , R 3 , R 4 and R 5 are defined as described in any one of the present invention.

[0119] The present invention also provides any one of the following compounds:

[0120]

[0121]

[0122] The present invention provides a pharmaceutical composition, which comprises:

[0123] (1) The compound shown in formula I above or a pharmaceutically acceptable salt thereof, and

[0124] (2) Pharmaceutically acceptable excipients.

[0125] The present invention also provides the use of the compound shown in Formula I above or a pharmaceutically acceptable salt thereof, and the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used for treating and / or preventing diseases mediated by JAK (such as JAK1, JAK2, JAK3 or Tyk2), preferably diseases mediated by Tyk2; preferably inflammation, autoimmune diseases, infectious diseases or tumors mediated by Tyk2, more preferably autoimmune diseases or tumors mediated by Tyk2.

[0126] In one embodiment of the present invention, the autoimmune disease is atopic dermatitis, vitiligo, alopecia areata, or hidradenitis suppurativa.

[0127] In one embodiment of the present invention, the tumor is gastric cancer, breast cancer, non-small cell lung cancer, urothelial carcinoma or pancreatic cancer.

[0128] The present invention also provides a method for preventing and / or treating Tyk2-mediated autoimmune diseases or tumors, which comprises administering to a subject a therapeutically effective amount of the compound shown in Formula I above or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0129] Definitions

[0130] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, the following definitions are set forth to illustrate and define the meanings and scopes of the various terms used to describe the present invention.

[0131] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0132] The term "alkyl" refers to a straight-chain or branched-chain alkyl having a specified number of carbon atoms (such as C1-C6). Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, etc.

[0133] The term "alkoxy" refers to the group R Z -O-, where R Z is the alkyl defined above.

[0134] The term "aromatic ring" refers to a cyclic group consisting only of carbon atoms having a specified number of carbon atoms (such as C6-C 10 ), which is a monocyclic or polycyclic ring, and each ring has aromaticity (complies with Hückel's rule). Aromatic rings include, but are not limited to, benzene rings, naphthalene rings, etc.

[0135] The term "heteroaromatic ring" refers to a cyclic group having a specified number of ring atoms (e.g., 5 - 10 membered), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one, two, or three of N, O, and S), which is monocyclic or polycyclic and each ring has aromaticity (complies with Hückel's rule). The heteroaromatic ring is connected to the rest of the molecule through a carbon atom or a heteroatom; the heteroaromatic ring is connected to the rest of the molecule through a ring having a heteroatom or a ring without a heteroatom. Heteroaromatic rings include, but are not limited to, furan ring, pyrrole ring, thiophene ring, pyrazole ring, imidazole ring, oxazole ring, thiazole ring, pyridine ring, pyrimidine ring, indole ring, benzopyrrole ring, etc.

[0136] The term "pharmaceutically acceptable salt" includes "pharmaceutically acceptable salts formed with organic acids or inorganic acids" and "pharmaceutically acceptable salts formed with organic bases or inorganic bases".

[0137] The term "pharmaceutically acceptable excipient" refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and is non-toxic and has no side effects on the host or patient. Representative excipients include water, oils, vegetables and minerals, paste bases, lotion bases, ointment bases, etc. These bases include suspending agents, thickening agents, transdermal promoters, etc. Their preparations are well known to those skilled in the art of the cosmetics field or the topical drug field.

[0138] The term "pharmaceutical composition" refers to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient, which is prepared for administration to a mammal in need thereof, such as a human.

[0139] The term "therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to an individual, has the following effects: (i) treating or preventing a specific disease, disorder, or condition; (ii) alleviating, improving, or eliminating one or more symptoms of a specific disease, disorder, or condition; or (iii) preventing or delaying the onset of one or more symptoms of a specific disease, disorder, or condition described herein. The therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the individual, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0140] On the basis of not violating the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain the preferred examples of the present invention.

[0141] The reagents and raw materials used in the present invention are all commercially available.

[0142] The positive progress of the present invention is that: the present invention discloses a 4-substituted phenyl-pyrimidine-2-amine compound, a preparation method, a pharmaceutical composition and an application thereof. A class of JAKs inhibitors with different structures from reported or disclosed compounds is provided, and the compounds of the present invention have better inhibitory activity in terms of JAK inhibitory effect, especially TYK2 inhibitory effect. DETAILED DESCRIPTION

[0143] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples where specific conditions are not specified are selected according to conventional methods and conditions, or according to the product specifications. The known starting materials of the present invention, if not specifically specified, are purchased from corresponding reagent companies (such as TCI, Sigma-Aldrich, MedChemExpress, etc.) through reagent purchasing platforms such as LabNetwork (www.labnetwork.com.cn) or through the official websites of various reagent companies, by default.

[0144] The compounds of the present invention can be prepared by any conventional method. Suitable methods and raw materials for synthesizing the compounds of the present invention are provided in the following schemes and examples. Unless otherwise indicated, all substituents are as defined above. In addition, unless otherwise clearly described, all reactions, reaction conditions, abbreviations and symbols have the well-known meanings of those of ordinary skill in the field of organic chemistry.

[0145] The English abbreviations and Chinese names of the compounds involved in the present invention are shown in Table 1.

[0146] Table 1

[0147]

[0148]

[0149] The structures of the compounds were confirmed by hydrogen nuclear magnetic resonance spectroscopy (1H-NMR, Bruker instrument, 400 MHz) and / or mass spectrometry (MS).

[0150] Mass spectrometry was performed using a Waters Acquity Xevo G2-XS QTof UPLC / MS ultra-high performance liquid chromatography-high resolution mass spectrometry system;

[0151] 1 H-NMR was performed using a Bruker AVANCE III 400 MHz NMR instrument;

[0152] In the following examples, room temperature refers to 20-30°C.

[0153] Example 1. Preparation of 2-(4-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}phenyl)acetonitrile (Compound 1)

[0154] Step 1. Preparation of 2-[4-(2-chloropyrimidin-4-yl)phenyl]acetonitrile (Intermediate 1)

[0155]

[0156] Compound 2,4-dichloropyrimidine (CAS: 3934-20-1, 202 mg, 1.36 mmol, 1.00 eq), compound 4-cyanomethylphenylboronic acid (CAS: 91983-26-5, 230 mg, 1.43 mmol, 1.05 eq) and Na2CO3 (CAS: 497-19-8, 432 mg, 4.08 mmol, 3.00 eq) were placed in a 100 mL three-necked round-bottom flask. After adding dioxane (CAS: 123-91-1, 2 mL) and water (1 mL), the reaction mixture was degassed and purged with nitrogen. Pd(PPh3)2Cl2 (CAS: 13965-03-2, 47.76 mg, 68.04 μmol, 0.05 eq) was added to the reaction system, and after degassing and purging again, the mixture was refluxed and stirred under nitrogen protection at 80 °C for 16 hours. When TLC (petroleum ether: ethyl acetate = 1:1 (V / V), Rf = 0.53) monitored the reaction and showed that 2,4-dichloropyrimidine was completely consumed, water (10 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 83%:17% (V / V), about 2 L) to obtain 2-[4-(2-chloropyrimidin-4-yl)phenyl]acetonitrile (Intermediate 1) as a yellow solid (190 mg, 827 μmol, 60.7% yield, 100% purity).

[0157] Step 2. Preparation of 2-(4-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}phenyl)acetonitrile (Compound 1)

[0158]

[0159] Intermediate 1 (190 mg, 827 μmol, 1.00 eq), 1-methyl-1H-pyrazol-4-amine (CAS: 69843-13-6, 120 mg, 1.24 mmol, 1.50 eq), Cs2CO3 (539 mg, 1.65 mmol, 2.00 eq), and XPhos (CAS: 564483-18-7, 39.4 mg, 82.7 μmol, 0.10 eq) were placed in a 10 mL flask, and dioxane (2 mL) was added. After degassing the reaction mixture and purging with N2, Pd(dba)2 (CAS: 32005-36-0, 23.7 mg, 41.3 μmol, 0.05 eq) was added. The reaction mixture was degassed and purged with nitrogen, and then stirred at 100 °C for 3 h under nitrogen protection. The formation of the desired target peak was detected by LCMS. Water (20 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (10 mL × 2, the same as extracting twice with 10 mL of ethyl acetate). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. Purification was carried out by preparative HPLC (column: Welch Xtimate C18 100*40 mm*3 μm; mobile phase: [aqueous phase (TFA 0.1 v / v%) - acetonitrile]; ACN v / v%: 22% - 52%, gradient time 8 min). The product fractions were collected, freeze-dried and concentrated to obtain 2-(4-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}phenyl)acetonitrile as a yellow solid (15.0 mg, 51.67 μmol, 6.25% yield).

[0160] 1 H NMR: (400 MHz, DMSO-d6) δ ppm 9.56 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.17 (d, J = 8.0 Hz, 2H), 7.93 (s, 1H), 7.54 - 7.51 (m, 3H), 7.29 (d, J = 5.2 Hz, 1H), 4.16 (s, 2H), 3.83 (s, 3H); MS(ESI) m / z = 290.9 [M+H] + 。

[0161] Example 2. Preparation of Ethyl 3-cyano-3-(4-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}phenyl)propionate (Compound 2)

[0162] Step 1. Preparation of Ethyl 3-[4-(2-chloropyrimidin-4-yl)phenyl]-3-cyanopropionate (Intermediate 2)

[0163]

[0164] 2-[4-(2-Chloropyrimidin-4-yl)phenyl]acetonitrile (Intermediate 1) (300 mg, 1.31 mmol, 1.00 eq) was placed in a 100 mL three-necked round-bottom flask. At 0 °C, DMF (CAS: 68-12-2, 3.00 mL) and potassium tert-butoxide (CAS: 865-47-4, 439 mg, 3.92 mmol, 3.00 eq) were added. After the resulting reaction mixture was stirred for 10 minutes, ethyl 2-bromoacetate (CAS: 105-36-2, 261 mg, 1.57 mmol, 173 μL, 1.20 eq) was added to the above reaction system. After addition, the resulting mixture was stirred at 20 °C for 5 hours. Monitoring the reaction by TLC (petroleum ether: ethyl acetate = 3:1 (V / V)) showed that Intermediate 1 was completely consumed, and two new spots were observed. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The resulting residue was purified by preparative HPLC (column: Welch Xtimate C18 100*40 mm*3 μm; mobile phase: [water (TFA 0.1 v / v%) - acetonitrile]; ACN v / v%: 36% - 66%, gradient time 8 min) to obtain Intermediate 2 (110 mg, 348 μmol, 13.3% yield), which was a yellow oil.

