PKMYT1 kinase inhibitors

Abstract

The invention discloses a PKMYT1 kinase inhibitor as shown in a general formula (I), a pharmaceutical composition and a preparation method of the PKMYT1 kinase inhibitor and application of the PKMYT1 kinase inhibitor to preparation of drugs for preventing and / or treating indications related to a PKMYT1 signal channel. The compound provided by the invention is an ideal high-activity PKMYT1 kinase inhibitor, and can be used for treating and / or preventing diseases including endometrioid cancer, gastrointestinal tract cancer, colorectal cancer and esophageal cancer, breast cancer and ovarian cancer, especially CCNE1 amplified and / or FBXW7 mutated endometrioid cancer, gastrointestinal tract cancer, colorectal cancer and esophageal cancer, breast cancer and ovarian cancer. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry and relates to a PKMYT1 kinase inhibitor, a pharmaceutical composition thereof, a preparation method thereof and use thereof in preparing, preventing and / or treating drugs for indications related to the PKMYT1 signaling pathway. Background Art

[0002] PKMYT1 (MYT1) is a member of the WEE1 family of kinases, which has three members: WEE1, PKMYT1, and WEE2. WEE1 and PKMYT1 are mainly associated with tumors. PKMYT1 can bind to the endoplasmic reticulum and Golgi apparatus, phosphorylate Tyr15 and Thr14, and retain CDK1 in the cytoplasm. In addition, PKMYT1 is also responsible for the reorganization of the endoplasmic reticulum and Golgi apparatus after cell mitosis. PKMYT1 is overexpressed in a variety of solid tumors such as hepatocellular carcinoma, colon cancer, glioma, non-small cell lung cancer, gastric cancer, etc. Its overexpression is associated with tumor progression, high malignancy of the disease, induction of metastasis, and poor prognosis.

[0003] At the G2 / M boundary, if no DNA damage is found, CDC25C phosphatase will quickly remove Tyr15 and Thr14 phosphorylation on CDK1, and after the CAK complex phosphorylates CDK1 (Thr161) and cyclin B1, it is activated and enters the nucleus. This process is necessary for mitosis. At the same time, the activated maturation promoting factor (MPF) can phosphorylate WEE1 and PKMYT1 to inactivate them.

[0004] Compared with normal cell cycle function, PKMYT1 mainly affects the recovery of checkpoints after DNA damage. Compared with WEE1, which functions in S phase, G2 / M and mitotic exit, PKMYT1 function is limited to MPF. Inhibition of WEE1 / PKMYT1 will cause tumor cells to overload the G2 / M cell cycle checkpoint, enter mitosis early, and the accumulation of a large amount of unrepaired DNA damage will eventually lead to "mitotic disaster" and induce apoptosis. Literature shows that PKMYT1 knockout can slow down the proliferation of HeLa cells and cause death within 10 days. PKMYT1 knockout can also significantly inhibit tumor growth in mice with transplanted tumors in vivo. In addition, CCNE1 amplification and FBXW7 mutation tumors may be more sensitive to PKMYT1 inhibitors. These results suggest that PKMYT1 inhibitors may have targeted inhibitory effects in a variety of solid tumors.

[0005] Currently, there is only one PKMYT1 inhibitor under development, namely Repare's RP-6306, which is an oral PKMYT1 inhibitor and is currently undergoing Phase II clinical studies in patients with CCNE1 overexpression tumors. RP-6306 has strong selective inhibitory activity against PKMYT1 kinase and also shows significant tumor proliferation inhibition against FUOV1 ovarian cancer cells, HCC1569 breast cancer cells, and various related mouse transplant tumor models in vivo.

[0006] As PKMYT1 inhibitors are expected to become powerful targeted drugs in the anti-tumor field in the future, more PKMYT1 inhibitors with stronger activity, better pharmacokinetic properties and lower toxic side effects are urgently needed. Summary of the invention

[0007] In order to solve the defects of the prior art, the object of the present invention is to provide a PKMYT1 kinase inhibitor, a pharmaceutical composition, a preparation method and use of the same in the preparation, prevention and / or treatment of drugs for indications related to the PKMYT1 signaling pathway.

[0008] In one aspect, the present invention provides a compound of formula (I):

[0009]

[0010] or a deuterated substance, a stereoisomer, a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof;

[0011] in

[0012] X 1 N or CR 2 ,

[0013] X 2 N or CH;

[0014] L 1 is -CO- or a chemical bond;

[0015] When L 1 When it is -CO-, R 1 For-NR 11 R 12 ;

[0016] R 11 , R 12 Independently selected from H, -OH, -NH 2 , -C 0-3 Alkyl-R 13 , -C 3-6 Cycloalkyl-R 13 , and R 11 , R 12 At least one is H, or

[0017] R 11 With R 12 and the N atom to which it is attached forms an optionally substituted 4-8 membered heterocyclic group;

[0018] R 13 Selected from -SO 2 -R 14 , An optionally substituted 4-10 membered heterocyclyl;

[0019] R 14 Selected from C 1-3 Alkyl, -NH 2 ;

[0020] When L 1 When it is a chemical bond, R 1 is an optionally substituted 5-6 membered heterocyclic group;

[0021] R 2 Selected from -OH, -SO 2 -R 14 、-N=SO(R 14 ) 2 , An optionally substituted 5-6 membered heterocyclic group, R 3 Selected from H, R 5 Selected from halogen, C 1-3 Alkyl, or

[0022] R 2 With R 3 and the connected C atom forms an optionally substituted 5-6 membered heterocyclic group, R 5 Selected from halogen, C 1-3 Alkyl, or

[0023] R 2 With R 5 and the connected C atom forms an optionally substituted 5-6 membered heterocyclic group, R 3 Selected from H;

[0024] R 4 For halogen, C 2-3 Alkynyl, cyano, C 1-3 Alkyl, 3-6 membered cycloalkyl;

[0025] R 6 , R 7 are independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl;

[0026] The compound of formula (I) does not include

[0027] In certain embodiments, the compounds provided by the present invention, or deuterated substances, stereoisomers, pharmaceutically acceptable salts, or pharmaceutically acceptable solvates thereof, further have the structure of formula (II):

[0028]

[0029] Preferably, the compound contains isomers of formula (IIA);

[0030]

[0031] In certain embodiments, the compounds provided by the present invention, or deuterated substances, stereoisomers, pharmaceutically acceptable salts, or pharmaceutically acceptable solvates thereof, further have the structure of formula (III):

[0032]

[0033] Preferably, the compound contains isomers of formula (IIIA);

[0034]

[0035] R 11 , R 12 Independently selected from H, -OH, -NH 2 , -C 0-3 Alkyl-R 13 , -C 3-6 Cycloalkyl-R 13 , and R 11 , R 12 At least one is H, or

[0036] R 11 With R 12 and the N atom to which it is attached forms an optionally R 16 substituted 4-8 membered heterocyclic group;

[0037] In some more preferred embodiments, R 11 , R 12 Independently selected from H, -OH, -NH 2 , -methylene-R 13 , -C 3-6 Cycloalkyl-R 13 , and R 11 , R 12 At least one is H;

[0038] R 13 Selected from -SO 2 -R 14 , Optional R 15 substituted 4-10 membered heterocyclyl;

[0039] R 14 Selected from C 1-3 Alkyl, -NH 2 ;

[0040] R 15 Selected from oxo, halogen, hydroxyl, -NH 2 , C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, (hydroxy)-C 1-3 Alkyl, 3-6 membered cycloalkyl, -SO 2 -(C 1-3 alkyl);

[0041] R 16 Selected from hydroxyl, -NH 2 ;

[0042] Preferably, R 13 Selected from -SO 2 -R 14 , Optional R 15 substituted 4-6 membered heterocycloalkyl, optionally substituted by R 15 substituted 5-6 membered heteroaryl;

[0043] R 13 Preferred-SO 2 -R 14 , Optional R 15 Replaced

[0044] R 13 More preferably -SO 2 -R 14 , Optional R 15 Replaced

[0045] It should be further explained that R 13 The group connected by the dotted line in the optional group is the "-C 0-3 Alkyl-" fragment and "-C 3-6 Cycloalkyl-" fragment; when "-C 0-3 When alkyl-" is absent, R 13 That is R 12 .

[0046] As a preference, R 11 With R12 and the N atom to which it is connected forms a bond consisting of 0-2 R 16 substituted 4-6 membered heterocycloalkyl, or optionally substituted by 0-2 R 16 substituted 5-6 membered heteroaryl; more preferably, R 11 With R 12 and the N atom to which it is connected forms a bond consisting of 0-2 R 16 Replaced

[0047] R 4 For halogen, C 2-3 Alkynyl, cyano, C 1-3 Alkyl, 3-6 membered cycloalkyl, preferably methyl;

[0048] R 5 Selected from C 1-3 Alkyl, preferably methyl;

[0049] R 6 , R 7 are independently selected from H, halogen, C 1-3 Alkyl, C 1-3 The haloalkyl group is preferably H, methyl or trifluoromethyl.

[0050] In some preferred embodiments:

[0051] R 11 , R 12 Independently selected from H, -OH, NH 2 , -C 1-3 Alkyl-SO 2 -R 14 , Optional R 15 Replaced

[0052]

[0053] And R 11 , R 12 At least one is H; or

[0054] R 11 With R 12 and the N atom connected to it Best

[0055] R 14 Selected from C 1-3 Alkyl, NH 2 ;

[0056] R 15Selected from oxo, halogen, hydroxyl, -NH 2 , C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, (hydroxy)-C 1-3 Alkyl, 3-6 membered cycloalkyl, -SO 2 -(C 1-3 Alkyl), -SO 2 -NH 2 ;

[0057] Preferably, R 11 , R 12 Independently selected from H, -OH, NH 2 、-(CH 2 ) 2 -SO 2 -Me, -(CH 2 ) 2 -SO 2 -NH 2 ,

[0058]

[0059]

[0060] More preferably -OH,

[0061] In some preferred embodiments, when R 11 , R 12 Independently selected from H, -OH, -NH 2 , -C 0-3 Alkyl-R 13 , -C 3-6 Cycloalkyl-R 13 , and R 11 , R 12 When at least one is H; R 13 Selected from -SO 2 -R 14 , Optional R 15 substituted 4-10 membered heterocyclic group;

[0062] In some preferred embodiments, R 13 Preferred-SO 2 -R 14 ,

[0063] R 13More preferably -SO 2 -R 14 ,

[0064] R 13 Further optimization -SO 2 -

[0065]

[0066] In some preferred embodiments, when R 11 , R 12 For -C 0-3 Alkyl-R 13 or -C 3-6 Cycloalkyl-R 13 When further limiting the 0-3 Alkyl" or "C 3-6 R 13 The attachment site of the group, R 13 Preferred-SO 2 -R 14 , -SO 2 -R 14 , Optional R 15 Replaced

[0067] R 13 More preferably -SO 2 -R 14 ,, Optional R 15 Replaced

[0068] R 13 Further optimization -SO 2 -R 14 , Optional R 15 Replaced

[0069] In some preferred embodiments, R 11 , R 12 is directly and independently selected from the following groups, and R 11 , R 12 At least one is H: H, -OH, NH 2 , -C 1-3 Alkyl-SO2 -R 14 , Optional R 15 Replaced

[0070] Preferred H, -OH, NH 2 , -C 1-3 Alkyl-SO 2 -R 14 , Optional R 15 Replaced

[0071] More preferably, H, -OH, NH 2 , -C 1-3 Alkyl-SO 2 -R 14 , Optional R 15 Replaced

[0072]

[0073] In some preferred embodiments, R 11 , R 12 is directly and independently selected from the following groups, and R 11 , R 12 At least one is H: H, -OH, NH 2 、-(CH 2 ) 2 -SO 2 -Me, -(CH 2 ) 2 -SO 2 -NH 2 ,

[0074] Preferred H, -OH, NH 2 、-(CH 2 ) 2 -SO 2 -Me, -(CH 2 ) 2 -SO 2 -NH 2 ,

[0075] More preferably H, -OH, NH 2 、-(CH 2 ) 2 -SO 2 -Me, -(CH 2 ) 2 -SO 2 -NH 2 ,

[0076] In some other preferred embodiments, R 11 With R 12 and the N atom to which it is attached forms an optionally R 16 substituted 4-8 membered heterocyclic group; further, R 11 With R 12 and the N atom to which it is connected forms a bond consisting of 0-2 R 16 substituted 4-6 membered heterocycloalkyl, or optionally substituted by 0-2 R 16 substituted 5-6 membered heteroaryl; more preferably, R 11 With R 12 and the N atom to which it is connected forms a bond consisting of 0-2 R 16 Replaced Further optimization, Best

[0077] In certain embodiments, the compounds provided by the present invention, or deuterated substances, stereoisomers, pharmaceutically acceptable salts, or pharmaceutically acceptable solvates thereof, further have the structure of formula (IV):

[0078]

[0079] Preferably, the compound contains isomers of formula (IVA);

[0080]

[0081] R 1 For optional R 17 substituted 5-membered heterocyclic group;

[0082] R 17 Selected from amino, oxo or 5-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N and O, preferably amino or oxo;

[0083] R 4 For halogen, C 2-3 Alkynyl, cyano, C 1-3 Alkyl, 3-6 membered cycloalkyl, preferably methyl;

[0084] R 5Selected from C 1-3 Alkyl, preferably methyl;

[0085] R 6 , R 7 are independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, preferably H, methyl, trifluoromethyl;

[0086] More preferably, R 1 For optional R 17 Replaced R 1 More preferably Furthermore, R 1 Best

[0087] In some preferred embodiments, R 1 For optional R 17 Replaced R 1 More preferably Furthermore, R 1 Best

[0088] In certain embodiments, the compounds provided by the present invention, or deuterated substances, stereoisomers, pharmaceutically acceptable salts, or pharmaceutically acceptable solvates thereof, further have the structure of formula (V):

[0089]

[0090] Preferably, the compound contains isomers of formula (VA);

[0091]

[0092] R 2 Selected from -OH, -SO 2 -R 14 、-N=SO(R 14 ) 2 , Optional R 18 Replaced

[0093] R 3 Selected from H,

[0094] R 5 Selected from halogen, C 1-3 Alkyl, preferably methyl;

[0095] or

[0096] R 2 With R 3 and the C atom to which it is attached forms an optional R 18 Substituted 5-6 membered heterocyclic group, and connected in parallel with the benzene ring to form R 5 Selected from halogen, C 1-3 Alkyl, preferably methyl;

[0097] or

[0098] R 2 With R 5 and the C atom to which it is attached forms an optional R 18 Substituted 5-6 membered heterocyclic group, and connected in parallel with the benzene ring to form R 3 Selected from H;

[0099] R 14 Selected from C 1-3 Alkyl, NH 2 , preferably methyl, NH 2 ;

[0100] R 18 Selected from C 1-3 Alkyl, C 1-3 Haloalkyl;

[0101] R 4 For halogen, C 2-3 Alkynyl, cyano, C 1-3 Alkyl, 3-6 membered cycloalkyl, preferably methyl;

[0102] R 6 , R 7 are independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, preferably H or methyl.

[0103] In some preferred embodiments:

[0104] R 2 Preferred -OH, -SO 2 -Me, -SO 2 -NH 2 , Optional R 18 Replaced More preferred

[0105] R 3 Selected from H;

[0106] R 5 Methyl is preferred.

[0107] In certain embodiments, the compounds provided by the present invention, or deuterated substances, stereoisomers, pharmaceutically acceptable salts, or pharmaceutically acceptable solvates thereof, further have the structure of formula (VI):

[0108]

[0109] Preferably, the compound contains isomers of formula (VIA);

[0110]

[0111] X 1 N or CR 2 ,

[0112] X 2 N or CH;

[0113] R 2 is -OH;

[0114] R 4 For halogen, C 2-3 Alkynyl, cyano, C 1-3 Alkyl, 3-6 membered cycloalkyl, preferably ethynyl, methyl, cyclopropyl;

[0115] R 5 Selected from halogen, C 1-3 Alkyl, preferably methyl;

[0116] R 6 , R 7 are independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, preferably H, methyl, trifluoromethyl;

[0117] When X 1 CR 2 , X 2 is CH, and R 2 When it is -OH, R 4 Not Cl, methyl.

[0118] The compounds of formula (I) include the following specific compounds, or deuterated compounds, stereoisomers, pharmaceutically acceptable salts, and pharmaceutically acceptable solvates thereof:

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128] Preferred:

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137] Another aspect of the present invention provides a pharmaceutical composition, which contains any one of the above-mentioned compounds, deuterated substances, stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier thereof.

[0138] Another aspect of the present invention provides a use of any one of the above-mentioned compounds, deuterated products, stereoisomers or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical composition in the preparation of drugs for treating and / or preventing PKMYT1-related diseases.

[0139] In some preferred embodiments, the PKMYT1-related disease is selected from solid tumors, especially solid tumors with CCNE1 amplification and / or FBXW7 mutation.

[0140] In some preferred embodiments, the PKMYT1-related disease is selected from endometrioid cancer, gastrointestinal cancer, colorectal cancer, esophageal cancer, breast cancer, and ovarian cancer, especially endometrioid cancer, gastrointestinal cancer, colorectal cancer, esophageal cancer, breast cancer, and ovarian cancer with CCNE1 amplification and / or FBXW7 mutation.

[0141] The compound provided by the present invention has strong efficacy, good pharmacokinetic properties, and low toxic and side effects, and is an ideal PKMYT1 inhibitor. The compound provided by the present invention has better PKMYT1 inhibitory activity. The compound of the present invention is an ideal high-activity PKMYT1 inhibitor, which can be used to treat and / or prevent diseases including endometrioid cancer, gastrointestinal cancer, colorectal cancer, esophageal cancer, breast cancer, and ovarian cancer, especially endometrioid cancer, gastrointestinal cancer, colorectal cancer, esophageal cancer, breast cancer, and ovarian cancer with CCNE1 amplification and / or FBXW7 mutation. DETAILED DESCRIPTION

[0142] The present invention is further described in detail below in conjunction with specific embodiments, but the present invention is not limited to the following embodiments.

[0143] definition

[0144] "Optional" or "optionally" used herein means that any optional item can be selected or not selected. For example, "group A is optionally replaced by 1-3 groups B" comprises that group A is not replaced by group B, group A is replaced by 1 group B, group A is replaced by 2 groups B, and group A is replaced by 3 groups B. These four situations.

[0145] As used herein, "substituted" or "substituted" means that any one or more hydrogen atoms on any atom in a group or fragment are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is "oxo" (i.e., =O), it means that two hydrogen atoms are replaced by oxygen, and when the atom replaced by oxygen is a carbon atom, a carbonyl group (C=O) is formed. Oxygen substitution does not occur on aromatic groups.

[0146] As used herein, "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents may be any on the basis of chemical practicability. For example, "optionally substituted 5-6 membered heterocyclic group" means a 5-6 membered heterocyclic group that is substituted or unsubstituted by any group.

[0147] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0148] When the number of a linking group is 0, such as -(CR a Rb ) 0 -, indicating that the connecting group is a single bond / chemical bond.

[0149] When one of the variables is selected from chemical bond / single bond, it means that the two groups connected are directly connected, such as AL 1 -R 1 Medium 1 When it represents a single bond, it means that the structure is actually AR 1 .

[0150] The "chemical bond" used herein generally refers to a covalent bond between two atoms in a compound molecule formed by sharing a pair of electrons.

