Fluoro-imidazopyridine compound as IRAK4 degradation agent and application of fluoro-imidazopyridine compound

Abstract

The invention provides a fluorinated imidazopyridine compound as an IRAK4 degradation agent and an application of the fluorinated imidazopyridine compound as the IRAK4 degradation agent. Specifically provided are a compound represented by formula (I), a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof. The compound provided by the invention is good in drug effect and can be used for preparing drugs for treating or preventing IRAK4 related diseases. # imgabs0 #

Description

[0001] This application claims the priority of Chinese patent application No. 202311008384.7 filed on August 9, 2023 and Chinese patent application No. 202410071644.3 filed on January 17, 2024. This application cites the full text of the above Chinese patent application. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to a class of fluoroimidazole pyridine compounds as IRAK4 degraders, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs and preparation methods thereof, as well as their use in preparing drugs for treating or preventing diseases related to IRAK4. Background Art

[0003] IRAK4, interleukin-1 receptor-associated kinase 4, is a serine / threonine-specific protein kinase with biologically important kinase activity and plays an important role in the kinase immune system. IRAK4 belongs to the IRAK family, which also includes IRAK1, IRAK2, IRAKM (I-RAK3), etc. The human IRAK-4 gene is located in the p11.12 region of the x chromosome and encodes a 52KDa ​​protein. Like other family members, the IRAK4 protein contains a serine-threonine kinase domain (KD) and a conserved death domain (DD) located at the N-terminus. It is a key molecule in the Toll-like receptor (TLRs) and interleukin 1 receptor (IL-1Rs) signaling pathways, and is involved in regulating intracellular signal cascades and inflammatory responses. TLRs are a family of transmembrane pattern recognition receptors that play a core role in innate immune signaling. The IL-1Rs family can initiate immune responses under the stimulation of a variety of IL-1 cytokines. However, traditional small molecule inhibitors are prone to drug resistance, and therefore, inhibiting IRAK4 kinase activity alone may not be sufficient to produce effective therapeutic effects.

[0004] PROTAC, or Proteolysis targeting chimera, is different from the technology of traditional small molecule inhibitors. Traditional small molecule inhibitors usually need to act on the active site of the target protein to inhibit its activity. PROTAC is a bifunctional small molecule. The PROTAC molecule includes an E3 ubiquitin ligase ligand and a target protein (POI) ligand. The two are connected by a linker, so that the target protein and the E3 ubiquitin ligase meet hand in hand, and the target protein is labeled with ubiquitin, and then the protein is degraded by the "cleaner" ubiquitin-proteasome pathway in the body. Therefore, compared with traditional small molecule inhibitors, the use of PROTAC technology for new drug development has high advantages and feasibility, and is expected to become the next generation of promising new drugs. Summary of the invention

[0005] The present invention aims to provide a novel structure and good efficacy compound for degrading IRAK4, which can be used to treat diseases related to IRAK4.

[0006] The present invention provides a compound, which is a compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug,

[0007]

[0008] in,

[0009] E 1 is -CH2- or -C(=O)-;

[0010] for

[0011] Ring A, Ring B and Ring D are each independently absent, C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, C 6-10 The aryl group and the 5-10 membered heteroaryl group are each optionally substituted by one or more R a replace;

[0012] L 1 , L 2 , L 3 and L 4 are independently a single bond, -O-, -C(O)-, -N(R 22 )-, -P(O)-, -P(O)2-, -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-、C 1-8Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl or C 1-12 Heteroalkyl, wherein the C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl and C 1-12 The heteroalkyl group is optionally substituted by one or more R b replace;

[0013] Ring C is C 6-10 Aryl or 5-10 membered heteroaryl;

[0014] L x -C(=O)-NR 2 -or-NR 2 -C(=O)-;

[0015] R 1 C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, each optionally substituted by one or more R 11 replace;

[0016] When R 1 C 1-6 When alkyl, R 1 By one or more R 11 Replaced with at least 1 R 11 for OH;

[0017] R 2 independently H or C 1-6 alkyl;

[0018] R 3 H, halogen, CN, OH, NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl or 5-10 membered heteroaryl, the C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 The cycloalkyl and 5-10 membered heteroaryl groups are each optionally substituted by one or more R 31 replace;

[0019] R 4 Halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6Cycloalkyl or -OC 3-6 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl and -OC 3-6 The cycloalkyl group is optionally substituted by one or more R 41 replace;

[0020] Each R 11 Independently H, C 1-6 Alkyl, halogen, OH or CN;

[0021] Each R 31 are independently H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 The cycloalkyl group is optionally substituted by one or more R c replace;

[0022] Each R 41 are independently halogen, =O, OH, NH2 or CN;

[0023] Each R 22 independently H or C 1-6 alkyl;

[0024] Each R a are independently H, halogen, =O, OH, NH2, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted by 1, 2 or 3 R groups;

[0025] Each R b are independently H, =O, halogen, OH, NH2 or C 1-6 alkyl;

[0026] Each R c are independently H, =O, halogen, OH or NH2;

[0027] Each R is independently H, =O, halogen, OH, CN or NH2;

[0028] g is 1, 2, or 3;

[0029] r is 1, 2, 3 or 4;

[0030] The "4-12 membered heterocycloalkyl", "4-7 membered heterocycloalkyl", "C 1-6heteroalkyl", "5-10 membered heteroaryl" and "C 1-12 The "hetero" in "heteroalkyl" refers to a heteroatom group; the number of the heteroatom groups is 1 or more, and the heteroatom groups are independently N, -O-, -C(O)-, -N(R 22 )-, -P(O)-, -P(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

[0031] In an optional embodiment of the present invention, the compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug,

[0032]

[0033] in,

[0034] E 1 is -CH2- or -C(=O)-;

[0035] for

[0036] Ring A, Ring B and Ring D are each independently absent, C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, C 6-10 The aryl group and the 5-10 membered heteroaryl group are each optionally substituted by one or more R a replace;

[0037] L 1 , L 2 , L 3 and L 4 are independently a single bond, -O-, -C(O)-, -N(R 22 )-, -P(O)-, -P(O)2-, -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-、C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl or C 1-12 Heteroalkyl, wherein the C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl and C 1-12 The heteroalkyl group is optionally substituted by one or more R b replace;

[0038] Ring C is C 6-10 Aryl or 5-10 membered heteroaryl;

[0039] L x -C(=O)-NR 2 -or-NR 2 -C(=O)-;

[0040] R 1 C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, each optionally substituted by one or more R 11 replace;

[0041] When R 1 C 1-6 When alkyl, R 1 By one or more R 11 Replaced with at least 1 R 11 for OH;

[0042] R 2 H or C 1-6 alkyl;

[0043] R 3 H, halogen, CN, OH, NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl or 5-10 membered heteroaryl, the C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 The cycloalkyl and 5-10 membered heteroaryl groups are each optionally substituted by one or more R 31 replace;

[0044] R 4 Halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl and -OC 3-6 The cycloalkyl group is optionally substituted by one or more R 41 replace;

[0045] Each R11 Independently H, C 1-6 Alkyl, halogen, OH or CN;

[0046] Each R 31 are independently H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 The cycloalkyl group is optionally substituted by one or more R c replace;

[0047] Each R 41 are independently halogen, =O, OH, NH2 or CN;

[0048] Each R 22 independently H or C 1-6 alkyl;

[0049] Each R a are independently H, halogen, =O, OH, NH2, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted by 1, 2 or 3 R groups;

[0050] Each R b are independently H, =O, halogen, OH, NH2 or C 1-6 alkyl;

[0051] Each R c are independently H, =O, halogen, OH or NH2;

[0052] Each R is independently H, =O, halogen, OH, CN or NH2;

[0053] g is 1, 2, or 3;

[0054] r is 1, 2, 3 or 4;

[0055] The “4-12 membered heterocycloalkyl”, “5-10 membered heteroaryl” and “C 1-12 The "hetero" in "heteroalkyl" refers to a heteroatom group; the number of the heteroatom groups is 1 or more, each independently being N, -O-, -C(O)-, -N(R 22 )-, -P(O)-, -P(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

[0056] In an optional embodiment of the present invention, the "4-12 membered heterocycloalkyl", "4-7 membered heterocycloalkyl", "C 1-6 heteroalkyl", "5-10 membered heteroaryl" and "C 1-12 The "hetero" in "heteroalkyl" refers to a heteroatom group; the number of the heteroatom groups is 1 or more, and the heteroatom groups are independently N, -O-, -C(O)-, -N(R 22 )-, -P(O)-, -P(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

[0057] In an optional embodiment of the present invention, each R a are independently halogen, =O, OH, NH2, C 1-6 Alkyl or C 1-6 Alkoxy.

[0058] In an optional embodiment of the present invention, the compound represented by the above compound formula (I) is

[0059]

[0060] in,

[0061] E 1 is -CH2- or -C(=O)-;

[0062] for

[0063] Ring A, Ring B and Ring D are each independently absent, C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, C 6-10 The aryl group and the 5-10 membered heteroaryl group are each optionally substituted by one or more R a replace;

[0064] L 1 , L 2 , L 3 and L 4 are independently a single bond, -O-, -C(O)-, -N(R 22 )-, -P(O)-, -P(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-、C 1-8 Alkyl, C2-8 Alkenyl, C 2-8 Alkynyl or C 1-12 Heteroalkyl, wherein the C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl and C 1-12 The heteroalkyl group is optionally substituted by one or more R b replace;

[0065] Ring C is C 6-10 Aryl or 5-10 membered heteroaryl;

[0066] L x -C(=O)-NR 2 -or-NR 2 -C(=O)-;

[0067] R 1 C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, each optionally substituted by one or more R 11 replace;

[0068] When R 1 C 1-6 When alkyl, R 1 By one or more R 11 Replaced with at least 1 R 11 for OH;

[0069] R 2 H or C 1-6 alkyl;

[0070] R 3 H, halogen, CN, OH, NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl or 5-10 membered heteroaryl, the C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 The cycloalkyl and 5-10 membered heteroaryl groups are each optionally substituted by one or more R 31 replace;

[0071] R 4 Halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or -OC3-6 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl and -OC 3-6 The cycloalkyl group is optionally substituted by one or more R 41 replace;

[0072] Each R 11 Independently H, C 1-6 Alkyl, halogen, OH or CN;

[0073] Each R 31 are independently H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 The cycloalkyl group is optionally substituted by one or more R c replace;

[0074] Each R 41 are independently halogen, =O, OH, NH2 or CN;

[0075] Each R 22 independently H or C 1-6 alkyl;

[0076] Each R a are independently halogen, =O, OH, NH2, C 1-6 Alkyl or C 1-6 Alkoxy;

[0077] Each R b are independently H, =O, halogen, OH, NH2 or C 1-6 alkyl;

[0078] Each R c are independently H, =O, halogen, OH or NH2;

[0079] g is 1, 2, or 3;

[0080] r is 1, 2, 3 or 4;

[0081] The “4-12 membered heterocycloalkyl”, “5-10 membered heteroaryl” and “C 1-12 The "hetero" in "heteroalkyl" refers to a heteroatom group; the number of the heteroatom groups is 1 or more, each independently being N, -O-, -C(O)-, -N(R 22 )-, -P(O)-, -P(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2-N(R22 )-; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

[0082] In an optional embodiment of the present invention, certain groups in the compound represented by formula (I), its tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs are defined as follows, and the unmentioned groups are the same as those described in any scheme of the present invention (referred to as "an optional embodiment of the present invention").

[0083] In an optional embodiment of the present invention, among ring A, ring B and ring D, the C 3-12 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclohexyl.

[0084] In an optional embodiment of the present invention, in ring A, ring B and ring D, the 4-12 membered heterocycloalkyl group is independently a 4-8 membered heterocycloalkyl group, the heteroatoms are preferably independently selected from one, two or three of N, O or S, and the number of heteroatoms is preferably independently 1, 2 or 3; preferably, the 4-12 membered heterocycloalkyl group is

[0085] In an optional embodiment of the present invention, among ring A, ring B and ring D, the C 6-10 Aryl is independently phenyl or naphthyl.

[0086] In an optional embodiment of the present invention, in ring A, ring B and ring D, the 5-10 membered heteroaryl group is independently a 5-6 membered heteroaryl group, the heteroatoms are preferably independently selected from one, two or three of N, O or S, and the number of heteroatoms is preferably independently 1, 2 or 3.

[0087] In an optional embodiment of the present invention, L 1 , L 2 , L 3 and L 4 , the C 1-8 The alkyl groups are independently C 1-6 The alkyl group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, is preferably methyl.

[0088] In an optional embodiment of the present invention, L 1 , L 2 , L 3 and L 4 , the C 2-8 The alkenyl groups are independently C 1-6 Alkenyl, wherein the number of carbon-carbon double bonds (C=C) is independently 1, 2 or 3, such as ethenyl, propenyl or butenyl.

[0089] In an optional embodiment of the present invention, L1 , L 2 , L 3 and L 4 , the C 2-8 The alkynyl groups are independently C 1-6 Alkynyl, wherein the carbon-carbon triple bond The number is independently 1, 2 or 3, for example ethynyl, propynyl or butynyl.

[0090] In an optional embodiment of the present invention, L 1 , L 2 , L 3 and L 4 , the C 1-12 Heteroalkyl is independently C 1-6 Heteroalkyl, wherein the heteroatom species is preferably independently selected from one, two or three of N, O or S, and the number of heteroatoms is preferably independently 1, 2 or 3.

[0091] In an optional embodiment of the present invention, in ring C, the C 6-10 Aryl is phenyl or naphthyl.

[0092] In an optional embodiment of the present invention, in ring C, the 5-10 membered heteroaryl is a 5-6 membered heteroaryl, the heteroatoms are preferably independently selected from one, two or three of N, O or S, and the number of heteroatoms is preferably independently 1, 2 or 3. For example, the 5-10 membered heteroaryl is

[0093] In an optional embodiment of the present invention, R 1 In the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0094] In an optional embodiment of the present invention, R 1 In the C 3-6 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0095] In an optional embodiment of the present invention, R 1 In the above, the 4-7 membered heterocycloalkyl is independently a 4-6 membered heterocycloalkyl, the heteroatoms are preferably independently selected from one, two or three of N, O or S, and the number of heteroatoms is preferably independently 1, 2 or 3.

[0096] In an optional embodiment of the present invention, R 2 In the C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0097] In an optional embodiment of the present invention, R 3 In the above, the halogen is independently fluorine, chlorine or bromine, for example fluorine.

[0098] In an optional embodiment of the present invention, R 3 In the C 1-6 Alkyl and -OC 1-6 C in alkyl 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0099] In an optional embodiment of the present invention, R 3 In, the -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.

[0100] In an optional embodiment of the present invention, R 3 In the above, the 5-10 membered heteroaryl group is independently a 5-6 membered heteroaryl group, the heteroatoms are preferably independently selected from one, two or three of N, O or S, and the number of heteroatoms is preferably independently 1, 2 or 3.

[0101] In an optional embodiment of the present invention, R 4 wherein the halogen is independently fluorine, chlorine or bromine.

[0102] In an optional embodiment of the present invention, R 4 In the C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0103] In an optional embodiment of the present invention, R 4 In the C 1-6 The types of heteroatoms in the heteroalkyl group are independently selected from one, two or three of N, O or S, and the number of heteroatoms is preferably 1, 2 or 3 independently.

[0104] In an optional embodiment of the present invention, R 3 In, the -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0105] In an optional embodiment of the present invention, R 11 wherein the halogen is independently fluorine, chlorine or bromine.

[0106] In an optional embodiment of the present invention, R11 In the C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0107] In an optional embodiment of the present invention, R 31 wherein the halogen is independently fluorine, chlorine or bromine.

[0108] In an optional embodiment of the present invention, R 31 In the C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0109] In an optional embodiment of the present invention, R 31 In the C 1-6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0110] In an optional embodiment of the present invention, R 31 In the C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0111] In an optional embodiment of the present invention, R 41 wherein the halogen is independently fluorine, chlorine or bromine.

[0112] In an optional embodiment of the present invention, R 22 In the C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0113] In an optional embodiment of the present invention, R a wherein the halogen is independently fluorine, chlorine or bromine.

[0114] In an optional embodiment of the present invention, R a In the C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0115] In an optional embodiment of the present invention, R a In the C 1-6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0116] In an optional embodiment of the present invention, R b , R cIn R and R, the halogen is independently fluorine, chlorine or bromine.

[0117] In an optional embodiment of the present invention, R b In the C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0118] In an optional embodiment of the present invention, the number of the heteroatom groups is 1, 2, 3 or 4.

[0119] In an optional embodiment of the present invention, R 1 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more R 11 replace.

[0120] In an optional embodiment of the present invention, R 1 for or cyclopropyl, and cyclopropyl are each independently substituted with OH.

[0121] In an optional embodiment of the present invention, R 1 It is a cyclopropyl group substituted by OH.

[0122] In an optional embodiment of the present invention, R 1 for

[0123] In an optional embodiment of the present invention, R 1 for

[0124] In an optional embodiment of the present invention, R 1 For one or more R 11 Substituted C 1-6 alkyl.

[0125] In an optional embodiment of the present invention, R 1 for

[0126] In an optional embodiment of the present invention, R 2 For H.

[0127] In an optional embodiment of the present invention, R 11 For OH.

[0128] In an optional embodiment of the present invention, each R 31 are independently halogen.

[0129] In an optional embodiment of the present invention, the substituent R 31The number of is 1, 2, 3 or 4.

[0130] In an optional embodiment of the present invention, the substituent R 31 The number of is 2.

[0131] In an optional embodiment of the present invention, each R 31 are independently H, halogen, OH or CN.

[0132] In an optional embodiment of the present invention, each R 31 are independently H, F, Cl, Br, OH or CN.

[0133] In an optional embodiment of the present invention, each R 31 is independently halogen, such as F.

[0134] In an optional embodiment of the present invention, each R 3 are independently H, halogen, CN, OH, NH2, CH3 or cyclopropyl, wherein CH3 and cyclopropyl are each optionally substituted by one or more R 31 Replacement, R 31 As defined in the present invention.

[0135] In an optional embodiment of the present invention, each R 3 are independently H, halogen, CN, OH, NH2 or cyclopropyl, the cyclopropyl being optionally substituted with one or more R 31 Replacement, R 31 As defined in the present invention.