[0165] Step 2. Preparation of Ethyl 3-cyano-3-(4-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}phenyl)propionate (Compound 2)

[0166]

[0167] Intermediate 2 (100 mg, 316 μmol, 1.00 eq), 1-methyl-1H-pyrazol-4-amine (46.1 mg, 475 μmol, 1.50 eq), Cs2CO3 (CAS: 534-17-8, 206 mg, 633 μmol, 2.00 eq) and XPhos (15.1 mg, 31.6 μmol, 0.10 eq) were placed in a 100 mL single-necked round-bottom flask, and dioxane (3 mL) was added. After degassing the reaction system and purging with nitrogen, Pd(dba)2 (9.11 mg, 15.8 μmol, 0.05 eq) was added and degassed and purged again. The reaction was stirred under nitrogen protection at 110 °C for 16 hours. LCMS monitoring of the reaction showed that Intermediate 2 was completely consumed and a new main peak was detected. The reaction mixture was diluted with water (10 mL) and extracted with DCM (CAS: 75-09-2, 10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by preparative HPLC (column: Welch Xtimate C18 100*40 mm*3 μm; mobile phase: [water (TFA 0.1 v / v%) - acetonitrile]; ACN v / v%: 20% - 50%, gradient time 8 min) to obtain ethyl 3-cyano-3-(4-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}phenyl)propionate as a yellow solid (20.0 mg, 51.5 μmol, yield 16.3%, purity 97.2%).

[0168] 1 H NMR: (400 MHz, DMSO-d6) δ ppm 12.40 (br s, 1H), 8.24 (br d, J = 8.0 Hz, 1H), 8.16 (d, J = 8.0 Hz, 2H), 8.02 (s, 1H), 7.76 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.27 - 7.24 (m, 1H), 4.44 (t, J = 8.0 Hz, 1H), 4.26 - 4.13 (m, 2H), 4.01 - 3.94 (m, 3H), 3.09 (dd, J = 8.0, 16.0 Hz, 1H), 2.98 - 2.87 (m, 1H), 1.27 (t, J = 8.0 Hz, 3H); MS(ESI) m / z = 377.0 [M+H] + 。

[0169] Example 3. Preparation of 3-cyano-3-(4-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}phenyl)propanoic acid (Compound 3)

[0170]

[0171] Compound 2 (10.0 mg, 26.5 μmol, 1.00 eq) was placed in a 100 mL single-necked round-bottom flask, THF (CAS: 109-99-9, 1 mL) was added, and NaOH (CAS: 1310-73-2, 1.06 mg, 26.5 μmol, 1.00 eq) was added to the reaction system at 0 °C. After addition, the mixture was stirred under nitrogen protection at 20 °C for 2 h. Monitoring the reaction by LCMS showed that the raw material was completely consumed and a new main peak was detected. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by preparative HPLC (column: Phenomenex C18 150*40 mm*5 μm; mobile phase: [water (HCl 0.1 v / v%) - acetonitrile]; ACN v / v%: 15% - 45%, gradient time 10 min) to obtain 3-cyano-3-(4-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}phenyl)propanoic acid as a yellow oil (5.00 mg, 13.51 μmol, yield 50.84%, purity 94.1%).

[0172] 1 1H NMR: (400 MHz, DMSO-d6) δ 11.43 (br s, 1H), 8.31 (br d, J = 8.0 Hz, 2H), 7.99 - 7.96 (m, 2H), 7.71 - 7.69 (m, 3H), 7.62 - 7.60 (m, 1H), 4.59 - 4.54 (m, 1H), 4.00 - 3.94 (m, 3H), 2.87 (m, 2H); MS (ESI) m / z = 348.9 [M + H] + 。

[0173] Example 4. Preparation of [3-({4-[4-(cyanomethyl)phenyl]pyrimidin-2-yl}amino)phenyl]methanesulfonic acid (Compound 4)

[0174] Step 1. Preparation of 2-[4-(2-{[3-(hydroxymethyl)phenyl]amino}pyrimidin-4-yl)phenyl]acetonitrile (Intermediate 3)

[0175]

[0176] In a 100 mL three-necked flask, intermediate 1 (200 mg, 870 μmol, 1.00 eq), 3-aminobenzyl alcohol (CAS: 1877-77-6, 160 mg, 1.31 mmol, 1.5 eq), Cs2CO3 (1.13 g, 3.48 mmol, 4.00 eq) and XPhos (41.5 mg, 87.0 μmol, 0.10 eq) were suspended in dioxane (10.0 mL). After degassing the reaction mixture and purging with nitrogen, Pd(dba)2 (25.0 mg, 43.5 μmol, 0.05 eq) was added to the reaction mixture, and degassing and purging were carried out again. After the addition was complete, the reaction mixture was stirred at 100 °C for 3 hours. Monitoring the reaction by LCMS showed that intermediate 1 was completely consumed and the desired target peak was detected. The reaction mixture was diluted with water (25.0 mL) and extracted with ethyl acetate (25.0 mL × 3). The combined organic layers were washed with saturated brine (25.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex C18 150*40 mm*5 μm; mobile phase: [water (HCl 0.1 v / v%) - acetonitrile]; ACN v / v%: 18% - 48%, gradient time 10 min) to give intermediate 3 as a yellow solid (60.0 mg, 189 μmol, 21.7% yield).

[0177] 1 H NMR: (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.58 - 8.54 (d, J = 14.0 Hz, 1H), 8.25 - 8.21 (d, J = 8.4 Hz, 2H), 7.2 (s, 1H), 7.66 - 7.62 (d, J = 7.2 Hz, 1H), 7.55 - 7.50 (d, J = 8.0 Hz, 2H), 7.44 - 7.40 (d, J = 5.2 Hz, 1H), 7.28 - 7.23 (t, J = 8.0 Hz, 1H), 6.94 - 6.90 (d, J = 7.2 Hz, 1H), 4.51 (s, 2H), 4.16 (s, 2H); MS(ESI) m / z = 316.9 [M+H] + 。

[0178] Step 2. Preparation of 2-[4-(2-{[3-(chloromethyl)phenyl]amino}pyrimidin-4-yl)phenyl]acetonitrile (Intermediate 29)

[0179]

[0180] In a 50 mL single-necked flask, intermediate 3 (60.0 mg, 189 μmol, 1.00 eq) was suspended in DCM (6.00 mL), and thionyl chloride (CAS: 7719-09-7, 568 μmol, 41.2 μL, 3.00 eq) was added dropwise to the reaction system under nitrogen protection at 0 °C. After the addition was complete, the reaction system was warmed to 20 °C and stirred for 2 hours under nitrogen protection. Monitoring the reaction by LCMS showed that intermediate 3 was still not completely reacted, but the desired target peak was detected. The reaction mixture was concentrated under reduced pressure to obtain intermediate 29 as a yellow solid (100 mg, crude product). MS (ESI) m / z = 334.9 [M+H] + 。

[0181] Step 3. Preparation of [3-({4-[4-(cyanomethyl)phenyl]pyrimidin-2-yl}amino)phenyl]methanesulfonic acid (Compound 4)

[0182]

[0183] In a 50 mL single-necked flask, intermediate 29 (100 mg, 298 μmol, 1.00 eq) was suspended in water (3.00 mL), and Na2SO3 (CAS: 7757-83-7, 75.2 mg, 597 μmol, 2.00 eq) was added. After the addition was complete, the reaction mixture was stirred at 50 °C under nitrogen protection for 16 hours. Monitoring the reaction by LCMS showed that intermediate 29 was still not completely reacted, but the desired target peak was detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. The obtained residue was purified by preparative HPLC (column: Phenomenex C18 150*40 mm*5 μm; mobile phase: [water (HCl 0.1 v / v%) - acetonitrile]; ACN v / v%: 28% - 58%, gradient time 10 min) to obtain [3-({4-[4-(cyanomethyl)phenyl]pyrimidin-2-yl}amino)phenyl]methanesulfonic acid as a yellow solid (20.0 mg, 51.2 μmol, 17.1% yield, 97.5% purity).

[0184] 11H NMR: (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.57 - 8.52 (d, J = 5.2 Hz, 1H), 8.27 - 8.22 (d, J = 8.0 Hz, 2H), 7.78 (s, 1H), 7.68 - 7.62 (d, J = 7.6 Hz, 1H), 7.54 - 7.48 (d, J = 8.4 Hz, 2H), 7.42 - 7.38 (m, J = 5.6 Hz, 1H), 7.22 - 7.15 (t, J = 8.0 Hz, 1H), 6.95 - 6.90 (d, J = 7.2 Hz, 1H), 4.15 (s, 2H), 3.68 (s, 2H);

[0185] MS(ESI) m / z = 381.0 [M + H] + 。

[0186] Example 5. Preparation of [3 - ({4 - [4 - (cyanomethyl)phenyl]pyrimidin - 2 - yl}amino)phenyl]methanesulfonamide (Compound 5)

[0187] Step 1. Preparation of O - ethyl xanthate (3 - nitrobenzyl) ester (Intermediate 4)

[0188]

[0189] Add m - nitrobenzyl chloride (CAS: 619 - 23 - 8, 5.00 g, 29.1 mmol, 1.00 eq) and DMSO (50 mL) to a 250 mL three - necked round - bottom flask, and then add potassium O - ethyl xanthate (CAS: 140 - 89 - 6, 5.61 g, 34.9 mmol, 1.20 eq). After the addition is complete, stir the mixture under nitrogen protection at 20 °C for 16 hours. Monitoring the reaction by TLC (petroleum ether: ethyl acetate = 10:1 (V / V)) shows that the raw materials are completely consumed, and a new spot is observed to form. Dilute the reaction mixture with water (50 mL) and extract with ethyl acetate (50 mL × 3). The combined organic phases are washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Intermediate 4 as a yellow oil (5.60 g, 21.7 mmol, 74.68% yield).

[0190] 1 1H NMR: (400 MHz, CDCl3) δ 8.26 - 8.21 (m, 1H), 8.13 (dd, J = 4.0, 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.54 - 7.46 (m, 1H), 4.66 (q, J = 8.0 Hz, 2H), 4.45 (s, 2H), 1.47 - 1.40 (m, 3H).