[0151] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A. When the listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom of it. For example, pyridyl as a substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0152] When the linking group is listed without specifying its direction of attachment, its direction of attachment is arbitrary. For example, ring AL 1 -R 1 The connecting group L 1 -MW- can connect rings A and R in the same direction as reading from left to right. 1 AMWR 1 , you can also connect rings A and R in the opposite direction of reading from left to right 1 Composition ring AWMR 1 Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0153] If there is no special description, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the connection mode of the chemical bond is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds and become a group with corresponding valence. The chemical bond connecting the site to other groups can be represented by a straight solid line bond straight line. Dotted key For example, -OCH 3 The straight solid bond in the group indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the carbon atoms in the group are connected to other groups; The dotted lines in the figure indicate that the 1- and 4-carbon atoms in the phenyl group are connected to other groups; It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0154] Unless otherwise specified, in a cyclic group, the attachment site of the group or fragment is located on the ring connected by the dotted line. For example, Any connection site on the benzene ring of the group can be connected to other groups through one chemical bond, including at least These are 4 connection methods.

[0155] Generally, in aromatic or heteroaromatic rings, double bonds and single bonds have no limiting meaning. For example, All refer to a benzene ring or a phenyl group, wherein the double bond or Specifically refers to the large π bond delocalized in the plane of the benzene ring; When ring C is limited to a 5-membered aryl or heteroaryl group, ring B and ring C form a conjugated cyclic aryl or cyclic heteroaryl group, and its non-limiting examples include even though The left ring in the Still includes In this group, the double bond represents a large π bond delocalized on the annular aromatic ring.

[0156] The numerical intervals used herein include the endpoint values ​​and any values ​​between the endpoint values. For example, "0-3" may include 0, 1, 2 or 3, and "1-3" may include 1, 2 or 3.

[0157] The “C 1-n "Including C 1-2 , C 1-3 , ...C 1-n For example, “C 1-6 " means that the moiety has 1-6 carbon atoms, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. Thus, for example, "C 1-4 "Alkyl" refers to an alkyl group containing 1-4 carbon atoms, that is, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The numerical ranges in this article, such as "1-6", refer to each integer in the given range.

[0158] The annular atom refers to the non-hydrogen atom in the ring group that is used to form the ring. The linking atoms in are 3 carbon atoms; The atoms in the middle ring are three carbon atoms and one oxygen atom; The atoms in the middle chain are 1 N atom and 5 carbon atoms; The atoms in the middle chain are 8 carbon atoms and 1 nitrogen atom.

[0159] As used herein, "nm members" refers to the number of annular atoms in a cyclic group. For example, a "3-8 member" group refers to a group having 3-8 annular atoms in the moiety, i.e., the group contains 3 annular atoms, 4 annular atoms, 5 annular atoms, 6 annular atoms, 7 annular atoms, or 8 annular atoms. Thus, for example, a "3-8 membered cycloalkyl" refers to a saturated cyclic alkyl group containing 3-8 carbon atoms, i.e., the alkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

[0160] The term "alkyl" used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched saturated aliphatic hydrocarbon. The "alkyl" herein preferably has 1-6 carbon atoms, for example 1-5 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, and the like. In the definitions of radicals herein, when the term “alkyl” appears in a numerical range, for example, “C 1 - 6 The term "alkyl" refers to an alkyl group which may be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, and the alkyl group herein also includes the case where no numerical range is specified. The alkyl group may be optionally substituted or unsubstituted.

[0161]

[0046] "Alkyl" as used herein in combination refers to an alkyl group attached to another group, for example, an alkyl group in an alkoxy group, and has the same definition as when used alone.

[0162] The term "alkoxy" or "-O-alkyl" as used herein, alone or in combination, is represented as "alkyl-O-". Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like. Alkoxy groups may be optionally substituted or unsubstituted.

[0163] The term "cycloalkyl" as used herein alone or in combination refers to a saturated monocyclic, bicyclic or polycyclic carbocyclic ring. Preferably, it is a 3-12-membered cycloalkyl, more preferably a 3-10-membered cycloalkyl, and most preferably a 3-8-membered cycloalkyl. Non-limiting examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like cycloalkyls, which may be optionally substituted or unsubstituted.

[0164] The term "aryl" used herein, alone or in combination, refers to an aromatic hydrocarbon ring. The term "aryl" includes monocyclic aromatic hydrocarbons and polycyclic condensed ring (and ring) aromatic hydrocarbons, wherein all condensed ring systems (excluding any ring system that is a part of an optional substituent or formed by an optional substituent) are aromatic. Examples of aryl groups / parts include phenyl, naphthyl, anthracenyl and phenanthrenyl. Unless otherwise indicated, the term "aryl" does not include "heteroaryl".

[0165] The term "heterocyclyl" used herein alone or in combination includes alicyclic and heteroaryl groups, wherein one or more (such as one, two, three or four) of the annular atoms are heteroatoms, such as oxygen, nitrogen, sulfur atoms, etc., including monocyclic, condensed, bridged and spirocyclic rings. Examples of heterocyclic groups include heterocycloalkyl, heterocycloalkenyl and heteroaryl groups as discussed below. Preferred herein are 3-10 membered monocyclic, bicyclic or tricyclic heterocyclic groups, which may contain 1, 2 or 3 annular atoms selected from nitrogen, oxygen and / or sulfur. Non-limiting examples of "heterocyclyl" include azetidinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, 2-oxo-piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, piperazin-2-one, dioxanyl, morpholinyl and thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, etc. The heterocyclyl group may be optionally substituted or unsubstituted.

[0166] In the definition of "heterocyclic group", "heterocyclic group" refers to a polycyclic group containing heteroatoms, which contains two or more cyclic structures and shares a pair of atoms with each other. Among them, one or more rings may contain several unsaturated bonds, or one ring may have a completely conjugated π-electron aromatic system, and the atoms in the rings are selected from nitrogen, oxygen or S(O) n(wherein n is selected from 0, 1 or 2) heteroatoms, and the remaining link atoms are carbon. It is preferably 6-12 members, more preferably 8-9 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic cyclic ring group, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic cyclic ring group.

[0167] The term "heterocycloalkyl" used herein alone or in combination refers to a saturated monocyclic, bicyclic or polycyclic, wherein one or more (such as one, two, three or four) ring atoms are saturated heterocyclic groups of heteroatoms, which can be spirocyclic or bridged rings.Preferred herein are 3-12 cycloalkyls, more preferably 3-10 cycloalkyls, most preferably 3-8 cycloalkyls.Non-limiting examples of monocyclic heterocycloalkyls include but are not limited to propylene oxide, thiirane, aziridine, azetidine, oxetane, thiamine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, oxazolidine, thiazolidine, imidazolidine, tetrahydropyran, piperidine, dioxane, azepane.

[0168] The term "heteroaryl" as used herein, alone or in combination, refers to a 5-12 membered (preferably 5-10 membered, more preferably 5-6 membered) monocyclic, bicyclic or tricyclic ring system, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and the heteroaryl group has one or more points of attachment to the rest of the molecule. Non-limiting examples of "heteroaryl" include furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, and the like; and also include, but are not limited to, the following bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indolyl, oxoindolyl, indolinyl, imidazopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, quinolyl, isoquinolyl, quinazolinyl, indazole, 1,8-naphthyridine, benzo[d]isoxazole, benzo[ d]thiazole, pyrrolo[3,2-b]pyridine, furano[3,2-b]pyridine, pyrrolo[1,2-b]pyridazine, imidazo[1,2-b]pyridazine, pyrazolo[1,5-a]pyrimidine, thiazolo[4,5-c]pyridine, thieno[3,2-b]pyridine, pyrrolo[1,2-b]pyridazine, 2,3-dihydrobenzofuran, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, benzo[d]oxazol-2(3H)-one, etc. The heteroaryl group may be optionally substituted or unsubstituted.

[0169] The term "halogen," as used herein, alone or in combination, refers to fluorine, chlorine, bromine or iodine.

[0170] The term "hydroxy," as used herein, alone or in combination, refers to -OH.

[0171] The term "cyano," as used herein, alone or in combination, refers to -CN.

[0172] The term "methylsulfonyl" as used herein, alone or in combination, refers to -S(O) 2 -CH 3 .

[0173] As used herein, the term "substituted" or "substituted by" means that one or more hydrogens on a particular atom are replaced by a specified group (such as halogen, alkyl, etc.), and if the normal valence of the specified atom is not exceeded under the existing circumstances, the substitution results in a stable compound.

[0174] The term "pharmaceutically acceptable salt" used herein is well known to those skilled in the art.

[0175] The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

[0176] The term "pharmaceutical composition" as used herein refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component, including but not limited to a carrier, stabilizer, diluent, dispersant, suspending agent, thickener and / or excipient.

[0177] As used herein, the term "carrier" refers to relatively nontoxic chemical compounds or agents that facilitate the introduction of a compound into cells or tissues.

[0178] The term "stereoisomer" as used herein includes, but is not limited to, enantiomers, cis-trans isomers, and the like.

[0179] The term "enantiomer" as used herein refers to the isomerism caused by the different spatial configuration of atoms or atomic groups (groups) in compounds with the same molecular formula, and two compounds that are enantiomers are mirror images of each other and cannot overlap. The term "cis-trans isomer" as used herein generally refers to the stereoisomerism of diastereoisomers that occur in compound molecules due to the restriction factor of free rotation, which makes each group arranged in space differently. Organic molecules containing such isomers such as olefins, azo compounds, alicyclic hydrocarbons, etc. are regarded as cis-trans isomers. In the present application, cis-trans isomerism is mainly embodied in the form of alicyclic hydrocarbons. For example, in cyclohexane, cis-trans isomerism will occur when cyclohexane is replaced by two substituents, and when the two substituents are replaced on the same side of the ring, they are "cis" isomers, and on different sides, they are "trans" isomers.

[0180] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, hindered isomers and geometric (conformation) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0181] Unless otherwise indicated, the structure described in the present invention also includes all isomers of the structure (e.g., diastereomers, enantiomers, cis-trans isomers, steric isomers, geometric (conformation) isomer forms), for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, cis-trans isomers of aliphatic cyclic hydrocarbons, steric isomers of biphenyl structures (see "Basic Organic Chemistry" (Second Edition), Volume 1, Xing Qiyi et al., p104-105); PAC, 1996, 68, 2193. (Basic terminology of stereochemistry (IUPAC Recommendations 1996, on page 2201)), (Z) and (E) conformational isomers. Therefore, single stereoisomers of the compounds of the present invention as well as enantiomeric mixtures, diastereomeric mixtures, steric isomers and geometric (conformation) isomer mixtures are all within the scope of the present invention.

[0182] The present invention will be further described below through some specific embodiments. For example:

[0183] The present invention is further described in detail below in conjunction with specific embodiments, but the present invention is not limited to the following embodiments.

[0184] Some of the preparation conditions used in the examples are as follows:

[0185] Preparative Pre-HPLC conditions: Instrument: GILSON-GX281; Wavelength: 220 nm & 254 nm; Column model: Waters X-bridge (30 × 100 mm, 10 μm) or Luna C18 (30 × 75 mm, 3 μm) or Luna C18 (30 × 75 mm, 3 μm); Mobile phase: A: 10 mM ammonium bicarbonate or H 2 O (0.1% formic acid) or H 2 O (0.1% trifluoroacetic acid), B: acetonitrile; running time: 15 min; flow rate: 25 mL / min.

[0186] Reverse phase column purification used a C18 reverse phase silica gel column (Spherical C18, 40-60 μm, 40 g-120 g) with water / acetonitrile (95 / 5 to 30 / 70) as the mobile phase.

[0187] The synthesis steps of some intermediates in the present invention are as follows:

[0188] Intermediate 1: 2-(bis(tert-butoxycarbonyl)amino)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

[0189]

[0190] (1) 1-Methoxy-2,4-dimethyl-3-nitrobenzene

[0191] 1-Bromo-2,4-dimethyl-3-nitrobenzene (1g, 4.3mmol) and cuprous bromide (62mg, 0.43mmol) were dissolved in N,N-dimethylformamide (15mL), and sodium methoxide solution (3.87g, 21.5mmol, 30% methanol solution) was added, and the reaction was stirred at 90°C overnight. The reaction solution was slowly added to water (30mL), and the aqueous phase was extracted with ethyl acetate (25mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (25mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 98 / 2) to obtain the title compound (320mg, yellow oil), yield: 41%. 1 H NMR (300 MHz, CDCl 3 )δ7.11(d,J=8.4Hz,1H),6.88(d,J=8.4Hz,1H),3.89(s,3H),2.27(s,3H),2.18(s,3H).

[0192] (2) 3-Methoxy-2,6-dimethylaniline

[0193] 1-Methoxy-2,4-dimethyl-3-nitrobenzene (1.77 g, 9.8 mmol) was dissolved in methanol (30 mL), 10% palladium carbon (200 mg) was added, the system was replaced with hydrogen three times, and the reaction was stirred at 40°C for 24 hours. The reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated to obtain the title compound (1.2 g, yellow oil), yield: 81%. MS (ESI): m / z 152.0 [M+H] + .

[0194] (3) 3-Bromo-N-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethylpyridin-2-amine

[0195] 3-Methoxy-2,6-dimethylaniline (1.2 g, 7.9 mmol) and 2,3-dibromo-5,6-dimethylpyridine (2.5 g, 9.5 mmol) were dissolved in 1,4-dioxane (40 mL), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (925 mg, 1.6 mmol), tris(dibenzylideneacetone)dipalladium (733 mg, 0.8 mmol) and cesium carbonate (6.5 g, 19.8 mmol) were added, nitrogen was replaced 3 times, and the mixture was heated to 90°C under nitrogen protection and stirred for 16 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 96 / 4) to obtain the title compound (1.62 g, white solid), yield: 61%. MS (ESI): m / z 334.9 [M+H] + .

[0196] (4) 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid benzyl ester

[0197] Benzyl 2-cyanoacetate (524 mg, 3.0 mmol) and sodium hydride (180 mg, 4.5 mmol, 60%) were dissolved in ethylene glycol dimethyl ether (10 mL) and stirred at room temperature for 5 minutes. Then 3-bromo-N-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethylpyridin-2-amine (500 mg, 1.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (122 mg, 0.15 mmol) were added, and the mixture was heated to 95 ° C under nitrogen protection and stirred overnight. The reaction solution was quenched with water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phases were combined and concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (100 mg, yellow oil), yield: 16%. MS (ESI): m / z 430.0 [M+H] + .

[0198] (5) Benzyl 2-(bis(tert-butoxycarbonyl)amino)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate

[0199] 2-Amino-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid benzyl ester (100 mg, 0.23 mmol) and di-tert-butyl dicarbonate (153 mg, 0.7 mmol) were dissolved in tetrahydrofuran (10 mL), triethylamine (71 mg, 0.7 mmol) and 4-dimethylaminopyridine (3 mg, 0.02 mmol) were added, and the reaction was stirred at room temperature overnight. Water (30 mL) was added to the reaction solution, and it was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (100 mg, colorless oil), yield: 68%. MS (ESI): m / z 630.1 [M+H] + .

[0200] (6) 2-(bis(tert-butoxycarbonyl)amino)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

[0201] Dissolve 2-(bis(tert-butoxycarbonyl)amino)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid benzyl ester (100 mg, 0.16 mmol) in methanol (10 mL), add 10% palladium carbon (10 mg), replace the system with hydrogen three times, and stir the reaction at room temperature overnight. The reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated to obtain the title compound (80 mg, colorless oil). MS (ESI): m / z 540.0 [M+H] + .

[0202] Intermediate 2: 2-(bis(tert-butoxycarbonyl)amino)-1-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

[0203]

[0204] (1) 1-(Methoxymethoxy)-2,4-dimethyl-3-nitrobenzene

[0205] Dissolve 2,4-dimethyl-3-nitrophenol (1g, 6mmol) in N,N-dimethylformamide (10mL), add sodium hydride (264mg, 6.6mmol, 60%) at 0°C, and stir under nitrogen for 20 minutes. Add bromomethyl methyl ether (900mg, 7.2mmol) in N,N-dimethylformamide (2mL), and stir at room temperature for 2 hours. Add water (30mL) to the reaction solution, and extract the aqueous phase with ethyl acetate (20mL x 3). Combine the organic phases, wash with saturated sodium chloride solution (30mL x4), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (1.2g, beige oil), yield: 95%. 1 HNMR (300 MHz, DMSO-d 6 )δ7.27-7.18(m,2H),5.27(s,2H),3.39(s,3H),2.17(s,3H),2.09(s,3H).

[0206] Steps (2) to (6) were carried out in accordance with the method of steps (2) to (6) of Intermediate 1, and 1-(methoxymethoxy)-2,4-dimethyl-3-nitrobenzene was used as the starting material to obtain Intermediate 2 (170 mg, white solid) through similar steps. MS (ESI): m / z 570.0 [M+H] + .

[0207] Intermediate 3: (S)-2-(bis(tert-butoxycarbonyl)amino)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

[0208]

[0209] (1) 1-Methoxy-2,4-dimethyl-3-nitrobenzene

[0210] 2,4-dimethyl-3-nitrophenol (16 g, 96 mmol) was dissolved in N,N-dimethylformamide (180 mL), iodomethane (20 g, 144 mmol) and potassium carbonate (26 g, 192 mmol) were added, and the mixture was heated to 50 ° C and stirred for 2 hours. The reaction solution was slowly added to water (400 mL), and the aqueous phase was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (300 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (17 g, light yellow oil), yield: 98%. 1 H NMR (300 MHz, DMSO-d 6)δ7.27(d,J=8.4Hz,1H),7.13(d,J=8.4Hz,1H),3.86(s,3H),2.19(s,3H),2.07(s,3H).

[0211] (2) 3-Methoxy-2,6-dimethylaniline

[0212] Dissolve 1-methoxy-2,4-dimethyl-3-nitrobenzene (17 g, 9 mmol) in methanol (400 mL), add 10% palladium carbon (1.7 g), replace the system with hydrogen three times, and stir at room temperature for 16 hours. The reaction solution is filtered through diatomaceous earth, and the filtrate is concentrated to obtain the title compound (14.4 g, yellow oil), yield: 100%. MS (ESI): m / z 152.1 [M+H] + .

[0213] (3) 3-Bromo-N-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethylpyridin-2-amine

[0214] 3-Methoxy-2,6-dimethylaniline (14.4 g, 95 mmol) and 2,3-dibromo-5,6-dimethylpyridine (30 g, 114 mmol) were dissolved in ethylene glycol dimethyl ether (300 mL), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (4.4 g, 7.6 mmol), tris(dibenzylideneacetone)dipalladium (3.5 g, 3.8 mmol) and cesium carbonate (77 g, 237.5 mmol) were added, and the mixture was heated to 90°C under nitrogen protection and stirred for 16 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound (25 g, white solid), yield: 78%. MS (ESI): m / z 335.0 [M+H] + .

[0215] (4) 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid benzyl ester

[0216] Benzyl 2-cyanoacetate (18 g, 102 mmol) and sodium hydride (6 g, 153 mmol, 60%) were dissolved in ethylene glycol dimethyl ether (200 mL) and stirred at room temperature for 20 minutes. Then 3-bromo-N-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethylpyridin-2-amine (17 g, 51 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (1.6 g, 2 mmol) were added. The mixture was heated to 90°C under nitrogen protection and stirred for 16 hours. The reaction solution was concentrated and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound (5.2 g, light yellow solid) with a yield of 23.7%. MS (ESI): m / z 430.1 [M+H] + .

[0217] (5) (S)-2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid benzyl ester

[0218] 2-Amino-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid benzyl ester (5.2 g) was separated and purified by Prep-SFC (chiral separation column conditions: IC column, diameter 3 cm, length 25 cm, filler particle size 10 μm; n-hexane / ethanol = 90 / 10; flow rate 25 mL / min) to obtain isomer 1 (2.15 g, retention time 6.943 minutes) and isomer 2 (2.3 g, retention time 8.309 minutes), both of which were light yellow solids, with a total recovery rate of 85.5%. After structural comparison and identification, isomer 2 was the title compound.