[0136] In an optional embodiment of the present invention, at least one R 3 is optionally represented by one or more R 31 Substituted cyclopropyl, the remaining R 3 are independently H, halogen, CN, OH, NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl or 5-10 membered heteroaryl, the C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 The cycloalkyl and 5-10 membered heteroaryl groups are each optionally substituted by one or more R 31 Replacement, R 31 As defined in the present invention.

[0137] In an optional embodiment of the present invention, each R 3 are independently halogen or C 3-6 Cycloalkyl, the C 3-6The cycloalkyl group is optionally substituted with one or more R 31 Replace (e.g. The C atoms marked with * are S-configuration C, R-configuration C or a mixture thereof).

[0138] In an optional embodiment of the present invention, R 3 It is CF3.

[0139] In an optional embodiment of the present invention, each R 3 Independently for F,

[0140] In an optional embodiment of the present invention, at least one R 3 for The remaining R 3 are independently H, F or Cl.

[0141] In an optional embodiment of the present invention, r is 2, one R 3 for Another R 3 are independently H, F or Cl.

[0142] In an optional embodiment of the present invention, for

[0143] in,

[0144] r' is 1, 2 or 3 (e.g., 1);

[0145] h is 1, 2 or 3 (e.g., 2);

[0146] The C atom marked with * is S-configuration C, R-configuration C or a mixture thereof (referring to S and R-configuration C).

[0147] In an optional embodiment of the present invention, each R 4 are independently F, Cl or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted by 1, 2 or 3 R 41 Replacement, R 41 As defined in the present invention.

[0148] In an optional embodiment of the present invention, each R 4 are independently F or Cl.

[0149] In an optional embodiment of the present invention, R 4 is a halogen, such as F.

[0150] In an optional embodiment of the present invention, each R 22 independently H or C 1-6 alkyl.

[0151] In an optional embodiment of the present invention, each R 22 are independently H or CH3.

[0152] In an optional embodiment of the present invention, each R 22 is independently H.

[0153] In an optional embodiment of the present invention, each R b are independently halogen, =O, OH, NH2 or CH3.

[0154] In an optional embodiment of the present invention, each R b Independently for C 1-6 alkyl.

[0155] In an optional embodiment of the present invention, each R is independently OH.

[0156] In an optional embodiment of the present invention, ring C is a 5-10 membered heteroaryl group, for example, a pyridyl group (for example ).

[0157] In an optional embodiment of the present invention, L x -C(=O)-NR 2 -.

[0158] In an optional embodiment of the present invention, g is 1.

[0159] In an optional embodiment of the present invention, r is 1 or 2.

[0160] In an optional embodiment of the present invention, the "hetero" of the "4-12 membered heterocycloalkyl", "4-7 membered heterocycloalkyl" and "5-10 membered heteroaryl" is a heteroatom group; the number of the heteroatom groups is 1 or more, and the heteroatom groups are independently 1 or more of N, -O- and -S-; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

[0161] In an optional embodiment of the present invention, the C 1-12 Heteroalkyl and C 1-6 The "hetero" of heteroalkyl refers to a heteroatom group; the number of the heteroatom groups is 1 or more, and the heteroatom groups are independently one or more of -S(O)2-, -C(O)-, N, -O- and -S-; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

[0162] In an optional embodiment of the present invention, L 1 , L 2 , L 3 and L 4are independently a single bond, -O-, -C(O)-, -N(R 22 )-, -P(O)-, -P(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-、C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl or C 1-12 Heteroalkyl, wherein the C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl and C 1-12 The heteroalkyl group is optionally substituted by one or more R b Replace; and, L 1 , L 2 , L 3 and L 4 The following conditions must be met: L 1 , L 2 , L 3 and L 4 At least one of them is -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )- or C 1-12 heteroalkyl, in this case, the C 1-12 At least one of the heteroatoms of the heteroalkyl group is -S-, -S(O)-, -S(O)2- or -S(O)2-N(R 22 )-,R 22 and R b As defined in the present invention.

[0163] In an optional embodiment of the present invention, L 1 , L 2 , L 3 and L 4 are independently a single bond, -O-, -C(O)-, -N(R 22 )-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-、-C 1-6 Alkyl-, -C 2-6 Alkynyl-, -C 1-6 Alkyl-O-, -C 1-6 Alkyl-C(O)-, -C 1-6 Alkyl-N(R 22 )-、-C 1-6 Alkyl-S(O)-, -C 1-6 Alkyl-S(O)2-, -C 1-6 Alkyl-S(O)2-N(R 22 )-、-S(O)2-N(R 22)-C 1-6 Alkyl-, -C 1-6 Alkyl-OC 1-6 Alkyl-, -C 1-6 Alkyl-N(R 22 )-C 1-6 Alkyl-, -C 1-6 Alkyl-S(O)-C 1-6 Alkyl-, -C 1-6 Alkyl-S(O)2-C 1-6 Alkyl-, -C 1-6 Alkyl-S(O)2-N(R 22 )-C 1-6 Alkyl-, -OC 1-6 Alkyl-O-, -N(R 22 )-C 1-6 Alkyl-N(R 22 )-、-S(O)-C 1-6 Alkyl-S(O)-, -S(O)2-C 1-6 Alkyl-S(O)2-, -S(O)2-N(R 22 )-C 1-6 Alkyl-S(O)2-N(R 22 )-、-OC 1-6 Alkyl-N(R 22 )-, wherein each C 1-6 Alkyl and -C 2-6 Alkynyl- is optionally substituted by 1, 2, 3 or 4 R b Replacement, R 22 and R b As defined in the present invention.

[0164] In an optional embodiment of the present invention, L 1 , L 2 , L 3 and L 4 are independently a single bond, -C(O)-, -S(O)2-, -S(O)2-CH2-, -CO-CH2- or C 1-8 Alkyl (such as methyl or ethyl), wherein the C 1-8 The alkyl group is optionally substituted by one or more R b replace.

[0165] In an optional embodiment of the present invention, L 1 is a single bond, -CH2-, -CH(CH3)-, -C(O)-,

[0166] In an optional embodiment of the present invention, L 1 For a single key.

[0167] In an optional embodiment of the present invention, L 2 is a single bond, -CH2-, -CH(CH3)-, -C(O)-, -S(O)2-, -S(O)2-CH2-, -CO-CH2-,

[0168] In an optional embodiment of the present invention, L 2 is a single bond, -CH2-, -CH(CH3)-, -C(O)-, -S(O)2-, -S(O)2-CH2-,

[0169] In an optional embodiment of the present invention, L 2 is a single bond, -CH2-, -CH(CH3)-, -C(O)-,

[0170] In an optional embodiment of the present invention, L 2 It is a single bond, -CH2-, -CH(CH3)-, -C(O)-, -S(O)2-, -CO-CH2- or -S(O)2-CH2-.

[0171] In an optional embodiment of the present invention, L 2 It is a single bond, -CH2-, -CH(CH3)-, -C(O)-, -S(O)2- or -S(O)2-CH2-.

[0172] In an optional embodiment of the present invention, L 3 is a single bond, -CH2-, -CH(CH3)-, -C(O)-, -S(O)2-, -S(O)2-CH2-,

[0173] In an optional embodiment of the present invention, L 3 is a single bond, -CH2-, -CH(CH3)-, -C(O)-,

[0174] In an optional embodiment of the present invention, L 3 For a single key.

[0175] In an optional embodiment of the present invention, L 4 It is a single bond, -CH2- or -CH(CH3)-.

[0176] In an optional embodiment of the present invention, L 4 For a single key.

[0177] In an optional embodiment of the present invention, the substituent R a The number of is 1, 2, 3 or 4.

[0178] In an optional embodiment of the present invention, each R a are independently H, =O, F, Cl, Br, OH, NH2, -CH3, -O-CH3 or -CH2OH.

[0179] In an optional embodiment of the present invention, each R a is independently =O, F, Cl, Br, OH, NH2, -CH3 or -O-CH3.

[0180] In an optional embodiment of the present invention, each R a are independently halogen, OH, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted by 1, 2 or 3 R groups, respectively.

[0181] In an optional embodiment of the present invention, Ring A, Ring B and Ring D are each independently absent, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl, the C 3-12 The cycloalkyl group and the 4-12 membered heterocycloalkyl group are each optionally substituted by one or more R a preferably absent or 4-12 membered heterocycloalkyl, the 4-12 membered heterocycloalkyl being optionally substituted by 1 or more R a replace.

[0182] In an optional embodiment of the present invention, Ring A, Ring B and Ring D are each independently absent, C 3-6 Cycloalkyl or 4-8 membered heterocycloalkyl, the C 3-6 The cycloalkyl group and the 4-8 membered heterocycloalkyl group are each optionally substituted by one or more R a Replacement, R a As defined in the present invention.

[0183] In an optional embodiment of the present invention, ring A, ring B and ring D are each independently absent, azetidinyl, cyclohexyl, piperidinyl, piperazinyl or 2-azaspiro[3.3]heptyl, and the cyclohexyl, piperidinyl, piperazinyl and 2-azaspiro[3.3]heptyl are each optionally replaced by one or more R a Replacement, R a As defined in the present invention.

[0184] In an optional embodiment of the present invention, ring A, ring B and ring D are each independently absent, azetidinyl, cyclohexyl, piperidinyl or piperazinyl, and the azetidinyl, cyclohexyl, piperidinyl or piperazinyl are each optionally replaced by one or more R a Replacement, R a As defined in any embodiment of the present invention.

[0185] In an optional embodiment of the present invention, ring A is absent, cyclohexyl, piperidinyl or piperazinyl, wherein the cyclohexyl, piperidinyl and piperazinyl are optionally substituted by 1, 2, 3 or 4 R a Replacement, R a As defined in the present invention.

[0186] In an optional embodiment of the present invention, ring A is cyclohexyl or piperidinyl, for example, ring A is piperidinyl.

[0187] In an optional embodiment of the present invention, ring A is absent,

[0188] In an optional embodiment of the present invention, Ring A is

[0189] In an optional embodiment of the present invention, Ring A is (For example, ring A is ), preferably, the right end With L 2 connect.

[0190] In an optional embodiment of the present invention, ring B is absent, azetidinyl, cyclohexyl, piperidinyl, piperazinyl or 2-azaspiro[3.3]heptyl, wherein the cyclohexyl, piperidinyl, piperazinyl and 2-azaspiro[3.3]heptyl are optionally substituted by 1, 2, 3 or 4 R a Replacement, R a As defined in the present invention.

[0191] In an optional embodiment of the present invention, ring B is azetidinyl, piperidinyl or piperazinyl, wherein the azetidinyl, piperidinyl and piperazinyl are optionally substituted by 1, 2, 3 or 4 R a Replacement, R a As defined in the present invention.

[0192] In an optional embodiment of the present invention, Ring B is absent,

[0193] In an optional embodiment of the present invention, Ring B is absent,

[0194] In an optional embodiment of the present invention, Ring B is

[0195] In an optional embodiment of the present invention, Ring B is (For example, ring B is ), preferably, the right end With L 3 connect.

[0196] In an optional embodiment of the present invention, ring D is absent, azetidinyl or piperidinyl, wherein the azetidinyl and piperidinyl are optionally substituted by 1, 2, 3 or 4 R a Replacement, R a As defined in the present invention.

[0197] In an optional embodiment of the present invention, ring D is absent or azetidinyl, wherein the azetidinyl is optionally substituted by 1, 2, 3 or 4 R a Replacement, R a As defined in the present invention.

[0198] In an optional embodiment of the present invention, ring D is absent,

[0199] In an optional embodiment of the present invention, ring D is absent or Preferably, the right end With L 4 connect.

[0200] In an optional embodiment of the present invention, ring D is absent or

[0201] In an optional embodiment of the present invention, for Among them, ring A, ring B, ring D, L 1 , L 2 and L 3 As defined in the present invention.

[0202] Preferably, for Among them, ring A, ring B, ring D, L 1 , L 2 and L 3 As defined in any embodiment of the present invention.

[0203] Preferably, when ring A, ring B, and ring D are dotted circles When it is present or not present, when ring A, ring B, and ring D are solid circles , indicating the existence of a ring structure.

[0204] For example, for L 2 It is -CH2-, -CH(CH3)-, -C(O)-, -S(O)2-, -C(O)-CH2- or -S(O)2-CH2-.

[0205] In an optional embodiment of the present invention, for Among them, ring A, ring B, ring D, L 1 , L 2 and L 3 As defined in the present invention.

[0206] In an optional embodiment of the present invention, for Among them, ring A, ring B, ring D, L 1 , L 2 and L 3 As defined in the present invention.

[0207] In an optional embodiment of the present invention, for For example

[0208] In an optional embodiment of the present invention, for

[0209] In an optional embodiment of the present invention, for

[0210] In an optional embodiment of the present invention, for

[0211]

[0212] In an optional embodiment of the present invention, for

[0213] In an optional embodiment of the present invention, the above compound is a compound represented by formula (IA):

[0214]

[0215] in,

[0216] h is 1, 2, or 3;

[0217] r' is 1, 2 or 3;

[0218] R 3 H, halogen, CN, OH, NH2, C 1-6 Alkyl or -OC 1-6 Alkyl, the C 1-6 Alkyl and -OC 1-6 The alkyl group is optionally substituted by one or more R 31 replace;

[0219] E 1 , L x , R 1 , R 4 , R 31 , g and As defined in the present invention.

[0220] In an optional embodiment of the present invention, the compound represented by the above formula (I) is a compound represented by the formula (ID):

[0221]

[0222] Wherein, h is 1, 2 or 3;

[0223] * The C atom marked is S-configuration C, R-configuration C or a mixture thereof (referring to S and R-configuration C);

[0224] R 31 , L x , R 1 , g、R 4 and E 1 Independently as described in any embodiment of the present invention.

[0225] In an optional embodiment of the present invention, the compound represented by the above formula (I) is a compound represented by formula (I-D1) or formula (I-D2):

[0226]

[0227] Wherein, h is 1, 2 or 3;

[0228] * The C atom marked is S-configuration C, R-configuration C or a mixture thereof (referring to S and R-configuration C);

[0229] R 31 , L x , R 1, Ring A, Ring B, Ring D, L 2 , L 3 , g, R 4 and E 1 Independently as described in any embodiment of the present invention.

[0230] In an optional embodiment of the present invention, the above compound is a compound represented by formula (I-A1) or formula (I-A2):

[0231]

[0232] in,

[0233] L x , R 3 , R 1 , R 4 , R 31 , r', h, g and As defined in the present invention.

[0234] In an optional embodiment of the present invention, the above compound is a compound represented by formula (IB):

[0235]

[0236] in,

[0237] h is 1, 2, or 3;

[0238] r' is 1, 2 or 3;

[0239] m is 1, 2, 3 or 4;

[0240] n is 1, 2, 3 or 4;

[0241] p is 0 or 1;

[0242] q is 0 or 1;

[0243] Z 1 , Z 2 , Z 3 and Z 4 are independently N or CH;

[0244] R 3 H, halogen, CN, OH, NH2, C 1-6 Alkyl or -OC 1-6 Alkyl, the C 1-6 Alkyl and -OC 1-6 The alkyl group is optionally substituted by one or more R 31 replace;

[0245] g、E 1 , L x , L2 , R 1 , R 4 , R 31 and R a As defined in the present invention.

[0246] In an optional embodiment of the present invention, the above compound is a compound represented by formula (I-B1):

[0247]

[0248] in,

[0249] h is 1, 2, or 3;

[0250] r' is 1, 2 or 3;

[0251] m is 1, 2, 3 or 4;

[0252] Z 1 and Z 2 are independently N or CH;

[0253] R 3 H, halogen, CN, OH, NH2, C 1-6 Alkyl or -OC 1-6 Alkyl, the C 1-6 Alkyl and -OC 1-6 The alkyl group is optionally substituted by one or more R 31 replace;

[0254] g、E 1 , L x , L 2 , R 1 , R 4 , R 31 and R a As defined in the present invention.

[0255] In an optional embodiment of the present invention, the above compound is a compound represented by formula (IC):

[0256]

[0257] in,

[0258] h is 1, 2, or 3;

[0259] r' is 1, 2 or 3;

[0260] L 2 -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-or optionally 1 or more R b Substituted C 1-12Heteroalkyl, the "C 1-12 The "hetero" in "heteroalkyl" is a heteroatom group, the number of which is 1 or more, each independently N, -O-, -C(O)-, -N(R 22 )-, -P(O)-, -P(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-; when the number of the heteroatom groups is multiple, the heteroatom groups are the same or different, and at least one of the heteroatom groups is -S-, -S(O)-, -S(O)2- or -S(O)2-N(R 22 )-;

[0261] Ring A, Ring B, g, E 1 , L x , R 22 , R 1 , R 4 , R 3 and R 31 As defined in the present invention.

[0262] In an optional embodiment of the present invention, the above compound is a compound represented by formula (I-C1):

[0263]

[0264] in,

[0265] g、E 1 , L x , R 1 , R 4 , R 31 and R a As defined in the present invention;

[0266] h is 1, 2, or 3;

[0267] r' is 1, 2 or 3;

[0268] m is 1, 2, 3 or 4;

[0269] n is 1, 2, 3 or 4;

[0270] p is 0 or 1;

[0271] q is 0 or 1;

[0272] Z 1 , Z 2 , Z 3 and Z 4 are independently N or CH;

[0273] R 3 H, halogen, CN, OH, NH2, C1-6 Alkyl or -OC 1-6 Alkyl, the C 1-6 Alkyl and -OC 1-6 The alkyl group is optionally substituted by one or more R 31 replace;

[0274] L 2 -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-or optionally 1 or more R b Substituted C 1-12 Heteroalkyl, the "C 1-12 The "hetero" in "heteroalkyl" is a heteroatom group, the number of which is 1 or more, each independently N, -O-, -C(O)-, -N(R 22 )-, -P(O)-, -P(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-; when the number of the heteroatom groups is multiple, the heteroatom groups are the same or different, and at least one of the heteroatom groups is -S-, -S(O)-, -S(O)2- or -S(O)2-N(R 22 )-,R 22 and R b As defined in the present invention.

[0275] In an optional embodiment of the present invention, the above L 2 -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-、-C 1-6 Alkyl-S(O)-, -C 1-6 Alkyl-S(O)2-, -C 1-6 Alkyl-S(O)2-N(R 22 )-、-S(O)2-N(R 22 )-C 1-6 Alkyl-, -C 1-6 Alkyl-S(O)-C 1-6 Alkyl-, -C 1-6 Alkyl-S(O)2-C 1-6 Alkyl-, -C 1-6 Alkyl-S(O)2-N(R 22 )-C 1-6 Alkyl-, -S(O)-C 1-6 Alkyl-S(O)-, -S(O)2-C 1-6 Alkyl-S(O)2- or -S(O)2-N(R 22 )-C 1-6 Alkyl-S(O)2-N(R 22)-, wherein each C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 R b Replacement, R b As defined in the present invention.