[0191] Step 2. Preparation of 3-Nitrobenzyl Mercaptan (Intermediate 5)

[0192]

[0193] Add intermediate 4 (5.60 g, 21.7 mmol, 1.00 eq) and DMSO (CAS: 67-68-5, 60 mL) into a 250 mL three-necked round-bottom flask. Slowly add ethylenediamine (CAS: 107-15-3, 2.27 g, 37.7 mmol, 2.53 mL, 1.74 eq) and HCl (CAS: 7647-01-0, concentration 37%, 906 μL, 0.5 eq) dropwise at 20 °C. After the addition is complete, stir the mixture under nitrogen protection at 20 °C for 1 hour. Monitoring the reaction by TLC (petroleum ether: ethyl acetate = 10:1 (V / V)) shows that intermediate 4 is completely consumed, and two new spots are observed to form. While stirring at 20 °C, add 1 M HCl (100 mL) dropwise to the above reaction mixture, and continue stirring for 30 minutes. Then extract the aqueous phase with MTBE (CAS: 1634-04-4, 100 mL × 3), and back-extract the combined organic phase with 5% aqueous NaOH solution (100 mL × 2). Acidify the combined aqueous phase with 37% HCl, and extract with DCM (100 mL × 2). Dry the combined organic phase over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a residue. The obtained residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 80 / 20 (V / V)) to obtain intermediate 5 as a pale yellow oil (1.0 g, 5.91 mmol, 27.1% yield).

[0194] 1 H NMR: (400 MHz, CDCl3) δ 8.21 (t, J = 4.0 Hz, 1H), 8.10 (dd, J = 4.0, 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 3.84 (d, J = 8.0 Hz, 2H), 1.87 (t, J = 8.0 Hz, 1H).

[0195] Step 3. Preparation of (3-Nitrophenyl)Methanesulfonyl Chloride (Intermediate 6)

[0196]

[0197] Add intermediate 5 (1.00 g, 5.91 mmol, 1.00 eq) and DCM (10.0 mL) to a 100 mL three-necked round-bottom flask, and add HCl (12 M, 9.85 mL, 20 eq) at 20 °C. Slowly add 0.5 mL of hydrogen peroxide (CAS: 7722-84-1, concentration 30%, 3.02 g, 26.6 mmol, 2.56 mL, 4.51 eq) dropwise to the reaction system. Rapidly stir the reaction mixture without external heating until reflux begins, and then continue to add 2 mL of hydrogen peroxide in portions at a rate sufficient to maintain a gentle reflux. After the addition is complete, stir the mixture under nitrogen protection at 20 °C for 1 hour. TLC (petroleum ether: ethyl acetate = 3:1 (V / V)) monitoring shows that intermediate 5 is consumed and a new spot is observed. After the reaction mixture is cooled, separate the green organic phase and carefully decolorize it with an aqueous Na2SO3 solution at 20 °C (note the exotherm). Extract the mixture with DCM (50 mL × 3), wash the combined organic phases with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain intermediate 6 as a yellow solid (600 mg, crude).

[0198] 1 1H NMR: (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.16 (dd, J = 4.0, 8.0 Hz, 1H), 8.07 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.75 - 7.65 (m, 1H), 4.97 (s, 2H), 3.73 (s, 3H).

[0199] Step 4. Preparation of (3-nitrophenyl)methanesulfonamide (intermediate 7)

[0200]

[0201] Place intermediate 6 (100 mg, 424 μmol, 1.00 eq) and acetonitrile (CAS: 75-05-8, 1 mL) in a 50 mL single-necked round-bottom flask, and add ammonia water (CAS: 1336-21-6, concentration 28%, 265 mg, 2.12 mmol, 291 μL, 5.00 eq) under nitrogen protection at 0 °C. After the addition is complete, stir the mixture at 20 °C for 1 hour. TLC (dichloromethane: methanol = 10:1 (V / V)) monitoring shows that intermediate 6 is completely consumed and a new spot is observed. Concentrate the reaction mixture under reduced pressure to remove the solvent, then dilute with water (5 mL) and extract with DCM (5 mL × 3). Wash the combined organic phases with saturated brine (5 mL × 3), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain intermediate 7 as a white solid (50.0 mg, crude).

[0202] 1 1H NMR: (400 MHz, DMSO-d6) δ 8.31 - 8.18 (m, 2H), 7.83 (d, J = 8.0 Hz, 1H), 7.72 - 7.65 (m, 1H), 6.96 (br s, 2H), 4.48 (s, 2H).

[0203] Step 5. Preparation of (3-aminophenyl)methanesulfonamide (Intermediate 8)

[0204]

[0205] Intermediate 7 (100 mg, 462 μmol, 1.00 eq) and methanol (CAS: 67 - 56 - 1, 2 mL) were placed in a 50 mL single-necked round-bottom flask. Under nitrogen protection, Pd / C (CAS: 7440 - 05 - 3, 10 wt% Pd, 10.0 mg) was added. After the addition was complete, the mixture was stirred and reacted under hydrogen (15 psi) at 20 °C for 3 hours. TLC (dichloromethane:methanol = 10:1 (V / V)) monitoring of the reaction showed that Intermediate 7 was consumed and a new spot was observed. The reaction mixture was filtered and concentrated under reduced pressure to obtain Intermediate 8 as a yellow solid (100 mg, crude).

[0206] Step 6. Preparation of [3-({4-[4-(cyanomethyl)phenyl]pyrimidin-2-yl}amino)phenyl]methanesulfonamide (Compound 5)

[0207]

[0208] Intermediate 8 (50.0 mg, 268 μmol, 1.00 eq) and Intermediate 1 (67.8 mg, 295 μmol, 1.10 eq) were placed in a 50 mL single-necked round-bottom flask. n-Butanol (CAS: 71 - 36 - 3, 0.5 mL) and HCl (2 M, 134 μL, 1.00 eq) were added. After the addition was complete, the mixture was refluxed and stirred under nitrogen protection at 100 °C for 16 hours. LCMS monitoring of the reaction showed that Intermediate 8 was completely consumed and a new product peak was observed. The reaction mixture was filtered, and the filtrate was washed with DCM (50 mL) and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by preparative HPLC (column: 1_Welch Xtimate 75*40 mm*3 μm; mobile phase: [water (HCl 0.1 v / v%) - acetonitrile]; ACN v / v%: 20% - 40%, gradient time 8 min) to obtain [3-({4-[4-(cyanomethyl)phenyl]pyrimidin-2-yl}amino)phenyl]methanesulfonamide as a white solid (5.00 mg, 13.1 μmol, 2.45% yield, 100% purity).

[0209] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.57 (d, J = 4.0 Hz, 1H), 8.24 (d, J = 8.0 Hz, 2H), 7.92 (s, 1H), 7.74 (br d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 4.0 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.88 (br s, 2H), 4.25 (s, 2H), 4.16 (s, 2H); MS(ESI) m / z = 379.8 [M+H] + 。

[0210] Example 6. Preparation of [3-Cyano-3-(4-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}phenyl)propanoyl]guanidine (Compound 6)

[0211] Step 1. Preparation of N-(tert-Butoxycarbonyl)-N’-[3-cyano-3-(4-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}phenyl)propanoyl]guanidine (Intermediate 9)

[0212]

[0213] Compound 3 (80.0 mg, 229 μmol, 1.00 eq) and 1-(tert-butoxycarbonyl)guanidine (CAS: 219511-71-4, 40.2 mg, 252 μmol, 1.10 eq) were placed in a 100 mL three-necked round-bottom flask, and DCM (2 mL) was added. At 0 °C, HATU (CAS: 148893-10-1, 130 mg, 344 μmol, 1.50 eq) was added to the above reaction system, and the mixture was stirred at 20 °C for 1 hour. DIEA (CAS: 7087-68-5, 74.2 mg, 574 μmol, 100 μL, 2.50 eq) was added to the above reaction system. After the addition was complete, the mixture was stirred under nitrogen protection at 20 °C for 3 hours. LCMS monitoring of the reaction showed that Compound 3 was consumed and the target peak was detected. The reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, dichloromethane:methanol = 100 / 0 to 95 / 5 (V / V)) to obtain Intermediate 9 as a yellow oil (70.0 mg, 142 μmol, 62.2% yield). MS(ESI) m / z = 286.9 [M+H]+ .

[0214] Step 2. Preparation of [3-cyano-3-(4-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}phenyl)propanoyl]guanidine (Compound 6)

[0215]

[0216] Place intermediate 9 (70.0 mg, 142 μmol, 1.00 eq) into a 40 mL single-neck round-bottom flask, and add a dioxane solution of HCl (CAS: 64990-51-8, 4 M, 5 mL, 139 eq). After the addition, stir the mixture under nitrogen protection at 20 °C for 16 hours. Monitoring the reaction by LCMS showed that intermediate 9 was still not completely reacted, but the target peak was detected. Concentrate the reaction mixture under reduced pressure to obtain a residue. The obtained residue was purified by preparative HPLC (column: Xtimate C18 150*40 mm*5 μm; mobile phase: [water (HCl 0.1 v / v%) - acetonitrile]; ACN v / v%: 1% - 25%, gradient time 10 min) to obtain a residue. The obtained residue was purified again by preparative column HPLC (column: Xtimate C18 150*40 mm*5 μm; mobile phase: [water (HCl 0.1 v / v%) - acetonitrile]; ACN v / v%: 5% - 20%, gradient time 10 min) to obtain [3-cyano-3-(4-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}phenyl)propanoyl]guanidine as a yellow solid (10.0 mg, 25.6 μmol, 20.0% yield, 100% purity).

[0217] 1 1H NMR: (400 MHz DMSO-d6) δ 12.39 (br s, 1H), 9.73 (br s, 1H), 8.55 (br s, 1H), 8.51 (br s, 1H), 8.34 - 8.26 (m, 1H), 8.22 (br s, 2H), 7.97 (br s, 1H), 7.67 (br d, J = 8.0 Hz, 2H), 7.58 (br s, 1H), 7.35 (br s, 1H), 4.75 (br s, 1H), 3.35 (br d, J = 8.0 Hz, 1H), 3.20 (br d, J = 8.0 Hz, 1H); MS (ESI) m / z = 390.1 [M+H] + .