[0219] (6) (S)-2-(bis(tert-butoxycarbonyl)amino)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid benzyl ester

[0220] (S)-2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid benzyl ester (2.3 g, 5.4 mmol) was dissolved in tetrahydrofuran (50 mL), di-tert-butyl dicarbonate (3.5 g, 16.2 mmol), triethylamine (1.6 g, 16.2 mmol) and 4-dimethylaminopyridine (66 mg, 0.54 mmol) were added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 93 / 7) to obtain the title compound (2.5 g, yellow solid), with a yield of 74%. MS (ESI): m / z 630.3 [M+H]+ .

[0221] (7) (S)-2-(bis(tert-butoxycarbonyl)amino)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

[0222] (S)-2-(bis(tert-butoxycarbonyl)amino)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid benzyl ester (1.3 g, 2 mmol) was dissolved in methanol (40 mL), 10% palladium carbon (120 mg) was added, the system was replaced with hydrogen three times, and the reaction was stirred at room temperature for 16 hours. The reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated to obtain the title compound (1.1 g, white solid), yield: 100%. MS (ESI): m / z 540.3 [M+H] + .

[0223] Example 1

[0224] 2-Amino-1-(2,6-dimethyl-3-(1H-pyrazol-3-yl)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0225]

[0226] (1) 3-(2,4-dimethyl-3-nitrophenyl)-1H-pyrazole

[0227] 1-Bromo-2,4-dimethyl-3-nitrobenzene (3g, 13mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.5g, 13mmol) were dissolved in a mixed solvent of 1,4-dioxane / water (70mL / 10mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (950mg, 1.3mmol) and potassium carbonate (5.4g, 39mmol) were added. The mixture was heated to 100°C under nitrogen protection and stirred overnight. The reaction solution was concentrated and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain the title compound (2.34g, yellow oil) with a yield of 83%. MS (ESI): m / z 218.0 [M+H] + .

[0228] (2) 2,6-Dimethyl-3-(1H-pyrazol-3-yl)aniline

[0229] 3-(2,4-dimethyl-3-nitrophenyl)-1H-pyrazole (1.24 g, 5.7 mmol) was dissolved in methanol (30 mL), 10% palladium on carbon (124 mg) was added, the reaction system was replaced with hydrogen three times, and the reaction was stirred at 40°C for 2 hours. The reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated to obtain the title compound (1.07 g, yellow oil), yield: 100%. MS (ESI): m / z 188.0 [M+H] + .

[0230] (3) 3-Bromo-N-(2,6-dimethyl-3-(1H-pyrazol-3-yl)phenyl)-5,6-dimethylpyridin-2-amine

[0231] 2,6-Dimethyl-3-(1H-pyrazol-3-yl)aniline (300 mg, 1.6 mmol) and 2,3-dibromo-5,6-dimethylpyridine (424 mg, 1.6 mmol) were dissolved in toluene (8 mL), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (100 mg, 0.16 mmol), tris(dibenzylideneacetone)dipalladium (73 mg, 0.08 mmol) and sodium tert-butoxide (307 mg, 3.2 mmol) were added, nitrogen was replaced, and the mixture was stirred at 110°C in a microwave reactor for 5 hours. The reaction solution was concentrated, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the title compound (100 mg, yellow solid), yield: 17%. MS (ESI): m / z 370.8 [M+H] + .

[0232] (4) 2-amino-1-(2,6-dimethyl-3-(1H-pyrazol-3-yl)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0233] Malononitrile (36 mg, 0.54 mmol) and sodium hydride (32 mg, 0.81 mmol, 60%) were dissolved in ethylene glycol dimethyl ether (5 mL) and stirred at room temperature for 1 hour. Then 3-bromo-N-(2,6-dimethyl-3-(1H-pyrazol-3-yl)phenyl)-5,6-dimethylpyridin-2-amine (100 mg, 0.27 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (22 mg, 0.027 mmol) were added, and the mixture was heated to 95°C and stirred overnight under nitrogen protection. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 4) to obtain the title compound (20 mg, yellow solid), yield: 21%. MS (ESI): m / z 356.9 [M+H] + . 1 H NMR (300 MHz, DMSO-d 6)δ12.97(brs,1H),7.81(s,1H),7.64(d,J=8.1Hz,1H),7.45(s,1H),7.38(d,J=8.4Hz ,1H),6.91(s,2H),6.55(s,1H),2.31(s,3H),2.30(s,3H),1.99(s,3H),1.93(s,3H).

[0234] (5) 2-amino-1-(2,6-dimethyl-3-(1H-pyrazol-3-yl)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0235] Concentrated sulfuric acid (4 mL) was added to methanesulfonic acid (4 mL), and then 2-amino-1-(2,6-dimethyl-3-(1H-pyrazol-3-yl)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (20 mg, 0.056 mmol) was added and stirred at 50°C overnight. The reaction solution was slowly added to water (20 mL), the pH was adjusted to alkaline with sodium hydroxide solution, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give the title compound (2.3 mg, light pink solid), yield: 11%. MS (ESI): m / z 375.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.87(s,1H),7.75(s,1H),7.60(d,J=8.0Hz,1H),7.34(d,J=8.0Hz,1H),6.83(brs,2H), 6.63(brs,2H),6.50(d,J=2.0Hz,1H),2.28(s,3H),2.25(s,3H),1.95(s,3H),1.89(s,3H).

[0236] Example 2

[0237] 2-Amino-1-(2,6-dimethyl-3-(1H-pyrazol-4-yl)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0238]

[0239] Referring to the method of Example 1, using 1-bromo-2,4-dimethyl-3-nitrobenzene (2 g, 8.7 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (2.56 g, 8.7 mmol) as starting materials, similar steps were followed to obtain the title compound (5.7 mg, white solid). MS (ESI): m / z 375.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ12.98(brs,1H),7.96(brs,1H),7.85(s,1H),7.74(brs,1H),7.47(d,J=8.0Hz,1H),7.29(d ,J=8.0Hz,1H),6.80(s,2H),6.66(s,2H),2.27(s,3H),2.25(s,3H),1.88(s,3H),1.86(s,3H).

[0240] Example 3

[0241] 2-Amino-1-(5,7-dimethyl-1H-indazol-6-yl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0242]

[0243] (1) 2,4,6-Trimethyl-3-nitroaniline

[0244] Dissolve 2,4,6-trimethylaniline (5.4 g, 40 mmol) in 98% concentrated sulfuric acid (25 mL), slowly add 65% concentrated nitric acid (3.87 g, 40 mmol) at 0°C, and control the temperature not to be higher than 10°C. After the addition is completed, react at 0°C for 1 hour. Slowly pour the reaction solution into ice water, slowly add 6N sodium hydroxide aqueous solution to adjust the pH to greater than 10, and a large amount of yellow solid precipitates. After filtering, wash the filter cake with water, dry the filter cake, and purify it with petroleum ether to obtain the title compound (5.8 g, yellow solid), yield: 80%. MS (ESI): m / z 181.0 [M+H] + .

[0245] (2) 5,7-Dimethyl-6-nitro-1H-indazole

[0246] Dissolve 2,4,6-trimethyl-3-nitroaniline (5.6 g, 31 mmol) in glacial acetic acid (30 mL), cool to 0°C, add sodium nitrite (2.15 g, 31 mmol) in water (6 mL), and react overnight at room temperature. Pour the reaction solution into water (150 mL), and a large amount of orange-red solid precipitates. Filter and dry the solid to obtain the title compound (5.9 g, orange-red solid), yield: 100%. MS (ESI): m / z 192.0 [M+H] + .

[0247] (3) tert-Butyl 5,7-dimethyl-6-nitro-1H-indazole-1-carboxylate

[0248] Dissolve 5,7-dimethyl-6-nitro-1H-indazole (5.9 g, 31 mmol) in acetonitrile (100 mL), add triethylamine (9.4 g, 93 mmol) and 4-dimethylaminopyridine (366 mg, 3 mmol), cool to 0°C, add di-tert-butyl dicarbonate (8 g, 37 mmol), and stir at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain the title compound (900 mg, orange-red solid), yield: 10%. MS (ESI): m / z 235.9 [M+H-56] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.96(s,1H),7.62(s,1H),2.47(s,3H),2.26(s,3H),1.66(s,9H).

[0249] (4) tert-Butyl 6-amino-5,7-dimethyl-1H-indazole-1-carboxylate

[0250] Dissolve tert-butyl 5,7-dimethyl-6-nitro-1H-indazole-1-carboxylate (500 mg, 1.7 mmol) in ethyl acetate (15 mL), add methanol (15 mL) and 10% palladium carbon (100 mg), and react overnight at 40°C under a hydrogen atmosphere. The reaction solution is filtered through diatomaceous earth, the filter cake is washed with a small amount of methanol, and the filtrate is concentrated to the title compound (360 mg, green oil), yield: 80%. MS (ESI): m / z 206.0 [M+H-56] + .

[0251] (5) N-(3-bromo-5,6-dimethylpyridin-2-yl)-5,7-dimethyl-1H-indazol-6-amine

[0252] In a 20 mL microwave tube, tert-butyl 6-amino-5,7-dimethyl-1H-indazole-1-carboxylate (360 mg, 1.38 mmol), 2,3-dibromo-5,6-dimethylpyridine (363 mg, 1.38 mmol), tris(dibenzylideneacetone)dipalladium (128 mg, 0.14 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (174 mg, 0.28 mmol) and sodium tert-butoxide (331 mg, 3.45 mmol) were added, toluene was added to dissolve, and microwave reaction was carried out at 110°C under nitrogen protection for 5 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the title compound (260 mg, light yellow solid), yield: 54.6%. MS (ESI): m / z 344.8 [M+H] + .

[0253] (6) 2-amino-1-(5,7-dimethyl-1H-indazol-6-yl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0254] Malononitrile (99 mg, 1.5 mmol) was dissolved in ethylene glycol dimethyl ether (8 mL), sodium hydride (92 mg, 2.3 mmol, 60%) was added, and N-(3-bromo-5,6-dimethylpyridin-2-yl)-5,7-dimethyl-1H-indazol-6-amine (261 mg, 0.76 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (58 mg, 0.08 mmol) were added after stirring at room temperature for 1 hour. The mixture was heated to 85°C under nitrogen protection for 16 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (120 mg, yellow-brown solid), yield: 48%. MS (ESI): m / z 331.0 [M+H] + .

[0255] (7) 2-amino-1-(5,7-dimethyl-1H-indazol-6-yl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0256] 2-Amino-1-(5,7-dimethyl-1H-indazol-6-yl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (40 mg, 0.12 mmol) was dissolved in a mixed solvent of methanesulfonic acid (1 mL) and concentrated sulfuric acid (0.5 mL), heated to 50 ° C and reacted overnight. The reaction solution was poured into water (20 mL), the pH was adjusted to greater than 10 with 1N sodium hydroxide aqueous solution, and the aqueous phase was extracted with ethyl acetate (2x25 mL). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Prep-HPLC to give the title compound (18.6 mg, white solid), yield: 44%. MS (ESI): m / z 349.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ13.31(s,1H),8.11(s,1H),7.86(s,1H),7.61(s,1H),6.84(s,2H),6.68(s,2H),2.27(s,3H),2.21(s,3H),2.11(s,3H),1.89(s,3H).

[0257] Example 4

[0258] 2-Amino-1-(6-cyclopropyl-3-hydroxy-2-methylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0259]

[0260] (1) 6-Bromo-3-methoxy-2-methylbenzoic acid

[0261] 3-Methoxy-2-methylbenzoic acid (1.0 g, 6.02 mmol) and bromine water (0.3 mL) were dissolved in acetic acid (50 mL) and stirred at room temperature overnight. The reaction solution was slowly added to a sodium bisulfite solution (150 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with a saturated sodium chloride solution (150 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.61 g, yellow oil), yield: 100%. MS (ESI): m / z 244.8 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ10.49(s,1H),7.36(d,J=9.2Hz,1H),6.76(d,J=8.8Hz,1H),3.82(s,3H),2.27(s,3H).

[0262] (2) tert-Butyl (6-bromo-3-methoxy-2-methylphenyl)carbamate

[0263] Dissolve 6-bromo-3-methoxy-2-methylbenzoic acid (1.60 g, 6.55 mmol) in tert-butyl alcohol (16 mL), add triethylamine (2.0 g, 19.65 mmol) and diphenylphosphoryl azide (2.7 g, 9.82 mmol) in turn, and stir at 100 ° C for 4 hours. The reaction solution is slowly added to water (150 mL), and the aqueous phase is extracted with ethyl acetate (100 mL x 3). The organic phases are combined, washed with saturated sodium chloride solution (150 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (1.40 g, yellow oil), yield: 70%. MS (ESI): m / z 259.8 [M+H-56] + .

[0264] (3) tert-Butyl (6-cyclopropyl-3-methoxy-2-methylphenyl)carbamate

[0265] Tert-butyl (6-bromo-3-methoxy-2-methylphenyl)carbamate (1.40 g, 4.44 mmol), cyclopropylboronic acid (1.14 g, 13.32 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (320 mg, 0.44 mmol) and potassium carbonate (1.83 g, 13.32 mmol) were dissolved in a mixed solvent of 1,4-dioxane / water (40 mL / 10 mL), and nitrogen was replaced 3 times. The mixture was heated to 90 ° C and stirred overnight under nitrogen protection. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain the title compound (0.8 g, yellow oil), yield: 65%. MS (ESI): m / z 222.0 [M+H-56] + .

[0266] (4) 6-Cyclopropyl-3-methoxy-2-methylaniline

[0267] Dissolve tert-butyl (6-cyclopropyl-3-methoxy-2-methylphenyl)carbamate (0.8 g, 2.88 mmol) in trifluoroacetic acid (8 mL) and stir at room temperature for 1 hour. The reaction solution is slowly added to a saturated sodium bicarbonate solution (100 mL), and the aqueous phase is extracted with ethyl acetate (100 mL x 3). The organic phases are combined, washed with a saturated sodium chloride solution (150 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (0.25 g, black oil), yield: 48%. MS (ESI): m / z 178.0 [M+H] + .

[0268] (5) 3-Bromo-N-(6-cyclopropyl-3-methoxy-2-methylphenyl)-5,6-dimethylpyridin-2-amine

[0269] 6-Cyclopropyl-3-methoxy-2-methylaniline (0.25 g, 1.40 mmol) and 2,3-dibromo-5,6-dimethylpyridine (0.56 g, 2.10 mmol) were dissolved in 1,4-dioxane (4 mL), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (161.28 mg, 0.28 mmol), tris(dibenzylideneacetone)dipalladium (128.24 mg, 0.14 mmol) and cesium carbonate (1.36 g, 4.20 mmol) were added in sequence. Nitrogen was replaced three times, and the mixture was heated to 90 ° C and stirred overnight under nitrogen protection. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain the title compound (0.25 g, yellow solid), yield: 48%. MS (ESI): m / z 360.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.63(s,1H),7.26(s,1H),6.87-6.78(m,2H),3.80(s,3H),2.11(s,3H),2.09 (s,3H),1.98(s,3H),1.80-1.74(m,1H),0.72-0.69(m,2H),0.49-0.47(m,2H).

[0270] (6) 2-amino-1-(6-cyclopropyl-3-methoxy-2-methylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0271] Malononitrile (137 mg, 2.07 mmol) and sodium hydride (82 mg, 2.07 mmol, 60%) were dissolved in ethylene glycol dimethyl ether (10 mL) and stirred in an ice-water bath for 1 hour. Then 3-bromo-N-(6-cyclopropyl-3-methoxy-2-methylphenyl)-5,6-dimethylpyridin-2-amine (0.25 g, 0.69 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (112 mg, 0.14 mmol) were added, and the mixture was heated to 90 ° C under nitrogen protection and stirred overnight. The reaction solution was slowly added to water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give the title compound (160 mg, white solid), yield: 66%. MS (ESI): m / z 347.0 [M+H]+ .

[0272] (7) 2-amino-1-(6-cyclopropyl-3-methoxy-2-methylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0273] 2-Amino-1-(6-cyclopropyl-3-methoxy-2-methylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (100 mg, 0.29 mmol) was dissolved in a mixture of ethanol and water (4 mL), lithium hydroxide (91 mg, 2.17 mmol) and hydrogen peroxide (425 mg, 3.77 mmol) were added, and the mixture was heated to 60°C under nitrogen protection and stirred for 20 minutes. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (60 mg, yellow solid), yield: 57%. MS (ESI): m / z 365.0 [M+H] + .

[0274] (8) 2-amino-1-(6-cyclopropyl-3-hydroxy-2-methylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0275] 2-Amino-1-(6-cyclopropyl-3-methoxy-2-methylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (60 mg, 0.16 mmol) was dissolved in anhydrous dichloromethane (2 mL), and boron tribromide (197 mg, 0.80 mmol) was slowly added dropwise under an ice-water bath. The mixture was stirred and reacted for 20 minutes under nitrogen protection at 0°C. The reaction solution was slowly added to an ammonia solution (20 mL), and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Pre-HPLC to obtain the title compound (5 mg, white solid), yield: 9%. MS (ESI): m / z 351.1 [M+H] + .1H NMR (400MHz, DMSO-d 6 )δ9.52(s,1H),7.81(s,1H),6.90(d,J=8.4Hz,1H),6.81(d,J=8.4Hz,1H),6.70(s,2H),6 .61(s,2H),2.26(s,3H),2.24(s,3H),1.65(s,3H),1.22-1.17(m,1H),0.51-0.34(m,4H).

[0276] Example 5

[0277] 2-Amino-1-(4,6-dimethylpyrimidin-5-yl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0278]

[0279] (1) N-(3-bromo-5,6-dimethylpyridin-2-yl)-4,6-dimethylpyrimidin-5-amine

[0280] 4,6-Dimethylpyrimidine-5-amine (400 mg, 3.25 mmol) and 2,3-dibromo-5,6-dimethylpyridine (1.03 g, 3.9 mmol) were dissolved in ethylene glycol dimethyl ether solution (20 mL), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (376 mg, 0.65 mmol), tris(dibenzylideneacetone)dipalladium (298 mg, 0.325 mmol) and cesium carbonate (2.65 g, 8.13 mmol) were added in sequence. Nitrogen was replaced 3 times, and the mixture was heated to 90°C under nitrogen protection and stirred for 18 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (dichloromethane / methanol=98 / 2) to obtain the title compound (840 mg, green solid), yield: 84%. MS (ESI): m / z 306.9 [M+H] + .

[0281] (2) 2-amino-1-(4,6-dimethylpyrimidin-5-yl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0282] Malononitrile (211 mg, 3.2 mmol) and sodium hydride (192 mg, 4.8 mmol, 60%) were dissolved in ethylene glycol dimethyl ether (10 mL) and stirred at room temperature for 1 hour. Then N-(3-bromo-5,6-dimethylpyridin-2-yl)-4,6-dimethylpyrimidin-5-amine (500 mg, 1.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (131 mg, 0.16 mmol) were added, and the mixture was heated to 95°C under nitrogen protection and stirred for 16 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (dichloromethane / methanol=96 / 4) to obtain the title compound (450 mg, yellow solid), yield: 95%. MS (ESI): m / z 293.0 [M+H] + .