[0276] In an optional embodiment of the present invention, the above L 2 It is -S(O)2- or -S(O)2-CH2-.

[0277] In an optional embodiment of the present invention, the above L 2 It is -S(O)2-, -S(O)2-CH2- or -C(O)-CH2-.

[0278] In an optional embodiment of the present invention, h is 2.

[0279] In an optional embodiment of the present invention, r' is 1.

[0280] In an optional embodiment of the present invention, m is 1.

[0281] In an optional embodiment of the present invention, n is 1.

[0282] In an optional embodiment of the present invention, in the compound represented by formula (I),

[0283] E 1 is -CH2- or -C(=O)-;

[0284] for

[0285] Ring A, Ring B and Ring D are each independently absent, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl, the C 3-12 The cycloalkyl group and the 4-12 membered heterocycloalkyl group are each optionally substituted by one or more R a replace;

[0286] L 1 , L 2 , L 3 and L 4 are independently a single bond, -C(O)-, -S(O)2-, -C(O)-CH2-, -S(O)2-CH2- or C 1-8 Alkyl, wherein the C 1-8 The alkyl group is optionally substituted by one or more R b replace;

[0287] Ring C is a 5-10 membered heteroaryl group;

[0288] L x -C(=O)-NR 2-;

[0289] R 1 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more R 11 replace;

[0290] When R 1 C 1-6 When alkyl, R 1 By one or more R 11 Replaced with at least 1 R 11 for OH;

[0291] R 2 independently H;

[0292] R 3 Halogen or C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted by one or more R 31 replace;

[0293] R 4 is a halogen;

[0294] Each R 11 independently OH;

[0295] Each R 31 are independently halogen;

[0296] Each R a are independently halogen, OH, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted by 1, 2 or 3 R groups;

[0297] Each R b Independently for C 1-6 alkyl;

[0298] Each R is independently OH;

[0299] g is 1;

[0300] r is 1 or 2;

[0301] The "hetero" of the "4-12 membered heterocycloalkyl" and the "5-10 membered heteroaryl" is a heteroatom group; the number of the heteroatom groups is 1 or more, and the heteroatom groups are independently 1 or more of N, O, and S; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

[0302] In an optional embodiment of the present invention, in the compound represented by formula (I),

[0303] E 1 is -CH2- or -C(=O)-;

[0304] for

[0305] Ring A, Ring B and Ring D are each independently absent or a 4-12 membered heterocycloalkyl group, wherein C 3-12 The cycloalkyl group and the 4-12 membered heterocycloalkyl group are each optionally substituted by one or more R a replace;

[0306] L 1 , L 2 , L 3 and L 4 are independently a single bond, -C(O)-, -S(O)2-, -C(O)-CH2-, -S(O)2-CH2- or C 1-8 Alkyl, wherein the C 1-8 The alkyl group is optionally substituted by one or more R b replace;

[0307] Ring C is a 5-10 membered heteroaryl group;

[0308] L x -C(=O)-NR 2 -;

[0309] R 1 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more R 11 replace;

[0310] When R 1 C 1-6 When alkyl, R 1 By one or more R 11 Replaced with at least 1 R 11 for OH;

[0311] R 2 independently H;

[0312] R 3 Halogen or C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted by one or more R 31 replace;

[0313] R 4 is a halogen;

[0314] Each R 11 independently OH;

[0315] Each R 31 are independently halogen;

[0316] Each R a are independently halogen, OH, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted by 1, 2 or 3 R groups;

[0317] Each R b Independently for C 1-6 alkyl;

[0318] Each R is independently OH;

[0319] g is 1;

[0320] r is 1 or 2;

[0321] The "hetero" of the "4-12 membered heterocycloalkyl" and the "5-10 membered heteroaryl" is a heteroatom group; the number of the heteroatom groups is 1 or more, and the heteroatom groups are independently 1 or more of N, O, and S; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

[0322] In an optional embodiment of the present invention, in the compound represented by formula (I),

[0323] E 1 is -CH2- or -C(=O)-;

[0324] for

[0325] Ring A is absent, cyclohexyl, piperidinyl or piperazinyl, wherein the cyclohexyl, piperidinyl and piperazinyl are optionally substituted by 1, 2, 3 or 4 R a replace;

[0326] Ring B is absent, azetidinyl, piperidinyl or piperazinyl, wherein the cyclohexyl, piperidinyl and piperazinyl are optionally substituted by 1, 2, 3 or 4 R a replace;

[0327] Ring D is absent, azetidinyl or piperidinyl, wherein the azetidinyl and piperidinyl are optionally substituted by 1, 2, 3 or 4 R a replace;

[0328] Ring C is pyridyl;

[0329] L 1 is a single bond;

[0330] L2 is a single bond, -CH2-, -CH(CH3)-, -C(O)-, -S(O)2-, -C(O)-CH2- or -S(O)2-CH2-;

[0331] L 3 is a single bond;

[0332] L 4 is a single bond, -CH2- or -CH(CH3)-;

[0333] L x -C(=O)-NR 2 -;

[0334] R 1 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more R 11 replace;

[0335] When R 1 C 1-6 When alkyl, R 1 By one or more R 11 Replaced with at least 1 R 11 for OH;

[0336] R 2 independently H;

[0337] R 3 Halogen or C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted by one or more R 31 replace;

[0338] R 4 is a halogen;

[0339] Each R 11 independently OH;

[0340] Each R 31 are independently halogen;

[0341] Each R a are independently halogen, OH, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted by 1, 2 or 3 R groups;

[0342] Each R b Independently for C 1-6 alkyl;

[0343] Each R is independently OH;

[0344] g is 1;

[0345] r is 1 or 2.

[0346] In an optional embodiment of the present invention, the compound represented by the above formula (I) is:

[0347]

[0348]

[0349] In an optional embodiment of the present invention, the compound represented by the above formula (I) is:

[0350]

[0351]

[0352]

[0353]

[0354] In an optional embodiment of the present invention, the pharmaceutically acceptable salt is trifluoroacetate.

[0355] In the second aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective dose of the above-mentioned compound, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs and a pharmaceutically acceptable excipient.

[0356] In the third aspect of the present invention, the present invention provides the use of the above-mentioned compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition in the preparation of a drug for treating or preventing diseases related to IRAK4.

[0357] According to a specific embodiment of the present invention, the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition is used in the preparation of a drug for treating or preventing a disease related to IRAK4, wherein the drug can be used to treat or prevent cancer, neurodegenerative disorders, viral diseases, autoimmune diseases, inflammatory diseases, genetic disorders, hormone-related diseases, metabolic disorders, diseases related to organ transplantation, immunodeficiency disorders, destructive bone diseases, proliferative disorders, infectious diseases, conditions related to cell death, thrombin-induced platelet aggregation, liver disease, pathological immune conditions involving T cell activation, cardiovascular disorders or CNS disorders.

[0358] According to a specific embodiment of the present invention, the use of the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition in the preparation of a drug for treating or preventing a disease related to IRAK4, the drug can be used to treat or prevent cancer, diseases affecting the nose, systemic lupus erythematosus, rheumatoid arthritis, hyaline membrane disease, kidney disease, glomerular disease, multiple sclerosis, interstitial pulmonary fibrosis, allergic reaction, systemic allergic reaction, sinusitis, eye allergy, silica-induced disease, disease, COPD, lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, colitis, suppurative hidradenitis, immunoglobulin A nephropathy, interstitial lung disease, psoriasis, otitis, mumps, alopecia areata, urticaria, acute or chronic gout, chronic gouty arthritis, psoriasis, psoriasis arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, cryptopyrin-associated peripheral syndrome or osteoarthritis disorder; the disease affecting the nose includes, for example, allergic rhinitis, and the colitis includes, for example, Crohn's disease and ulcerative colitis.

[0359] The present invention also provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps: in a halogenated alkane solvent (e.g., dichloromethane) or an ether solvent (e.g., tetrahydrofuran), in the presence of a catalyst (e.g., sodium triacetoxyborohydride or sodium acetate borohydride), a compound of formula I-11 and a compound of formula I-12 are subjected to a coupling reaction to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0360]

[0361] Among them, E 1 , g, R 4 , R 1 , L x , ring C, r, R 3 , Ring A, Ring B, Ring D, L 1 , L 3 , L 4 As described in any scheme of the present invention.

[0362] Preferably, in the preparation method, the coupling reaction further comprises an auxiliary agent, such as an organic acid alkali metal salt (such as potassium acetate) or an amine compound (such as N,N-diisopropylethylamine).

[0363] The present invention also provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps: in an amide solvent (e.g., N,N-dimethylformamide), in the presence of a base (e.g., triethylamine), coupling a compound of formula I-13 with a compound of formula I-16 to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0364]

[0365] Wherein, X is a halogen (e.g., Cl);

[0366] E 1 , g, R 4 , R 1 , L x , ring C, r, R 3 , Ring A, Ring D, L 1 , L 2 , L 3 , L 4 As described in any scheme of the present invention.

[0367] The present invention also provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps: in a sulfoxide solvent (e.g., dimethyl sulfoxide), in the presence of an amine compound (e.g., N,N-diisopropylethylamine), coupling a compound of formula I-13 with a compound of formula I-14 to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0368]

[0369] Wherein, X is a halogen, such as F;

[0370] E 1 , g, R 4 , R 1 , L x , ring C, r, R 3 , Ring A, Ring B, Ring D, L 1 , L 2 , L 3 , L 4 As described in any solution of the present invention;

[0371] Preferably, in the preparation method, in the compound represented by formula I-13, ring A, ring B and ring D are all present (ring B and ring D are not absent);

[0372] Alternatively, ring D is absent, L 2 -S(O)2-, -S(O)2-CH2-, one or more Rb Substituted C 1-8 Alkyl, each R b are independently =O, halogen, OH, NH2 or C 1-6 alkyl;

[0373] Alternatively, ring D is absent, and ring B is replaced by one or more R a Substituted 4-12 membered heterocycloalkyl, each R a are independently halogen, =O, OH, NH2, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted by 1, 2 or 3 R groups, respectively.

[0374] The present invention provides a compound as shown in formula I-13;

[0375]

[0376] Among them, R 1 , L x , ring C, r, R 3 , Ring A, Ring B, Ring D, L 1 , L 2 , L 3 Independently as described in any embodiment of the present invention.

[0377] Preferably, the compound represented by formula I-13 is any of the following compounds:

[0378]

[0379] Terms and Definitions

[0380] Unless otherwise specified, the terms and definitions used in this application, including the specification and claims, are as follows.

[0381] Those skilled in the art will appreciate that, according to the conventions used in the art, in the structural formula of the present application, Used to depict chemical bonds, which are the points at which a moiety or substituent is attached to a core or backbone structure.

[0382] Unless otherwise specified, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0383] Unless otherwise specified, the term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable non-toxic acids or bases including salts of inorganic acids and bases, and organic acids and bases.

[0384] In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be useful in the identification, characterization or purification of the compounds of the present invention.

[0385] Unless otherwise specified, the term "pharmaceutical composition" means a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.

[0386] Unless otherwise specified, the terms "excipients" and "excipients" refer to pharmaceutically acceptable inert ingredients. Examples of the term "excipients" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling characteristics of a pharmaceutical formulation, i.e., make the formulation more suitable for direct compression by increasing fluidity and / or adhesion.

[0387] Unless otherwise specified, the term "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrug of the present invention is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. The prodrug includes a compound formed by connecting a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group and a free amino group, respectively.

[0388] Unless otherwise specified, the term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, and includes cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0389] Depending on the choice of raw materials and methods, the compounds of the present invention may exist in the form of one of the possible isomers or a mixture thereof, for example as a pure optical isomer, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing optically active compounds, prefixes D and L or R and S are used to represent the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols for the rotation of plane polarized light caused by the specified compound, where (–) or L indicates that the compound is left-handed. Compounds prefixed with (+) or D are right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of the isomers are generally referred to as mixtures of enantiomers. A mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Many geometric isomers of alkenes, C=N double bonds, etc. may also exist in the compounds described herein, and all such stable isomers are contemplated in the present invention. When the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis- or trans- configuration.

[0390] When the bonds to the chiral carbon in the formula of the present invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the enantiomerically pure compounds and mixtures thereof produced therefrom are included within the scope of the general formula. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by a wedge-shaped bond and a dashed bond.

[0391] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. Compounds of the invention containing asymmetrically substituted carbon atoms can be separated in optically active form or racemic form. Resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolution acid that is an optically active salified organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include α-methyl-benzylamine (e.g., S and R forms or diastereomeric pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. The resolution of the racemic mixture can also be carried out by eluting on a chromatographic column filled with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High performance liquid chromatography (HPLC) can also be used to carry out supercritical fluid chromatography (SFC). The selection of specific methods and elution conditions, the selection of chromatographic columns can be selected by those skilled in the art according to the structure of the compound and the test results. Further, optically pure starting materials or reagents of known configurations can also be used to obtain any enantiomer or diastereomer of the compounds described in the present invention through stereo organic synthesis.

[0392] Unless otherwise specified, the term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is predominant; while in phenols, the enol form is predominant. The present invention includes all tautomeric forms of the compounds.

[0393] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0394] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. For oral dosage forms of the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0395] Unless otherwise specified, the terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0396] Unless otherwise specified, the term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, including 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 a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups. When the number of substituents is multiple, each substituent is independent and can be the same or different, for example, "Ring A and Ring B are optionally replaced by one or more R a Replace", each R a Are independent and can be the same or different.

[0397] Unless otherwise specified, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0398] Unless otherwise specified, the term "alkyl" refers to a group having a specified number of carbon atoms (e.g., C1 to C 12 , C1-C8) of straight or branched chain alkyl. The alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0399] Unless otherwise specified, the term “C 1-12 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 12 carbon atoms. 1-12 Alkyl groups include C 1-11 , C 1-10 , C 1-8 , C 1-6 , C 2-10 , C 2-8 , C 2-6 , C 3-10 , C3-8 , C 3-6 ,C1,C2,C3,C4,C5,C6,C7,C8,C9,C 10 , C 11 and C 12 Alkyl, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-12 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, heptyl and the like.

[0400] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6 and C5 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, and the like.

[0401] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0402] The term "halo" by itself or as part of another substituent is used interchangeably with the term "halogen-substituted."

[0403] Unless otherwise specified, "haloalkyl" or "halogen-substituted alkyl" refers to saturated aliphatic hydrocarbon groups including branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens.

[0404] Unless otherwise specified, "alkenyl" is used to refer to a straight or branched hydrocarbon group having a specified number of carbon atoms and containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-4 , C 2-3 , C4, C3 and C2 alkenyl, etc.; it can be monovalent, divalent or polyvalent. Examples of alkenyl include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, etc.

[0405] Unless otherwise specified, "alkynyl" is used to refer to a straight or branched hydrocarbon group having a specified number of carbon atoms and containing at least one carbon-carbon triple bond, which may be located at any position of the group. 2-4 , C 2-3 , C4, C3 and C2 alkynyl, etc. It can be monovalent, divalent or polyvalent. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, etc.

[0406] Unless otherwise specified, “C 2-6 "Alkenyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-6 Alkenyl includes C 2-4 , C 2-3 , C4, C3 and C2 alkenyl, etc.; which may be monovalent, divalent or polyvalent. 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperyl, hexadienyl, and the like.

[0407] Unless otherwise specified, “C 2-6 "Alkynyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. 2-6 Alkynyl groups include C 2-4 , C 2-3 , C4, C3 and C2 alkynyl, etc. It can be monovalent, divalent or polyvalent. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.

[0408] Unless otherwise specified, the term "alkoxy" refers to -O-alkyl, where alkyl is defined as above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentyl and neopentyl), hexyl and the like.

[0409] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule via an oxygen atom. 1-6 Alkoxy includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy, and the like.

[0410] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. 1-3 Alkoxy includes C 1-2 , C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0411] Unless otherwise specified, the term "cycloalkyl" refers to a saturated monocyclic ring group consisting only of carbon atoms, having a specified number of carbon atoms (e.g., 3-6, 3-12 members). Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0412] Unless otherwise specified, the term “C 3-8 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings. 3-8 Cycloalkyl groups include C 3-6 , C 3-5 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, and the like.

[0413] Unless otherwise specified, the term “C 3-6"Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic system. 3-6 Cycloalkyl groups include C 3-5 , C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0414] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 Etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.

[0415] Unless otherwise specified, the term "hetero" refers to a heteroatom group, including N, O, S, P, -C(O)-, -NH-, -P(O)-, -P(O)O-, -S(O)-, -S(O)2- or -S(O)2-NH-, etc. (preferably, the heteroatom group is N, O or S); when the number of the heteroatom groups is multiple, the heteroatom groups are the same or different; for example, when L 1 When it is -S(O)2-CH2-, it is considered to contain one heteroatom group "-S(O)2-" and is no longer counted in the number of heteroatom groups "-S"; when L 1When it is -S(O)2-NH-CH2-, it is considered to contain one heteroatom group "-S(O)2-NH-", and the number of heteroatom groups "-S(O)2-" and "-NH-" is no longer counted, nor the number of heteroatom groups "S" and "N" is no longer counted; L 1 When it is -S(O)2-CH2-O-, it is considered to contain two heteroatom groups "-S(O)2-" and "O"; in addition, if the heteroatom group contains a hydrogen atom, the hydrogen atom can be further substituted.

[0416] Unless otherwise specified, the term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and hydrogen atoms attached thereto) are each independently replaced by the same or different heteroatom groups. 1-12 A "heteroalkyl" group typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, and further contains 1, 2, 3, or 4 heteroatom groups. The heteroatom groups can be placed at any position (e.g., internal or terminal) of the heteroalkyl group, including the position that connects the heteroalkyl group to the rest of the molecule. Typically, when more than one heteroatom group is present, the heteroatom groups are not adjacent to each other.

[0417] Unless otherwise specified, the term "4-12 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 4 to 12 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S, N and P, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, cyclic and bridged rings. In addition, with respect to the "4-12 membered heterocycloalkyl", heteroatoms may occupy the position where the heterocycloalkyl is connected to the rest of the molecule. For example, 4-12 membered heterocycloalkyl includes, but is not limited to, 4, 5, 6, 7, 8, 9, 10, 11, and 12 members. Examples of 4-12 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, and hexahydropyridazinyl.