[0218] Preparation of Example 7. N-[3-Amino-5-({4-[4-(cyanomethyl)phenyl]pyrimidin-2-yl}amino)phenyl]methanesulfonamide (Compound 7) and N,N'-bis(methanesulfonyl)-5-({4-[4-(cyanomethyl)phenyl]pyrimidin-2-yl}amino)-1,3-benzenediamine (Compound 8)

[0219] Step 1. Preparation of 2-[4-(2-aminopyrimidin-4-yl)phenyl]acetonitrile (Intermediate 10)

[0220]

[0221] Coupling was carried out using a method similar to the preparation of Intermediate 1, except that the 2,4-dichloropyrimidine substrate was replaced with 2-amino-4-chloropyrimidine (CAS: 3993-78-0). The resulting Intermediate 10 was a yellow solid (yield 61.6%, purity 100.0%).

[0222] 1 H NMR: (400 MHz DMSO-d6) δ 8.31 (d, J = 5.2 Hz, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.54 - 7.46 (m, 2H), 7.13 (d, J = 5.2 Hz, 1H), 6.69 (s, 2H), 4.13 (s, 2H)

[0223] Step 2. Preparation of 2-(4-{2-[(3,5-dinitrophenyl)amino]pyrimidin-4-yl}phenyl)acetonitrile (Intermediate 11)

[0224]

[0225] Intermediate 10 (100 mg, 475 μmol, 1.00 eq), 1-bromo-3,5-dinitrobenzene (CAS: 18242-39-2, 117 mg, 475 μmol, 1.00 eq), sodium tert-butoxide (CAS: 865-48-5, 91.4 mg, 951 μmol, 2.00 eq) and XPhos (22.6 mg, 47.5 μmol, 0.10 eq) were placed in a 100 mL single-necked round-bottom flask, and toluene (5 mL) was added. The reaction mixture was degassed and purged with nitrogen, Pd(dba)2 (13.6 mg, 23.7 μmol, 0.05 eq) was added and degassed and purged again. After the addition was complete, the mixture was refluxed and stirred at 95 °C under nitrogen protection for 0.5 h. TLC (dichloromethane:methanol = 10:1 (V / V)) monitoring of the reaction showed that the starting materials had not completely reacted, but two new spots were observed to form. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol = 100 / 0 to 90 / 10 (V / V)) to obtain Intermediate 11 as a yellow solid (50.0 mg, 112 μmol, 4.72% yield, 84.5% purity).

[0226] MS(ESI) m / z = 377.0 [M+H] + 。

[0227] Step 3. Preparation of 2-(4-{2-[(3,5-diaminophenyl)amino]pyrimidin-4-yl}phenyl)acetonitrile (Intermediate 12)

[0228]

[0229] Intermediate 11 (25.0 mg, 66.4 μmol, 1.00 eq) and methanol (2 mL) were placed in a 50 mL single-necked round-bottom flask, and Pd / C (10 wt% Pd, 132 μmol, 2.00 eq) was added. After the addition was complete, the mixture was stirred and reacted under hydrogen (15 psi) at 20 °C for 3 h. LCMS monitoring of the reaction showed that Intermediate 11 was completely consumed and the target peak was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain Intermediate 12 as a yellow solid (40.0 mg, crude product).

[0230] MS(ESI) m / z = 316.8 [M+H] + 。

[0231] Step 4. Preparation of N-[3-amino-5-({4-[4-(cyanomethyl)phenyl]pyrimidin-2-yl}amino)phenyl]methanesulfonamide (Compound 7) and N,N'-bis(methanesulfonyl)-5-({4-[4-(cyanomethyl)phenyl]pyrimidin-2-yl}amino)-1,3-benzenediamine (Compound 8)

[0232]

[0233] Intermediate 12 (40.0 mg, 126 μmol, 1.00 eq) and DCM (1.00 mL) were placed in a 100 mL single-necked round-bottom flask, and TEA (CAS: 121-44-8, 25.5 mg, 252 μmol, 35.2 μL, 2.00 eq) was added. At 0 °C, MsCl (CAS: 124-63-0, 0.01 g, 87.3 μmol, 6.76 μL, 0.69 eq) was added dropwise to the above reaction system. After the addition was complete, the mixture was stirred and reacted under nitrogen protection at 20 °C for 4 hours. LCMS monitoring of the reaction showed that Intermediate 12 was completely consumed, and two new peaks were detected. The reaction mixture was quenched with saturated NaOH (10 mL) and extracted with DCM (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by preparative HPLC (column: Phenomenex C18 150*40 mm*5 μm; mobile phase: [water (HCl 0.1 v / v%) - acetonitrile]; ACN v / v%: 20% - 50%, gradient time 10 min) to obtain respectively:

[0234] N-[3-amino-5-({4-[4-(cyanomethyl)phenyl]pyrimidin-2-yl}amino)phenyl]methanesulfonamide, as a yellow solid (5.00 mg, 12.68 μmol, yield 20.05%, purity 100%).

[0235] 1 1H NMR: (400 MHz CDCl3) δ 8.56 (d, J = 8.0 Hz, 1H), 8.28 (br d, J = 8.0 Hz, 2H), 7.84 - 7.67 (m, 2H), 7.59 (br d, J = 8.0 Hz, 3H), 7.09 (br s, 1H), 4.04 (s, 2H), 3.08 (s, 3H); MS (ESI) m / z = 394.9 [M + H] + 。

[0236] N,N’-Bis(methylsulfonyl)-5-({4-[4-(cyanomethyl)phenyl]pyrimidin-2-yl}amino)-1,3-benzenediamine, a yellow solid (12.0 mg, 23.16 μmol, yield 36.6%, purity 91.2%).

[0237] 1 1H NMR: (400 MHz CDCl3) δ 8.47 (d, J = 8.0 Hz, 1H), 8.34 (d, J = 8.0 Hz, 2H), 7.68 - 7.55 (m, 3H), 7.43 (d, J = 4.0 Hz, 2H), 6.98 (s, 1H), 4.05 (s, 2H), 3.06 (s, 6H); MS(ESI) m / z = 472.7 [M+H] + 。

[0238] Example 8. Preparation of N-[6-({4-[4-(cyanomethyl)phenyl]pyrimidin-2-yl}amino)-1H-indol-4-yl]methanesulfonamide (Compound 9)

[0239] Step 1. Preparation of 1-(tert-butoxycarbonyl)-6-bromo-4-nitro-1H-indole (Intermediate 13)

[0240]

[0241] To THF (20.0 mL) was added 6-bromo-4-nitro-1H-indole (CAS: 885520-50-3, 2.0 g, 8.30 mmol, 1.0 eq) and DMAP (CAS: 1122-58-3, 200 mg, 1.64 mmol, 0.01 eq), and a solution of di-tert-butyl dicarbonate (CAS: 24424-99-5, 2.40 g, 11.0 mmol, 2.53 mL, 1.33 eq) in THF (10 mL) was slowly added at 10 °C. The reaction mixture was stirred at 10 - 15 °C for 16 h, and the color turned yellow. Monitoring the reaction by TLC (petroleum ether: ethyl acetate = 8:1 (V / V), UV) showed that most of the starting material had been consumed. The reaction mixture was concentrated, and the residue was separated and purified by FLASH silica gel chromatography ( 40 g silica FLASH column, eluent with a 5 v / v% ethyl acetate / petroleum ether gradient, flow rate 35 mL / min), and the target product Intermediate 13 was obtained by monitoring with TLC (petroleum ether: ethyl acetate = 8:1 (V / V), Rf = 0.62, UV) as a yellow solid (2.60 g, 7.62 mmol, 91.8% yield).

[0242] 11H NMR: (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.35 (d, J = 1.6 Hz, 1H), 7.80 (d, J = 3.6 Hz, 1H), 7.33 (d, J = 3.6 Hz, 1H), 1.70 (s, 10H).

[0243] Step 2. Preparation of 1-(tert-butoxycarbonyl)-6-({4-[4-(cyanomethyl)phenyl]pyrimidin-2-yl}amino)-4-nitro-1H-indole (Intermediate 14)

[0244]

[0245] Coupling was carried out using a method similar to the preparation of Intermediate 11, except that the substrate was changed from 1-bromo-3,5-dinitrobenzene to Intermediate 13, the base used was changed from sodium tert-butoxide to Cs2CO3, and the solvent was changed from toluene to dioxane. The resulting Intermediate 14 was a yellow solid (15.6% yield, 89.0% purity). MS (ESI) m / z = 471.0 [M+H] + .

[0246] Step 3. Preparation of 4-amino-1-(tert-butoxycarbonyl)-6-({4-[4-(cyanomethyl)phenyl]pyrimidin-2-yl}amino)-1H-indole (Intermediate 15)

[0247]

[0248] Reduction was carried out using a method similar to the preparation of Intermediate 12, except that the substrate of Intermediate 11 was changed to Intermediate 14. The resulting Intermediate 15 was a yellow solid (93.6% yield, crude product). MS (ESI) m / z = 441.0 [M+H] + .

[0249] Step 4. Preparation of N-[1-(tert-butoxycarbonyl)-6-({4-[4-(cyanomethyl)phenyl]pyrimidin-2-yl}amino)-1H-indol-4-yl]methanesulfonamide (Intermediate 16)

[0250]

[0251] Methanesulfonylation was carried out using a method similar to Step 4 of the preparation of Compound 7 and Compound 8, except that the substrate was changed from Intermediate 12 to Intermediate 15, and the sulfonylation reagent used was changed from MsCl to methanesulfonic anhydride (CAS: 7143-01-3). The resulting Intermediate 16 was a yellow solid (yield 98.1%, crude product). MS (ESI) m / z = 519.0 [M+H] + .

[0252] Preparation of N-[6-({4-[4-(Cyanomethyl)phenyl]pyrimidin-2-yl}amino)-1H-indol-4-yl]methanesulfonamide

[0253]

[0254] Intermediate 16 (120 mg, 231 μmol, 1.00 eq) was charged into a 100 mL single-necked round-bottom flask, and a dioxane solution of HCl (4 M, 57.8 μL, 1.00 eq) was added. After the addition was complete, the mixture was stirred at 20 °C for 2 hours. Monitoring the reaction by LCMS showed that Intermediate 16 was completely consumed and the target peak was detected to be generated. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (column: Welch Xtimate C18 100*40 mm*3 μm; mobile phase: [water (HCl 0.1 v / v%) - acetonitrile; ACN v / v%: 10% - 40%, gradient time 8 min]) to obtain N-[6-({4-[4-(cyanomethyl)phenyl]pyrimidin-2-yl}amino)-1H-indol-4-yl]methanesulfonamide as a yellow solid (22 mg, 52.5 μmol, 22.7% yield, 100% purity).