[0283] (3) 2-amino-1-(4,6-dimethylpyrimidin-5-yl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0284] Concentrated sulfuric acid (1 mL) was added to methanesulfonic acid (3 mL), and then 2-amino-1-(4,6-dimethylpyrimidin-5-yl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (150 mg, 0.5 mmol) was added, and the reaction was stirred at 45 ° C for 16 hours. The reaction solution was slowly added to water (20 mL), and the pH was adjusted to alkaline with aqueous sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate (20x3 mL). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Prep-HPLC to give the title compound (61.4 mg, white solid), yield: 38.6%. MS (ESI): m / z 311.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.04(s,1H),7.89(s,1H),7.19(s,2H),6.74(s,2H),2.27(s,3H),2.25(s,3H),2.10(s,6H).

[0285] Example 6

[0286] 2-Amino-1-(2,6-dimethyl-3-(methylsulfonyl)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0287]

[0288] (1) 1,3-Dimethyl-4-(methylsulfonyl)-2-nitrobenzene

[0289] 1-Bromo-2,4-dimethyl-3-nitrobenzene (2.3 g, 10 mmol) was dissolved in dimethyl sulfoxide (25 mL), and sodium methanesulfonate (1.22 g, 12 mmol), trifluoromethanesulfonate copper benzene complex (503 mg, 1 mmol) and N 1 ,N 2 -dimethylethane-1,2-diamine (176 mg, 2 mmol), the mixture was heated to 130 ° C under nitrogen protection for 18 hours. The reaction solution was poured into water (150 mL), and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, washed with saturated brine (75 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 2) to obtain the title compound (657 mg, white solid), yield: 28.7%. MS (ESI): m / z 229.9 [M+H] + .

[0290] (2) 2,6-Dimethyl-3-(methylsulfonyl)aniline

[0291] Dissolve 1,3-dimethyl-4-(methylsulfonyl)-2-nitrobenzene (657 mg, 2.87 mmol) in ethyl acetate (10 mL), add methanol (10 mL) and 10% palladium on carbon (100 mg), and react overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with a small amount of methanol, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (360 mg, white solid), yield: 63%. MS (ESI): m / z 200.0 [M+H] + .

[0292] (3) 3-Bromo-N-(2,6-dimethyl-3-(methylsulfonyl)phenyl)-5,6-dimethylpyridin-2-amine

[0293] 2,6-Dimethyl-3-(methylsulfonyl)aniline (320 mg, 1.6 mmol) and 2,3-dibromo-5,6-dimethylpyridine (421 mg, 1.6 mmol) were dissolved in toluene (5 mL), tri(dibenzylideneacetone)dipalladium (73 mg, 0.08 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (100 mg, 0.16 mmol) and cesium carbonate (1.3 g, 4 mmol) were added, and the mixture was heated to 110°C and stirred for 18 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (278 mg, yellow solid), yield: 60%. MS (ESI): m / z 382.8 [M+H] + .

[0294] (4) 2-amino-1-(2,6-dimethyl-3-(methylsulfonyl)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0295] Malononitrile (40 mg, 0.6 mmol) was dissolved in ethylene glycol dimethyl ether (5 mL), sodium hydride (48 mg, 1.2 mmol, 60%) was added, and 3-bromo-N-(2,6-dimethyl-3-(methylsulfonyl)phenyl)-5,6-dimethylpyridin-2-amine (115 mg, 0.3 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (25 mg, 0.03 mmol) were added after stirring at room temperature for 1 hour. The mixture was heated to 85°C under nitrogen protection for 16 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (28 mg, light yellow solid), yield: 25%. MS (ESI): m / z 369.2 [M+H]+ .

[0296] (5) 2-amino-1-(2,6-dimethyl-3-(methylsulfonyl)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0297] 2-Amino-1-(2,6-dimethyl-3-(methylsulfonyl)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (28 mg, 0.076 mmol) was dissolved in a mixed solvent of methanesulfonic acid (1 mL) and concentrated sulfuric acid (0.5 mL) and reacted at 50°C for 1 hour. The reaction solution was poured into water (20 mL), the pH was adjusted to greater than 10 with 1N sodium hydroxide aqueous solution, and the aqueous phase was extracted with ethyl acetate (2 x 25 mL). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Prep-HPLC to give the title compound (5.4 mg, white solid) in a yield of 18.4%. MS (ESI): m / z 387.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.02(d,J=8.0Hz,1H),7.88(s,1H),7.57(d,J=8.0Hz,1H),6.98(s,2H),6. 71(s,2H),3.26(s,3H),2.27(s,3H),2.24(s,3H),2.17(s,3H),1.93(s,3H).

[0298] Example 7

[0299] 2-amino-1-(3-((dimethyl(oxo)-λ 6 -sulfinyl)amino)-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0300]

[0301] (1) ((2,4-dimethyl-3-nitrophenyl)imino)dimethyl-λ 6 -Sulfothone

[0302] 1-Bromo-2,4-dimethyl-3-nitrobenzene (1g, 4.35mmol) and dimethylsulfenyl imide (405mg, 4.35mmol) were dissolved in toluene (20mL), BINAP (271mg, 0.435mmol), tris(dibenzylideneacetone)dipalladium (200mg, 0.218mmol) and sodium tert-butoxide (835mg, 8.7mmol) were added, and the mixture was heated to 110°C under nitrogen protection and stirred for 16 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (850mg, yellow oil), yield: 81%. MS (ESI): m / z 242.9 [M+H] + .

[0303] (2) ((3-amino-2,4-dimethylphenyl)imino)dimethyl-λ 6 -Sulfothone

[0304] ((2,4-dimethyl-3-nitrophenyl)imino)dimethyl-λ 6 -sulfonone (850 mg, 3.5 mmol) was dissolved in methanol (20 mL), 10% palladium carbon (85 mg) was added, the system was replaced with hydrogen three times, and the reaction was stirred at room temperature for 36 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the title compound (700 mg, yellow oil), yield: 94%. MS (ESI): m / z 213.0 [M+H] + .

[0305] (3)((3-((3-bromo-5,6-dimethylpyridin-2-yl)amino)-2,4-dimethylphenyl)imino)dimethyl-λ 6 -Sulfothone

[0306] ((3-amino-2,4-dimethylphenyl)imino)dimethyl-λ 6 -sulfonone (700 mg, 3.3 mmol) and 2,3-dibromo-5,6-dimethylpyridine (875 mg, 3.3 mmol) were dissolved in toluene (15 mL), BINAP (205 mg, 0.33 mmol), tris(dibenzylideneacetone)dipalladium (151 mg, 0.165 mmol) and sodium tert-butoxide (634 mg, 6.6 mmol) were added, and the mixture was heated to 110 ° C under nitrogen protection and stirred for 16 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (450 mg, green oil), yield: 35%. MS (ESI): m / z 395.9 [M+H] + .

[0307] (4) 2-amino-1-(3-((dimethyl(oxo)-λ 6 -sulfinyl)amino)-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0308] Malononitrile (132 mg, 2.0 mmol) and sodium hydride (120 mg, 3.0 mmol, 60%) were dissolved in ethylene glycol dimethyl ether (5 mL) and stirred at room temperature for 1 hour. Then ((3-((3-bromo-5,6-dimethylpyridin-2-yl)amino)-2,4-dimethylphenyl)imino)dimethyl-λ 6 -sulfonone (400 mg, 1.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (82 mg, 0.1 mmol), the mixture was heated to 95°C under nitrogen protection and stirred for 16 hours. The reaction solution was concentrated and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 7) to obtain the title compound (300 mg, yellow solid), yield: 79%. MS (ESI): m / z 382.0 [M+H] + .

[0309] (5) 2-amino-1-(3-((dimethyl(oxo)-λ 6 -sulfinyl)amino)-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0310] Concentrated sulfuric acid (1 mL) was added to methanesulfonic acid (3 mL), and then 2-amino-1-(3-((dimethyl(oxo)-λ 6 -sulfinyl)amino)-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (100 mg, 0.26 mmol) was added and stirred at room temperature for 2 hours. The reaction solution was slowly added to water (15 mL), the pH was adjusted to alkaline with sodium hydroxide aqueous solution, and the aqueous phase was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Prep-HPLC to obtain the title compound (58 mg, white solid), yield: 55%. MS (ESI): m / z 400.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ7.82(s,1H),7.13(d,J=8.0Hz,1H),7.08(d,J=8.4Hz,1H),6.73(s,2H),6.63(s, 2H),3.25(s,3H),3.22(s,3H),2.26(s,3H),2.24(s,3H),1.78(s,3H),1.70(s,3H).

[0311] Example 8

[0312] (2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(piperazin-1-yl)methanone

[0313]

[0314] (1) tert-butyl 4-(2-(bis(tert-butoxycarbonyl)amino)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl ester-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)piperazine-1-carboxylate

[0315] Intermediate 1 (45 mg, 0.08 mmol) and tert-butyl piperazine-1-carboxylate (23 mg, 0.12 mmol) were dissolved in N, N-dimethylformamide (5 mL), HATU (61 mg, 0.16 mmol) and N, N-diisopropylethylamine (31 mg, 0.24 mmol) were added, and the mixture was stirred at room temperature overnight. Water (20 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 8 / 1) to obtain the title compound (50 mg, yellow solid), yield: 85%. MS (ESI): m / z 708.2 [M+H] + .

[0316] (2) (2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(piperazin-1-yl)methanone

[0317] 4-(2-(bis(tert-butoxycarbonyl)amino)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethylester-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)piperazine-1-carboxylic acid tert-butyl ester (30 mg, 0.04 mmol) was dissolved in dichloromethane (5 mL), and boron tribromide (1 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction solution was slowly added to water (20 mL), and sodium bicarbonate aqueous solution (10 mL) was added. The aqueous phase was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by Prep-HPLC to give the title compound (1.3 mg, white solid), yield: 8%. MS (ESI): m / z 394.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.49(s,1H),7.28(s,1H),7.04(d,J=8.4Hz,1H),6.90(d,J=8.0Hz,1H),6.13(s,2H),3.40-3.39 (m,4H),2.77-2.75(m,4H),2.26(s,3H),2.24(s,3H),2.03-1.97(m,1H),1.75(s,3H),1.66(s,3H).

[0318] Example 9

[0319] (2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(4-hydroxypiperidin-1-yl)methanone

[0320]

[0321] Referring to the method of Example 8, in step 1, intermediate 1 and piperidine-4-ol were used as raw materials, and the title compound (5.0 mg, white solid) was obtained through similar steps. MS (ESI): m / z 409.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ9.47(s,1H),7.28(s,1H),7.04(d,J=8.0Hz,1H),6.89(d,J=8.4Hz,1H),6.12(s,2H),4.71(d,J=4.0Hz,1H),3.85-3.82(m,2H), 3.72-3.69(m,1H),3.14-3.08(m,2H),2.26(s,3H),2.24(s,3H),1.82-1.79(m,2H),1.75(s,3H),1.66(s,3H),1.43-1.36(m,2H).

[0322] Example 10

[0323] (S)-(2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(3-hydroxypiperidin-1-yl)methanone

[0324]

[0325] Referring to the method of Example 8, in step 1, intermediate 1 and (S)-piperidin-3-ol were used as raw materials, and the title compound (2.2 mg, white solid) was obtained through similar steps. MS (ESI): m / z 409.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.47(brs,1H),7.31(s,1H),7.04(d,J=8.0Hz,1H),6.90(d,J=8.0Hz,1H),6 .12(s,2H),4.88(brs,1H),3.95-3.92(m,1H),3.79-3.75(m,1H),3.57-3.48( m,1H),3.01-2.98(m,1H),2.85-2.80(m,1H),2.26(s,3H),2.24(s,3H),1.91- 1.89(m,1H),1.75(s,3H),1.72-1.69(m,1H),1.66(s,3H),1.50-1.32(m,2H).

[0326] Embodiment 11

[0327] (R)-(2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(3-hydroxypiperidin-1-yl)methanone

[0328]

[0329] (1) Tert-butyl (R)-(tert-butyloxycarbonyl)(3-(3-hydroxypiperidine-1-carbonyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate

[0330] Intermediate 2 (40 mg, 0.07 mmol), N,N-diisopropylethylamine (45 mg, 0.35 mmol) and HATU (53 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (2 mL), (R)-piperidin-3-ol (21 mg, 0.21 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction solution was added to a saturated sodium bicarbonate solution (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with a saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 7) to give the title compound (18 mg, light yellow solid), yield: 39%. MS (ESI): m / z 653.1 [M+H] + .

[0331] (2) (R)-(2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(3-hydroxypiperidin-1-yl)methanone

[0332] Dissolve (R)-(tert-butyloxycarbonyl)(3-(3-hydroxypiperidine-1-carbonyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamic acid tert-butyl ester (18 mg, 0.03 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir the reaction at room temperature for 1.5 hours. The reaction solution was slowly added to a saturated aqueous sodium bicarbonate solution (20 mL), and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with a saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Prep-HPLC to give the title compound (2.0 mg, white solid), yield: 18%. MS (ESI): m / z 409.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ9.48(s,1H),7.31(s,1H),7.05(d,J=8.0Hz,1H),6.90(d,J=8.0Hz,1H),6.1 2(s,2H),4.89-4.88(m,1H),3.95-3.92(m,1H),3.81-3.72(m,1H),3.56-3.50 (m,1H),3.02-2.97(m,1H),2.86-2.80(m,1H),2.26(s,3H),2.24(s,3H),1.91 -1.88(m,1H),1.75(s,3H),1.71-1.70(m,1H),1.66(s,3H),1.47-1.41(m,2H).

[0333] Example 12

[0334] (2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(3-amino-1H-pyrazol-1-yl)methanone

[0335]

[0336] Referring to the method of Example 11, in step 1, intermediate 2 and 1H-pyrazole-3-amine were used as raw materials, and the title compound (2.1 mg, white solid) was obtained through similar steps. MS (ESI): m / z 391.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.53(s,1H),8.21(s,1H),8.15(d,J=2.8Hz,1H),7.71(s,2H),7.08(d,J=8.4Hz,1H),6.93(d,J=8 .4Hz,1H),5.88(d,J=2.8Hz,1H),5.51(s,2H),2.26(s,3H),2.25(s,3H),1.79(s,3H),1.70(s,3H).

[0337] Example 13

[0338] (2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)methanone

[0339]

[0340] Referring to the method of Example 11, in step 1, intermediate 2 and (3S,4S)-pyrrolidine-3,4-diol were used as raw materials, and the title compound (5.0 mg, white solid) was obtained through similar steps. MS (ESI): m / z 411.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.47(s,1H),7.33(s,1H),7.04(d,J=8.4Hz,1H),6.90(d,J=8.4Hz,1H),6.06(s,2H),5.09(d,J=3.2H z,2H),3.95(s,2H),3.84-3.81(m,2H),3.25-3.22(m,2H),2.26(s,3H),2.24(s,3H),1.77-1.64(m,6H).

[0341] Embodiment 14

[0342] 2-Amino-N-hydroxy-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0343]

[0344] (1) tert-butyl (3-((benzyloxy)carbamoyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl ester-1H-pyrrolo[2,3-b]pyridin-2-yl)(tert-butoxycarbonyl)carbamate

[0345] Dissolve intermediate 1 (200 mg, 0.37 mmol), phosphorus oxychloride (113 mg, 0.74 mmol) and pyridine (146 mg, 1.85 mmol) in dichloromethane (5 mL) and stir at room temperature for 10 minutes. Slowly add O-benzylhydroxylamine (137 mg, 1.11 mmol) and continue to stir at room temperature for 1 hour. The reaction solution is concentrated and the residue is purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain the title compound (40 mg, white solid), yield: 17%. MS (ESI): m / z 645.1 [M+H] + .

[0346] (2) 2-amino-N-hydroxy-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0347] Dissolve tert-butyl (3-((benzyloxy)carbamoyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)(tert-butoxycarbonyl)carbamate (40 mg, 0.06 mmol) in dichloromethane (2 mL), add boron tribromide (2 mL), and stir at room temperature for 3 hours. The reaction solution was slowly added to a saturated sodium bicarbonate aqueous solution (10 mL), and the dichloromethane was removed by concentration under reduced pressure. The residue was purified by reverse phase column to obtain a crude product, and then purified by Prep-HPLC to obtain the title compound (5.2 mg, beige solid), yield: 25%. MS (ESI): m / z 341.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.70(s,1H),9.49(s,1H),8.42(s,1H),7.69(s,1H),7.05(d,J=7.6Hz,1H),6.90 (d,J=8.0Hz,1H),6.59(s,2H),2.26(s,3H),2.24(s,3H),1.74(s,3H),1.65(s,3H).

[0348] Embodiment 15

[0349] 3-(2-amino-5,6-dimethyl-3-(4H-1,2,4-triazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2,4-dimethylphenol

[0350]

[0351] (1) tert-butyl (tert-butoxycarbonyl)(3-formyl-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethylester-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate

[0352] Intermediate 1 (100 mg, 0.19 mmol) and ammonium chloride (20 mg, 0.38 mmol) were dissolved in N, N-dimethylformamide (5 mL), HATU (144 mg, 0.38 mmol) and N, N-diisopropylethylamine (74 mg, 0.57 mmol) were added, and the mixture was stirred at room temperature overnight. Water (20 mL) was added to the reaction system, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (66 mg, white solid), yield: 66%. MS (ESI): m / z 539.1 [M+H] + .

[0353] (2) tert-Butyl (E)-(tert-butoxycarbonyl)(3-(((dimethylamino)methylene)carbamoyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate

[0354] Dissolve tert-butyl (tert-butoxycarbonyl)(3-formyl-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethylester-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate (66 mg, 0.12 mmol) and N,N-dimethylformamide dimethyl acetal (43 mg, 0.36 mmol) in toluene (5 mL) and react at 100°C for 3 hours. The reaction solution was concentrated and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (68 mg, yellow solid) in a yield of 93%. MS (ESI): m / z 594.1 [M+H] + .

[0355] (3) tert-butyl (tert-butoxycarbonyl)(1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-3-(4H-1,2,4-triazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate

[0356] Dissolve tert-butyl (E)-(tert-butoxycarbonyl)(3-(((dimethylamino)methylene)carbamoyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate (60 mg, 0.1 mmol) and 80% hydrazine hydrate (0.5 mL) in acetic acid (5 mL) and react at 90°C for 1 hour. The reaction solution was concentrated to obtain the title compound (57 mg, containing the product of two Boc removal, colorless oil). MS (ESI): m / z 563.1 [M+H] + .

[0357] (4) 3-(2-amino-5,6-dimethyl-3-(4H-1,2,4-triazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2,4-dimethylphenol

[0358] Dissolve tert-butyl (tert-butyloxycarbonyl)(1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-3-(4H-1,2,4-triazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate (64 mg, 0.11 mmol) in dichloromethane (2 mL), add boron tribromide (1 mL), and stir at room temperature for 2 hours. The reaction solution was slowly added to water (10 mL), and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Prep-HPLC to give the title compound (9 mg, white solid) in a yield of 23%. MS (ESI): m / z 349.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ13.68-13.43(m,1H),9.47(s,1H),8.52-8.17(m,1H),8.09-7.83(m,1H),7.06(d,J=8.0Hz,1H ),6.91(d,J=8.4Hz,1H),6.55-6.06(m,2H),2.30(s,3H),2.28(s,3H),1.78(s,3H),1.69(s,3H).

[0359] Example 16

[0360] 3-(2-amino-3-(5-amino-1,3,4-oxadiazol-2-yl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-1-yl)-2,4-dimethylphenol

[0361]

[0362] (1) Benzyl 2-(2-(bis(tert-butoxycarbonyl)amino)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)hydrazine-1-carboxylate

[0363] Intermediate 1 (100 mg, 0.19 mmol) and benzyl hydrazinecarboxylate (63 mg, 0.38 mmol) were dissolved in N, N-dimethylformamide (5 mL), HATU (144 mg, 0.38 mmol) and N, N-diisopropylethylamine (70 mg, 0.54 mmol) were added, and the mixture was stirred at room temperature overnight. Water (20 mL) was added to the reaction system, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (100 mg, colorless oil), yield: 79%. MS (ESI): m / z 688.1 [M+H] + .