[0418] Unless otherwise specified, the term "4-7 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 4 to 7 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S, N and P, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, cyclic and bridged rings. In addition, with respect to the "4-7 membered heterocycloalkyl", heteroatoms may occupy the position where the heterocycloalkyl is connected to the rest of the molecule. For example, 4-7 membered heterocycloalkyl includes, but is not limited to, 4-membered, 5-membered, 6-membered, and 7-membered. Examples of 4-7 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl and oxepanyl.

[0419] Unless otherwise specified, the term "6-8 membered heterocycloalkenyl" by itself or in combination with other terms refers to a partially unsaturated cyclic group consisting of 6 to 8 ring atoms containing at least one carbon-carbon double bond, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S, N and P, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., C(=O), NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings, and any ring of this system is non-aromatic. In addition, with respect to the "6-8 membered heterocycloalkenyl", heteroatoms may occupy the position where the heterocycloalkenyl is connected to the rest of the molecule. The 6-8 membered heterocycloalkenyl includes 6-membered, 7-membered and 8-membered heterocycloalkenyl, etc.

[0420] Unless otherwise specified, the term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0421] Unless otherwise specified, the term "aryl" means a polyunsaturated aromatic hydrocarbon substituent, which may be mono- or poly-substituted, mono-, di- or poly-valent, and which may be monocyclic or polycyclic (e.g., 1 to 3 rings; at least one of which is aromatic), fused together or linked covalently.

[0422] The term "heteroaryl" refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, heteroatoms are selected from B, N, O and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen atom is optionally quaternized. Heteroaryl can be connected to the rest of the molecule by heteroatoms. The non-limiting examples of aryl or heteroaryl include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl 4-Pyridyl, 5-Benzothiazolyl, 2-Benzimidazolyl, 5-Indolyl, 1-Isoquinolyl, 5-Isoquinolyl, 2-Benzimidazolyl, 5-Indolyl, 1-Isoquinolyl, 5-Isoquinolyl, 2-Benzimidazolyl, 5-Indolyl, 2-Benzimidazolyl, 5-Indolyl, 3-Isoquinolyl, 4-Isoquinolyl, 5-Indolyl, 6-Indolyl, 1-Isoquinolyl, 5-Indolyl, 2-Benzimidazolyl, 5-Indolyl, 3-Isoquinolyl, 2-Benzimidazolyl ...

[0423] In addition, it should be noted that, unless otherwise clearly indicated, the description method "...independently" used in the present invention should be understood in a broad sense, meaning that the individuals described are independent of each other and can be independently the same or different specific groups. In more detail, the description method "...independently" can mean that in different groups, the specific options expressed by the same symbols do not affect each other, and can also mean that in the same group, the specific options expressed by the same symbols do not affect each other.

[0424] Unless otherwise specified, the term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0425] Unless otherwise specified, the term "therapeutically effective amount" refers to the amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and includes one or more of the following: (1) Preventing disease: e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but does not yet experience or develop the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting a disease, disorder or condition (i.e., preventing further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: e.g., alleviating a disease, disorder or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition.

[0426] As used herein, the term "treatment" and other similar synonyms include the following meanings:

[0427] (i) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition;

[0428] (ii) inhibiting a disease or condition, i.e. arresting its development;

[0429] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0430] (iv) alleviating the symptoms caused by the disease or condition.

[0431] Unless otherwise specified, the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10 -6 The solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).

[0432] The abbreviations of the present invention are defined as follows:

[0433] M: molar concentration, such as 1M hydrochloric acid means 1 mol / L hydrochloric acid solution

[0434] N: equivalent concentration, for example, 2N hydrochloric acid means 2 mol / L hydrochloric acid solution

[0435] DMSO: dimethyl sulfoxide

[0436] LC-MS: Liquid chromatography-mass spectrometry

[0437] IC 50 : Half inhibitory concentration refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0438] Beneficial Effects

[0439] According to the embodiments of the present invention, the present invention has at least one of the following technical effects:

[0440] (1) The present invention provides a compound for degrading IRAK4 with novel structure, excellent pharmacokinetic properties, good efficacy or drugability, which can be used to effectively treat IRAK4-related diseases and conditions;

[0441] (2) The degradation activity of the compounds of the present invention on IRAK4 protein reached the nM level, showing excellent degradation effect and being dose-dependent;

[0442] (3) The compounds of the present invention have good pharmacokinetic properties;

[0443] (4) The compounds of the present invention do not degrade or only slightly degrade IKZF1 / 2 / 3, have low toxicity and side effects, and have good drugability;

[0444] (5) Good drug metabolism and higher bioavailability;

[0445] (6) Better safety;

[0446] (7) The compounds of the present invention can significantly inhibit the activation of the NF-kB signaling pathway induced by IL-1β; in the LPS-stimulated THP1 cell model and the RAW264.7 cell model, the compounds of the present invention can significantly inhibit the production of TNF, and the inhibitory function is positively correlated with the dose;

[0447] (8) The compounds of the present invention have good liver microsomal stability.

[0448] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0449] Figure 1 represents the degradation of IKZF1 / 3 by the compounds, and GAPDH represents glyceraldehyde-3-phosphate dehydrogenase, which is used as an internal control for Western blotting. DETAILED DESCRIPTION

[0450] The present invention is further described below in conjunction with specific examples. It should be understood that the following description is only the most preferred embodiment of the present invention and should not be considered as limiting the scope of protection of the present invention. On the basis of a full understanding of the present invention, the experimental methods in the following examples that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Those skilled in the art may make non-essential changes to the technical solution of the present invention, and such changes should be deemed to be included in the scope of protection of the present invention.

[0451] Preparation of Intermediate I

[0452] 4-(6-bromo-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (target compound I)

[0453]

[0454] The synthetic route of target intermediate I is as follows:

[0455]

[0456] Step 1: 2-(2-amino-5-bromo-3-fluoropyridin-4-yl)propan-2-ol (4b)

[0457]

[0458] 2-(5-bromo-2,3-difluoropyridin-4-yl)propan-2-ol (15.0 g, 59.5 mmol) was dissolved in 1,4-dioxane (15 mL), and then ammonia water (54.6 g, 514 mmol, 60.0 mL, 33% purity) was added, and stirred at 90°C for 12 hours under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to obtain compound 2-(2-amino-5-bromo-3-fluoropyridin-4-yl)propan-2-ol (4b) (10.0 g, yield 63.2%).

[0459] LC-MS, M / Z (ESI): 250.9 (M+H + )

[0460] Step 2: Synthesis of tert-butyl 4-(6-bromo-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (I)

[0461]

[0462] Dissolve 2-(2-amino-5-bromo-3-fluoropyridin-4-yl)propan-2-ol (5.50 g, 22.1 mmol) in isopropanol (70 mL), replace the atmosphere with nitrogen three times, add N-tert-butoxycarbonyl-4-(2-bromoacetyl)piperidine (10.1 g, 33.1 mmol) and sodium bicarbonate (1.85 g, 22.1 mmol), and stir at 80 °C for 12 hours. After the reaction was completed, water (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL*3). The organic phases were combined and then washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 0:1) to obtain compound 4-(6-bromo-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate I) (14.0 g, yield 69.4%).

[0463] LC-MS, M / Z (ESI): 456.1 (M+H + )

[0464] Synthesis of intermediates II-P1 and II-P2

[0465] Synthesis of (R&S)-tert-butyl 4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (Intermediates II-P1 and 1I-P2)

[0466] for

[0467]

[0468] for

[0469] Another configuration different from II-P1.

[0470] The synthetic routes of target intermediate II-P1 and intermediate II-P2 are as follows:

[0471]

[0472] Step 1: Synthesis of tert-butyl 6-bromopyridine-2-carboxylate (II-2)

[0473]

[0474] 6-Bromo-2-pyridinecarboxylic acid (10.0 g, 49.5 mmol) was dissolved in tetrahydrofuran (100 mL), 4-dimethylaminopyridine (3.02 g, 24.7 mmol) and di-tert-butyl dicarbonate (21.6 g, 99.0 mmol, 22.7 mL) were added, and the mixture was stirred at 25°C for 1 hour under nitrogen protection. After the reaction was complete, the reaction solution was poured into water (20 mL) at 0°C, extracted with ethyl acetate (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 100:1 to 5:1) to obtain compound 6-bromopyridine-2-carboxylic acid tert-butyl ester (II-2) (11.2 g, yield 87.6%).

[0475] Step 2: Synthesis of tert-butyl 6-vinylpyridine-2-carboxylate (II-3)

[0476]

[0477] Dissolve tert-butyl 6-bromopyridine-2-carboxylate (II-2) (11.0 g, 42.6 mmol) in isopropanol (110 mL), add potassium vinyl trifluoroborate (11.4 g, 85.2 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (3.12 g, 4.26 mmol) and triethylamine (12.9 g, 127 mmol, 17.8 mL), and stir at 90 ° C for 12 hours under nitrogen protection. After the reaction is complete, pour the reaction solution into water (50 mL), extract with ethyl acetate (50 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product, which is purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 100:1 to 5:1) to obtain compound tert-butyl 6-vinylpyridine-2-carboxylate (II-3) (8.10 g, yield 92.6%).

[0478] LC-MS, M / Z (ESI): 206.3 (M+H + )

[0479] Step 3: Synthesis of tert-butyl 6-(2,2-difluorocyclopropyl)pyridine-2-carboxylate (II-4)

[0480]

[0481] Dissolve tert-butyl 6-vinylpyridine-2-carboxylate (II-3) (3.00 g, 14.6 mmol) in toluene (30 mL), add (bromodifluoromethyl)trimethylsilane (7.42 g, 36.5 mmol) and tetrabutylammonium bromide (471 mg, 1.46 mmol), and stir at 70 ° C for 12 hours under nitrogen protection. After the reaction is complete, pour the reaction solution into water (20 mL), extract with ethyl acetate (15 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product, which is purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 100:1 to 10:1) to obtain compound tert-butyl 6-(2,2-difluorocyclopropyl)pyridine-2-carboxylate (II-4) (5.00 g, yield 67.0%).

[0482] LC-MS, M / Z (ESI): 200.0 (M-56+H + )

[0483] Step 4: Synthesis of 6-(2,2-difluorocyclopropyl)pyridine-2-carboxylic acid (II-5)

[0484]

[0485] Dissolve tert-butyl 6-(2,2-difluorocyclopropyl)pyridine-2-carboxylate (II-4) (5.00 g, 19.6 mmol) in dichloromethane (50 mL), add trifluoroacetic acid (11.1 g, 97.9 mmol, 7.28 mL) under nitrogen protection, and stir the reaction solution at 25°C for 2 hours. After the reaction is complete, the reaction solution is directly dried to obtain compound 6-(2,2-difluorocyclopropyl)pyridine-2-carboxylic acid (II-5) (3.80 g, yield 97.4%).

[0486] LC-MS, M / Z (ESI): 200.0 (M+H + )

[0487] Step 5: Synthesis of 6-(2,2-difluorocyclopropyl)pyridine-2-carboxamide (II-5a)

[0488]

[0489] 6-(2,2-difluorocyclopropyl)pyridine-2-carboxylic acid (II-5) (3.70 g, 18.5 mmol) was dissolved in tetrahydrofuran (50 mL), 1,1-carbonyldiimidazole (6.03 g, 37.1 mmol) was added, and the mixture was stirred at 25°C for 2 hours under nitrogen protection, and then ammonia water (6.51 g, 55.7 mmol, 7.15 mL, 30% purity) was added, and the reaction solution was stirred at 25°C for 1 hour. After the reaction was complete, the reaction solution was concentrated to obtain a crude product, which was purified by preparative liquid chromatography (chromatographic column: Welch Ultimate XB-C18 20-40 μm, mobile phase: A = 0.1% ammonia water, B = methanol; gradient: 10%-100%, 10 min) to obtain compound 6-(2,2-difluorocyclopropyl)pyridine-2-carboxamide (II-5a) (2.00 g, yield 54.3%).

[0490] LC-MS, M / Z (ESI): 199.2 (M+H + )

[0491] 1 H NMR(400MHz,DMSO-d6)δ8.11(s,1H),7.99-7.85(m,2H),7.70-7.52(m,2H),3.29-3.19(m,1H),2.82-2.65(m,1H),2.08-1.88(m,1H)

[0492] Step 6: Synthesis of tert-butyl 4-(6-(6-(2,2-difluorocyclopropyl)pyridinecarboxamido)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (Intermediate II)

[0493]

[0494] Dissolve 6-(2,2-difluorocyclopropyl)pyridine-2-carboxamide (500 mg, 2.52 mmol) in toluene (10 mL), add tert-butyl 4-(6-bromo-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (Intermediate 1) (1.73 g, 3.78 mmol), potassium phosphate (1.61 g, 7.57 mmol), 1,10-phenanthroline (150 mg, 756 μmol) and cuprous iodide (144 mg, 756 μmol), and stir at 95 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was poured into water (15 mL), extracted with ethyl acetate (15 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: dichloromethane / ethyl acetate (V / V) = 10:1 to 1:1) to obtain compound 4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate II) (1.30 g, yield 89.8%).

[0495] LC-MS, M / Z (ESI): 574.3 (M+H + )

[0496] Step 7: Synthesis of (R or S)-tert-butyl 4-(6-(6-(2,2-difluorocyclopropyl)pyridinecarboxamido)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (II-P1)

[0497]

[0498] Synthesis of tert-butyl (S or R)-4-(6-(6-(2,2-difluorocyclopropyl)pyridinecarboxamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (II-P2)

[0499]

[0500] ( Another configuration different from II-P1)

[0501] 4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate II) (700 mg) was separated by supercritical fluid chromatography (Column: Chiralcel OD-3 50*4.6mm ID, 3μm; Mobile phase A: supercritical fluid carbon dioxide; Mobile phase B: isopropanol (0.05% diethylamine), gradient elution: supercritical fluid carbon dioxide containing isopropanol (0.05% diethylamine), the ratio of which is from 5% to 40%; Flow rate: 3mL / min; Detector: PDA; Column temperature: 35°C; Column pressure: 100bar) to obtain compound (R or S)-tert-butyl 4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (Intermediate II-P1) (300 mg, 523 μmol, peak 1, retention time = 1.65 min, 42.8% yield) and compound (S or R)-tert-butyl 4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (Intermediate II-P2, another configuration corresponding to II-P1) (300 mg, 523 μmol, peak 2, retention time = 1.99 min 42.8% yield).

[0502] LC-MS, M / Z (ESI): 574.3 (M+H + )

[0503] Example: Synthesis of Intermediate III-P1

[0504] Synthesis of (R or S)-6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropane-2-yl)-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)picolinamide (III-P1)

[0505] for

[0506]

[0507] The synthesis route of intermediate III-A is as follows:

[0508]

[0509] Dissolve (R or S)-tert-butyl 4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (Intermediate II-P1) (280 mg, 488 μmol) in dichloromethane (3 mL), replace nitrogen three times, add trifluoroacetic acid (2.87 g, 25.1 mmol) dropwise into the reaction solution at 0°C, and stir at 0°C for 0.5 hours. After the reaction, sodium bicarbonate aqueous solution (50 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound (R or S)-6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropane-2-yl)-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)picolinamide (Intermediate III-P1) (200 mg, yield 86.5%).

[0510] Example: Synthesis of Intermediate III-P2

[0511] Synthesis of (S or R)-6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropane-2-yl)-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)methylpicolinamide (III-P2)

[0512] for

[0513] Another configuration different from III-P1

[0514] The synthesis route of intermediate III-P2 is as follows:

[0515]

[0516] Dissolve (S or R)-tert-butyl 4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (Intermediate II-P2) (300 mg, 523 μmol) in dichloromethane (3 mL), replace nitrogen three times, add trifluoroacetic acid (3.07 g, 26.9 mmol, 2 mL) dropwise into the reaction solution at 0°C, and keep the reaction temperature at 0°C with stirring for 0.5 hours. After the reaction, sodium bicarbonate aqueous solution (50 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound (S or R)-6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropane-2-yl)-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)methylpicolinamide (Intermediate III-P2) (200 mg, yield 74.30%).

[0517] LC-MS, M / Z: 474.2 (M+H + )

[0518] Example: Preparation of Intermediate IV

[0519] Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperidine-4-carboxaldehyde (IV)

[0520]

[0521] The synthetic route of intermediate IV is as follows:

[0522]

[0523] Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(hydroxymethyl)piperidin-1-yl)-dihydroisoindole-1,3-dione (7b)

[0524]

[0525] 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoro-isoindole-1,3-dione (2.00 g, 6.80 mmol) and 4-piperidinol (861 mg, 7.48 mmol) were dissolved in dimethyl sulfoxide (20 mL), and N,N-diisopropylethylamine (2.64 g, 20.3 mmol, 3.55 mL) was added. The mixture was stirred at 100 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was concentrated to obtain compound 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(hydroxymethyl)piperidin-1-yl)-isoindole-1,3-dione (7b) (2.10 g, yield 79.3%).

[0526] LC-MS, M / Z (ESI): 390.0 (M+H + )

[0527] Step 2: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperidine-4-carboxaldehyde (IV)

[0528]

[0529] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(hydroxymethyl)piperidin-1-yl)-dihydroisoindole-1,3-dione (7b) (1.00 g, 2.57 mmol) in dichloromethane (20 mL), add Dess-Martin periodinane (1.31 g, 3.08 mmol), and stir at 25 °C for 1 hour under nitrogen protection. After the reaction was complete, the reaction solution was poured into a sodium sulfite solution (100 mL), extracted with ethyl acetate (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 5:1 to 1:1) to obtain compound 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxodihydroisoindol-5-yl)piperidine-4-carboxaldehyde (Intermediate IV) (800 mg, yield 80.4%).

[0530] LC-MS, M / Z (ESI): 388.1 (M+H + )

[0531] Example: Preparation of Intermediate V

[0532] Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (Intermediate V)

[0533]

[0534] The synthetic route of intermediate V is as follows:

[0535]

[0536] Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(3-(hydroxymethyl)azetidin-1-yl)isoindoline-1,3-dione (V-1)

[0537]

[0538] 2-(2,6-Dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (1.00 g, 3.40 mmol) was dissolved in dimethyl sulfoxide (10 mL), triethylamine (1.03 g, 10.2 mmol) and (azetidine-3-yl)methanol hydrochloride (504 mg, 4.08 mmol) were added, and the reaction solution was stirred at 90 ° C for 2 hours. After the reaction, the reaction solution was cooled to room temperature, quenched with water (100 mL), extracted with ethyl acetate (50 mL*3), and the organic phases were combined, washed with saturated brine (50 mL), and then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6-(3-(hydroxymethyl)azetidine-1-yl)isoindoline-1,3-dione (V-1) (1.00 g, yield 81.4%).