[0255] 1 1H NMR: (400 MHz DMSO-d6) δ 11.18 (br s, 1H), 9.86 (br s, 1H), 9.52 (s, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.27 (d, J = 8.3 Hz, 2H), 7.90 (s, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 5.3 Hz, 1H), 7.37 (s, 1H), 7.25 - 7.18 (m, 1H), 6.69 (br s, 1H), 4.18 (s, 2H), 3.00 (s, 3H); MS (ESI) m / z = 418.9 [M+H].

[0256] Example 9. Preparation of [3-({4-[4-(Cyanomethyl)phenyl]-5-fluoropyrimidin-2-yl}amino)-5-nitrophenyl]methanesulfonic acid (Compound 10)

[0257] Step 1. Preparation of 2-[4-(2-Chloro-5-fluoropyrimidin-4-yl)phenyl]acetonitrile (Intermediate 17)

[0258]

[0259] Obtained using a method similar to that of Intermediate 1, except that the substrate was changed from 2,4-dichloropyrimidine to 5-fluoro-2,4-dichloropyrimidine (CAS: 2927-71-1). The resulting Intermediate 17 was a white solid (61.4% yield).

[0260] 1 H NMR: (400 MHz DMSO-d6) δ 8.96 (d, J = 3.2 Hz, 1H), 8.06 (d, J = 7.2 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 4.19 (s, 2H).

[0261] Step 2. Preparation of 2-[4-(5-fluoro-2-{[3-(hydroxymethyl)-5-nitrophenyl]amino}pyrimidin-4-yl)phenyl]acetonitrile (Intermediate 18)

[0262]

[0263] Obtained using a method similar to that for preparing Intermediate 3, except that the substrates were changed from Intermediate 1 and m-aminobenzyl alcohol to Intermediate 17 and 3-amino-5-nitrobenzyl alcohol (CAS: 90390-46-8), the base used was changed to K2CO3, and the solvent used was changed to n-butanol. The resulting Intermediate 18 (97.9% yield) was a yellow solid.

[0264] 1 H NMR: (400 MHz DMSO-d6) 10.34 (s, 1H), 8.86 (t, J = 2.00 Hz, 1H), 8.75 (d, J = 3.60 Hz, 1H), 8.17 (d, J = 8.00 Hz, 2H), 8.09 (s, 1H), 7.77 (s, 1H), 7.59 (d, J = 8.40 Hz, 2H), 5.54 (t, J = 5.60 Hz, 1H), 4.61 (d, J = 5.60 Hz, 2H), 4.19 (s, 2H).

[0265] Step 3. Preparation of 2-[4-(2-{[3-(bromomethyl)-5-nitrophenyl]amino}-5-fluoro-pyrimidin-4-yl)phenyl]acetonitrile (Intermediate 19)

[0266]

[0267] At 25 °C, intermediate 18 (800 mg, 2.11 mmol, 1.00 eq), DMF (15.0 mL) and PPh3 (CAS: 603-35-0, 2.21 g, 8.44 mmol, 4.00 eq) were successively charged into a 40 mL sealed tube. At 0 °C, CBr4 (CAS: 558-13-4, 2.80 g, 8.44 mmol, 4.00 eq) was added portionwise to the reaction system within 5 minutes, and the reaction was stirred at 25 °C for 12 hours. TLC (petroleum ether / ethyl acetate = 1 / 1 (V / V)) monitoring of the reaction showed that intermediate 18 was completely consumed, and a new spot (Rf = 0.61) was observed to form. The reaction mixture was transferred to a 250 mL conical flask, water (150 mL) was added, and after stirring at 25 °C for 20 minutes, the mixture was transferred to a 500 mL separatory funnel, ethyl acetate (100 mL) was added, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50.0 mL × 2). The combined organic phases were washed with water (50.0 mL × 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1.00 - 100 / 25 (V / V)) to give intermediate 19 as a yellow solid (700 mg, 1.49 mmol, 70.6% yield).

[0268] 1 H NMR: (400 MHz DMSO-d6) δ 10.5 (br s, 1H), 8.89 - 8.71 (m, 2H), 8.24 (br s, 1H), 8.18 (br d, J = 8.00 Hz, 2H), 7.93 (br s, 1H), 7.59 (br d, J = 7.60 Hz, 2H), 4.84 (s, 2H), 4.20 (s, 2H).

[0269] Step 4. Preparation of [3-({4-[4-(cyanomethyl)phenyl]-5-fluoropyrimidin-2-yl}amino)-5-nitrophenyl]methanesulfonic acid

[0270]

[0271] It was obtained using a method similar to Step 2 for preparing Compound 4, except that the substrate was changed from intermediate 29 to intermediate 19, and the solvent was changed from water to water-dioxane (volume ratio 1:1). The obtained [3-({4-[4-(cyanomethyl)phenyl]-5-fluoropyrimidin-2-yl}amino)-5-nitrophenyl]methanesulfonic acid was a yellow solid (74.3% yield, 98.6% purity).

[0272] 11H NMR: (400 MHz, DMSO-d6) δ 10.3 (s, 1H), 8.90 (m, J = 3.60 Hz, 1H), 8.74 (d, J = 3.60 Hz, 1H), 8.18 (d, J = 8.40 Hz, 2H), 7.97 (s, 1H), 7.79 (s, 1H), 7.58 (d, J = 8.40 Hz, 2H), 4.20 (s, 2H), 3.80 (s, 2H); MS (ESI) m / z = 443.9 [M+H] + 。

[0273] Example 10. Preparation of [3-Amino-5-({4-[4-(cyanomethyl)phenyl]-5-fluoropyrimidin-2-yl}amino)phenyl]methanesulfonic acid (Compound 11)

[0274]

[0275] At 25 °C, Compound 10 (35.0 mg, 78.9 μmol, 1.00 eq), ethanol (3.00 mL), water (3.00 mL), ammonium chloride (CAS: 12125-02-9, 25.3 mg, 474 μmol, 6.00 eq), and iron powder (CAS: 7439-89-6, 26.5 mg, 474 μmol, 6.00 eq) were successively added to a 40.0 mL sealed tube. The reaction system was stirred at 80 °C for 2 hours, and the target peak was detected by LCMS. The reaction system was cooled to 25 °C, and the reaction mixture was filtered through diatomaceous earth. The filter cake was washed with methanol (20.0 mL), and the filtrate was concentrated to obtain a residue as the crude product. The obtained crude product was purified by a reverse-phase HPLC column (Xtimate C18 12.150*40 mm*10 μm; mobile phase: [water (TFA 0.1 v / v%) - acetonitrile]; ACN v / v%: 2.00% - 42.0%; gradient time 36 min) to obtain [3-Amino-5-(4-(4-(cyanomethyl)phenyl)-5-fluoro-pyrimidin-2-yl)aminophenyl]methanesulfonic acid (17.0 mg, 39.9 μmol, yield 50.5%, purity 97.0%) as a white solid.

[0276] 1 1H NMR: (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.71–9.54 (brs, 2H), 8.68 (s, 1H), 8.13 (s, 2H), 7.75 (s, 1H), 7.56 (br s, 3H), 6.92 (s, 1H), 4.19 (s, 2H), 3.69 (s, 2H); MS (ESI) m / z = 414.3 [M+H] + 。

[0277] Example 1 Preparation of (3-[(2-aminoethyl)amino]-5-[{4-[4-(cyanomethyl)phenyl]pyrimidin-2-yl}amino]phenyl)methanesulfonic acid (Compound 12)

[0278] Step 1. Preparation of 2-[4-(2-{[3-(hydroxymethyl)-5-nitrophenyl]amino}pyrimidin-4-yl)phenyl]acetonitrile (Intermediate 20)

[0279]

[0280] Obtained by coupling using a method similar to the preparation of Intermediate 3, except that the substrate was changed from m-aminobenzyl alcohol to 3-amino-5-nitrobenzyl alcohol. The resulting Intermediate 20 (78.2% yield, 88.4% purity) was a yellow solid.

[0281] 1 H NMR: (400 MHz DMSO-d6) δ 10.28 (s, 1H), 8.96 (s, 1H), 8.66 (d, J = 5.60 Hz, 1H), 8.29 (d, J = 8.40 Hz, 2H), 8.15 (s, 1H), 7.77 (s, 1H), 7.60 - 7.40 (m, 3H), 5.88 - 5.20 (m, 1H), 4.62 (s, 2H), 4.18 (s, 2H); MS(ESI) m / z = 362.1 [M+H] + 。

[0282] Step 2. Preparation of 2-[4-(2-{[3-amino-5-(hydroxymethyl)phenyl]amino}pyrimidin-4-yl)phenyl]acetonitrile (Intermediate 21)

[0283]

[0284] Obtained by reduction using a method similar to the preparation of Compound 11, except that the substrate was changed from Compound 10 to Intermediate 20. The resulting Intermediate 21 (64.4% yield, 97.8% purity) was a yellow solid.

[0285] 1 H NMR: (400 MHz DMSO-d6) δ 9.36 (s, 1H), 8.51 (d, J = 5.20 Hz, 1H), 8.23 (d, J = 8.40 Hz, 2H), 7.52 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 5.20 Hz, 1H), 7.03 (s, 1H), 6.96 (s, 1H), 6.22 (s, 1H), 5.11 - 4.91 (m, 3H), 4.35 (d, J = 5.60 Hz, 2H), 4.16 (s, 2H); MS(ESI) m / z = 332.2 [M+H] +。

[0286] Step 3. Preparation of 2-(4-{2-[(3-{[2-(tert-Butoxycarbonylamino)ethyl]amino}-5-(hydroxymethyl)phenyl)amino]pyrimidin-4-yl}phenyl)acetonitrile (Intermediate 22)

[0287]

[0288] Place dry DCM (60.0 mL) and methanol (6.00 mL) in a 250 mL three-necked flask equipped with a nitrogen balloon. At 25 °C, sequentially add Intermediate 21 (1.50 g, 4.53 mmol, 1.00 eq), compound N-tert-butoxycarbonyl-2-aminoacetaldehyde (CAS: 89711-08-0, 750 mg, 4.71 mmol, 1.04 eq), then sequentially add AcOH (CAS: 64-19-7, 272 mg, 4.53 mmol, 258 uL, 1.00 eq) and NaBH(OAc)3 (CAS: 56553-60-7, 4.80 g, 22.6 mmol, 5.00 eq). Stir the reaction system at 25 °C for 1 hour. Monitoring the reaction by LCMS shows that Intermediate 21 is completely consumed and the target peak (RT = 0.953 min) is detected. Concentrate the reaction mixture under reduced pressure to obtain a residue. After cooling the residue to 0 °C, slowly add saturated sodium bicarbonate solution (100 mL) and keep the internal temperature at 10 - 20 °C. After addition, transfer it to a 500 mL separatory funnel and add DCM (100 mL), separate the organic phase, and extract the aqueous phase with DCM (100 mL × 2). Wash the combined organic phases with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a residue. The obtained residue is purified by prep-HPLC (column: Phenomenex C18 75*30mm*3um; mobile phase: [water (TFA 0.1 v / v%) - acetonitrile]; ACN v / v%: 26% - 66%, gradient time 36 min) to obtain Intermediate 22 as a yellow solid (1.70 g, 3.58 mmol, 79.1% yield).