[0364] (2) tert-butyl (tert-butyloxycarbonyl)(3-(hydrazinecarbonyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate

[0365] Benzyl 2-(2-(bis(tert-butoxycarbonyl)amino)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)hydrazine-1-carboxylate (50 mg, 0.07 mmol) was dissolved in methanol (5 mL), 10% palladium carbon (10 mg) was added, and the mixture was reacted at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain the title compound (40 mg, colorless oil). MS (ESI): m / z 554.1 [M+H] + .

[0366] (3) tert-butyl (3-(5-amino-1,3,4-oxadiazol-2-yl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)(tert-butyloxycarbonyl)carbamate

[0367] Dissolve tert-butyl (tert-butyloxycarbonyl)(3-(hydrazinecarbonyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate (40 mg, 0.07 mmol) in ethanol (5 mL), add cyanogen bromide (7 mg, 0.07 mmol) and potassium bicarbonate (7 mg, 0.09 mmol), and react at 50°C for 3 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (14 mg, colorless oil). Yield: 34.6%. MS (ESI): m / z 579.1 [M+H] + .

[0368] (4) 3-(2-amino-3-(5-amino-1,3,4-oxadiazol-2-yl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-1-yl)-2,4-dimethylphenol

[0369] Dissolve tert-butyl (3-(5-amino-1,3,4-oxadiazol-2-yl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)(tert-butoxycarbonyl)carbamate (14 mg, 0.024 mmol) in dichloromethane (3 mL), add boron tribromide (0.5 mL), and react at room temperature for 3 hours. The reaction solution was slowly added dropwise to a saturated sodium bicarbonate aqueous solution (30 mL), dichloromethane (10 mL) was added to the aqueous phase, and filtered to obtain a solid crude product, which was purified by Prep-HPLC to obtain the title compound (2.6 mg, white solid), yield: 30%. MS (ESI): m / z 365.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.52(s,1H),7.62(s,1H),7.07(d,J=8.0Hz,1H),6.92(d,J=8.4Hz,1H),6. 83(s,2H),6.18(s,2H),2.29(s,3H),2.28(s,3H),1.77(s,3H),1.68(s,3H).

[0370] Embodiment 17

[0371] 2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-N-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0372]

[0373] (1) 3-(2-(bis(tert-butoxycarbonyl)amino)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethylester-1H-pyrrolo[2,3-b]pyridine-3-carboxamido)-1H-pyrazole-1-carboxylic acid tert-butyl ester

[0374] Intermediate 1 (108 mg, 0.2 mmol) and tert-butyl 3-amino-1H-pyrazole-1-carboxylate (110 mg, 0.6 mmol) were dissolved in anhydrous dichloromethane (5 mL), and pyridine (79 mg, 1 mmol) and phosphorus oxychloride (61 mg, 0.4 mmol) were added in sequence. After 5 minutes, tert-butyl 3-amino-1H-pyrazole-1-carboxylate (110 mg, 0.6 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 65 / 35) to obtain the title compound (60 mg, colorless oil), with a yield of 42.5%. MS (ESI): m / z 705.1 [M+H] + .

[0375] (2) 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-N-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0376] Dissolve tert-butyl 3-(2-(bis(tert-butoxycarbonyl)amino)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamido)-1H-pyrazole-1-carboxylate (60 mg, 0.085 mmol) in dichloromethane (5 mL), add boron tribromide (1 g, 4 mmol), and stir at room temperature for 3 hours. The reaction solution was slowly added dropwise to a saturated sodium bicarbonate aqueous solution (40 mL), and flocculent solids gradually precipitated in the aqueous phase. After standing for 10 minutes, filter. The obtained solid crude product was purified by Prep-HPLC to obtain the title compound (8.2 mg, white solid), yield: 24.8%. MS (ESI): m / z 391.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.80(s,1H),7.85(s,1H),7.58(s,1H),7.06(d,J=8.4Hz,1H),6.92(d,J=8.0Hz, 1H),6.76(s,2H),6.48(s,1H),2.31(s,3H),2.27(s,3H),1.77(s,3H),1.68(s,3H).

[0377] Embodiment 18

[0378] 2-Amino-1-(2,6-dimethyl-3-sulfamoylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0379]

[0380] (1) 2-Ethylhexyl 3-((2,4-dimethyl-3-nitrophenyl)thio)propionate

[0381] 1-Bromo-2,4-dimethyl-3-nitrobenzene (1.15 g, 5.0 mmol) and 2-ethylhexyl 3-mercaptopropionate (1.31 g, 6 mmol) were dissolved in 1,4-dioxane (20 mL). Tris(dibenzylideneacetone)dipalladium (229 mg, 0.25 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (289 mg, 0.5 mmol) and N,N-diisopropylethylamine (1.29 g, 10 mmol) were added, and the mixture was heated to 100°C under nitrogen protection for 16 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 93 / 7) to obtain the title compound (1.83 g, orange oil), yield: 100%.

[0382] (2) 2,4-Dimethyl-3-nitrobenzenethiol

[0383] 2-Ethylhexyl 3-((2,4-dimethyl-3-nitrophenyl)thio)propanoate (1.88 g, 5.1 mmol) was dissolved in ethanol (30 mL), potassium tert-butoxide (1.17 g, 15.3 mmol) was added under ice bath, and the reaction was stirred at room temperature for 16 hours. After the reaction solution was concentrated, it was poured into water (100 mL), and the pH was adjusted to <3 with 1M dilute hydrochloric acid aqueous solution, and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, washed with saturated brine (75 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (750 mg, orange oil), yield: 80%.

[0384] (3) Benzyl (2,4-dimethyl-3-nitrophenyl) sulfide

[0385] Dissolve 2,4-dimethyl-3-nitrobenzenethiol (732 mg, 4.0 mmol) in acetonitrile (20 mL), add potassium carbonate (1.1 g, 8.0 mmol) and benzyl bromide (752 mg, 4.4 mmol), and stir at room temperature for 16 hours. The reaction solution is concentrated, and the residue is purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound (900 mg, light yellow solid), yield: 82%.

[0386] (4) 3-(Benzylthio)-2,6-dimethylaniline

[0387] Dissolve benzyl (2,4-dimethyl-3-nitrophenyl) sulfide (273 mg, 1 mmol) in ethanol (8 mL), add water (4 mL), reduced iron powder (168 mg, 3 mmol) and ammonium chloride (160 mg, 3 mmol), and heat the mixture to 80 ° C and stir for 3 hours. The reaction solution is filtered through diatomaceous earth and the filtrate is concentrated. The residue is purified by column chromatography (dichloromethane / methanol = 99 / 1) to obtain the title compound (200 mg, colorless oil), yield: 82%. MS (ESI): m / z 244.0 [M+H] + .

[0388] (5) N-(3-(Benzylthio)-2,6-dimethylphenyl)-3-bromo-5,6-dimethylpyridin-2-amine

[0389] 3-(Benzylthio)-2,6-dimethylaniline (200 mg, 0.8 mmol) was dissolved in ethylene glycol dimethyl ether (10 mL), and 2,3-dibromo-5,6-dimethylpyridine (253 mg, 0.96 mmol), tris(dibenzylideneacetone)dipalladium (73 mg, 0.08 mmol), cesium carbonate (652 mg, 2.0 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (93 mg, 0.16 mmol) were added. The mixture was heated to 90 ° C and stirred for 16 hours under nitrogen protection. The reaction solution was concentrated and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain the title compound (210 mg, light yellow solid), yield: 61.5%. MS (ESI): m / z 426.9 [M+H] + .

[0390] (6) 2-amino-1-(3-(benzylthio)-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0391] Malononitrile (66 mg, 1 mmol) was dissolved in ethylene glycol dimethyl ether (10 mL), sodium hydride (80 mg, 2 mmol, 60%) was added, and the mixture was stirred at room temperature for 1 hour. N-(3-(benzylthio)-2,6-dimethylphenyl)-3-bromo-5,6-dimethylpyridin-2-amine (213 mg, 0.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (41 mg, 0.05 mmol) were added. The mixture was heated to 95°C and stirred for 16 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (116 mg, yellow oil), yield: 56%. MS (ESI): m / z 413.0 [M+H] + .

[0392] (7) tert-Butyl (tert-butyloxycarbonyl)(1-(3-(benzylthio)-2,6-dimethylphenyl)-3-cyano-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate

[0393] 2-Amino-1-(3-(benzylthio)-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (116 mg, 0.28 mmol) was dissolved in tetrahydrofuran (5 mL), and di-tert-butyl dicarbonate (183 mg, 0.84 mmol), triethylamine (85 mg, 0.84 mmol) and 4-dimethylaminopyridine (4 mg, 0.03 mmol) were added, and the mixture was reacted at room temperature for 3 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 85 / 15) to give the title compound (210 mg, light yellow solid), yield: 55.6%. MS (ESI): m / z 613.1 [M+H] + .

[0394] (8) tert-butyl (tert-butyloxycarbonyl)(1-(3-(chlorosulfonyl)-2,6-dimethylphenyl)-3-cyano-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate

[0395] Dissolve tert-butyl (tert-butyloxycarbonyl)(1-(3-(benzylthio)-2,6-dimethylphenyl)-3-cyano-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate (61 mg, 0.1 mmol) in a mixed solvent (acetonitrile / acetic acid / water = 40 / 1.5 / 1, 10 mL), add dichlorodimethylhydantoin (40 mg, 0.2 mmol) under ice bath, and keep ice bath for 3 hours. After the reaction solution is concentrated, it is diluted with dichloromethane (20 mL), and saturated sodium bicarbonate (20 mL) is added dropwise under ice bath. After stirring for 15 minutes, the liquids are separated. The organic phase is washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (59 mg, colorless oil), which is directly used in the next step.

[0396] (9) tert-butyl (tert-butyloxycarbonyl)(3-cyano-1-(2,6-dimethyl-3-sulfamoylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate

[0397] Dissolve tert-butyl (tert-butyloxycarbonyl)(1-(3-(chlorosulfonyl)-2,6-dimethylphenyl)-3-cyano-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate (59 mg, 0.1 mmol) in tetrahydrofuran (4 mL), add concentrated aqueous ammonia (1 mL), and react at room temperature for 3 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate=60 / 40) to obtain the title compound (40 mg, white solid), yield: 70%. MS (ESI): m / z 570.0 [M+H] + .

[0398] (10) 3-(2-amino-3-cyano-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-1-yl)-2,4-dimethylbenzenesulfonamide

[0399] Dissolve tert-butyl (tert-butyloxycarbonyl)(3-cyano-1-(2,6-dimethyl-3-sulfamoylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate (17 mg, 0.03 mmol) in dichloromethane (2 mL), add boron tribromide (0.5 mL), and react at room temperature for 1 hour. Slowly add the reaction solution dropwise to a saturated sodium bicarbonate aqueous solution (10 mL). The aqueous phase is extracted with dichloromethane (2 x 10 mL), and the organic phases are combined and concentrated to give the title compound (15 mg, white solid), which is used directly in the next step. MS (ESI): m / z 370.0 [M+H] + .

[0400] (11) 2-Amino-1-(2,6-dimethyl-3-sulfamoylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0401] 3-(2-amino-3-cyano-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-1-yl)-2,4-dimethylbenzenesulfonamide (11 mg, 0.03 mmol) was dissolved in methanesulfonic acid (1 mL) and concentrated sulfuric acid (0.5 mL), and heated to 80°C for 1 hour. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (20 mL), filtered to obtain a flocculent solid, dissolved in a small amount of methanol and purified by Prep-HPLC to obtain the title compound (1 mg, white solid), yield: 9.5%. MS (ESI): m / z 388.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ7.96(d,J=8.4Hz,1H),7.86(s,1H),7.48(s,2H),7.45(d,J=8.4Hz,1H),6. 88(s,2H),6.68(s,2H),2.27(s,3H),2.24(s,3H),2.01(s,3H),1.92(s,3H).

[0402] Embodiment 19

[0403] 2-Amino-1-(2,6-dimethyl-3-(S-methylsulfonylimino)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0404]

[0405] (1) (2,4-Dimethyl-3-nitrophenyl) methyl sulfide

[0406] 2,4-dimethyl-3-nitrobenzenethiol (915 mg, 5 mmol, step 2 of Example 18) was dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (2.07 g, 15 mmol) and iodomethane (1.42 g, 10 mmol) were added, and the reaction was stirred at room temperature for 16 hours. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (2 x 25 mL). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (630 mg, yellow solid), yield: 63%.

[0407] (2) 2,6-Dimethyl-3-(methylthio)aniline

[0408] Dissolve (2,4-dimethyl-3-nitrophenyl) methyl sulfide (230 mg, 1.17 mmol) in ethanol (10 mL), add water (5 mL), reduced iron powder (197 mg, 3.51 mmol) and ammonium chloride (188 mg, 3.51 mmol), heat to 80 ° C and stir for 3 hours. The reaction solution is filtered with diatomaceous earth, the filtrate is concentrated, and the residue is purified by column chromatography (petroleum ether / ethyl acetate = 80 / 20) to obtain the title compound (140 mg, colorless oil), yield: 72%. MS (ESI): m / z 167.8 [M+H] + .

[0409] (3) 3-Bromo-N-(2,6-dimethyl-3-(methylthio)phenyl)-5,6-dimethylpyridin-2-amine

[0410] 2,6-Dimethyl-3-(methylthio)aniline (140 mg, 0.84 mmol) was dissolved in ethylene glycol dimethyl ether (10 mL), and 2,3-dibromo-5,6-dimethylpyridine (263 mg, 1 mmol), tris(dibenzylideneacetone)dipalladium (156 mg, 0.17 mmol), cesium carbonate (685 mg, 2.1 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (197 mg, 0.34 mmol) were added. The mixture was heated to 90 ° C and stirred for 16 hours under nitrogen protection. The reaction solution was concentrated and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 95 / 5) to obtain the title compound (180 mg, light yellow solid), yield: 61.0%. MS (ESI): m / z 350.9 [M+H] + .

[0411] (4) 2-amino-1-(2,6-dimethyl-3-(methylthio)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0412] Malononitrile (52 mg, 0.78 mmol) was dissolved in ethylene glycol dimethyl ether (8 mL), sodium hydride (63 mg, 1.56 mmol, 60%) was added, and the mixture was stirred at room temperature for 1 hour. 3-Bromo-N-(2,6-dimethyl-3-(methylthio)phenyl)-5,6-dimethylpyridin-2-amine (136 mg, 0.39 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (33 mg, 0.04 mmol) were added, and the mixture was heated to 95°C and stirred for 16 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 65 / 35) to obtain the title compound (77 mg, light yellow oil), yield: 60.6%. MS (ESI): m / z 337.0 [M+H] + .

[0413] (5) tert-butyl (tert-butyloxycarbonyl)(3-cyano-1-(2,6-dimethyl-3-(methylthio)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate

[0414] 2-Amino-1-(2,6-dimethyl-3-(methylthio)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (77 mg, 0.23 mmol) was dissolved in tetrahydrofuran (5 mL), and di-tert-butyl dicarbonate (150 mg, 0.69 mmol), triethylamine (70 mg, 0.69 mmol) and 4-dimethylaminopyridine (4 mg, 0.03 mmol) were added, and the mixture was reacted at room temperature for 3 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 90 / 10) to give the title compound (75 mg, white solid), yield: 61%. MS (ESI): m / z 537.0 [M+H] + .

[0415] (6) tert-butyl (tert-butyloxycarbonyl)(3-cyano-1-(2,6-dimethyl-3-(S-methylsulfonylimino)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate

[0416] Dissolve tert-butyl (tert-butyloxycarbonyl)(3-cyano-1-(2,6-dimethyl-3-(methylthio)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate (75 mg, 0.14 mmol) in methanol (6 mL), add iodobenzene acetate (95 mg, 0.3 mmol) and ammonium carbamate (16 mg, 0.21 mmol), stir at room temperature until the solution is clear, and continue to react for 1 hour. The reaction solution is concentrated, and the residue is purified by column chromatography (100% ethyl acetate) to obtain the title compound (40 mg, light yellow solid), yield: 56.4%. MS (ESI): m / z 568.0 [M+H] + .

[0417] (7) 2-Amino-1-(2,6-dimethyl-3-(S-methylsulfonylimino)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0418] Dissolve tert-butyl (tert-butyloxycarbonyl)(3-cyano-1-(2,6-dimethyl-3-(S-methylsulfonylimino)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate (28 mg, 0.05 mmol) in dichloromethane (2 mL), add boron tribromide (0.5 mL), and react at room temperature for 1 hour. Slowly add the reaction solution dropwise to a saturated sodium bicarbonate aqueous solution (10 mL). The aqueous phase is extracted with dichloromethane (2 x 10 mL), and the organic phases are combined and concentrated to give the title compound (17 mg, white solid), which is used directly in the next step. MS (ESI): m / z 368.0 [M+H] + .

[0419] (8) 2-amino-1-(2,6-dimethyl-3-(S-methylsulfonylimino)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0420] 2-Amino-1-(2,6-dimethyl-3-(S-methylsulfonylimino)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (18 mg, 0.05 mmol) was dissolved in methanesulfonic acid (1 mL) and concentrated sulfuric acid (0.5 mL), and heated to 80°C for 1 hour. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (20 mL), filtered to obtain a flocculent solid, dissolved in a small amount of methanol, and purified by Prep-HPLC to obtain the title compound (1.1 mg, white solid), yield: 6.4%. MS (ESI): m / z 386.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.10(d,J=8.0Hz,1H),7.87(s,1H),7.51(d,J=8.0Hz,1H),6.90(s,2H),6.68(s, 2H),4.34(s,1H),3.12(s,3H),2.27(s,3H),2.24(s,3H),2.20(s,3H),1.91(s,3H).

[0421] Embodiment 20

[0422] 2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-N-(2-(methylsulfonyl)ethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0423]

[0424] Referring to the method of Example 8, in step 1, intermediate 1 and 2-(methylsulfonyl)ethane-1-amine hydrochloride were used as raw materials, and the title compound (4.5 mg, white solid) was obtained through similar steps. MS (ESI): m / z 431.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ9.47(s,1H),7.80(s,1H),7.08-7.05(m,1H),7.05(d,J=8.0Hz,1H),6.90(d,J=8.0Hz,1H),6.68(s,2H), 3.77-3.72(m,2H),3.42(t,J=6.8Hz,2H),3.06(s,3H),2.28(s,3H),2.25(s,3H),1.74(s,3H),1.65(s,3H).

[0425] Embodiment 21

[0426] N-((1H-pyrazol-3-yl)methyl)-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0427]

[0428] Referring to the method of Example 8, in step 1, intermediate 1 and (1H-pyrazol-3-yl)methylamine were used as raw materials, and the title compound (11.0 mg, white solid) was obtained through similar steps. MS (ESI): m / z 405.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.50(s,1H),9.46(s,1H),7.85(s,1H),7.58(brs,1H),7.26(brs,1H),7.05(d,J=8.4Hz,1H),6.90(d,J=8. 0Hz,1H),6.67(s,2H),6.19(s,1H),4.50(d,J=5.6Hz,2H),2.28(s,3H),2.25(s,3H),1.74(s,3H),1.65(s,3H).