[0539] LC-MS, M / Z (ESI): 362.0 [M+H) +

[0540] Step 2: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (V)

[0541]

[0542] 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(3-(hydroxymethyl)azetidin-1-yl)isoindoline-1,3-dione (1.00 g, 2.77 mmol) was dissolved in dichloromethane (10 mL), Dess-Martin periodinane (1.41 g, 3.32 mmol) was added, and the mixture was stirred at 25°C for 2 hours. After the reaction was completed, water (100 mL) was added to quench the reaction, and the reaction mixture was extracted with dichloromethane (150 mL). The organic phase was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 1 / 1 to 0 / 1) to obtain compound 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindole-5-yl)azetidine-3-carbaldehyde (intermediate V) (650 mg, yield 65.3%).

[0543] LC-MS, M / Z (ESI): 359.9 (M+H) +

[0544] Example 1: Preparation of target compound 1

[0545] Synthesis of 6-(2,2-difluorocyclopropyl)-N-(2-(1-((1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl]piperidin-4-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-6-yl)picolinamide (Compound 1)

[0546]

[0547] The synthetic route of target compound 1 is as follows:

[0548]

[0549] Step 1: Synthesis of 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropane-2-yl)-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)pyridine-2-carboxamide (III)

[0550]

[0551] 4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate II) (400 mg, 697 μmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (2 mL) was added at 0°C under nitrogen protection, and the reaction solution was stirred at 0°C for 2 hours. After the reaction is complete, the reaction solution is poured into sodium bicarbonate (25 mL) at 0°C, the pH is adjusted to 7, the solid is collected by filtration, and dried to obtain compound 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropane-2-yl)-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)pyridine-2-carboxamide (Intermediate III) (280 mg, yield 84.8%).

[0552] LC-MS, M / Z (ESI): 474.2 (M+H + )

[0553] Step 2: Synthesis of 6-(2,2-difluorocyclopropyl)-N-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-6-yl)picolinamide (Compound 1)

[0554]

[0555] 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropane-2-yl)-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)pyridine-2-carboxamide (Intermediate III) (100 mg, 211 μmol) and 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperidine-4-carboxaldehyde (Intermediate IV) (98.1 mg, 253 μmol) were dissolved in dichloromethane (1 mL) and stirred at 25°C for 11 hours. Sodium triacetoxyborohydride (134 mg, 633 μmol) was added and stirred at 25°C for 1 hour. After the reaction was complete, the reaction solution was poured into sodium bicarbonate (15 mL), the pH was adjusted to 7, and extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150*25mm*10μm; mobile phase: A=0.1% formic acid, B=acetonitrile; gradient: 18%-48%, 9min) to obtain compound 6-(2,2-difluorocyclopropyl)-N-(2-(1-((1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxodihydroisoindol-5-yl]piperidin-4-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-6-yl)picolinamide (Compound 1).

[0556] LC-MS, M / Z (ESI): 845.4 (M+H + )

[0557] H NMR(400MHz,DMSO-d6)δ12.53(s,1H)11.04-11.16(m,1H)9.50(s,1H)8.02-8.10(m,2H )7.89(d,1H)7.77(dd,1H)7.70(d,1H)7.44(d,1H)6.70(s,1H)5.05-5.14(m,1H)3.62(d ,2H)3.02(s,8H)2.65-2.73(m,2H)2.33(dt,1H)2.22(d,2H)1.94-2.07(m,6H)1.81-1. 88(m,1H)1.81-1.82(m,1H)1.72(d,3H)1.70(d,3H)1.62-1.67(m,1H)1.21-1.32(m,3H)

[0558] Example 2A: Preparation of target compound 2-P1

[0559] 6-((R)-2,2-difluorocyclopropyl)-N-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-6-yl)methylpicolinamide (target compound 2-P1)

[0560] for

[0561]

[0562] The synthetic route of the target compound 2-P1 is as follows:

[0563]

[0564] Step 1: 6-((R or S)-2,2-difluorocyclopropyl)-N-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-6-yl)methylpicolinamide (Compound 2-P1)

[0565] for

[0566]

[0567] (R or S)-6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropane-2-yl)-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)picolinamide (Intermediate III-P1) (60.0 mg, 127 μmol), 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (68.3 mg, 190 μmol) were dissolved in tetrahydrofuran (2 mL), potassium acetate (37.3 mg, 380 μmol) was added, and the mixture was stirred at 25°C for 12 hours. Sodium acetate borohydride (53.7 mg, 253 μmol) was added to the reaction solution, and stirring was continued at 25°C for 0.5 hours. After the reaction, sodium bicarbonate aqueous solution (50 mL) was added to the reaction solution, and extracted with ethyl acetate (60 mL). The organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by high performance liquid chromatography (chromatographic column: Waters Xbridge 150*25mm*5μm; mobile phase: A=water (NH4HCO3), B=acetonitrile; gradient: acetonitrile 44%-74%, 9min) to obtain compound 6-((R or S)-2,2-difluorocyclopropyl)-N-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-6-yl)methylpicolinamide (Compound 2-P1).

[0568] LC-MS, M / Z (ESI): 817.4 (M+H) +

[0569] 1 H NMR(400MHz,DMSO-d6)δ12.31(s,1H),11.07(s,1H),9.46(s,1H),8.19-8.12(m,1H),7.88( d,1H),7.78-7.76(m,1H),7.58(d,1H),6.91(d,1H),6.71(s,1H),5.08-5.03(m,1H),4.30-4 .26(m,2H),3.86-3.83(m,2H),3.08-2.93(m,3H),2.92-2.86(m,2H),2.69-2.59(m,5H),2. 56-2.55(m,2H),2.15-2.06(m,2H),2.06-1.93(m,4H),1.74-1.69(m,6H),1.65-1.61(m,1H)

[0570] Example 2B: Preparation of target compound 2-P2

[0571] 6-((S or R)-2,2-difluorocyclopropyl)-N-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-6-yl)methylpicolinamide (target compound 2-P2)

[0572] for

[0573]

[0574] Another configuration different from compound 2-P1

[0575] The synthetic route of the target compound 2-P2 is as follows:

[0576]

[0577] Step 1: Synthesis of 6-((S or R)-2,2-difluorocyclopropyl)-N-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-6-yl)picolinamide (Compound 2-P2)

[0578] for

[0579]

[0580] Another configuration different from compound 2-P1

[0581] (S or R)-6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropane-2-yl)-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)picolinamide (Intermediate III-P2) (60.0 mg, 127 μmol), 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (68.3 mg, 190 μmol) were dissolved in tetrahydrofuran (2.00 mL), potassium acetate (37.3 mg, 380 μmol) was added, the reaction solution was stirred at 25°C for 12 hours, then sodium acetate borohydride (53.7 mg, 253 μmol) was added, and the reaction solution was stirred at 25°C for 0.5 hours. After the reaction, sodium bicarbonate aqueous solution (50 mL) was added to the reaction solution, and extracted with ethyl acetate (60 mL). The organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by high performance liquid chromatography (chromatographic column: Waters Xbridge 150*25mm*5μm; mobile phase: A=water (NH4HCO3), B=acetonitrile; gradient: acetonitrile 44%-74%, 9min) to obtain compound 6-((S or R)-2,2-difluorocyclopropyl)-N-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-6-yl)picolinamide (Compound 2-P2).

[0582] LC-MS, M / Z (ESI): 817.4 (M+H + );

[0583] 1 H NMR(400MHz,DMSO-d6)δ12.53(s,1H),11.08(s,1H),9.50(s,1H),8.14-8.00(m,2H),7.88( d,1H),7.78-7.76(m,1H),7.58(d,1H),6.91(d,1H),6.71(s,1H),5.08-5.03(m,1H),4.30-4 .26(m,2H),3.86-3.83(m,2H),3.08-2.93(m,3H),2.92-2.86(m,2H),2.69-2.59(m,5H),2.5 6-2.55(m,2H),2.15-2.06(m,2H),2.06-1.93(m,4H),1.74-1.69(m,6H),1.65-1.61(m,1H).

[0584] Example 3: Preparation of target compound 3

[0585] Synthesis of 6-(2,2-difluorocyclopropyl)-N-{2-[1-({1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]-3-fluoroazetidine-3-yl}methyl)piperidin-4-yl]-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-6-yl}pyridine-2-carboxamide (Compound 3)

[0586]

[0587] The synthetic route of target compound 3 is as follows:

[0588]

[0589] Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-[3-fluoro-3-(hydroxymethyl)azetidine-1-yl]-2,3-dihydro-1H-isoindole-1,3-dione (Compound 3-2)

[0590]

[0591] Dissolve (3-fluoroazetidine-3-yl)methanol hydrochloride (compound 3-1) (300 mg, 2.12 mmol) and 2-(2,6-dioxypiperidin-3-yl)-5,6-difluoro-2,3-dihydro-1H-isoindole-1,3-dione (4a) (561 mg, 1.91 mmol) in dimethyl sulfoxide (3 mL), add N,N-diisopropylethylamine (273 mg, 2.12 mmol), and stir at 100 ° C for 3 hours under nitrogen protection. After the reaction is complete, the reaction solution is poured into water (25 mL), extracted with ethyl acetate (10 mL*3), and the organic phase is dried and concentrated to obtain compound 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-[3-fluoro-3-(hydroxymethyl)azetidine-1-yl]-2,3-dihydro-1H-isoindole-1,3-dione (compound 3-2) (650 mg, 80.8% yield).

[0592] LC-MS, M / Z(ESI):380.0[M+H] +

[0593] Step 2: Synthesis of 1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]-3-fluoroazetidine-3-carboxaldehyde (Compound 3-3)

[0594]

[0595] 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-[3-fluoro-3-(hydroxymethyl)azetidine-1-yl]-2,3-dihydro-1H-isoindole-1,3-dione (Compound 3-2) (400 mg, 1.05 mmol) was dissolved in dichloromethane (8 mL), and then Dess-Martin periodinane (536 mg, 1.27 mmol) was added, and the reaction solution was stirred at 25 ° C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 3:1 to 1:1) to obtain compound 1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]-3-fluoroazetidine-3-carbaldehyde (compound 3-3) (200 mg, 50.3% yield).

[0596] LC-MS, M / Z(ESI):396.1[M+H2O+H] +

[0597] Step 3: Synthesis of 6-(2,2-difluorocyclopropyl)-N-{2-[1-({1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]-3-fluoroazetidine-3-yl}methyl)piperidin-4-yl]-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridine-6-yl}pyridine-2-carboxamide (Compound 3)

[0598]

[0599] 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropane-2-yl)-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)pyridine-2-carboxamide (Intermediate III) (90.0 mg, 190 μmol) and 1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1 H-isoindol-5-yl]-3-fluoroazetidine-3-carboxaldehyde (Compound 3-3) (143 mg, 380 μmol) was dissolved in dichloromethane (3 mL), N, N-diisopropylethylamine (122 mg, 950 μmol) was added, and stirred at 25°C for 10 hours, and then sodium triacetoxyborohydride (120 mg, 570 μmol) was added, and the reaction solution was stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was poured into water (15 mL), extracted with ethyl acetate (10 mL*3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by high performance liquid chromatography (chromatographic column: Waters Xbridge150*25mm*5μm; mobile phase: solvent A=water+ammonium bicarbonate, B=acetonitrile; gradient: 35%-65%, 15min) to obtain compound 6-(2,2-difluorocyclopropyl)-N-{2-[1-({1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]-3-fluoroazetidine-3-yl}methyl)piperidin-4-yl]-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridine-6-yl}pyridine-2-carboxamide (compound 3).

[0600] LC-MS, M / Z (ESI): 835.1 (M+H + );

[0601] 1 H NMR(400MHz, CDCl3-d)δ12.31(s,1H)9.55(s,1H)8.49-8.79(m,1H)8.23(d,1H)7.89(t,1H)7.48(d,1H)7.41(d,1H)7.33(d,1H)7.27-7.2 9(m,1H)6.92(d,1H)4.87-4.99(m,1H)4.26-4.36(m,4H)2.89-3.02(m,4H)2.80-2.87(m,3H)2.70-2.79(m,3H)2.31-2.44(m,2H)2.24(br d,4H)1.89(d,3H)1.85(br d, 3H) 1.26-1.32 (m, 2H).

[0602] Example 4: Preparation of target compound 4

[0603] 6-(2,2-difluorocyclopropyl)-N-(2-(1-(1'-(2-((2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)-(1,3'-diazetidine)-3-yl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide

[0604]

[0605] The synthetic route of compound 4 is as follows:

[0606]

[0607] Step 1: Synthesis of tert-butyl 3-(4-(6-(6-(2,2-difluorocyclopropyl)pyridinecarboxamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidin-1-yl)azetidine-1-carboxylate (Compound 4-1)

[0608]

[0609] Under nitrogen protection, tert-butyl 3-oxoazetidine-1-carboxylate (3.62 g, 21.1 mmol) and 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropane-2-yl)-2-(piperidin-4-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Intermediate III) (500 mg, 1.05 mmol) were added to dichloromethane (5 mL). The mixture was stirred at 25 ° C for 3 hours, and then sodium triacetoxyborohydride (671 mg, 3.17 mmol) was added. The resulting mixture was stirred at 25 ° C for 15 hours. The resulting mixture was diluted with water (20 mL), and then extracted with ethyl acetate (10 mL×3). The organic layer was separated, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel column (dichloromethane: methanol (V / V) = 100:0 to 95:5, gradient elution) to obtain compound 3-(4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (compound 4-1).

[0610] LC-MS, M / Z (ESI): 629.2 (M+H) +

[0611] Step 2: Synthesis of N-(2-(1-(azetidin-3-yl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-bipyridin-6-yl)-6-(2,2-difluorocyclopropyl)picolinamide (Compound 4-2)

[0612]

[0613] Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl 3-(4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidin-1-yl)azetidine-1-carboxylate (Compound 4-1) (240 mg, 0.38 mmol) in dichloromethane (2 mL) at 0° C. The mixture was stirred at 0° C. for 2 hours. The resulting mixture was quenched with saturated sodium bicarbonate at 0°C, filtered to obtain a filter cake, which was dried at 50°C to obtain N-(2-(1-(azetidin-3-yl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-bipyridin-6-yl)-6-(2,2-difluorocyclopropyl)picolinamide (compound 4-2). The crude product was used directly in the next step without purification.

[0614] LC-MS, M / Z (ESI): 529.0 (M+H) +

[0615] Step 3: Synthesis of tert-butyl 3-(4-(6-(6-(2,2-difluorocyclopropyl)pyridinecarboxamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidin-1-yl)-(1,3'-diazetidine)-1'-carboxylate (Compound 4-3)

[0616]

[0617] Under nitrogen protection, N-(2-(1-(azetidin-3-yl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-bipyridin-6-yl)-6-(2,2-difluorocyclopropyl)picolinamide (180 mg, 0.34 mmol)) and tert-butyl 3-oxoazetidine-1-carboxylate (Compound 4-2) (1.17 g, 6.81 mmol), sodium triacetoxyborohydride (217 mg, 1.02 mmol) were added to dichloromethane (5 mL), and the reaction solution was stirred at 25 ° C for 15 hours. The reaction mixture was diluted with water (20 mL), and then extracted with ethyl acetate (10 mL×3). The organic layer was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The product was separated and purified by silica gel column (dichloromethane:methanol (V / V)=100:0-95:5, gradient elution) to obtain compound 3-(4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidin-1-yl)-(1,3'-diazetidine)-1'-carboxylic acid tert-butyl ester (compound 4-3).

[0618] LC-MS, M / Z(ESI):684.3(M+H) +

[0619] Step 4: Synthesis of N-(2-(1-((1,3'-diazetidine)-3-yl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)-6-(2,2-difluorocyclopropyl)picolinamide (Compound 4-4)

[0620]

[0621] To a solution of tert-butyl 3-(4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidin-1-yl)-(1,3'-diazetidine)-1'-carboxylate (Compound 4-3) (80.0 mg, 0.12 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL) dropwise at 0°C, and the reaction solution was stirred at 0°C for 2 h. The resulting mixture was quenched with a saturated sodium bicarbonate solution and then filtered to obtain a filter cake, which was dried at 50°C to obtain N-(2-(1-((1,3'-diazetidine)-3-yl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)-6-(2,2-difluorocyclopropyl)picolinamide (Compound 4-4). The crude product was used directly in the next step without purification.

[0622] LC-MS, M / Z (ESI): 584.5 (M+H) +

[0623] Step 5: Synthesis of 6-(2,2-difluorocyclopropyl)-N-(2-(1-(1'-(2-((2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)-(1,3'-diazetidine)-3-yl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 4)

[0624]

[0625] To a solution of N-(2-(1-((1,3'-diazetidine)-3-yl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)-6-(2,2-difluorocyclopropyl)picolinamide (compound 4-4) (40.0 mg, 0.07 mmol) in dimethyl sulfoxide (5 mL) were added 2-(2,6-dioxopiperidine-3-yl)-5,6-difluoroindoline-1,3-dione (compound 7c) (22.0 mg, 0.08 mmol) and N,N-diisopropylethylamine (27.0 mg, 0.21 mmol), and the reaction solution was stirred at 110° C. for 1 hour. The resulting mixture was cooled to room temperature and purified by preparative liquid chromatography (Xtimate C18 21.2×250mm5μm; solvent A=water+0.05% ammonia water, B=acetonitrile; gradient: 52%-82%, 20mL / min) to give 6-(2,2-difluorocyclopropyl)-N-(2-(1-(1'-(2-((2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)-(1,3'-diazetidine)-3-yl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 4).

[0626] LC-MS, M / Z (ESI): 858.6 (M+H) +

[0627] 1H NMR (400MHz, DMSO-d6): δ12.54(s,1H),11.08(s,1H),9.50(s,1H),8.10–8.03(m,2H) ,7.89(d,1H),7.78(dd,1H),7.60(d,1H),6.93(d,1H),6.71(s,1H),5.07(dd,1H),4. 23–4.14(m,2H),3.96–3.89(m,2H),3.64–3.54(m,2H),3.44–3.42(m,2H),2.98–2.91 (m,4H),2.85–2.73(m,3H),2.69–2.60(m,3H),2.05–1.89(m,6H),1.73–1.59(m,8H).