[0289] 11H NMR: (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.52 (d, J = 5.20 Hz, 1H), 8.23 (d, J = 8.40 Hz, 2H), 7.52 (d, J = 8.00 Hz, 2H), 7.37 (d, J = 5.20 Hz, 1H), 7.13 - 6.98 (m, 2H), 6.89 (brt, J = 5.20 Hz, 1H), 6.22 (s, 1H), 5.46 (br t, J = 5.20 Hz, 1H), 5.03 (t, J = 5.60 Hz, 1H), 4.38 (d, J = 5.60 Hz, 2H), 4.15 (s, 2H), 3.21 - 3.02 (m, 4H), 1.38 (s, 9H); MS (ESI) m / z = 475.2 [M+H] + 。

[0290] Step 4. Preparation of 2-{4-[2-({3-[(2-aminoethyl)amino]-5-(chloromethyl)phenyl}amino)pyrimidin-4-yl]phenyl}acetonitrile (Intermediate 23)

[0291]

[0292] Place Intermediate 22 (70.0 mg, 147 μmol, 1.00 eq) in a 100 mL three-necked flask equipped with a nitrogen balloon, and add THF (3.00 mL). At 25 °C, add thionyl chloride (386 mg, 3.25 mmol, 235 μL, 22.0 eq) dropwise to the reaction system, and stir the reaction at 25 °C for 2 hours. Monitoring the reaction by LCMS shows that Intermediate 22 is completely consumed, and at the same time, the target peak (RT = 0.60 min) is observed. Concentrate the mixture at 30 °C, and purify the obtained residue by reverse-phase HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (HCl 0.1 v / v%) - acetonitrile]; ACN v / v%: 0% - 40%, gradient time 36 min) to obtain Intermediate 23 as a yellow solid (80.0 mg, crude product).

[0293] MS (ESI) m / z = 393.1 [M+H] + 。

[0294] Step 5. Preparation of 3-[(2-aminoethyl)amino]-5-[{4-[4-(cyanomethyl)phenyl]pyrimidin-2-yl}amino]phenyl methanesulfonate

[0295]

[0296] Obtained using a method similar to Step 3 for preparing Compound 4, except that the substrate was changed from Intermediate 29 to Intermediate 23, and the solvent was changed from water to water-dioxane (volume ratio 1:1). The resulting {3-[(2-aminoethyl)amino]-5-[{4-[4-(cyanomethyl)phenyl]pyrimidin-2-yl}amino]phenyl}methanesulfonic acid was a yellow solid (4.88% yield, 99.0% purity).

[0297] 1 H NMR: (400 MHz DMSO-d6) δ 9.74 (s, 1H), 8.51 (d, J = 5.52 Hz, 1H), 8.22 (d, J = 8.52 Hz, 2H), 7.97 (br s, 3H), 7.51 (d, J = 8.52 Hz, 2H), 7.43 (d, J = 5.52 Hz, 1H), 7.19 (br d, J = 14.4 Hz, 2H), 6.52 (s, 1H), 4.15 (s, 2H), 3.69 (s, 2H), 3.30 (br t, J = 6.00 Hz, 2H), 3.03 (br d, J = 5.52 Hz, 2H); MS(ESI) m / z = 438.9 [M+H] + 。

[0298] Example 12. Preparation of 2-(4-{2-[(6-{[2-(tert-butoxycarbonylamino)ethyl]amino}-5-(hydroxymethyl)pyridin-3-yl)amino]pyrimidin-4-yl}phenyl)acetonitrile (Compound 13)

[0299] Step 1. Preparation of methyl 2-hydroxy-5-nicotinate (Intermediate 24)

[0300]

[0301] Charge anhydrous methanol (150 mL) into a 500 mL three-necked flask equipped with a nitrogen balloon. At 25 °C, add 2-hydroxy-5-nicotinic acid (CAS: 6854-07-5, 15.0 g, 81.5 mmol, 1.00 eq), and add H2SO4 (CAS: 7664-93-9, 27.6 g, 281.4 mmol, 15.0 mL, 3.45 eq) in one portion. Stir the reaction system at 50 °C for 12 hours. Monitoring the reaction by LCMS showed that the raw material was completely consumed and the target main peak (RT = 0.372 min) was detected. Concentrate the reaction mixture under reduced pressure to remove methanol. Dilute the residue with water (100 mL), adjust the pH to 7.00 with saturated aqueous sodium carbonate solution and then filter. Pulp the filter cake with acetonitrile (50.0 mL) to obtain Intermediate 24 as an off-white solid (13.3 g, 67.1 mmol, 82.4% yield).

[0302] 1 1H NMR: (400 MHz, DMSO-d6) δ 13.98 - 12.06 (m, 1H), 8.88 (d, J = 3.20 Hz, 1H), 8.61 (d, J = 3.20 Hz, 1H), 3.79 (s, 3H); MS (ESI) m / z = 198.9 [M+H] + 。

[0303] Step 2. Preparation of methyl 2-chloro-5-nicotinicate (Intermediate 25)

[0304]

[0305] Charge thionyl chloride (75.0 mL) into a 250 mL three-necked flask equipped with a nitrogen balloon. Add Intermediate 24 (12.0 g, 60.57 mmol, 1.00 eq) at 25 °C, and add DMF (2.85 g, 39.0 mmol, 3.00 mL, 6.44e-1 eq) dropwise at 25 °C. Stir the reaction system at 75 °C for 2 hours. LCMS monitoring shows that Intermediate 24 is completely consumed, and the target main peak (RT = 2.11 min) is detected. Concentrate the mixture to obtain a residue. Slowly add methanol (100 mL) to the residue at 0 °C, keeping the internal temperature at 0 - 5 °C. Transfer the mixture to a 500 mL conical flask, add water (200 mL) and saturated sodium bicarbonate (150 mL) at 0 °C, and stir at 20 °C for 0.5 hour. Filter the mixture, wash the filter cake with water (30 mL) and dry it to obtain Intermediate 25 as an off-white solid (11.0 g, 50.8 mmol, 83.9% yield).

[0306] 1 1H NMR: (400 MHz, DMSO-d6) δ 13.98 - 12.06 (m, 1H), 8.88 (d, J = 3.20 Hz, 1H), 8.61 (d, J = 3.20 Hz, 1H), 3.79 (s, 3H); MS (ESI) m / z = 217.0 [M+H] + 。

[0307] Step 3. Preparation of methyl 2-{[2-(tert-butoxycarbonylamino)ethyl]amino}-5-nicotinicate (Intermediate 26)

[0308]

[0309] Charge DMSO (100 mL) into a 250 mL three-necked flask equipped with a nitrogen balloon. Add intermediate 25 (10.0 g, 46.2 mmol, 1.00 eq) at 25 °C, and add compound N-Boc-1,2-ethylenediamine (16.3 g, 102 mmol, 16.0 mL, 2.20 eq) in one portion. Stir the reaction at 25 °C for 16 h. Monitoring the reaction by TLC (petroleum ether / ethyl acetate = 2 / 1 (V / V)) shows that intermediate 25 is completely consumed and a new spot (Rf = 0.21) is formed. Pour the reaction mixture into water (800 mL), and stir at 25 °C for 1 h. Filter the mixture, and slurry the filter cake with acetonitrile (150 mL) to obtain intermediate 26 as an off-white solid (14.0 g, 41.1 mmol, 89.1% yield).

[0310] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.11 (d, J = 2.40 Hz, 1H), 8.85 (br s, 1H), 8.68 (d, J = 2.40 Hz, 1H), 6.97 (br s, 1H), 3.88 (s, 3H), 3.69 - 3.61 (m, 2H), 3.23 - 3.14 (m, 2H), 1.35 (s, 9H).

[0311] Step 4. Preparation of methyl 5-amino-2-{[2-(tert-butoxycarbonylamino)ethyl]amino}nicotinate (intermediate 27)

[0312]

[0313] Obtained by a method similar to the preparation of compound 11, except that the substrate is changed from compound 10 to intermediate 26. The resulting intermediate 27 (61.2% yield, crude product) is a brownish-black solid.

[0314] 1 1H NMR: (400 MHz, DMSO-d6) δ 7.84 - 7.78 (m, 1H), 7.47 (d, J = 2.80 Hz, 1H), 7.37 - 7.23 (m, 1H), 6.88 (br t, J = 5.20 Hz, 1H), 4.60 (s, 2H), 3.78 (s, 3H), 3.39 (q, J = 6.00 Hz, 2H), 3.08 (q, J = 6.00 Hz, 2H), 1.36 (s, 9H).

[0315] Step 5. Preparation of (5-amino-2-{[2-(tert-butoxycarbonylamino)ethyl]amino}pyridin-3-yl)methanol (intermediate 28)

[0316]

[0317] THF (30.0 mL) was charged into a 100 mL three-necked flask equipped with a nitrogen balloon and cooled to 0 °C under nitrogen protection. LiAlH4 (CAS: 16853-85-3, 437 mg, 11.5 mmol, 6.50 eq) was added while maintaining the temperature at 0 °C under nitrogen protection, and intermediate 27 (550 mg, 1.77 mmol, 1.00 eq) was added in portions. The reaction system was stirred at 25 °C for 4 hours. Monitoring the reaction by LCMS showed that intermediate 27 was completely consumed, and the target peak (RT = 1.01 min) was observed to form. Water (0.50 mL) was slowly added to the reaction system while maintaining the internal temperature at 0 °C, and NaOH (15.0% wt, 0.50 mL) was added at 0 °C. Water (1.50 mL) was further added, and then the mixture was stirred at 25 °C for 30 minutes. The mixture was filtered, and the filtrate was transferred to a 250 mL separatory funnel. Ethyl acetate (50.0 mL) was added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phases were washed with water (50.0 mL × 2) and saturated brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 28 (500 mg, 1.13 mmol, 64.0% yield) as a brown solid.