[0429] Embodiment 22

[0430] 2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-N-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0431]

[0432] Referring to the method of Example 8, in step 1, intermediate 1 and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol were used as raw materials, and the title compound (1.3 mg, white solid) was obtained through similar steps. MS (ESI): m / z 439.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ9.47(s,1H),7.73(s,1H),7.04(d,J=8.4Hz,1H),6.90(d,J=8.4Hz,1H),6.63(s,2H),6.42(d,J=8.0Hz,1H),4.63(t,J=5.6Hz,1H ),3.96-3.89(m,2H),3.26-3.22(m,3H),2.29(s,3H),2.25(s,3H),2.03-1.94(m,2H),1.74(s,3H),1.64(s,3H),1.48-1.44(m,2H).

[0433] Embodiment 23

[0434] 2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-N-(2-(S-methylsulfonyl)ethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0435]

[0436] (1) tert-butyl (tert-butyloxycarbonyl)(1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-3-((2-(methylthio)ethyl)carbamoyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate

[0437] Intermediate 1 (54 mg, 0.1 mmol) and 2-(methylthio)ethane-1-amine hydrochloride (26 mg, 0.2 mol) were dissolved in N,N-dimethylformamide (2 mL), HATU (76 mg, 0.2 mmol) and N,N-diisopropylethylamine (65 mg, 0.5 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was purified by reverse phase column (acetonitrile / water = 80 / 20) to obtain the title compound (40 mg, light yellow oil), yield: 65.6%. MS (ESI): m / z 613.1 [M+H] + .

[0438] (2) tert-butyl (tert-butyloxycarbonyl)(1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-3-((2-(S-methylsulfonylimino)ethyl)carbamoyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate

[0439] Dissolve tert-butyl (tert-butyloxycarbonyl)(1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-3-((2-(methylthio)ethyl)carbamoyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate (40 mg, 0.065 mmol) in methanol (5 mL), add diacetyl iodobenzene (45 mg, 0.14 mmol) and ammonium carbamate (8 mg, 0.1 mmol), and stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol=95 / 5) to obtain the title compound (25 mg, light yellow oil), yield: 59.5%. MS (ESI): m / z 644.1 [M+H] + .

[0440] (3) 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-N-(2-(S-methylsulfonyl)ethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0441] Dissolve tert-butyl (tert-butyloxycarbonyl)(1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-3-((2-(S-methylsulfonylimino)ethyl)carbamoyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate (25 mg, 0.04 mmol) in dichloromethane (3 mL), add boron tribromide (0.5 mL), and stir at room temperature for 3 hours. Slowly drop the reaction solution into a saturated sodium bicarbonate aqueous solution (20 mL), separate the organic phase and the flocs at the junction of the two phases, concentrate and dissolve in a small amount of methanol, and purify by Prep-HPLC to obtain the title compound (5.2 mg, white solid), yield: 31%. MS (ESI): m / z 430.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ9.48(s,1H),7.82(s,1H),7.27(t,J=5.6Hz,1H),7.05(d,J=8.0Hz,1H),6.90(d,J=8.0Hz,1H),6.69(s,2H),4.0 0(s,1H),3.79-3.74(m,2H),3.41-3.36(m,2H),3.01(s,3H),2.27(s,3H),2.25(s,3H),1.74(s,3H),1.65(s,3H).

[0442] Embodiment 24

[0443] 2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-N-(pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0444]

[0445] Referring to the method of Example 8, in step 1, intermediate 1 and tert-butyl 3-aminopyrrolidine-1-carboxylate were used as raw materials, and the title compound (2 mg, white solid) was obtained through similar steps. MS (ESI): m / z 394.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.50(brs,1H),7.71(s,1H),7.04(d,J=8.0Hz,1H),6.90(d,J=8.4Hz,1H),6.65(d,J=7.6Hz,1H),6.61(s,2H),4.39 (s,1H),3.02-2.99(m,2H),2.80-2.77(m,2H),2.29(s,3H),2.25(s,3H),2.04-1.99(m,2H),1.74(s,3H),1.65(s,3H).

[0446] Embodiment 25

[0447] 2-Amino-5,6-dimethyl-1-(5-methyl-2,2-dioxo-1,3-dihydrobenzo[c]isothiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0448]

[0449] (1) 1-Chloro-N-(4-methyl-3-nitrophenyl)methanesulfonamide

[0450] Dissolve 4-methyl-3-nitroaniline (2.0 g, 13.14 mmol) and chloromethanesulfonyl chloride (2.15 g, 14.46 mmol) in dichloromethane (100 mL), add triethylamine (2.0 g, 19.72 mmol) under ice bath, and stir at room temperature for 4 hours. After the reaction solution is concentrated, pour it into water (100 mL), wash the organic phase with saturated sodium chloride (100 mL), dry it with anhydrous sodium sulfate, filter it, and concentrate it. The residue is purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the title compound (800 mg, yellow solid), yield: 23%.

[0451] (2) 1-Chloro-N-(4-methoxybenzyl)-N-(4-methyl-3-nitrophenyl)methanesulfonamide

[0452] 1-Chloro-N-(4-methyl-3-nitrophenyl)methanesulfonamide (800 mg, 3.02 mmol) was dissolved in N,N-dimethylformamide (20 mL), potassium carbonate (1.1 g, 8 mmol), 4-methoxybenzyl chloride (710 mg, 4.53 mmol) and tetrabutylammonium bromide (97 mg, 0.30 mmol) were added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain the title compound (760 mg, yellow solid), with a yield of 65%.

[0453] (3) 1-(4-methoxybenzyl)-5-methyl-4-nitro-1,3-dihydrobenzo[c]isothiazole 2,2-dioxide

[0454] Dissolve 1-chloro-N-(4-methoxybenzyl)-N-(4-methyl-3-nitrophenyl)methanesulfonamide (760 mg, 1.97 mmol) in dimethyl sulfoxide (20 mL), add sodium hydroxide (1.58 g, 39.50 mmol), and stir at room temperature for 2 hours. Pour the reaction solution into water (100 mL), add dichloromethane (100 mL) for extraction. The organic phase is washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (720 mg, yellow solid), yield: 100%.

[0455] (4) 4-Amino-1-(4-methoxybenzyl)-5-methyl-1,3-dihydrobenzo[c]isothiazole 2,2-dioxide

[0456] Dissolve 1-(4-methoxybenzyl)-5-methyl-4-nitro-1,3-dihydrobenzo[c]isothiazole 2,2-dioxide (720 mg, 2.07 mmol) in tetrahydrofuran (18 mL), add water (2 mL), reduced iron powder (346 mg, 6.20 mmol) and ammonium chloride (553 mg, 10.33 mmol), and stir at 80°C for 12 hours. The reaction solution was filtered through diatomaceous earth and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (645 mg, black solid), yield: 98%. MS (ESI): m / z 318.8 [M+H] + .

[0457] (5) 4-((3-bromo-5,6-dimethylpyridin-2-yl)amino)-1-(4-methoxybenzyl)-5-methyl-1,3-dihydrobenzo[c]isothiazole 2,2-dioxide

[0458] 4-Amino-1-(4-methoxybenzyl)-5-methyl-1,3-dihydrobenzo[c]isothiazole 2,2-dioxide (550 mg, 1.73 mmol) was dissolved in ethylene glycol dimethyl ether (10 mL), 2,3-dibromo-5,6-dimethylpyridine (686 mg, 2.59 mmol), tris(dibenzylideneacetone)dipalladium (172 mg, 0.17 mmol), cesium carbonate (1.41 g, 4.32 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (200 mg, 0.35 mmol) were added, and the mixture was heated to 90°C under nitrogen protection and stirred for 12 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain the title compound (220 mg, yellow solid), yield: 25%. MS (ESI): m / z 501.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.65(s,1H),7.53(s,1H),7.39(d,J=8.8Hz,2H),7.10(d,J=8.4Hz,1H),6.93(d,J=8.4Hz,2H) ,6.51(d,J=8.0Hz,1H),4.67(s,2H),4.44(s,2H),3.74(s,3H),2.11-2.10(m,6H),2.04(s,3H).

[0459] (6) 4-((3-bromo-5,6-dimethylpyridin-2-yl)amino)-5-methyl-1,3-dihydrobenzo[c]isothiazole 2,2-dioxide

[0460] 4-((3-bromo-5,6-dimethylpyridin-2-yl)amino)-1-(4-methoxybenzyl)-5-methyl-1,3-dihydrobenzo[c]isothiazole 2,2-dioxide (100 mg, 0.20 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3.0 mL) was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated to give the title compound (120 mg, yellow oil), yield: 100%. MS (ESI): m / z 381.8 [M+H] + .

[0461] (7) 2-Amino-5,6-dimethyl-1-(5-methyl-2,2-dioxo-1,3-dihydrobenzo[c]isothiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0462] Malononitrile (100 mg, 0.26 mmol) was dissolved in ethylene glycol dimethyl ether (10 mL), sodium hydride (19 mg, 0.78 mmol) was added, and 4-((3-bromo-5,6-dimethylpyridin-2-yl)amino)-5-methyl-1,3-dihydrobenzo[c]isothiazole 2,2-dioxide (100 mg, 0.26 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (21 mg, 0.03 mmol) were added after stirring at room temperature for 1 hour. The mixture was heated to 95°C under nitrogen protection and stirred for 12 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (110 mg, yellow solid), yield: 99%. MS (ESI): m / z 368.0 [M+H] + .

[0463] (8) 2-amino-5,6-dimethyl-1-(5-methyl-2,2-dioxo-1,3-dihydrobenzo[c]isothiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0464] 2-Amino-5,6-dimethyl-1-(5-methyl-2,2-dioxo-1,3-dihydrobenzo[c]isothiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (70 mg, 0.19 mmol) was dissolved in concentrated sulfuric acid (0.8 mL) and methanesulfonic acid (0.8 mL) and reacted at room temperature for 18 minutes. The reaction solution was slowly added dropwise to a saturated sodium hydroxide solution (5 mL), the pH was adjusted to 13, and the mixture was concentrated to a white solid. 5 mL of anhydrous methanol was added to dissolve the mixture, and the insoluble matter was filtered out and the solution was purified by Prep-HPLC to obtain the title compound (6.8 mg, white solid) with a yield of 9.3%. MS (ESI): m / z 386.0 [M+H] + . 1H NMR (400 MHz, DMSO-d 6 )δ10.68(brs,1H),7.85(s,1H),7.31(d,J=8.0Hz,1H),6.96(s,2H),6.89(d,J=8.0Hz,1H ),6.68(s,2H),4.16(d,J=16.4Hz,1H),3.93(d,J=16.8Hz,1H),2.26(s,6H),1.84(s,3H).

[0465] Embodiment 26

[0466] 2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-N-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0467]

[0468] Referring to the method of Example 17, in step 1, intermediate 1 and tert-butyl 4-amino-1H-pyrazole-1-carboxylate were used as raw materials, and the title compound (0.6 mg, white solid) was obtained through similar steps. MS (ESI): m / z 391.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.49(s,1H),8.65(s,1H),7.94(s,1H),7.82(brs,1H),7.06(d,J=8.0Hz,1H),6.9 1(d,J=8.4Hz,1H),6.71(s,2H),2.32(s,3H),2.27(s,3H),1.76(s,3H),1.67(s,3H).

[0469] Embodiment 27

[0470] 2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-N-((5-oxopyrrolidin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0471]

[0472] Referring to the method of Example 8, in step 1, intermediate 1 and 5-(aminomethyl)pyrrolidin-2-one were used as raw materials, and the title compound (12 mg, white solid) was obtained through similar steps. MS (ESI): m / z 422.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ9.48(s,1H),7.82-7.81(m,2H),7.05(d,J=8.0Hz,1H),6.94(t,J=5.6Hz,1H),6.90(d,J=8.4Hz,1H),6.64(s,2H),3.75(t, J=6.8Hz,1H),3.32-3.29(m,2H),2.29(s,3H),2.25(s,3H),2.18-2.08(m,3H),1.86-1.80(m,1H),1.74(s,3H),1.65(s,3H).

[0473] Embodiment 28

[0474] N-((1H-1,2,4-triazol-3-yl)methyl)-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0475]

[0476] Referring to the method of Example 8, in step 1, intermediate 1 and (1H-1,2,4-triazol-3-yl)methylamine were used as raw materials, and the title compound (2 mg, white solid) was obtained through similar steps. MS (ESI): m / z 406.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ13.71(s,1H),9.47(s,1H),7.90(s,1H),7.38(brs,1H),7.05(d,J=8.4Hz,1H),6.90(d,J=8.0 Hz,1H),6.67(s,2H),4.59(d,J=5.2Hz,2H),2.29(s,3H),2.26(s,3H),1.75(s,3H),1.66(s,3H).

[0477] Embodiment 29

[0478] 2-Amino-1-(2,6-dimethyl-3-(1H-1,2,4-triazol-5-yl)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0479]

[0480] (1) 3-Bromo-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole

[0481] 3-Bromo-4H-1,2,4-triazole (200 mg, 1.4 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (467 mg, 2.8 mmol) were dissolved in dimethyl sulfoxide (10 mL), and potassium tert-butoxide (403 mg, 4.2 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phases were combined and washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (170 mg, colorless oil), yield: 45%.

[0482] (2) 2-(2,4-dimethyl-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0483] Dissolve 1-bromo-2,4-dimethyl-3-nitrobenzene (2.3 g, 10 mmol) and diboronic acid pinacol ester (3.8 g, 10 mmol) in 1,4-dioxane (80 mL), and then add [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (731 mg, 1 mmol) and potassium acetate (2.9 g, 30 mmol). The mixture was heated to 100°C under nitrogen protection and stirred for overnight reaction. The reaction solution was concentrated and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound (1.8 g, white solid), yield: 65%.

[0484] (3) 3-(2,4-dimethyl-3-nitrophenyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole

[0485] 2-(2,4-dimethyl-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100 mg, 0.36 mmol) and 3-bromo-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole (100 mg, 0.36 mmol) were dissolved in 1,4-dioxane / water (10 mL / 2 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (29 mg, 0.036 mmol) and potassium carbonate (99 mg, 0.72 mmol) were added. The mixture was heated to 100°C under nitrogen protection and stirred for overnight reaction. The reaction solution was concentrated and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (90 mg, yellow oil) with a yield of 71%. MS (ESI): m / z 348.8 [M+H] + .

[0486] (4) 2,6-Dimethyl-3-(4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)aniline

[0487] 3-(2,4-dimethyl-3-nitrophenyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole (90 mg, 0.26 mmol) was dissolved in tetrahydrofuran / water (10 mL / 5 mL), iron powder (72 mg, 1.3 mmol) and ammonium chloride (70 mg, 1.3 mmol) were added, and the reaction was stirred at 80°C overnight. The reaction solution was filtered through diatomaceous earth, the filtrate was poured into water (10 mL), and extracted with ethyl acetate (2 x 10 mL). The organic phases were combined and washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (82 mg, yellow oil). MS (ESI): m / z 318.8 [M+H] + .

[0488] (5) 3-Bromo-N-(2,6-dimethyl-3-(4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)phenyl)-5,6-dimethylpyridin-2-amine

[0489] 2,6-dimethyl-3-(4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)aniline (80 mg, 0.25 mmol), 2,3-dibromo-5,6-dimethylpyridine (66 mg, 0.25 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (29 mg, 0.05 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol) and cesium carbonate (163 mg, 0.5 mmol) were dissolved in ethylene glycol dimethyl ether (8 mL). The reaction system was replaced with nitrogen three times, and heated to 90°C under nitrogen protection and stirred overnight. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain the title compound (50 mg, yellow oil), yield: 40%. MS (ESI): m / z 502.2 [M+H] + .

[0490] (6) 2-amino-1-(2,6-dimethyl-3-(4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0491] Malononitrile (13.2 mg, 0.2 mmol) and sodium hydride (12 mg, 0.3 mmol) were dissolved in ethylene glycol dimethyl ether (5 mL) and stirred at room temperature for 5 minutes. Then 3-bromo-N-(2,6-dimethyl-3-(4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)phenyl)-5,6-dimethylpyridin-2-amine (50 mg, 0.1 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (8.2 mg, 0.01 mmol) were added. The mixture was heated to 95 ° C under nitrogen protection and stirred overnight. The reaction solution was quenched by adding water (10 mL), and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (40 mg, yellow solid), yield: 82%. MS (ESI): m / z 488.0 [M+H] + .

[0492] (7) 2-amino-1-(2,6-dimethyl-3-(1H-1,2,4-triazol-5-yl)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0493] 2-Amino-1-(2,6-dimethyl-3-(4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)phenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (15 mg, 0.03 mmol) was dissolved in trifluoroacetic acid (5 mL), and a drop of water was added. The mixture was stirred at 80°C for 4 hours. The reaction solution was concentrated and the residue was purified by Prep-HPLC to give the title compound (1.2 mg, white solid). The yield was 10%. MS (ESI): m / z 376.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ14.16(s,1H),8.57(s,1H),7.94-7.86(m,2H),7.39(d,J=7.6Hz,1H),6.8 6(s,2H),6.67(s,2H),2.27(s,3H),2.24(s,3H),2.08(s,3H),1.91(s,3H).

[0494] Embodiment 30

[0495] 2-Amino-N-((2-aminothiazol-4-yl)methyl)-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0496]

[0497] (1) 4-(Aminomethyl)thiazol-2-amine

[0498] 4-(Chloromethyl)thiazol-2-amine (200 mg, 1.3 mmol) was dissolved in ammonia / methanol solution (10 mL) and stirred at room temperature for 36 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (174 mg, yellow oil), yield: 100%. MS (ESI): m / z 130.2 [M+H] + .

[0499] (2) tert-butyl (3-(((2-aminothiazol-4-yl)methyl)carbamoyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl ester-1H-pyrrolo[2,3-b]pyridin-2-yl)(tert-butyloxycarbonyl)carbamate

[0500] Intermediate 1 (60 mg, 0.11 mmol), HATU (84 mg, 0.22 mmol) and N,N-diisopropylethylamine (71 mg, 0.55 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 5 minutes. A solution of 4-(aminomethyl)thiazole-2-amine (17 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) was added and stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution (10 mL) was slowly added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (25 mg, yellow oil), yield: 35%. MS (ESI): m / z 651.3 [M+H] + .

[0501] (3) 2-amino-N-((2-aminothiazol-4-yl)methyl)-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0502] Tert-butyl (3-(((2-aminothiazol-4-yl)methyl)carbamoyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)(tert-butyloxycarbonyl)carbamate (25 mg, 0.04 mmol) was dissolved in dichloromethane (2 mL), and then boron tribromide (1 mL) was added and stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution (15 mL) was slowly added to the reaction solution, concentrated, and the residue was purified by reverse phase column (acetonitrile / water=53 / 47) to obtain a crude product. The crude product was purified by Prep-HPLC to obtain the title compound (4.7 mg, white solid), yield: 28%. MS (ESI): m / z 437.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.47(s,1H),7.87(s,1H),7.15(t,J=5.6Hz,1H),7.05(d,J=8.4Hz,1H),6.90(d,J=8.4Hz,1H),6.86(s, 2H),6.66(s,2H),6.21(s,1H),4.32(d,J=5.2Hz,2H),2.29(s,3H),2.25(s,3H),1.75(s,3H),1.66(s,3H).