[0628] Example 5: Preparation of target compound 5

[0629] 6-(2,2-difluorocyclopropyl)-N-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)ethyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-6-yl)picolinamide (Compound 5)

[0630]

[0631] The synthetic route of compound 5 is as follows:

[0632]

[0633] Step 1: Synthesis of tert-butyl 3-(1-(4-(6-(6-(2,2-difluorocyclopropyl)pyridinecarboxamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidin-1-yl)ethyl)azetidine-1-carboxylate (Compound 5-2)

[0634]

[0635] Under nitrogen protection, 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropan-2-yl)-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)picolinamide (Intermediate III) (800 mg, 1.69 mmol) and tert-butyl 3-acetylazetidine-1-carboxylate (1.01 g, 5.07 mmol), sodium cyanoborohydride (159 mg, 2.53 mmol) and glacial acetic acid (0.19 mL, 3.38 mmol) were added to methanol (25 mL), and the resulting mixture was stirred at 80° C. for 3 days. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol (V / V) = 50:1 to 10:1, gradient elution) to obtain tert-butyl 3-(1-(4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidin-1-yl)ethyl)azetidine-1-carboxylate (Compound 5-2).

[0636] LC-MS, M / Z(ESI):657.4[M+H] +

[0637] Step 2: Synthesis of N-(2-(1-(1-(azetidin-3-yl)ethyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-6-yl)-6-(2,2-difluorocyclopropyl)picolinamide (Compound 5-3)

[0638]

[0639] To a solution of tert-butyl 3-(1-(4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidin-1-yl)ethyl)azetidine-1-carboxylate (compound 5-2) (400 mg, 0.61 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) dropwise at 0°C, and the reaction solution was stirred at 0°C for 2 h under nitrogen protection. The reaction solution was added dropwise with a saturated sodium bicarbonate solution at 0°C until the pH of the reaction solution was 7, and the filter cake was filtered to obtain a filter cake, which was dried at 50°C to obtain N-(2-(1-(1-(azetidin-3-yl)ethyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-6-yl)-6-(2,2-difluorocyclopropyl)picolinamide (Compound 5-3). The crude product was directly used for the next step reaction.

[0640] LC-MS, M / Z(ESI):557.2[M+H]+

[0641] Step 3: Synthesis of 6-(2,2-difluorocyclopropyl)-N-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)azetidin-3-yl)ethyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-6-yl)picolinamide (Compound 5)

[0642]

[0643] N,N-diisopropylethylamine (348 mg, 270 mmol) was added to a solution of N-(2-(1-(1-(azetidin-3-yl)ethyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-6-yl)-6-(2,2-difluorocyclopropyl)picolinamide (compound 5-3) (300 mg, 0.54 mmol) and 2-(2,6-dioxahexahydropyridin-3-yl)-5,6-difluorodihydropyridine 1,3-dione (compound 7c) (238 mg, 081 mmol) in dimethyl sulfoxide (5 mL). The reaction solution was stirred at 110° C. for 1 hour under nitrogen protection. 15 mL of water was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (15 mL×5). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was concentrated by distillation under reduced pressure and purified by preparative liquid chromatography (chromatographic column: Xtimate C18 21.2*250 mm 5 μm; solvent A=water+0.05% ammonia water, B=acetonitrile; gradient: 52%-82%, 20 mL / min) to obtain 6-(2,2-difluorocyclopropyl)-N-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)ethyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-6-yl)picolinamide (Compound 5).

[0644] LC-MS, M / Z(ESI):831.2[M+H] +

[0645] 1H NMR (400MHz, DMSO-d6): δ12.54(s,1H),11.09(s,1H),9.52(s,1H),8.11–8.03(m,2H),7. 90(d,1H),7.79(dd,1H),7.60(d,1H),6.93(d,1H),6.71(s,1H),5.07(dd,1H),4.32–4.1 7(m,2H),4.05–3.97(m,1H),3.89–3.81(m,1H),3.42–3.35(m,1H),3.07–2.53(m,10H),2 .28–2.20(m,1H),2.07–1.95(m,4H),1.75–1.70(m,6H),1.69–1.54(m,2H),0.94(d,3H).

[0646] Example 6: Preparation of target compound 6

[0647] 6-(2,2-difluorocyclopropyl)-N-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 6)

[0648]

[0649] The synthetic route of compound 6 is as follows:

[0650]

[0651] Step 1: Synthesis of tert-butyl 3-hydroxy-3-(hydroxymethyl)azetidine-1-carboxylate (Compound 6-2)

[0652]

[0653] Potassium osmate (21.8 mg, 0.06 mmol) and N-methylmorpholine oxide (761 mg, 6.50 mmol) were added to a solution of tert-butyl 3-methyleneazetidine-1-carboxylate (1.00 g, 5.91 mmol) in acetone (12 mL) and water (7 mL), and the reaction solution was stirred at 25 ° C for 2 hours. The solution was quenched with saturated aqueous sodium bisulfite solution (20 mL), extracted with ethyl acetate (10 mL × 3), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude product, which was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100: 0-70: 30, gradient elution) to give tert-butyl 3-hydroxy-3-(hydroxymethyl)azetidine-1-carboxylate (compound 6-2).

[0654] LC-MS, M / Z (ESI): 204.4 (M+H) +

[0655] Step 2: Synthesis of tert-butyl 3-hydroxy-3-((tolyloxy)methyl)azetidine-1-carboxylate (Compound 6-3)

[0656]

[0657] 4-Methylbenzenesulfonyl chloride (260 mg, 1.36 mmol) and pyridine (0.33 mL, 4.09 mmol) were added to a solution of 3-hydroxy-3-(hydroxymethyl)azetidine-1-carboxylic acid tert-butyl ester (compound 6-2) (320 mg, 1.57 mmol) in dichloromethane (10 mL), and the reaction solution was stirred at 25 ° C for 18 hours. The resulting mixture was diluted with water (10 mL) and extracted with dichloromethane (25 mL × 3). The organic layers were combined and washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100: 0-50: 50, gradient elution) to obtain 3-hydroxy-3-((tolyloxy)methyl)azetidine-1-carboxylic acid tert-butyl ester (compound 6-3).

[0658] 1 H NMR (400MHz, DMSO-d6): δ7.99(d,J=8.0Hz,2H),7.57(d,J=8.0Hz,2H),4.09(s,2H),3.60-3.78(m,4H),2.50(s,3H),1.42(s,9H).

[0659] Step 3: Synthesis of tert-butyl 3-((4-(6-(6-(2,2-difluorocyclopropyl)pyridinecarboxamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidin-1-yl)methyl)-3-hydroxyazetidine-1-carboxylate (Compound 6-4)

[0660]

[0661] Potassium carbonate (325 mg, 2.35 mmol) was added to a solution of tert-butyl 3-hydroxy-3-((tolyloxy)methyl)azetidine-1-carboxylate (Compound 6-3) (280 mg, 0.78 mmol) and 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-2-(hexahydropyridin-4-yl))-7-(2-hydroxypropane-2-yl)imidazole(3,2-a)pyridin-6-yl)pyridine-2-carboxamide (Intermediate III) (371 mg, 0.78 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 80° C. under a nitrogen atmosphere for 3 hours. The reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (25 mL×3). The organic layers were combined and washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified by column chromatography (dichloromethane: methanol (V / V) = 100:0-90:10, gradient elution) to give tert-butyl-3-((4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidin-1-yl)methyl)-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (Compound 6-4).

[0662] LC-MS, M / Z(ESI):659.5[M+H] +

[0663] Step 4: Synthesis of 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-2-(1-((3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 6-5)

[0664]

[0665] To a solution of tert-butyl-3-((4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidin-1-yl)methyl)-3-hydroxyazetidine-1-carboxylate (compound 6-4) (110 mg, 0.17 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL), and the resulting mixture was stirred at 0°C for 2 h under nitrogen protection. The reaction solution was added dropwise with a saturated sodium bicarbonate solution at 0°C until the pH of the reaction solution was 7, and the filter cake was filtered to obtain a filter cake, which was dried at 50°C to obtain 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-2-(1-((3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 6-5). The crude product was used directly in the next step without purification.

[0666] LC-MS, M / Z(ESI):559.4[M+H] +

[0667] Step 5: Synthesis of 6-(2,2-difluorocyclopropyl)-N-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 6)

[0668]

[0669] To a solution of 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-2-(1-((3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (compound 6-5) (60.0 mg, 0.11 mmol) in dimethyl sulfoxide (5 mL) were added 2-(2,6-dioxahexahydropyridin-3-yl)-5,6-difluorodihydropyridine 1,3-dione (compound 7c) (31.4 mg, 0.11 mmol) and N,N-diisopropylethylamine (41.7 mg, 0.32 mmol), and the resulting mixture was stirred at 110° C. for 1 hour under nitrogen protection. The reaction solution was concentrated to obtain a crude product, which was purified by preparative liquid chromatography (chromatographic column: Xtimate C18×21.2 250mm 5um; solvent A=water+0.05% ammonia water, B=acetonitrile; gradient: 52%-82%; 20mL / min) to obtain compound 6-(2,2-difluorocyclopropyl)-N-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 6).

[0670] LC-MS, M / Z(ESI):833.5[M+H] +

[0671] 1 H NMR (400MHz, DMSO-d6): δ12.54(s,1H),11.09(s,1H),9.51(s,1H),8.10–8.03(m,2H),7.88(d ,J=3.2Hz,1H),7.78(dd,J=6.8,2.0Hz,1H),7.60(d,J=11.2Hz,1H),6.96(d,J=7.6Hz,1H),6. 71(s,1H),5.66(s,1H),5.07(dd,J=12.8,5.2Hz,1H),4.27–4.14(m,2H),4.03–3.93(m,2H),3 .06–2.82(m,4H),2.70–2.51(m,6H),2.33–2.22(m,2H),2.08–1.91(m,4H),1.76–1.66(m,8H).

[0672] Example 6A: Preparation of target compound 6-P1

[0673] 6-((R)-2,2-difluorocyclopropyl)-N-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 6-P1)

[0674] for

[0675]

[0676] Referring to compound 6, in the third step, intermediate III is replaced with intermediate III-P1 to obtain compound 6-P1.

[0677] LC-MS, M / Z(ESI):833.2[M+H] +

[0678] 1 H NMR (400MHz, DMSO-d6): δ12.53(s,1H),11.08(s,1H),9.50(s,1H),8.09–8.02(m,2H),7 .88(d,J=3.2Hz,1H),7.77(dd,J=6.4,2.4Hz,1H),7.60(d,J=11.2Hz,1H),6.96(d,J=7. 6Hz,1H),6.70(s,1H),5.12–5.03(m,1H),4.23–4.16(m,2H),4.02–3.92(m,2H),3.14–2 .80(m,5H),2.74–2.51(m,6H),2.32–2.23(m,2H),2.07–1.90(m,4H),1.76–1.58(m,8H).

[0679] Example 6B: Preparation of target compound 6-P2

[0680] 6-((S)-2,2-difluorocyclopropyl)-N-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 6-P2)

[0681] for

[0682]

[0683] Referring to compound 6, in the third step, intermediate III is replaced with intermediate III-P2 to obtain compound 6-P2.

[0684] LC-MS, M / Z(ESI):833.2[M+H] +

[0685] 1 H NMR (400MHz, DMSO-d6): δ12.54(s,1H),11.08(s,1H),9.51(s,1H),8.09–8.03(m,2H),7.88(s, 1H),7.77(dd,J=6.4,2.4Hz,1H),7.65–7.57(m,1H),6.97(d,J=7.6Hz,1H),6.70(s,1H),5.64( s,1H),5.07(dd,J=12.8,5.2Hz,1H),4.34–4.14(m,2H),4.07–3.77(m,2H),3.40–3.35(m,1H), 3.09–2.82(m,4H),2.79–2.51(m,5H),2.34–2.15(m,2H),2.08–1.89(m,4H),1.80–1.56(m,8H).

[0686] Example 7: Preparation of target compound 7

[0687] 6-(2,2-difluorocyclopropyl)-N-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 7)

[0688]

[0689] The synthetic route of compound 7 is as follows:

[0690]

[0691] Step 1: Synthesis of tert-butyl-3-(hydroxymethyl)-3-((methylene-(p-tolyl)sulfinyl)oxy)methyl)azetidine-1-carboxylate (Compound 7-2)

[0692]

[0693] 4-Methylbenzenesulfonyl chloride (415 mg, 2.18 mmol) and pyridine (0.48 mL, 5.94 mmol) were added to a solution of tert-butyl-3,3-bis(hydroxymethyl)azetidine-1-carboxylic acid tert-butyl ester (Compound 7-1) (430 mg, 1.98 mmol) in dichloromethane (10 mL), and the reaction mixture was stirred at 25 ° C under a nitrogen atmosphere for 18 hours. Water (25 mL) was added to the reaction solution, the aqueous layer was extracted with dichloromethane (25 mL × 3), the organic layers were combined and washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0-50:50, gradient elution) to obtain tert-butyl 3-hydroxy-3-((tolyloxy)methyl)azetidine-1-carboxylate (Compound 7-2).

[0694] 1 H NMR (400MHz, DMSO-d6): δ7.82(d,2H),7.51(d,2H),5.03(s,1H),4.11(s,2H),3.55(s,2H),3.44–3.52(m,4H),2.44(s,3H),1.36(s,9H).

[0695] Step 2: Synthesis of tert-butyl-3-(4-(6-(6-(2,2-difluorocyclopropyl)pyridinecarboxamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidin-1-yl)methyl)-3-(hydroxymethyl)azetidine-1-carboxylate (Compound 7-3)

[0696]

[0697] To a solution of tert-butyl 3-hydroxy-3-((tolyloxy)methyl)azetidine-1-carboxylate (Compound 7-2) (335 mg, 0.90 mmol) in N,N-dimethylformamide (10 mL) was added 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-2-(hexahydropyridin-4-yl))-7-(2-hydroxypropane-2-yl)imidazole(3,2-a)pyridin-6-yl)pyridine-2-carboxamide (Intermediate III) (427 mg, 0.90 mmol) and potassium carbonate (374 mg, 2.71 mmol), and the reaction mixture was stirred at 80° C. under a nitrogen atmosphere for 3 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (10 mL×3). The organic layers were combined and washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (dichloromethane: methanol (V / V) = 100:0-90:10, gradient elution) to give the product tert-butyl-3-((4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidin-1-yl)methyl)-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (Compound 7-3).

[0698] LC-MS, M / Z(ESI):673.5[M+H] +

[0699] Step 3: Synthesis of 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-2-(1-((3-(hydroxymethyl)azetidin-3-yl)methyl)piperidin-4-yl)-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 7-4)

[0700]

[0701] At 0°C, trifluoroacetic acid (2 mL) was added dropwise to a solution of tert-butyl-3-((4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidin-1-yl)methyl)-3-hydroxyazetidine-1-carboxylate (Compound 7-3) (80.0 mg, 0.12 mmol) in dichloromethane (2 mL), and the resulting mixture was stirred at 0°C for 2 h under nitrogen protection. Saturated sodium bicarbonate solution was added dropwise to the reaction solution at 0°C until the pH reached 7, and the filter cake was filtered and dried at 50°C to obtain 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-2-(1-((3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 7-4). The crude product was used directly in the next step without purification.

[0702] LC-MS, M / Z(ESI):573.35[M+H] +

[0703] Step 4: Synthesis of 6-(2,2-difluorocyclopropyl)-N-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-(hydroxymethyl)azetidin-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 7)

[0704]

[0705] To a solution of 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-2-(1-((3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (compound 7-4) (40.0 mg, 0.07 mmol) in dimethyl sulfoxide (5 mL) were added 2-(2,6-dioxahexahydropyridin-3-yl)-5,6-difluorodihydropyridine 1,3-dione (31.4 mg, 0.11 mmol) and N,N-diisopropylethylamine (41.7 mg, 0.32 mmol), and the resulting mixture was stirred at 110° C. for 1 hour under nitrogen protection. Water (15 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (15 mL×5). The organic phase was collected and dried over anhydrous sodium sulfate, and the organic phase was concentrated by distillation under reduced pressure. The crude product was purified by preparative liquid chromatography (chromatographic column: Xtimate C18 21.2×250 mm 5 μm; solvent A=water+0.05% ammonia water, B=can acetonitrile; gradient: 52%-82%; 20 mL / min) to obtain compound 6-(2,2-difluorocyclopropyl)-N-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (compound 7).

[0706] LC-MS, M / Z(ESI):847.5[M+H] +

[0707] 1 H NMR (400MHz, DMSO-d6): δ12.54(s,1H),11.08(s,1H),9.50(s,1H),8.10–8.03 (m,2H),7.89(d,1H),7.78(dd,1H),7.59(d,1H),6.92(d,1H),6.71(s,1H),5.0 7(dd,1H),4.10–3.98(m,2H),3.93–3.82(m,2H),3.66(s,2H),3.11–2.74(m,5H ),2.69–2.52(m,5H),2.25–2.16(m,2H),2.15–1.79(m,5H),1.74–1.63(m,8H).

[0708] Example 8: Preparation of target compound 8

[0709] 6-(2,2-difluorocyclopropyl)-N-(2-(1-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)-5-fluoropicolinamide (target compound 8)

[0710]

[0711] The synthetic route of compound 8 is as follows:

[0712]

[0713] Step 1: Referring to the preparation method of tert-butyl 4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (Intermediate II), tert-butyl 4-(6-(6-(2,2-difluorocyclopropyl)-5-fluoropicolinamido)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidine-1-carboxylate (Compound 8-1) was prepared.

[0714] Step 2: Synthesis of 6-(2,2-difluorocyclopropyl)-5-fluoro-N-(8-fluoro-7-(2-hydroxypropan-2-yl)-2-(piperidin-4-yl)imidazo(1,2-a)pyridin-6-yl)pyridineamide (Compound 8-2)

[0715]

[0716] Trifluoroacetic acid (2 mL) was added to a solution of 4-(6-(6-(2,2-difluorocyclopropyl)-5-fluoropyridinecarboxamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (Compound 8-1) (480 mg, 0.81 mmol) in dichloromethane (5 mL), and the reaction solution was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction solution was adjusted to pH=8 with a saturated sodium carbonate aqueous solution, filtered, the filter cake was washed with water, and the filter cake was vacuum dried to obtain 6-(2,2-difluorocyclopropyl)-5-fluoro-N-(8-fluoro-7-(2-hydroxypropan-2-yl)-2-(piperidin-4-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 8-2), which was directly used in the next step reaction.