[0318] 1 1H NMR: (400 MHz, DMSO-d6) δ 7.37 (d, J = 2.80 Hz, 1H), 6.87 (br d, J = 2.60 Hz, 2H), 5.09 (br t, J = 5.20 Hz, 2H), 4.33 (br d, J = 2.80 Hz, 2H), 4.26 (d, J = 5.20 Hz, 2H), 3.25 (q, J = 6.00 Hz, 2H), 3.08 (q, J = 6.00 Hz, 2H), 1.37 (s, 9H); MS (ESI) m / z = 282.9 [M+H] + 。

[0319] Step 6. Preparation of 2-(4-{2-[(6-{[2-(tert-Butoxycarbonylamino)ethyl]amino}-5-(hydroxymethyl)pyridin-3-yl)amino]pyrimidin-4-yl}phenyl)acetonitrile

[0320]

[0321] Obtained using a method similar to that for preparing Compound 1, except that the substrate was changed from 1-methyl-1H-pyrazol-4-amine to Intermediate 28, and the catalytic ligand was changed from XPhos to SPhos (CAS: 657408-07-6). The resulting 2-(4-{2-[(6-{[2-(tert-butoxycarbonylamino)ethyl]amino}-5-(hydroxymethyl)pyridin-3-yl)amino]pyrimidin-4-yl}phenyl)acetonitrile was a yellow solid (17.4% yield, 91.4% purity).

[0322] 1 H NMR: (400 MHz DMSO-d6) δ 9.99 (br s, 1H), 8.69 - 8.54 (m, 2H), 8.29 (br s, 1H), 8.20 (d, J = 8.20 Hz, 2H), 7.54 (d, J = 8.40 Hz, 2H), 7.50 (d, J = 5.20 Hz, 1H), 7.04 (br t, J = 5.60 Hz, 1H), 4.46 (s, 2H), 4.18 (s, 3H), 3.44 (br s, 2H), 3.24 (br d, J = 6.00 Hz, 2H), 1.36 (s, 9H); MS(ESI) m / z = 476.0 [M + H] + 。

[0323] Test Example A: Enzyme Inhibition Study

[0324] The method for determining the in vitro activity of JAKs kinases in this test example is a homogeneous time-resolved fluorescence based on fluorescence resonance energy transfer (FRET) and time-resolved fluorescence (TRF). Homogeneous Time-Resolved Fluorescence) technology. The instrument used is Molecular Devices (model: Spectramax M5e), and the kit used is KinEASE TK. This kit provides a biotin-labeled substrate, a Eu-labeled phosphorylation site-specific antibody, an XL665-labeled avidin, and a buffer. The kinase phosphorylates the substrate, Eu-Ab recognizes the phosphorylated substrate, and XL665-SA binds to the biotin on the substrate. Eu and XL665 come close and generate an HTRF signal.

[0325] The specific reagents and consumables used in the experiment are shown in Table 2 below:

[0326] Table 2

[0327]

[0328]

[0329] Establishment of Kinase Assay Method

[0330] The test compound is first dissolved in DMSO to prepare a stock solution, and then serially diluted with the kinase buffer provided in the kit to 2.5 times the final concentration in the enzyme reaction system (10 μL).

[0331] Enzyme reaction procedure: The reaction is carried out in a 96- or 384-well plate. 4 μL of the test or control compound solution, 2 μL of TK-Substrate-biotin (manufacturer: cisbio, catalog number 62TK0PEC), 2 μL of the JAKs kinase solution to be tested, and 2 μL of ATP solution are added to each well. The plate is sealed and incubated at 37 °C for the corresponding time.

[0332] Assay procedure: 5 μL of streptavidin-XL665 and 5 μL of TK Antibody-Cryptate (manufacturer: cisbio, catalog number 62TK0PEC) are added to the wells. The plate is sealed again and incubated at room temperature for 1 h. After removing the seal film, the light signal is read using a compatible instrument.

[0333] The experimental data are calculated according to the following formula:

[0334] 1 Calculate the ratio of the emission light signals of the acceptor and donor in each well

[0335] 2 Calculate each delta ratio, with the negative control as the internal reference.

[0336] delta Ratio = Ratio Standard or sample - Ratio Standard 0

[0337] 3 Calculate %CVs.

[0338]

[0339] The control compounds used in the experiment are:

[0340] (1) Staurosporine is the validated control compound provided by the kit.

[0341] (2) Tofacitinib, Ropsacitinib (PF-06826647) are reference compounds with clear experimental data for JAKs

[0342] Through the above control compounds, the operation error of each experiment is minimized, and a stable and reliable assay platform is established.

[0343] Optimization and Exploration of Kinase Assay Conditions

[0344] It is carried out according to the following steps:

[0345] 1. Enzyme titration: Determine the optimal enzyme concentration by fixing the concentrations of TK-Substrate-biotin (1 μM), ATP (100 μM), fixing the biotin / streptavidin molar ratio (8:1, i.e., 62.5 nM Sa-XL665), and fixing the reaction time at 30 min.

[0346] 2. Enzyme kinetics study: Conduct the enzyme kinetics study under the conditions of fixed kinase concentration (determined in the previous step), ATP (100 μM), substrate (1 μM), and fixed biotin / streptavidin molar ratio (8:1), and confirm the time endpoint for stopping the reaction by adding the detection reagent.

[0347] 3. Substrate titration: Determine the Km of the substrate by using different concentrations of TK Substrate-biotin at the optimal enzyme concentration, saturated ATP concentration (100 μM), fixed biotin / streptavidin molar ratio (8:1), and the optimal incubation duration.

[0348] 4. ATP titration: Determine the Km of ATP by using different concentrations of ATP at the optimal enzyme concentration, saturated TK Substrate-biotin concentration (1 μM), fixed biotin / streptavidin molar ratio (8:1), and the optimal incubation duration.

[0349] 5. Optimization of biotin-streptavidin molar ratio: Determine the optimal biotin / streptavidin molar ratio under the conditions of the optimal enzyme, ATP, and substrate concentrations.

[0350] (For tyrosine kinases that require the addition of SEB reagent to obtain the optimal enzyme activity, the optimal SEB concentration needs to be determined first before all the above steps.)

[0351] Kinase Level IC50 Assay

[0352] Using the optimal experimental conditions determined in the previous steps, measure the concentration of the inhibitor within a relatively wide range (0 - 10000 nM), and use Graphpad Prism 8.0 to perform [Inhibitor] vs. response–Variable slope (four parameters) fitting to generate a dose-response curve, and obtain the IC 50 value of the inhibitor against JAKs kinases. (The unit of IC 50 is nM, and N.D. means not determined) (Table 3)

[0353] A: <20 nM B: 20 - 50 nM C: 50 - 200 nM D: 200 - 1000 nM E: 1000 - 10000 nM F: >10 μM

[0354] Table 3

[0355] Example Compound JAK1 JAK2 JAK3 TYK2 Example 1 Compound 1 C N.D. N.D. C Example 2 Compound 2 C A D B Example 3 Compound 3 E N.D. N.D. D Example 4 Compound 4 C C D A Example 5 Compound 5 B C E C Example 6 Compound 6 D N.D. N.D. E Example 7 Compound 7 A A A A Example 7 Compound 8 B A B A Example 8 Compound 9 A A C B Example 9 Compound 10 B N.D. N.D. B Example 10 Compound 11 A A C A Example 11 Compound 12 A B D B Example 12 Compound 13 D N.D. N.D. E Comparative Example (Tobatinib) A A A B Comparative Example (Ropsacitinib) C N.D. N.D. A

[0356] In terms of the JAK inhibitory effect, especially the TYK2 inhibitory effect, the inhibitory activity of the compounds of the present invention is better.

[0357] Test Example B: Cellular STAT-Luc Assay

[0358] The cell viability assay method in this test example is based on the response of different phosphorylated subunits of the intracellular domain of the cell surface IFN-α receptor and IL-6 receptor to the corresponding JAKs inhibitors. STAT3(Luc)-HEK293 cells carrying the reporter gene (manufacturer: BPS Bioscience, product number: 79800-P) will phosphorylate intracellular STAT through the corresponding receptor intracellular subunits (IFN-α receptor: Tyk2 / Jak1, IL-6 receptor: Jak1 / Jak2) after being stimulated by exogenous IFN-α or IL-6. The phosphorylated STAT3 enters the cell nucleus and activates the expression of the Luc reporter gene. The expressed luciferase will react with the added substrate to produce chemiluminescence, and it will be read through the ONE-Glo TM Luciferase Assay System (Promega, product number E6110).

[0359] STAT3 Reporter Gene Chemiluminescence Assay

[0360] Carry out according to the following steps:

[0361] 1. Seed 3×10 4 cells / well in a white opaque 96-well plate, with 100 μl / well of the test medium. Incubate overnight.

[0362] 2. Treat the cells with 90 μl of the compound solution diluted three-fold with the experimental medium and incubate for 1 h. The corresponding control group uses 90 μl of the test medium without compound and without treatment.

[0363] 3. The following operating steps are repeated at least three times for each treatment:

[0364] 3a. Add 10 μl of human IFN-α (manufacturer: R&D System, catalog number 11200-1) or IL-6 (manufacturer: R&D System, catalog number 206-IL-10) diluted with the test medium to stimulate the cells in the wells (final concentration of IL-6 = 10 ng / ml, IFN = 200 U / ml).

[0365] 3b. Correspondingly, add 10 μl of blank test medium to the control wells without the stimulating reagent to determine the basal activity.

[0366] 3c. Correspondingly, add 100 μl of blank test medium to the blank control wells without inoculated cells to determine the background fluorescence.

[0367] 4. Incubate the microplate in an incubator at 37 °C for 6 h.

[0368] 5. Add ONE-Glo TM Luciferase Assay reagent at 100 μl / well to the wells, incubate at room temperature for 15 - 30 min, and then read the chemiluminescence value using the corresponding system.