[0503] Example 31 and Example 32

[0504] (R / S)-N-(1-(1H-pyrazol-3-yl)ethyl)-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0505]

[0506] Referring to the method of Example 8, in step 1, intermediate 1 and (1-(1H-pyrazol-3-yl)ethane-1-amine hydrochloride were used as raw materials, and similar steps were used to obtain the title compound isomer 1 (6.5 mg, white solid) and isomer 2 (8.0 mg, white solid), the structure of which was not determined. Isomer 1: MS (ESI): m / z 419.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ12.60(s,1H),9.48(s,1H),7.73(s,1H),7.60(brs,1H),7.05(d,J=8.4Hz,1H),6.96(d,J=8.0Hz,1H),6.90(d,J=8.0Hz,1H),6.65(s,2H),6.26(s,1H),5.30(s,1H),2.29(s,3H),2.25(s,3H),1.74(s,3H),1.67(s,3H),1.54(d,J=6.8Hz,3H). Isomer 2: MS (ESI): m / z 419.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.60(s,1H),9.48(s,1H),7.73(s,1H),7.60(brs,1H),7.05(d,J=8.4Hz,1H),6.96(d,J=8.0Hz,1H),6.90(d,J=8.4Hz ,1H),6.65(s,2H),6.26(s,1H),5.30(s,1H),2.29(s,3H),2.26(s,3H),1.76(s,3H),1.65(s,3H),1.54(d,J=6.8Hz,3H).

[0507] Embodiment 33

[0508] 2-Amino-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0509]

[0510] Referring to the method of Example 8, in step 1, intermediate 1 and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one were used as raw materials to obtain the title compound (28 mg, white solid) through similar steps. MS (ESI): m / z 460.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6)δ11.71(s,1H),9.48(s,1H),7.58(s,1H),7.45(t,J=6.0Hz,1H),7.04(d,J=8.4Hz,1H),6.90(d,J=8.4Hz,1H),6.65(s, 2H),5.92(s,1H),4.36(d,J=5.6Hz,2H),2.28(s,3H),2.26(s,3H),2.25(s,3H),2.13(s,3H),1.73(s,3H),1.64(s,3H).

[0511] Embodiment 34

[0512] 2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-N-((1-(2-hydroxyethyl)-1H-pyrazol-3-yl)methyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0513]

[0514] (1) 1-(2-Hydroxyethyl)-1H-pyrazole-3-carbonitrile

[0515] 1H-pyrazole-3-carbonitrile (400 mg, 4.3 mmol) was dissolved in acetonitrile (10 mL), bromoethanol (1.07 g, 8.6 mmol) and potassium carbonate (1.18 g, 8.6 mmol) were added, and the mixture was stirred at 50°C for 3 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (200 mg, colorless oil), yield: 34%. MS (ESI): m / z 138.0 [M+H] + .

[0516] (2) tert-Butyl (1-(2-hydroxyethyl)-1H-pyrazol-3-yl)methyl)carbamate

[0517] 1-(2-Hydroxyethyl)-1H-pyrazole-3-carbonitrile (200 mg, 1.4 mmol), di-tert-butyl dicarbonate (610 mg, 2.8 mmol) and nickel chloride hexahydrate (33 mg, 0.14 mmol) were dissolved in methanol (10 mL), sodium borohydride (372 mg, 9.8 mmol) was added at 0°C, and the reaction was stirred at room temperature overnight. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the title compound (200 mg, colorless oil), yield: 57%. MS (ESI): m / z 264.1 [M+Na] + .

[0518] (3) 2-(3-(Aminomethyl)-1H-pyrazol-1-yl)ethan-1-ol

[0519] Dissolve tert-butyl (1-(2-hydroxyethyl)-1H-pyrazol-3-yl)methyl)carbamate (50 mg, 0.2 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (5 mL), and stir at room temperature for 1 hour. The reaction solution is concentrated to obtain the title compound (29 mg, colorless oil). MS (ESI): m / z 142.1 [M+H] + .

[0520] (4) to (5) 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-N-((1-(2-hydroxyethyl)-1H-pyrazol-3-yl)methyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0521] Referring to the method of step 1 and step 2 of Example 8, wherein in step 1, intermediate 1 and 2-(3-(aminomethyl)-1H-pyrazol-1-yl)ethan-1-ol were used as raw materials, the title compound (3.9 mg, white solid) was obtained through similar steps. MS (ESI): m / z 449.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.47(s,1H),7.81(s,1H),7.34-7.30(m,2H),7.04(d,J=8.4Hz,1H),6.90(d,J=8.4Hz,1H),6.68(s,2H),6.17(d,J=1.6Hz,1H),5.01(t ,J=5.2Hz,1H),4.56(d,J=5.6Hz,2H),4.29(t,J=6.0Hz,2H),3.74(q,J=5.6Hz,2H),2.28(s,3H),2.24(s,3H),1.74(s,3H),1.65(s,3H).

[0522] Embodiment 35

[0523] 2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-N-((2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0524]

[0525] Referring to the method of Example 8, in step 1, intermediate 1 and 3-(aminomethyl)pyridin-2(1H)-one were used as raw materials, and the title compound (27.5 mg, white solid) was obtained through similar steps. MS (ESI): m / z 432.1 [M+H]+ . 1 H NMR (400 MHz, DMSO-d 6 )δ11.69(brs,1H),9.47(s,1H),7.84(s,1H),7.33-7.29(m,3H),7.04(d,J=8.8Hz,1H),6.90(d,J=8.4Hz,1H), 6.67(s,2H),6.20(t,J=6.4Hz,1H),4.30(d,J=6.0Hz,2H),2.28(s,3H),2.26(s,3H),1.75(s,3H),1.66(s,3H).

[0526] Embodiment 36

[0527] N-((1H-pyrrolo[2,3-b]pyridin-6-yl)methyl)-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0528]

[0529] Referring to the method of Example 8, in step 1, intermediate 1 and (1H-pyrrolo[2,3-b]pyridin-6-yl)methylamine were used as raw materials, and the title compound (28.6 mg, white solid) was obtained through similar steps. MS (ESI): m / z 455.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.52(brs,1H),9.48(s,1H),7.95(s,1H),7.91(d,J=8.0Hz,1H),7.49(t, J=6.0Hz,1H),7.40(dd,J=3.2Hz,2.8Hz,1H),7.11(d,J=8.0Hz,1H),7.05(d,J =8.0Hz,1H),6.90(d,J=8.0Hz,1H),6.69(s,2H),6.41(dd,J=3.2Hz,2.0Hz,1H ),4.68(d,J=6.0Hz,2H),2.30(s,3H),2.26(s,3H),1.76(s,3H),1.67(s,3H).

[0530] Embodiment 37

[0531] 2-Amino-N-((2-aminothiazol-5-yl)methyl)-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0532]

[0533] (1) tert-Butyl (5-cyanothiazol-2-yl)carbamate

[0534] Dissolve 2-aminothiazole-5-carbonitrile (500 mg, 4.0 mmol) and di-tert-butyl dicarbonate (1.7 g, 8.0 mmol) in tetrahydrofuran (15 mL), add triethylamine (808 mg, 8.0 mmol) and 4-dimethylaminopyridine (49 mg, 0.4 mmol), and stir at room temperature overnight. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (650 mg, yellow solid), yield: 72%. MS (ESI): m / z 170.0 [M+H-56] + .

[0535] (2) tert-Butyl (5-(aminomethyl)thiazol-2-yl)carbamate

[0536] Dissolve tert-butyl (5-cyanothiazol-2-yl)carbamate (150 mg, 0.67 mmol) and nickel chloride hexahydrate (14 mg, 0.06 mmol) in methanol (10 mL), add sodium borohydride (178 mg, 4.7 mmol) at 0°C, and stir at room temperature overnight. The reaction solution was concentrated, and the residue was purified by reverse phase column to obtain the title compound (30 mg, colorless oil), yield: 20%. MS (ESI): m / z 174.0 [M+H-56] + .

[0537] (3) to (4) 2-amino-N-((2-aminothiazol-5-yl)methyl)-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0538] Referring to the method of step 1 and step 2 of Example 8, wherein in step 1, intermediate 1 and tert-butyl (5-(aminomethyl)thiazol-2-yl)carbamate are used as raw materials, the title compound (3.7 mg, white solid) is obtained through similar steps. MS (ESI): m / z 437.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ9.46(s,1H),7.83(s,1H),7.33(t,J=5.6Hz,1H),7.04(d,J=8.0Hz,1H),6.90(d,J=8.0Hz,1H),6. 79(s,1H),6.67(s,4H),4.40(d,J=5.6Hz,2H),2.28(s,3H),2.24(s,3H),1.74(s,3H),1.65(s,3H).

[0539] Embodiment 38

[0540] (S)-N-((1H-pyrazol-3-yl)methyl)-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0541]

[0542] (1) tert-Butyl (S)-(3-(((1H-pyrazol-3-yl)methyl)carbamoyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)(tert-butyloxycarbonyl)carbamate

[0543] Intermediate 3 (55 mg, 0.1 mmol) and (1H-pyrazol-3-yl)methylamine (12 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (3 mL), HATU (76 mg, 0.2 mmol) and N,N-diisopropylethylamine (65 mg, 0.5 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 30 / 70) to give the title compound (50 mg, colorless oil), yield: 79%. MS (ESI): m / z 619.3 [M+H] + .

[0544] (2) (S)-N-((1H-pyrazol-3-yl)methyl)-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0545] Dissolve (S)-tert-butyl (3-(((1H-pyrazol-3-yl)methyl)carbamoyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)(tert-butyloxycarbonyl)carbamate (50 mg, 0.08 mmol) in dichloromethane (2 mL), add boron tribromide (1 mL), and stir at room temperature for 1 hour. The reaction solution was slowly added to a saturated sodium bicarbonate solution (20 mL), and a white solid precipitated in the solution. The filtered solid was purified by Prep-HPLC to give the title compound (13.8 mg, white solid), yield: 42%. MS (ESI): m / z 405.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ12.52(brs,1H),9.47(s,1H),7.86(s,1H),7.54(brs,1H),7.26(brs,1H),7.05(d,J=7.6Hz,1H),6.90(d,J=8 .0Hz,1H),6.67(s,2H),6.19(s,1H),4.50(d,J=5.6Hz,2H),2.28(s,3H),2.25(s,3H),1.74(s,3H),1.65(s,3H).

[0546] Embodiment 39

[0547] (S)-N-((1H-1,2,4-triazol-3-yl)methyl)-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0548]

[0549] (1) tert-Butyl (S)-(3-(((1H-1,2,4-triazol-3-yl)methyl)carbamoyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)(tert-butyloxycarbonyl)carbamate

[0550] Intermediate 3 (56 mg, 0.1 mmol) was dissolved in N, N-dimethylformamide (2 mL), HATU (76 mg, 0.2 mmol) and N, N-diisopropylethylamine (65 mg, 0.5 mmol) were added, and the mixture was stirred at room temperature for 5 minutes. A solution of (1H-1,2,4-triazol-3-yl)methylamine (12 mg, 0.12 mmol) in N, N-dimethylformamide (1 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution (10 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 90) to give the title compound (40 mg, yellow oil), yield: 63%. MS (ESI): m / z 620.4 [M+H] + .

[0551] (2) (S)-N-((1H-1,2,4-triazol-3-yl)methyl)-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0552] Tert-butyl (S)-(3-(((1H-1,2,4-triazol-3-yl)methyl)carbamoyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)(tert-butyloxycarbonyl)carbamate (40 mg, 0.06 mmol) was dissolved in dichloromethane (2 mL), and boron tribromide (1 mL) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was slowly added to a saturated sodium bicarbonate solution (15 mL), and a white solid precipitated in the solution. The solid obtained by filtration was purified by Prep-HPLC to obtain the title compound (9.3 mg, white solid), yield: 36%. MS (ESI): m / z 406.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ13.78-13.74(m,1H),9.48(s,1H),8.48-7.93(m,1H),7.88-7.85(m,1H),7.44-7.23(m,1H),7.05(d,J=8.0Hz,1H ),6.90(d,J=8.4Hz,1H),6.68-6.67(m,2H),4.61-4.56(m,2H),2.29(s,3H),2.26(s,3H),1.75(s,3H),1.66(s,3H).

[0553] Embodiment 40

[0554] (S)-2-Amino-N-hydroxy-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0555]

[0556] Referring to the method of Example 14, in step 1, intermediate 3 and O-benzylhydroxylamine were used as raw materials, and the title compound (3.2 mg, white solid) was obtained through similar steps. MS (ESI): m / z 341.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.70(d,J=1.2Hz,1H),9.48(s,1H),8.41(d,J=1.6Hz,1H),7.69(s,1H),7.05(d,J=8.4Hz, 1H), 6.90 (d, J = 8.0Hz, 1H), 6.58 (s, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 1.74 (s, 3H), 1.65 (s, 3H).

[0557] Embodiment 41

[0558] (S)-3-(2-amino-3-(5-amino-1,3,4-oxadiazol-2-yl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-1-yl)-2,4-dimethylphenol

[0559]

[0560] Referring to the method of Example 16, in step 1, intermediate 3 and benzyl hydrazinecarboxylate were used as raw materials, and the title compound (4.7 mg, white solid) was obtained through similar steps. MS (ESI): m / z 365.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.51(s,1H),7.62(s,1H),7.07(d,J=8.0Hz,1H),6.92(d,J=8.4Hz,1H),6.8 2(s,2H),6.17(s,2H),2.284(s,3H),2.281(s,3H),1.77(s,3H),1.68(s,3H).

[0561] Embodiment 42

[0562] (S)-2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-N-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0563]

[0564] Referring to the method of Example 17, in step 1, intermediate 3 and tert-butyl 3-amino-1H-pyrazole-1-carboxylate were used as raw materials, and the title compound (0.9 mg, white solid) was obtained through similar steps. MS (ESI): m / z 391.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.30(s,1H),9.49(s,1H),8.77(s,1H),7.85(s,1H),7.59(s,1H),7.06(d,J=8.0Hz,1H),6.91 (d,J=8.0Hz,1H),6.76(s,2H),6.49(s,1H),2.31(s,3H),2.27(s,3H),1.77(s,3H),1.68(s,3H).

[0565] Embodiment 43

[0566] (S)-N-((1,2,4-oxadiazol-3-yl)methyl)-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0567]

[0568] (1) tert-Butyl (S)-(3-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)(tert-butyloxycarbonyl)carbamate

[0569] Intermediate 3 (40 mg, 0.07 mmol) was dissolved in N,N-dimethylformamide (2 mL), HATU (53 mg, 0.14 mmol) and N,N-diisopropylethylamine (45 mg, 0.35 mmol) were added, and the mixture was stirred at room temperature for 5 minutes. A solution of (1,2,4-oxadiazole-3-yl)methylamine (11 mg, 0.08 mmol) in N,N-dimethylformamide (1 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution (15 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 60 / 40) to give the title compound (30 mg, yellow oil), yield: 65%. MS (ESI): m / z 621.1 [M+H] + .

[0570] (2) (S)-N-((1,2,4-oxadiazol-3-yl)methyl)-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0571] Tert-butyl (S)-(3-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)(tert-butyloxycarbonyl)carbamate (30 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL), and boron tribromide (1 mL) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was slowly added to a saturated sodium bicarbonate solution (15 mL), and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phases were combined and concentrated. The residue was purified by Prep-HPLC to give the title compound (7.8 mg, white solid), yield: 39%. MS (ESI): m / z 407.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.53(s,1H),9.48(s,1H),7.90(s,1H),7.47(t,J=6.0Hz,1H),7.05(d,J=8.0Hz,1H),6.90(d,J= 8.4Hz,1H),6.68(s,2H)4.65(d,J=6.0Hz,2H),2.29(s,3H),2.26(s,3H),1.75(s,3H),1.66(s,3H).

[0572] Embodiment 44

[0573] (S)-N-((1H-imidazol-4-yl)methyl)-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0574]

[0575] Referring to the method of Example 38, in step 1, intermediate 3 and (1H-imidazol-4-yl)methylamine were used as raw materials, and the title compound (9 mg, white solid) was obtained through similar steps. MS (ESI): m / z 405.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.90-11.71(m,1H),9.48(s,1H),7.82(s,1H),7.58(s,1H),7.25(s,0.5H),7.12(s,0.5H),7.05(d,J=8.4Hz,1H),6.95(s,0.5 H),6.90(d,J=8.4Hz,1H),6.79(s,0.5H),6.68(s,2H),4.42(d,J=3.6Hz,2H),2.28(s,3H),2.25(s,3H),1.74(s,3H),1.65(s,3H).

[0576] Embodiment 45

[0577] (S)-N-((1H-pyrazol-3-yl)methyl-d 2 )-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0578]

[0579] (1) 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonitrile

[0580] 1H-pyrazole-3-carbonitrile (400 mg, 4.3 mmol) was dissolved in dichloromethane (5 mL), (2-(chloromethoxy)ethyl)trimethylsilane (1.07 g, 6.4 mmol) and N,N-diisopropylethylamine (826 mg, 6.4 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain the title compound (560 mg, colorless oil). Yield: 58%. 1 H NMR (300 MHz, CDCl 3)δ7.67(d,J=1.8Hz,1H),6.92(d,J=1.8Hz,1H),5.64(s,2H),3.68-3.63(m,2H),0.99-0.94(m,2H),0.05(s,9H).

[0581] (2) (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methane-d 2 -amine

[0582] 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonitrile (300 mg, 1.3 mmol) was dissolved in tetrahydrofuran (10 mL), lithium aluminum deuteride (273 mg, 6.5 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water (20 mL) was slowly added to the reaction solution, and the aqueous phase was extracted three times with a mixed solvent of dichloromethane / methanol (20 mL / 2 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase column to give the title compound (190 mg, colorless oil), yield: 62%. MS (ESI): m / z 230.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ7.46(d,J=1.6Hz,1H),6.25(d,J=1.6Hz,1H),5.51(s,2H),3.60-3.56(m,2H),0.93-0.89(m,2H),0.03(s,9H).

[0583] (3) (S)-(1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-3-((1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methyl-d 2 tert-Butyl)carbamoyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)(tert-butoxycarbonyl)carbamate

[0584] Intermediate 3 (30 mg, 0.06 mmol) and (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methane-d 2-amine (20.6 mg, 0.09 mmol) was dissolved in N, N-dimethylformamide (5 mL), HATU (34.2 mg, 0.09 mmol) and N, N-diisopropylethylamine (15 mg, 0.12 mmol) were added, and the mixture was stirred at room temperature overnight. Water (20 mL) was added to the reaction system, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (35 mg, yellow oil), yield: 84%. MS (ESI): m / z 751.2 [M+H] + .

[0585] (4) (S)-N-((1H-pyrazol-3-yl)methyl-d 2 )-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0586] (S)-(1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-3-((1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methyl-d 2 )carbamoyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)(tert-butoxycarbonyl)carbamic acid tert-butyl ester (35 mg, 0.05 mmol) was dissolved in dichloromethane (3 mL), boron tribromide (0.5 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was slowly added dropwise to a saturated sodium bicarbonate solution (30 mL), the aqueous phase was extracted with dichloromethane / methanol (10 mL / 1 mL), the organic phase was concentrated, and the residue was purified by Pre-HPLC to obtain the title compound (8.6 mg, white solid), yield: 84%. MS (ESI): m / z 407.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.54(s,1H),9.47(s,1H),7.86(s,1H),7.62(s,1H),7.23(s,1H),7.05(d,J=8.0Hz,1H),6.90 (d,J=8.4Hz,1H),6.67(s,2H),6.19(s,1H),2.28(s,3H),2.25(s,3H),1.74(s,3H),1.65(s,3H).

[0587] Embodiment 46 to Embodiment 66

[0588] The preparation of Examples 46 to 66 refers to the method of Example 38, and the corresponding raw material amines and intermediate 3 are synthesized through similar steps.

[0589]

[0590]

[0591]

[0592]

[0593] The NMR data of the compounds of Examples 46 to 49 are as follows:

[0594] Embodiment 46: 1 H NMR (400 MHz, DMSO-d 6 )δ9.48(s,1H),7.87(s,1H),7.57(d,J=2.0Hz,1H),7.24(t,J=6.4Hz,1H),7.05(d,J=8.4Hz,1H),6.90(d,J=8.0Hz,1H),6. 67(s,2H),6.16(d,J=2.4Hz,1H),4.44(d,J=6.0Hz,2H),3.79(s,3H),2.28(s,3H),2.25(s,3H),1.74(s,3H),1.65(s,3H).