[0717] LC-MS, M / Z(ESI):492.4[M+H] + .

[0718] Step 3: Synthesis of tert-butyl 3-((4-(6-(6-(2,2-difluorocyclopropyl)-5-fluoropyridinecarboxamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidin-1-yl)methyl)-3-hydroxyazetidine-1-carboxylate (Compound 8-3)

[0719]

[0720] To a solution of 6-(2,2-difluorocyclopropyl)-5-fluoro-N-(8-fluoro-7-(2-hydroxypropan-2-yl)-2-(piperidin-4-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (compound 8-2) (100 mg, 0.20 mmol) in N,N-dimethylformamide (4 mL), tert-butyl 3-hydroxy-3-(p-tolyloxymethyl)azetidine-1-carboxylate (compound 6-2) (72.7 mg, 0.20 mmol), potassium carbonate (84.4 mg, 0.61 mmol) and potassium iodide (67.6 mg, 0.41 mmol) were added in sequence, and the resulting mixture was stirred at 80°C for 14 hours. The reaction was completed by LC-MS detection, and water (50 mL) was added to the reaction system, extracted with ethyl acetate (20 mL × 3), the organic layers were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol (V / V) = 100:0 to 100:5, gradient elution) to obtain 3-((4-(6-(6-(2,2-difluorocyclopropyl)-5-fluoropyridinecarboxamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo (1,2-a) pyridin-2-yl) piperidin-1-yl) methyl)-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (Compound 8-3).

[0721] LC-MS, M / Z(ESI):677.4[M+H] + .

[0722] Step 4: Synthesis of 6-(2,2-difluorocyclopropyl)-5-fluoro-N-(8-fluoro-2-(1-((3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 8-4)

[0723]

[0724] To a solution of tert-butyl 3-((4-(6-(6-(2,2-difluorocyclopropyl)-5-fluoropicolinamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidin-1-yl)methyl)-3-hydroxyazetidine-1-carboxylate (Compound 8-3) (100 mg, 0.15 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL), and the reaction solution was stirred at 20°C for 2 hours. The reaction was completed by LC-MS detection, and the reaction solution was adjusted to pH = 8 with a saturated sodium carbonate aqueous solution, filtered, the filter cake was washed with water, and the filter cake was vacuum dried to obtain 6-(2,2-difluorocyclopropyl)-5-fluoro-N-(8-fluoro-2-(1-((3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 8-4). This crude product was directly used in the next step without purification.

[0725] LC-MS, M / Z(ESI):577.2[M+H] + .

[0726] Step 5: Synthesis of 6-(2,2-difluorocyclopropyl)-N-(2-(1-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)-5-fluoropicolinamide (Compound 8)

[0727]

[0728] To a solution of 6-(2,2-difluorocyclopropyl)-5-fluoro-N-(8-fluoro-2-(1-((3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (compound 8-5) (75.0 mg, 0.13 mmol) and 2-(2,6-dioxyhexahydropyridin-3-yl)-5,6-difluoroisoindole-1,3-dione (38.3 mg, 0.13 mmol) in dimethyl sulfoxide (2 mL) was added N,N-diisopropylethylamine (50.3 mg, 0.39 mmol), and the reaction solution was stirred at 110°C under N2 protection for 1 hour. LC-MS detected that the reaction was complete, and the reaction solution was purified by preparative liquid chromatography (chromatographic column: Xtimate C18 21.2*250mm 5μm, mobile phase: A=0.05% ammonia water, B=acetonitrile; gradient: 48%-68%, 2h) to obtain 6-(2,2-difluorocyclopropyl)-N-(2-(1-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)-5-fluoropicolinamide (Compound 8).

[0729] LC-MS, M / Z(ESI):851.1[M+H] + .

[0730] 1 H NMR (400MHz, CD3OD): δ9.54(s,1H),8.24(dd,1H),7.82(t,1H),7.70(d,1H),7.45(d,1H),6.98(d,1H),5.10(dd,1H),4. 28(d,2H),4.10(d,2H),3.20–3.10(m,3H),2.89–2.72(m,6H),2.57–2.35(m,2H),2.20–1.92(m,5H),1.85–1.74(m,8H).

[0731] Example 9: Preparation of target compound 9

[0732] Synthesis of 6-(2,2-difluorocyclopropyl)-N-[2-(1-{1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl]azetidine-3-carbonyl}piperidin-4-yl)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-6-yl]pyridine-2-carboxamide (Compound 9)

[0733]

[0734] The synthetic route of target compound 9 is as follows:

[0735]

[0736] Step 1: Synthesis of 1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl]azetidine-3-carboxylic acid (1-2)

[0737]

[0738] Azetidine-3-carboxylic acid (Compound 9-1) (258 mg, 2.55 mmol) and 2-(2,6-dioxopiperidine-3-yl)-5,6-difluoro-2,3-dihydro-1H-isoindole-1,3-dione (501 mg, 1.70 mmol) were dissolved in dimethyl sulfoxide (3 mL), N,N-diisopropylethylamine (660 mg, 5.11 mmol, 889 μL) was added, and the mixture was stirred at 90°C for 12 hours. After the reaction was complete, the reaction solution was purified by preparative HPLC (column: Welch Ultimate_C18 20-40um, mobile phase 0.1% formic acid / methanol, gradient: 10-80%, 10 min) to obtain compound 1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl]azetidine-3-carboxylic acid (compound 9-2).

[0739] LC-MS, M / Z(ESI):376.0[M+H] +

[0740] Step 2: Synthesis of 6-(2,2-difluorocyclopropyl)-N-[2-(1-{1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl]azetidine-3-carbonyl}piperidin-4-yl)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-6-yl]pyridine-2-carboxamide (Compound 9)

[0741]

[0742] 1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl]azetidine-3-carboxylic acid (Compound 9-2) (100 mg, 266 μmol) was dissolved in dimethyl sulfoxide (1 mL), and O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethyluronium hexafluorophosphonate (131 mg, 346 μmol) and N,N-dioxopiperidin-3-yl were added. Isopropylethylamine (103 mg, 799 μmol) was added and stirred at 25 °C for 0.5 hours, and then 6-(2,2-difluorocyclopropyl)-N-[8-fluoro-7-(2-hydroxypropane-2-yl)-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl]pyridine-2-carboxamide (Intermediate III) (138 mg, 293 μmol) was added, and the reaction solution was stirred at 25 °C for 11 hours. After the reaction was complete, the reaction solution was purified by high performance liquid chromatography (chromatographic column: C18150*30mm; mobile phase: solvent A=water+0.1% formic acid, B=acetonitrile; gradient: 32%-62%, 1 min) to obtain compound 6-(2,2-difluorocyclopropyl)-N-[2-(1-{1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl]azetidine-3-carbonyl}piperidin-4-yl)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-6-yl]pyridine-2-carboxamide (compound 9).

[0743] LC-MS, M / Z (ESI): 831.2 (M+H + )

[0744] 1 H NMR(400MHz,DMSO-d)δ12.63(s,1H)11.08(s,1H)9.63(s,1H)8.03-8.11(m,3H)7.79(dd,1H)7.62(d,1H)6.99(d,1H)6.84(br s,1H)5.07(dd,1H)4.37-4.47(m,2H)4.25-4.34(m,2H)3.89-4.00(m,1H)3.70(br d,1H)3.16-3.23(m,2H)2.93-3.08(m,2H)2.80-2.89(m,2H)2.56-2.61(m,1H)2.54(s,2H)1.98-2.09(m,4H)1.72(dd,6H)1.53-1.68(m,2H).

[0745] Example 10: Preparation of target compound 11

[0746] 6-(2,2-difluorocyclopropyl)-N-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)sulfonyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 11), trifluoroacetate

[0747]

[0748] The synthetic route of compound 11 is as follows:

[0749]

[0750] Step 1: Synthesis of tert-butyl 4-((4-(6-(6-(2,2-difluorocyclopropyl)pyridineamido)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidin-1-yl)sulfonyl)piperidine-1-carboxylate (Compound 11-1)

[0751]

[0752] To a solution of 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropane-2-yl)-2-(piperidin-4-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Intermediate III) (310 mg, 0.66 mmol) in N,N-dimethylformamide (8 mL) were added tert-butyl 4-(chlorosulfonyl)piperidine-1-carboxylate (279 mg, 0.98 mmol) and triethylamine (265 mg, 2.62 mmol) in turn, and the mixture was stirred at 10°C for 2 hours. LCMS detected that the reaction was complete. The reaction solution was diluted with saturated brine (50 mL), then extracted with ethyl acetate (50 mL×3), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol (V / V) = 100:0-90:10, gradient elution) to obtain tert-butyl 4-((4-(6-(6-(2,2-difluorocyclopropyl)pyridineamide)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidin-1-yl)sulfonyl)piperidine-1-carboxylate (Compound 11-1).

[0753] LC-MS, M / Z(ESI):721.4[M+H] +

[0754] Step 2: Synthesis of 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropane-2-yl)-2-(1-(piperidin-4-ylsulfonyl)piperidin-4-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 11-2)

[0755]

[0756] Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl 4-((4-(6-(6-(2,2-difluorocyclopropyl)pyridinecarboxamide)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo(1,2-a)pyridine-2-yl)piperidin-1-yl)sulfonyl)piperidine-1-carboxylate (compound 11-1) (220 mg, 0.31 mmol) in dichloromethane (10 mL), and the resulting mixture was stirred at 10 ° C for 1 hour. LCMS detected that the reaction was complete. The reaction solution was concentrated to give a crude product 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropane-2-yl)-2-(1-(piperidin-4-ylsulfonyl)piperidin-4-yl)imidazo(1,2-a)pyridine-6-yl)picolinamide (compound 11-2). The crude product was directly used in the next step reaction.

[0757] LC-MS, M / Z(ESI):621.4[M+H] +

[0758] Step 3: Synthesis of trifluoroacetate salt of 6-(2,2-difluorocyclopropyl)-N-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)sulfonyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo(1,2-a)pyridin-6-yl)pyridineamide (Compound 11)

[0759]

[0760] 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (66.4 mg, 0.23 mmol) and N,N-diisopropylethylamine (87.5 mg, 0.68 mmol) were added to a solution of 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropane-2-yl)-2-(1-(piperidin-4-ylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)picolinamide (Compound 11-2) (200 mg, 0.23 mmol) in dimethyl sulfoxide (3 mL) in sequence, and the resulting mixture was reacted at 110° C. for 18 hours. The reaction was completed by LCMS. The reaction solution was diluted with saturated brine (50 mL), then extracted with ethyl acetate (50 mL×3), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by high performance liquid chromatography (Kinetex EVO C18, 21.2*250mm, 5μm; 0.01% FA-ACN; 32-62; 60mL / min) to obtain the trifluoroacetate salt of 6-(2,2-difluorocyclopropyl)-N-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)sulfonyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropane-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 11).

[0761] LC-MS, M / Z (ESI): 895.2 (M+H) +

[0762] 1 H NMR (400MHz, CD3OD): δ9.80(s,1H),8.16(d,J=7.6Hz,1H),8.03–7.99(m,2H),7.68(d,J=7.6 Hz,1H),7.58(d,J=11.2Hz,1H),7.54(d,J=7.2Hz,1H),5.12(dd,J=12.4,5.6Hz,1H),4.03–3 .96(m,2H),3.88–3.78(m,2H),3.45–3.36(m,2H),3.25–3.10(m,4H),3.06–2.97(m,3H),2.9 1–2.83(m,1H),2.81–2.71(m,2H),2.27–2.17(m,4H),2.17–1.90(m,5H),1.87–1.84(m,6H).

[0763] Example 12: Preparation of target compound 12

[0764] 6-(2,2-difluorocyclopropyl)-N-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)-3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (target compound 12)

[0765]

[0766] The synthetic route of compound 12 is as follows:

[0767]

[0768] Step 1: Synthesis of 6-(2,2-difluorocyclopropyl)-N-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)-3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (12)

[0769]

[0770] 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-2-(1-((3-hydroxyazetidin-3-yl)methyl)piperidin-4-yl)-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (50.0 mg, 0.090 mmol) and 3-(5,6-difluoro-1-oxoisoindol-2-yl)piperidine-2,6-dione (30.1 mg, 0.107 mmol) were dissolved in anhydrous dimethyl sulfoxide (5 mL), and N,N-diisopropylethylamine (34.7 mg, 0.269 mmol) was added. The reaction solution was stirred at 110° C. for 18 hours under nitrogen protection. The reaction was completed after LC-MS detection, and the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (Kinetex EVOC18, 21.2*250mm, 5μm; 0.01% FA-ACN; 20-80; 60mL / min) to obtain compound 6-(2,2-difluorocyclopropyl)-N-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)-3-hydroxyazetidine-3-yl)methyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 12).

[0771] 1H NMR (400MHz, CD3OD): δ9.49(s,1H),8.47(s,1H),8.08(dd,1H),7.92(t,1H),7.80(s, 2H),7.64(d,1H),7.58(d,1H),7.31(d,1H),6.63(d,1H),5.06(dd,1H),4.34(s,2H),4 .16(d,2H),3.99(d,2H),3.24–3.19(m,2H),2.98(td,3H),2.89–2.80(m,3H),2.79–2 .71(m,2H),2.62(s,1H),2.41(dd,1H),2.16–2.06(m,3H),1.84(dd,3H),1.78(t,6H).

[0772] LC-MS, M / Z (ESI): 819.4 (M+H) + .

[0773] Example 13: Preparation of target compound: 13

[0774] 6-(2,2-difluorocyclopropyl)-N-(2-(1-(2-(4-(2-(2,6-dioxyhexahydropyridin-3-yl)-6-fluoro-1,3-dioxyhexahydropyridin-2,3-dihydro-1H-isoindol-5-yl)piperazin-1-yl)-2-oxyylideneethyl)hexahydropyridin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)pyridine-2-carboxamide (target compound 13)

[0775]

[0776] The synthetic route of compound 13 is as follows:

[0777]

[0778] Step 1: Synthesis of 4-(2-(2,6-dioxypyridin-3-yl)-5-fluoro-1,3-dioxy-2,3-dihydro-1H-isoindol-6-yl)piperazine-1-carboxylic acid-2-methylpropan-2-yl ester (Compound 13-1)

[0779]

[0780] 2-(2,6-Dioxypyridin-3-yl)-5,6-difluoroisoindole-1,3-dione (Intermediate 7c) (500 mg, 1.70 mmol) was dissolved in dimethyl sulfoxide (5 mL), and N-Boc-piperazine (348 mg, 1.87 mmol) and triethylamine (344 mg, 3.40 mmol) were added. The reaction solution was reacted at 110° C. for 4 hours. LC-MS detected that the reaction was completed, and water (50 mL) was added to the reaction system, extracted with ethyl acetate (50 mL×3), and the organic phases were combined, washed with saturated brine (30 mL×2), and then dried over anhydrous sodium sulfate. The filtrate was concentrated to obtain a crude product, which was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100:0 to 50:50) to obtain compound 4-(2-(2,6-dioxyhexahydropyridin-3-yl)-5-fluoro-1,3-dioxy-2,3-dihydro-1H-isoindol-6-yl)piperazine-1-carboxylic acid-2-methylpropan-2-yl ester (compound 13-1) (700 mg, yield 89.5%).

[0781] LC-MS, M / Z(ESI):405.0[M-tBu+H] + .

[0782] Step 2: Synthesis of 2-(2,6-dioxypyridin-3-yl)-5-fluoro-6-(piperazine-1-yl)isoindole-1,3-dione (Compound 13-2)

[0783]

[0784] 4-(2-(2,6-dioxypyridin-3-yl)-5-fluoro-1,3-dioxypyridin-2,3-dihydro-1H-isoindol-6-yl)piperazine-1-carboxylic acid-2-methylpropan-2-yl ester (Compound 13-1) (700 mg, 1.52 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2.5 mL) was added, and the reaction solution was stirred at 25° C. for 14 hours. LC-MS detected that the reaction was complete, and the reaction solution was directly concentrated under reduced pressure to obtain a crude compound 2-(2,6-dioxypyridin-3-yl)-5-fluoro-6-(piperazine-1-yl)isoindole-1,3-dione (Compound 13-2) (1.10 g, yield 98.4%).

[0785] LC-MS, M / Z(ESI):361.4[M+H] + .

[0786] Step 3: Synthesis of 6-(4-(2-chloroacetyl)piperazine-1-yl)-2-(2,6-dioxypyridin-3-yl)-5-fluoroisoindole-1,3-dione (Compound 13-3)

[0787]

[0788] 2-(2,6-Dioxypyridin-3-yl)-5-fluoro-6-(piperazine-1-yl)isoindole-1,3-dione (Compound 13-2) (550 mg, 0.763 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (386 mg, 3.82 mol) and chloroacetyl chloride (130 mg, 1.15 mol) were added to the reaction solution at 0°C in sequence, and the resulting reaction solution was stirred at 25°C for 3 hours. LC-MS detected that the reaction was completed, and water (50 mL) was added to the reaction system, extracted with ethyl acetate (50 mL×3), washed with saturated brine (30 mL×2), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude compound 6-(4-(2-chloroacetyl)piperazine-1-yl)-2-(2,6-dioxypyridin-3-yl)-5-fluoroisoindole-1,3-dione (compound 13-3) (500 mg, yield 90%).

[0789] LC-MS, M / Z(ESI):437.3[M+H] + .

[0790] Step 4: Synthesis of 6-(2,2-difluorocyclopropyl)-N-(2-(1-(2-(4-(2-(2,6-dioxyhexahydropyridin-3-yl)-6-fluoro-1,3-dioxyhexahydropyridin-2,3-dihydro-1H-isoindol-5-yl)piperazine-1-yl)-2-oxyylideneethyl)hexahydropyridin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)pyridine-2-carboxamide (target compound 13)

[0791]

[0792] 6-(4-(2-chloroacetyl)piperazine-1-yl)-2-(2,6-dioxypyridin-3-yl)-5-fluoroisoindole-1,3-dione (Compound 13-3) (150 mg, 0.206 mmol) and 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-2-(pyridin-4-yl)-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)pyridine-2-carboxylate (75.0 mg, 0.158 mmol) were dissolved in N,N-dimethylformamide (2 mL), and triethylamine (48.1 mg, 0.475 mmol) was added. The reaction solution was reacted at 25° C. under N2 protection for 18 hours. The reaction was completed after LC-MS detection, and the reaction solution was purified by high performance liquid chromatography (KinetexEVO C18, 21.2*250mm, 5μm; 0.01% FA-ACN; 32-62; 60mL / min) to obtain compound 6-(2,2-difluorocyclopropyl)-N-(2-(1-(2-(4-(2-(2,6-dioxyhexahydropyridin-3-yl)-6-fluoro-1,3-dioxy-2,3-dihydro-1H-isoindol-5-yl)piperazine-1-yl)-2-oxyylideneethyl)hexahydropyridin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)pyridine-2-carboxamide (Compound 13).