[0369] IC50 determination at the cellular level

[0370] Determine the concentration of the inhibitor within a relatively wide range (0 - 10000 nM), use Graphpad Prism 8.0 to perform [Inhibitor] vs. response - Variable slope (four parameters) fitting to generate a dose - response curve, and obtain the IC50 value of the inhibitor for the corresponding STAT3. (The unit of IC50 is nM) (Table 4)

[0371] A: <100 nM B: 100 - 500 nM C: 500 - 3000 nM D: >3000 nM

[0372] Table 4

[0373] Example Compound IFN-α (TYK2 / JAK1) IL-6 (JAK1 / JAK2) Example 1 Compound 1 B C Example 2 Compound 2 C C Example 7 Compound 7 A B Example 7 Compound 8 C C Comparative Example (Tobatinib) A A Comparative Example (Ropsacitinib) A C

[0374] Although the specific embodiments of the present invention are described above, those skilled in the art should understand that these are only examples. Without departing from the principles and essence of the present invention, various changes or modifications can be made to these embodiments. Therefore, the protection scope of the present invention is defined by the appended claims.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein: Ring A is a C6-C 10 aryl ring or a 5- to 10-membered heteroaryl ring; the heteroatoms in the 5- to 10-membered heteroaryl ring are independently selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; m is 0, 1, 2, 3, 4 or 5; R 1 Independently a halogen, C1-C6 alkyl, C1-C6 alkyl substituted by one, two or three R 1-1 groups, C1-C6 alkoxy, C1-C6 alkoxy substituted by one, two or three R 1-2 groups, -NR 1-3 R 1-4 , -C(O)R 1-5 , nitro or -SO2R 1-6 ; R 1-1 independently is hydroxy or -SO2R 1-1-1 ; R 1-1-1 is hydrogen, hydroxyl, -NR a R b or a C1-C6 alkyl group; R 1-2 independently a hydroxyl group; R 1-3 is hydrogen or a C1-C6 alkyl group; R 1-4 is -SO2R 1-4-1 , hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted by one, two or three R 1-4-2 or -C(O)R 1-4-3 ; R 1-4-1 is -OH or C1-C6 alkyl; R 1-4-2 independently -NR 1-4-2a R 1-4-2b ; R 1-4-2a and R 1-4-2b are independently hydrogen, C1-C6 alkyl or -C(O)OR 1-4-2c ; R 1-4-2c is a C1-C6 alkyl group; R 1-4-3 is a C1-C6 alkyl group; R 1-5 is -OH, -NR 1-5-1 R 1-5-2 or C1-C6 alkoxy; R 1-5-1 and R 1-5-2 are independently hydrogen or C1-C6 alkyl; R 1-6 is -OH, -NR a R b or C1-C6 alkyl; R 2 is hydrogen or -(CH2) m1 -C(=O)-R 2-1 ; R 2-1 is hydroxyl, -NR a R b , guanidino, C1-C6 alkoxy or C1-C6 alkoxy substituted by one, two or three R 2-1-1 ; m1 is 1, 2, 3 or 4; R 2-1-1 independently a C1-C6 alkyl group; R 3 is CN-(CH2) n -, where n is 0 or 1; R 4 and R 5 are independently hydrogen, halogen, hydroxyl, or -NR a R b ; R a and R b are independently hydrogen or C1-C6 alkyl.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The C6-C 10 aromatic ring is a benzene ring or a naphthalene ring; (2) The 5- to 10-membered heteroaryl ring is independently a 5- or 6-membered monocyclic heteroaryl ring or a 9- or 10-membered bicyclic heteroaryl ring; (3) The heteroatoms in the 5- to 10-membered heteroaryl ring are independently selected from N, and the number of heteroatoms is 1, 2 or 3; (4) Each of the halogens is independently F, Cl, Br or I; (5) Each of the C1-C6 alkyl groups and the C1-C6 alkyl groups in the substituted C1-C6 alkyl groups is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and (6) Each of the C1-C6 alkoxy groups and the C1-C6 alkoxy groups in the substituted C1-C6 alkoxy groups is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

3. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein, It satisfies one or more of the following conditions: (1) The C6-C 10 aromatic ring is a benzene ring; (2) The 5- to 10-membered heteroaromatic ring is a pyrazole ring (such as ), a pyridine ring (such as ), or a benzopyrrole ring (such as ); (3) Each of the halogens is independently F, Cl or Br, for example, F; (4) Each of the C1-C6 alkyl groups and the C1-C6 alkyl groups in the substituted C1-C6 alkyl groups is independently methyl or ethyl; and (5) Each of the C1-C6 alkoxy groups and the C1-C6 alkoxy groups in the substituted C1-C6 alkoxy groups is independently ethoxy.

4. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The m is 1 or 2; (2) The R 1 is independently a C1-C6 alkyl group, a C1-C6 alkyl group substituted by one, two or three R 1-1 groups, -NR 1-3 R 1-4 or nitro; (3) The R 1-1 is independently -SO2R 1-1-1 ; (4) The R 1-1-1 is a hydroxyl group or -NR a R b ; (5) The R 1-3 is hydrogen; (6) said R 1-4 is -SO2R 1-4-1 , hydrogen or a C1-C6 alkyl group substituted by one, two or three Rs 1-4-2 ; (7) The R 1-4-1 is a C1-C6 alkyl group; (8) said R 1-4-2a and R 1-4-2b are independently hydrogen or -C(O)OR 1-4-2c ; (9) The R 2 is hydrogen; (10) The R 2-1 is a hydroxyl group, a guanidyl group or a C1-C6 alkoxy group; (11) The m1 is 1; (12) The n is 0; and (13) The R 4 and R 5 are each independently hydrogen or a halogen.

5. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein, It satisfies one or more of the following conditions: (1) The R 1 is independently a C1-C6 alkyl group substituted by one, two or three R 1-1 groups or -NR 1-3 R 1-4 ; (2) The R 1-1-1 is a hydroxyl group; (3) The R 1-4 is -SO2R 1-4-1 or hydrogen; preferably -SO2R 1-4-1 ; and (4) The R 2-1 is a C1-C6 alkoxy group.

6. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, characterized in that, The compound of formula I is a compound of formula I-1, Among them, ring A, R 1 , R 2 , R 3 , R 4 and R 5 are defined as described in any one of claims 1-5; R 6 is -NR 1-3 R 1-4 or a C1 - C6 alkyl group substituted by one, two or three R 1-1 groups; R 1-4 is -SO2R 1-4-1 ; R 1-3 and R 1-1 are as defined in any one of claims 1 - 5; m2 is m - 1, and m is 1, 2, 3, 4 or 5.

7. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 6, characterized in that, It satisfies one or more of the following conditions: (1) In formula I-1, R 1 is independently -NR 1-3 R 1-4 or nitro; preferably -NR 1-3 R 1-4 ; and (2)R 6 is -NH-SO2R 1-4-1 or -CH2-SO2R 1-1-1 .

8. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 6, characterized in that, The compound of formula I is a compound of formula I-2, Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and m2 are defined as described in claim 6.

9. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 6, wherein The compound of formula I is a compound of formula I-3, Among them, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are defined as described in claim 6.

10. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) For (2)R 2 is hydrogen, (3)R 3 For (4)R 4 is hydrogen or fluorine; and (5)R 5 is hydrogen.

11. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein The compound of formula I is any of the following compounds:

12. A method for preparing a compound of formula I as described in any one of claims 1-11, which comprises any of the following methods: Method 1: Reacting compound C with compound D to prepare the compound of formula I; R x is F, Cl, Br, I, OTf, OTs or OMe; Method 2: Reacting compound F with compound G to prepare the compound of formula I; Among them, Y is F, Cl, Br, I, OTf or OTs; Method 3: Obtaining the compound of formula I by deprotection reaction of compound I'; wherein R 1 ’, R 2 ’, R 3 ’, R 4 ’ and R 5 ’ have the definitions respectively for any one of the present invention for R 1 , R 2 , R 3 , R 4 and R 5 ; wherein at least one possible activating functional group is protected with a protecting group; Method 4: Obtaining the compound of formula I by hydrolysis reaction of compound II-1; In Method 4, R 2-1’ is a C1-C6 alkoxy group, and R 2 is -(CH2) m1 -C(=O)OH; Method 5: Compound II-2 reacts with Cl-SO2R 1-4-1 to obtain the compound of formula I; In Method 5, R 1 is independently -NR 1-3 R 1-4 wherein R 1-4 is -SO2R 1-4-1 or hydrogen, and at least one R 1 is -NR 1-3 -SO2R 1-4-1 and the remaining Rs 1 are -NHR 1-3 ; Method 6: Reacting compound II-3 with Na2SO3 to obtain the compound of formula I; In Method 6, in Formula II-3, at least one R 7 is a C1-C6 alkyl group substituted by one, two or three halogens, and the remaining Rs 7 are defined the same as R 1 , correspondingly, in Formula I, at least one R 1 is a C1-C6 alkyl group substituted by one, two or three -SO2OH groups; Method 7: Reacting compound II-4 with a reducing agent to obtain the compound of formula I; In Method 7, in Formula II-4, at least one R 8 is nitro, and the remaining Rs 8 are defined the same as R 1 ; correspondingly, in Formula I, at least one R 1 is amino; In Methods 1 to 7, the rings A, R 1 , R 2 , R 3 , R 4 , R 5 and m are defined as described in any one of Claims 1 to 11.

13. The compound shown below: Among them, R X is F, Cl, Br, I, OTf, OTs or OMe; preferably Cl; R 2 、R 3 、R 4 and R 5 are defined as described in any one of claims 1-11.

14. Any of the following compounds:

15. A pharmaceutical composition, the pharmaceutical composition comprising: (1) A compound of formula I as described in any one of claims 1-11 or a pharmaceutically acceptable salt thereof, and (2) Pharmaceutically acceptable excipients.

16. Use of a compound represented by formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1-11, and the pharmaceutical composition as described in claim 15, in the preparation of a medicament, wherein the medicament is used for treating and / or preventing a disease mediated by JAK (such as JAK1, JAK2, JAK3 or Tyk2), preferably a disease mediated by Tyk2; preferably an inflammation, an autoimmune disease, an infectious disease or a tumor mediated by Tyk2, more preferably an autoimmune disease or a tumor mediated by Tyk2; The autoimmune disease is preferably atopic dermatitis, vitiligo, alopecia areata, hidradenitis suppurativa; The tumor is preferably gastric cancer, breast cancer, non-small cell lung cancer, urothelial carcinoma or pancreatic cancer.

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