[0595] Embodiment 47: 1 H NMR (400 MHz, DMSO-d 6 )δ9.48(s,1H),8.37(s,1H),7.89(s,1H),7.25(t,J=6.0Hz,1H),7.05(d,J=8.4Hz,1H),6.90(d,J=8.4Hz, 1H),6.67(s,2H),4.51(d,J=5.6Hz,2H),3.82(s,3H),2.28(s,3H),2.25(s,3H),1.75(s,3H),1.66(s,3H).

[0596] Embodiment 48: 1 H NMR (400 MHz, DMSO-d 6)δ9.47(s,1H),7.84(s,1H),7.59(s,1H),7.37(s,1H),7.23(t,J=5.2Hz,1H),7.04(d,J=8.4Hz,1H),6.90(d,J=8 .4Hz,1H),6.67(s,2H),4.30(d,J=5.6Hz,2H),3.78(s,3H),2.28(s,3H),2.24(s,3H),1.73(s,3H),1.64(s,3H).

[0597] Embodiment 49: 1 H NMR (400 MHz, DMSO-d 6 )δ12.59(s,1H),9.48(s,1H),7.83(s,1H),7.63-7.47(m,2H),7.22(t,J=6.0Hz,1H),7.04(d,J=8.4Hz,1H),6 .90(d,J=8.4Hz,1H),6.67(s,2H),4.35(d,J=6.0Hz,2H),2.28(s,3H),2.24(s,3H),1.73(s,3H),1.64(s,3H).

[0598] Embodiment 67

[0599] (S)-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-N-((4-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0600]

[0601] (1) 4-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylic acid ethyl ester

[0602] Dissolve 4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (500 mg, 3.2 mmol) in dichloromethane (15 mL), add 2-(trimethylsilyl)ethoxymethyl chloride (802 mg, 4.8 mmol) and N,N-diisopropylethylamine (827 mg, 6.4 mmol), and react at room temperature for 3 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound (700 mg, colorless oil), yield: 76%. MS (ESI): m / z 307.0 [M+Na] + .

[0603] (2) (4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methanol

[0604] Dissolve 4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylic acid ethyl ester (200 mg, 0.7 mmol) in tetrahydrofuran (10 mL), add lithium aluminum hydride (40 mg, 1.0 mmol), and react at room temperature overnight. Add water (20 mL) to the reaction system, and extract the mixture with dichloromethane / methanol (20 mL / 2 mL). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (160 mg, colorless oil). MS (ESI): m / z 243.0 [M+H] + .

[0605] (3) 3-(Azidomethyl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0606] (4-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methanol (160 mg, 0.66 mmol) was dissolved in dichloromethane (10 mL), diphenylphosphoryl azide (182 mg, 0.66 mmol) and 1,8-diazobispiro[5.4.0]undec-7-ene (100 mg, 0.66 mmol) were added, and the mixture was reacted at 50°C overnight. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (50 mg, colorless oil), yield: 28%. MS (ESI): m / z 268.2 [M+H] + .

[0607] (4) (4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methanamine

[0608] 3-(Azidomethyl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (50 mg, 0.19 mmol) was dissolved in methanol (10 mL), 10% palladium on carbon (10 mg) was added, and the mixture was reacted at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated to give the title compound (46 mg, colorless oil), yield: 100%. MS (ESI): m / z 242.2 [M+H] + .

[0609] (5) (S)-tert-butyl (tert-butyloxycarbonyl)(1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-3-((4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate

[0610] Intermediate 3 (20 mg, 0.04 mmol) and (4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methanamine (19 mg, 0.08 mmol) were dissolved in N,N-dimethylformamide (5 mL), HATU (30.4 mg, 0.08 mmol) and N,N-diisopropylethylamine (10 mg, 0.08 mmol) were added, and the mixture was stirred at room temperature overnight. Water (20 mL) was added to the reaction system, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (20 mg, colorless oil) in a yield of 71%. MS (ESI): m / z 763.5 [M+H] + .

[0611] (6) (S)-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-N-((4-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0612] (S)-(tert-Butyloxycarbonyl)(1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-3-((4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamic acid tert-butyl ester (20 mg, 0.03 mmol) was dissolved in dichloromethane (3 mL), and boron tribromide (0.5 mL) was added. The mixture was reacted at room temperature for 3 hours. The reaction solution was slowly added dropwise to a saturated sodium bicarbonate aqueous solution (10 mL), extracted with dichloromethane / methanol (10 mL / 1 mL), the organic phase was concentrated, and the residue was purified by Prep-HPLC to give the title compound (4.9 mg, white solid), yield: 45%. MS (ESI): m / z 419.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.31(s,1H),9.48(s,1H),7.80(s,1H),7.43-7.11(m,2H),7.05(d,J=8.4Hz,1H),6.90(d,J=8.0Hz,1 H),6.68(s,2H),4.46(d,J=5.6Hz,2H),2.28(s,3H),2.25(s,3H),2.04(s,3H),1.74(s,3H),1.65(s,3H).

[0613] Embodiment 68

[0614] (S)-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-N-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0615]

[0616] (1) 5-(Azidomethyl)-1-methyl-1H-1,2,4-triazole

[0617] Dissolve (1-methyl-1H-1,2,4-triazol-5-yl)methanol (100 mg, 0.88 mmol) in dichloromethane (10 mL), add diphenylphosphoryl azide (243 mg, 0.88 mmol) and 1,8-diazobispiro[5.4.0]undec-7-ene (134 mg, 0.88 mmol), and react at 50°C overnight. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (100 mg, yellow oil), yield: 82%. MS (ESI): m / z 139.0 [M+H] + .

[0618] (2) tert-Butyl ((1-methyl-1H-1,2,4-triazol-5-yl)methyl)carbamate

[0619] Dissolve 5-(azidomethyl)-1-methyl-1H-1,2,4-triazole (100 mg, 0.72 mmol) in methanol (10 mL), add 10% palladium on carbon (10 mg) and di-tert-butyl dicarbonate (316 mg, 1.4 mmol), and react at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated, and the residue was purified by column chromatography (100% ethyl acetate) to obtain the title compound (80 mg, colorless oil), yield: 52%. MS (ESI): m / z 234.9 [M+Na] + .

[0620] (3) (1-methyl-1H-1,2,4-triazol-5-yl)methanamine

[0621] Dissolve tert-butyl ((1-methyl-1H-1,2,4-triazol-5-yl)methyl)carbamate (40 mg, 0.19 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (3 mL), and react at room temperature for 2 hours. The reaction solution is concentrated to obtain the title compound (20 mg, crude product). MS (ESI): m / z 113.2 [M+H] + .

[0622] (4) (S)-tert-butyl (tert-butyloxycarbonyl)(1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-3-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)carbamoyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate

[0623] Intermediate 3 (20 mg, 0.04 mmol) and (1-methyl-1H-1,2,4-triazol-5-yl)methylamine (9 mg, 0.08 mmol) were dissolved in N,N-dimethylformamide (5 mL), HATU (23 mg, 0.06 mmol) and N,N-diisopropylethylamine (10 mg, 0.08 mmol) were added, and the mixture was stirred at room temperature overnight. Water (20 mL) was added to the reaction system, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (7 mg, yellow oil), yield: 30%. MS (ESI): m / z 634.4 [M+H] + .

[0624] (5) (S)-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-N-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0625] Dissolve (S)-(tert-butyloxycarbonyl)(1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-3-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)carbamoyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamic acid tert-butyl ester (7 mg, 0.01 mmol) in dichloromethane (3 mL), add boron tribromide (0.5 mL), and react at room temperature for 1 hour. The reaction solution was slowly added dropwise to a saturated sodium bicarbonate aqueous solution (10 mL), extracted with dichloromethane / methanol (10 mL / 1 mL), and the organic phase was concentrated. The residue was purified by Prep-HPLC to give the title compound (1.3 mg, white solid), yield: 28%. MS (ESI): m / z 420.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ9.50(s,1H),7.90(s,1H),7.82(s,1H),7.47(t,J=5.6Hz,1H),7.05(d,J=8.4Hz,1H),6.90(d,J=8.0Hz, 1H), 6.70 (s, 2H), 4.59 (d, J = 5.6Hz, 2H), 3.94 (s, 3H), 2.29 (s, 3H), 2.25 (s, 3H), 1.74 (s, 3H), 1.65 (s, 3H).

[0626] Embodiment 69 to Embodiment 70

[0627] The preparation of Examples 69 to 70 refers to the method of Example 67 and is obtained through similar steps.

[0628]

[0629] Example 71 to Example 72

[0630] The preparation of Examples 71 to 72 was carried out by referring to the method of Example 68 and the preparations were obtained through similar steps.

[0631]

[0632] Embodiment 73 to Embodiment 123

[0633] The preparation of Examples 73 to 123 refers to the method of Example 38, and the corresponding raw material amines and intermediate 3 are synthesized through similar steps.

[0634]

[0635]

[0636]

[0637] Test Example 1: Kinase activity test

[0638] Compounds were serially diluted with DMSO in the 384PP Plate compound dilution plate, and 0.1 μL of compound was transferred to the 384 reaction microplate (Optiplate 384) using Echo, ensuring that the final DMSO content was 1% (duplicate). 5 μL of 2X MYT1 enzyme solution was added to each well of the 384 reaction microplate and incubated at 25°C for 10 minutes. Wells containing 1% DMSO and enzyme were used as High Controls, and wells containing 1% DMSO and buffer were used as Low Controls. 5 μL of 2X ATP and Unactive CDK1 solution were added to each well and incubated at 25°C for 180 minutes. (Final concentrations: 5 nM MYT1, 10 nM Unactive CDK1, 20 μM ATP). RLU (Relative luminescence unit) signals were read on a BMG (PHERAstar FSX) microplate reader.

[0639] The inhibition percentage of the compound-treated wells was normalized between High Control and Low Control (%inhibition = (RLU High Control - RLU compound reading) / (RLU High Control - RLU Low Control) * 100). Then, the four-parameter IC50 curve was fitted and analyzed by XLfit5.5.0, where IC50 is the compound concentration corresponding to 50% inhibition.

[0640] Among them, the positive compound RP-6306 (and its racemate) was prepared according to Example 182 (Example 181) of patent WO2021195781.

[0641] The results of each compound are shown in Table 1, wherein A represents <10 nM, B represents 10-100 nM, and C represents 100-1000 nM.

[0642] Table 1

[0643]

[0644]

[0645] Test Example 2: Cell test method

[0646] The proliferation inhibitory activity of the compounds on HCC1569 cells was tested by the CTG method.

[0647] The cells were seeded in a black bottom 96-well cell plate with 200 μL of cell suspension per well and placed in an incubator at 37°C and 5% CO 2Incubate overnight in an incubator; dilute the test compound to 10mM with 100% DMSO, and then dilute it 3 times to the 9th concentration. Take 5μL of the compound after gradient dilution and add it to 45μL of cell culture medium for secondary dilution. After mixing, take 2μL of the compound after secondary dilution and add it to the corresponding 200μL cell plate wells. Return the cell plate to the carbon dioxide incubator and incubate for 7 days. At this time, the compound concentration is 10μM to 1.52nM, and the DMSO concentration is 0.1%; after the incubation, discard 100μL of cell supernatant, add 60μL CTG to each well, and incubate at room temperature at 200rpm for 30 minutes; read the luminescence signal value in the BMG microplate reader. Use the nonlinear fitting formula to calculate the IC of the test compound 50 The results of each compound are shown in Table 2, where A represents <10 μM, B represents 10-100 μM, and C represents 100-1000 μM.

[0648] Table 2

[0649] Example IC50 38 A 39 A 40 A 41 A 46 A 47 A 48 A 68 A

Claims

1. A compound of formula (I): or a deuterated substance, a stereoisomer, a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof; in X1 is N or CR2, X2 is N or CH; L1 is -CO- or a chemical bond; When L1 is -CO-, R1 is -NR 11 R 12 ; R 11 , R 12 independently selected from H, -OH, -NH2, -C 0-3 Alkyl-R 13 , -C 3-6 Cycloalkyl-R 13 , and R 11 , R 12 At least one is H, or R 11 With R 12 and the N atom to which it is attached forms an optionally substituted 4-8 membered heterocyclic group; R 13 Selected from -SO2-R 14 , An optionally substituted 4-10 membered heterocyclyl; R 14 Selected from C 1-3 Alkyl, -NH2; When L1 is a chemical bond, R1 is an optionally substituted 5-6 membered heterocyclic group; R2 is selected from -OH, -SO2-R 14 、-N=SO(R 14 )2. An optionally substituted 5-6 membered heterocyclic group, R3 is selected from H, R5 is selected from halogen, C 1-3 Alkyl, or R2, R3 and the connected C atom form an optionally substituted 5-6 membered heterocyclic group, R5 is selected from halogen, C 1-3 Alkyl, or R2, R5 and the attached C atom form an optionally substituted 5-6 membered heterocyclic group, and R3 is selected from H; R4 is halogen, C 2-3 Alkynyl, cyano, C 1-3 Alkyl, 3-6 membered cycloalkyl; R6, R7 are independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl; The compound of formula (I) does not include 2. The compound according to claim 1, or its deuterated form, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate, characterized in that: It has the structure of formula (II): Preferably, the compound contains isomers of formula (IIA); 3. The compound according to claim 2, or its deuterated substance, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, characterized in that: It has the structure of formula (III): Preferably, the compound contains isomers of formula (IIIA); R 11 , R 12 independently selected from H, -OH, -NH2, -C 0-3 Alkyl-R 13 , -C 3-6 Cycloalkyl-R 13 , and R 11 , R 12 At least one is H, or R 11 With R 12 and the N atom to which it is attached forms an optionally R 16 substituted 4-8 membered heterocyclic group; R 13 Selected from -SO2-R 14 , Optional R 15 substituted 4-10 membered heterocyclyl; R 14 Selected from C 1-3 Alkyl, -NH2; R 15 Selected from oxo, halogen, hydroxyl, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, (hydroxy)-C 1-3 Alkyl, 3-6 membered cycloalkyl, -SO2-(C 1-3 alkyl); R 16 Selected from hydroxyl, -NH2; As a preference, R 13 Selected from -SO2-R 14 , Optional R 15 substituted 4-6 membered heterocycloalkyl, optionally substituted by R 15 substituted 5-6 membered heteroaryl; R 13 Preferred -SO2-R 14 , Optional R 15 Replaced R 13 More preferably -SO2-R 14 , Optional R 15 Replaced As a preference, R 11 With R 12 and the N atom to which it is connected forms a bond consisting of 0-2 R 16 substituted 4-6 membered heterocycloalkyl, or optionally substituted by 0-2 R 16 substituted 5-6 membered heteroaryl; more preferably, R 11 With R 12 and the N atom to which it is connected forms a bond consisting of 0-2 R 16 Replaced R4 is halogen, C 2-3 Alkynyl, cyano, C 1-3 Alkyl, 3-6 membered cycloalkyl, preferably methyl; R5 is selected from C 1-3 Alkyl, preferably methyl; R6, R7 are independently selected from H, halogen, C 1-3 Alkyl, C 1-3 The haloalkyl group is preferably H, methyl or trifluoromethyl.

4. The compound according to claim 3, or its deuterated form, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate, characterized in that: R 11 , R 12 independently selected from H, -OH, NH2, -C 1-3 Alkyl-SO2-R 14 , Optional R 15 Replaced And R 11 , R 12 At least one is H; or R 11 With R 12 and the N atom connected to it Best R 14 Selected from C 1-3 Alkyl, NH2; R 15 Selected from oxo, halogen, hydroxyl, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, (hydroxy)-C 1-3 Alkyl, 3-6 membered cycloalkyl, -SO2-(C 1-3 Alkyl), -SO2-NH2; Preferably, R 11 , R 12 independently selected from H, -OH, NH2, -(CH2)2-SO2-Me, -(CH2)2-SO2-NH2, More preferably -OH, 5. The compound according to claim 2, or its deuterated substance, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, characterized in that: It has the structure of formula (IV): Preferably, the compound contains isomers of formula (IVA); R1 is optionally replaced by R 17 substituted 5-membered heterocyclic group; R 17 is selected from amino, oxo or a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, preferably amino or oxo; R4 is halogen, C 2-3 Alkynyl, cyano, C 1-3 Alkyl, 3-6 membered cycloalkyl, preferably methyl; R5 is selected from C 1-3 Alkyl, preferably methyl; R6, R7 are independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, preferably H, methyl, trifluoromethyl; More preferably, R1 is optionally replaced by R 17 Replaced R1 is more preferably Furthermore, R1 is preferred 6. The compound according to claim 2, or its deuterated substance, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, characterized in that: It has the structure of formula (V): Preferably, the compound contains isomers of formula (VA); R2 is selected from -OH, -SO2-R 14 、-N=SO(R 14 )2. Optional R 18 Replaced R3 is selected from H, R5 is selected from halogen, C 1-3 Alkyl, preferably methyl; or R2 and R3 and the C atom to which they are connected form an optional R 18 Substituted 5-6 membered heterocyclic group, and connected in parallel with the benzene ring to form R5 is selected from halogen, C 1-3 Alkyl, preferably methyl; or R2 and R5 and the C atom to which they are connected form an optional R 18 Substituted 5-6 membered heterocyclic group, and connected in parallel with the benzene ring to form R3 is selected from H; R 14 Selected from C 1-3 Alkyl, NH2, preferably methyl, NH2; R 18 Selected from C 1-3 Alkyl, C 1-3 Haloalkyl; R4 is halogen, C 2-3 Alkynyl, cyano, C 1-3 Alkyl, 3-6 membered cycloalkyl, preferably methyl; R6, R7 are independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, preferably H or methyl.

7. The compound according to claim 6, or its deuterated form, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate, characterized in that: R2 is preferably -OH, -SO2-Me, -SO2-NH2, Optional R 18 Replaced More preferred R3 is selected from H; R5 is preferably methyl.

8. The compound according to claim 1, or its deuterated form, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate, wherein: It has the structure of formula (VI): Preferably, the compound contains isomers of formula (VIA); X1 is N or CR2, X2 is N or CH; R2 is -OH; R4 is halogen, C 2-3 Alkynyl, cyano, C 1-3 Alkyl, 3-6 membered cycloalkyl, preferably ethynyl, methyl, cyclopropyl; R5 is selected from halogen, C 1-3 Alkyl, preferably methyl; R6, R7 are independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, preferably H, methyl, trifluoromethyl; When X1 is CR2, X2 is CH, and R2 is -OH, R4 is not Cl or methyl.

9. The compound according to claim 1, or its deuterated substance, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, characterized in that: Include any of the following:

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, its deuterated substance, stereoisomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier thereof.

11. Use of the compound according to any one of claims 1 to 9, its deuterated product, stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating and / or preventing a PKMYT1-related disease.

12. The use according to claim 11, characterized in that: The PKMYT1-related disease is selected from solid tumors, especially solid tumors with CCNE1 amplification and / or FBXW7 mutation.

13. The use according to claim 11, characterized in that: The PKMYT1-related diseases are selected from endometrioid cancer, gastrointestinal cancer, colorectal cancer, esophageal cancer, breast cancer, and ovarian cancer, especially endometrioid cancer, gastrointestinal cancer, colorectal cancer, esophageal cancer, breast cancer, and ovarian cancer with CCNE1 amplification and / or FBXW7 mutation.

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