[0793] 1 H NMR (400MHz, DMSO-d6): δ12.53(s,1H),11.10(s,1H),9.50(s,1H),8.10–7.98 (m,2H),7.89(d,1H),7.81–7.71(m,2H),7.50(d,1H),6.69(s,1H),5.11(dd,1 H),3.83–3.74(m,2H),3.67–3.61(m,2H),3.26–3.20(m,4H),3.02–2.83(m,5H ),2.73–2.54(m,5H),2.22–2.13(m,2H),2.06–1.95(m,4H),1.76–1.64(m,8H).

[0794] LC-MS, M / Z(ESI):874.4[M+H] + .

[0795] Example 14: Preparation of target compound 14

[0796] 6-(2,2-difluorocyclopropyl)-N-(2-(1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperazin-1-yl)acetyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (target compound 14)

[0797]

[0798] The synthetic route of compound 14 is as follows:

[0799]

[0800] Step 1: Synthesis of N-(2-(1-(2-chloroacetyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)-6-(2,2-difluorocyclopropyl)pyridineamide (Compound 14-1)

[0801]

[0802] 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropan-2-yl)-2-(piperidin-4-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Intermediate III) (300 mg, 0.634 mmol) was dissolved in dichloromethane (5 mL), triethylamine (192 mg, 1.901 mmol) was added, and chloroacetyl chloride (71.0 mg, 0.634 mmol) was added at 0°C, and the reaction solution was stirred at 20°C for 1 hour. LC-MS detected that the reaction was completed, and water (20 mL) was added to the reaction solution, extracted with dichloromethane (50 mL×3), and the organic phase was washed with saturated brine (10 mL×2), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100:0 to 50:50) to obtain compound N-(2-(1-(2-chloroacetyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridine-6-yl)-6-(2,2-difluorocyclopropyl)picolinamide (compound 14-1) (270 mg, yield 77.4%).

[0803] LC-MS, M / Z(ESI):549.7[M+H] + .

[0804] Step 2: Synthesis of tert-butyl 4-(2-(4-(6-(6-(2,2-difluorocyclopropyl)pyridinecarboxamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidin-1-yl)-2-oxoethyl)piperazine-1-carboxylate (Compound 14-2)

[0805]

[0806] N-(2-(1-(2-chloroacetyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)-6-(2,2-difluorocyclopropyl)picolinamide (Compound 14-1) (250 mg, 0.455 mmol) was dissolved in N,N-dimethylformamide (5 mL), and triethylamine (138 mg, 1.364 mmol), potassium iodide (75.0 mg, 0.455 mmol) and tert-butyl piperazine-1-carboxylate (254 mg, 1.36 mmol) were added in sequence. The reaction solution was reacted at 20°C for 4 hours. LC-MS detected that the reaction was complete. Water (20 mL) was added to the reaction system, extracted with dichloromethane (50 mL×3), washed with saturated brine (10 mL×2), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100:0-50:50) to obtain compound 4-(2-(4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidin-1-yl)-2-oxoethyl)piperazine-1-carboxylic acid tert-butyl ester (compound 14-2) (260 mg, yield 81.7%).

[0807] LC-MS, M / Z(ESI):700.3[M+H] + .

[0808] Step 3: Synthesis of 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropan-2-yl)-2-(1-(2-(piperazin-1-yl)acetyl)piperidin-4-yl)imidazo(1,2-a)pyridin-6-yl)pyridineamide (Compound 14-3)

[0809]

[0810] 4-(2-(4-(6-(6-(2,2-difluorocyclopropyl)picolinamido)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-2-yl)piperidin-1-yl)-2-oxoethyl)piperazine-1-carboxylic acid tert-butyl ester (Compound 14-2) (250 mg, 0.357 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the reaction solution was reacted at 25°C for 1 hour. The reaction was completed by LC-MS detection. A saturated sodium carbonate solution was added to the reaction system to adjust the pH to 8. A yellow solid was precipitated and filtered. The filter cake was washed with water and then dried to obtain compound 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropan-2-yl)-2-(1-(2-(piperazine-1-yl)acetyl)piperidin-4-yl)imidazo(1,2-a)pyridin-6-yl)pyridineamide (compound 14-3).

[0811] LC-MS, M / Z(ESI):599.8[M+H] + .

[0812] Step 4: Synthesis of 6-(2,2-difluorocyclopropyl)-N-(2-(1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperazin-1-yl)acetyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)pyridineamide (Compound 14)

[0813]

[0814] 6-(2,2-difluorocyclopropyl)-N-(8-fluoro-7-(2-hydroxypropan-2-yl)-2-(1-(2-(piperazin-1-yl)acetyl)piperidin-4-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 14-3) (200 mg, 0.334 mmol) and 2-(2,6-dioxypyridin-3-yl)-5,6-difluoroisoindole-1,3-dione (98.0 mg, 0.334 mmol) were dissolved in anhydrous dimethyl sulfoxide (5 mL), and N,N-diisopropylethylamine (129 mg, 1.001 mmol) was added. The reaction solution was reacted at 110° C. for 1 hour under nitrogen protection. The reaction was completed after LC-MS detection. The reaction solution was concentrated under reduced pressure and purified by preparative liquid chromatography (KinetexEVO C18, 21.2*250mm, 5μm; 0.01% FA-ACN; 25-95; 60mL / min) to obtain compound 6-(2,2-difluorocyclopropyl)-N-(2-(1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperazin-1-yl)acetyl)piperidin-4-yl)-8-fluoro-7-(2-hydroxypropan-2-yl)imidazo(1,2-a)pyridin-6-yl)picolinamide (Compound 14).

[0815] 1 H NMR (400MHz, DMSO-d6): δ12.53(s,1H),11.10(s,1H),9.51(s,1H),8.09–8.02(m,2H),7.92(d, 1H),7.77(dd,1H),7.73(d,1H),7.47(d,1H),6.70(s,1H),5.10(dd,1H),4.50–4.33(m,1H),4. 20–4.06(m,1H),3.39–3.33(m,3H),3.30–3.23(m,5H),3.21–3.13(m,2H),3.01–2.94(m,2H),2 .89–2.73(m,2H),2.64–2.59(m,4H),2.08–1.98(m,4H),1.73–1.67(m,6H),1.55–1.45(m,1H).

[0816] LC-MS, M / Z(ESI):874.4[M+H] + .

[0817] Biological Testing

[0818] Experimental Example 1: Effects of compounds on IRAK4 protein in HEK293 cells

[0819] Experimental methods

[0820] 1) Cell culture. The culture medium for cell culture is DMEM medium containing inactivated 10% fetal bovine serum, 100U / ml penicillin and 100μg / ml streptomycin. HEK293-IRAK4-Hibit cells are cultured in an incubator at 37°C and 5% CO2. When the cell confluence reaches 80-90%, the cells are subcultured. Cells in the logarithmic growth phase are used for plating. HEK293-IRAK4-Hibit cells are plated in a 96-well plate with 100μL culture medium, 20,000-30,000 cells per well, and cultured overnight.

[0821] 2) Compound dilution. The compound was dissolved in DMSO to a concentration of 10 mM. The compound was then gradiently diluted with DMSO.

[0822] The mixture was then released so that the concentrations were 2000 μM, 500 μM, 125 μM, 32.25 μM, 7.81 μM, 1.95 μM, 0.49 μM, 0.12 μM and 0.031 μM, respectively.

[0823] 3) Adding drugs. Take 1 μL of the diluted compound and add it to 1 ml of complete medium. After mixing, take 100 μL and add it to a 96-well plate. The working concentrations reach 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.91 nM, 0.98 nM, 0.24 nM, 0.061 nM, 0.015 nM and 0 nM.

[0824] 4) Activity detection. The drug treatment was performed for 24 hours and the detection method was based on the Nano- HiBiT Lytic

[0825] Detection System Instructions.

[0826] 5) DC50 calculation. Relative IRAK4 (%) = (Lumninence experiment - Lumninence blank) / (Lumninence DMSO -

[0827] Lumninence blank), calculated using a fit based on log(inhibitor) vs.response--Variable slope(four parameters).

[0828] The experimental results are shown in Table 1, showing the data of the degradation of IRAK4 protein by the compounds of the present invention.

[0829] Table 1. Results of the degradation of IRAK4 protein by the compounds of the present invention

[0830] Compound No. DC50(nM) Dmax(%) Compound 2-P1 5 96 Compound 2-P2 2.7 96 Compound 4 4.25 93 Compound 5 3.75 96 Compound 6 4.49 95 Compound 3 9.91 93 Compound 6-P1 8 97 Compound 6-P2 4.5 97 Compound 7 7.34 91 Compound 8 7.55 94 Trifluoroacetate salt of compound 11 10.4 94 Compound 12 7.41 95 Compound 13 32.7 94 Compound 14 28.7 93

[0831] Experimental conclusion: The degradation activity of the compound of the present invention on IRAK4 protein reached nM level, showing excellent degradation effect and being dose-dependent.

[0832] Example 2: Pharmacokinetics of Compounds in Mice

[0833] 1. Animal husbandry: Five male ICR mice were purchased and adaptively raised for one week, and three were selected for the experiment.

[0834] 2. Compound preparation: Prepare the compound on the day of administration, with the solvent being 5% DMSO + 10% Solutol + 85% Saline. Weigh the compound and prepare the -PO administration concentration to 1 mg / mL.

[0835] 3. Animal administration: Weigh the animals before administration and calculate the dosage based on body weight. The compound dosage is 10 mpk for oral administration.

[0836] 4. Blood collection from animals: 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after administration. Blood was collected from the cheek, and about 0.05mL of each sample was collected. Sodium heparin was used for anticoagulation and the samples were placed on wet ice after collection.

[0837] 5. Plasma processing. After blood samples are collected, they are placed on ice and centrifuged within 1 hour to separate plasma (centrifugation conditions: 6000g, 3 minutes, 2-8°C). Plasma samples are stored in a -80°C refrigerator before analysis.

[0838] 6. LC-MS analysis. After all samples are completely melted, mix for 10 to 30 seconds and centrifuge at 4000 rpm and 4°C for 0.5 minutes. Transfer 20 μL of plasma sample (blank sample and internal standard blank sample plus 20.0 μL of blank plasma) to a 96-well plate and add 200

[0839] μL of 50% methanol-acetonitrile solution containing internal standard (100 ng / mL) (200 μL of 50% methanol-acetonitrile solution was added to the Doubleblank sample). The sample was vortexed for 5 minutes, centrifuged at 4000 rpm and 4°C for 10 minutes, and 100 μL was added to 100

[0840] μL of water, mixed well, and analyzed by LC-MS / MS.

[0841] 7. Result analysis: Phoenix WinNonlin8.2.0 was used to calculate pharmacokinetic parameters based on the blood drug concentration data at different time points, providing parameters such as AUC0-t, AUC0-∞, MRT0-∞, Cmax, Tmax, and T1 / 2 and their mean and standard deviation.

[0842] Table 2: Results of pharmacokinetic studies in mice

[0843]

[0844] Experimental conclusion: The compound of the present invention has good pharmacokinetic properties and good drugability.

[0845] Example 3: Degradation of IKZF1 / 2 / 3 by Compounds

[0846] SU-DHL-2 tumor cells were cultured in RPMI-1640 medium containing inactivated 10% fetal bovine serum, 100 U / ml penicillin and 100 μg / ml streptomycin at 37°C in a 5% CO2 incubator until the cell density reached 1*10^ 6 After subculturing and splitting, the tumor cells in the logarithmic growth phase were cultured at 7×10 5 Plated in 12-well plates. After overnight cell culture, dilute the drug and add it to the cell culture medium to a final concentration of 0nM, 10nM and 100Nm, and treat with the drug for 24 hours. Remove the cells treated with the drug for 24 hours from the incubator, transfer them to a 1.5mL EP tube, and centrifuge to remove the supernatant. Add 150μL RIPA lysis buffer to each tube and incubate on ice for 30 minutes. Perform BCA quantification. Run protein gel detection. Anti-IKZF1 1:5000 dilution, Anti-IKZF3 1:1000 dilution, Anti-GAPDH 1:5000 dilution, 4℃ overnight. HRP secondary antibody 1:10000 dilution, RT 1 hour. Finally, perform protein development and grayscale analysis.

[0847] The degradation effects of compound 5 and compound 6 on IKZF1 and IKZF3 are as follows Figure 1 As shown, GAPDH represents glyceraldehyde-3-phosphate dehydrogenase, which is used as an internal reference for western blot. The experimental results show that the compound of the present invention does not degrade or only slightly degrades IKZF1 / 2 / 3, has little toxicity and side effects, and has good drugability.

[0848] Experimental Example 4: Determination of the effect of compounds on IL-1β-induced HEK293-NF-kB-Luciferase cell reporter gene activity

[0849] HEK293-NF-kB-Luciferase cells were cultured in a 37°C, 5% CO2 incubator with DMEM medium containing inactivated 10% fetal bovine serum, 100U / ml penicillin and 100μg / ml streptomycin. The cells were passaged and divided into bottles after the cell density reached 80-90%. Cells in the logarithmic growth phase were plated on 96-well plates at 30,000. After the cells were cultured overnight, different concentrations of drugs were added and treated for 18 hours. IL-1β was added to a final concentration of 1ng / ml and treated for 4 hours. The detection was performed using Vazyme's One-Lite Luciferase Assay System.

[0850] Experimental conclusion: As shown in Table 3 below, the compounds of the present invention can significantly inhibit the activation of NF-kB signaling pathway induced by IL-1β.

[0851] Table 3: Inhibitory activity of compounds on IL-1β signaling pathway

[0852] Compound No. IC50(nM) Compound 2-P2 41.77 Compound 12 123.3

[0853] Example 5: Determination of the effect of compounds on the content of inflammatory factors in THP1 cells induced by LPS

[0854] THP1 cells were cultured in RPMI-1640 medium containing inactivated 10% fetal bovine serum, 100U / ml penicillin and 100μg / ml streptomycin at 37°C and 5% CO2 in an incubator. The cells were passaged and divided into bottles after the cell density reached 1*10^6. Tumor cells in the logarithmic growth phase were plated on a 96-well plate at 40,000 cells per well and PMA was added to induce differentiation. After 72 hours of cell culture, different concentrations of drugs were added and treated for 18 hours. LPS was added to a final concentration of 100ng / ml and treated for 4 hours. The cell supernatant was taken and the TNF content was detected by ELISA.

[0855] Experimental conclusion: In the LPS-stimulated THP1 cell model, the compound of the present invention can significantly inhibit the production of TNF, and the inhibitory function is positively correlated with the dose.

[0856] Example 6: Determination of the effect of compounds on the content of inflammatory factors in RAW264.7 cells induced by LPS

[0857] RAW264.7 cells were cultured in a 37°C, 5% CO2 incubator with DMEM containing inactivated 10% fetal bovine serum, 100U / ml penicillin and 100μg / ml streptomycin. The cells were subcultured and divided into bottles after the cell density reached 1*10^6. Tumor cells in the logarithmic growth phase were plated on a 96-well plate at 40,000 cells, cultured overnight, and different concentrations of drugs were added for 18 hours. LPS was added to a final concentration of 2ng / ml and treated for 4 hours. The cell supernatant was taken and the TNF content was detected by ELISA.

[0858] Experimental conclusion: In the LPS-stimulated RAW264.7 cell model, the compound of the present invention can significantly inhibit the production of TNF, and the inhibitory function is positively correlated with the dose.

[0859] Example 7: Stability determination of compounds on liver microsomes

[0860] The human liver microsome stability of the compound of the present invention was determined according to the following experimental method. The liver microsome stability test of the compound was detected by incubating the compound with human liver microsomes in vitro. First, the compound to be tested was prepared into a 10mM stock solution in DMSO solvent, and then the compound was diluted to 0.5mM using acetonitrile. Liver microsomes (Corning) were diluted with PBS to form a microsome / buffer solution, and the solution was used to dilute 0.5mM of the compound to form a working solution, in which the compound concentration in the working solution was 1.5μM and the liver microsome concentration was 0.75mg / ml. Take a deep well plate, add 30μL of working solution to each well, then add 15μL of preheated 6mM NADPH solution to start the reaction, and incubate at 37°C. At 0, 5, 15, 30, and 45 minutes of incubation, add 135μL of acetonitrile to the corresponding well to terminate the reaction. After terminating the reaction with acetonitrile at the last 45 minutes, the deep well plate was vortexed for 10 minutes (600rpm / min) and then centrifuged for 15 minutes. After centrifugation, the supernatant was collected and purified water was added in a 1:1 ratio for LC-MS / MS detection. The ratio of the peak area of ​​the compound to the peak area of ​​the internal standard at each time point was obtained. The peak area ratios of the compound at 5, 15, 30, and 45 minutes were compared with the peak area ratio at 0 minute, and the remaining percentage of the compound at each time point was calculated. T1 / 2 was calculated using Graphpad 5 software.

[0861] Experimental conclusion: The compound of the present invention has good liver microsome stability.

Claims

1. A compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, in, E 1 is -CH2- or -C(=O)-; for Ring A, Ring B and Ring D are each independently absent, C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, C 6-10 The aryl group and the 5-10 membered heteroaryl group are each optionally substituted by one or more R a replace; L 1 , L 2 , L 3 and L 4 are independently a single bond, -O-, -C(O)-, -N(R 22 )-, -P(O)-, -P(O)2-, -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-、C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl or C 1-12 Heteroalkyl, wherein the C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl and C 1-12 The heteroalkyl group is optionally substituted by one or more R b replace; Ring C is C 6-10 Aryl or 5-10 membered heteroaryl; L x -C(=O)-NR 2 -or-NR 2 -C(=O)-; R 1 C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl and 4-7 membered heterocycloalkyl are each optionally substituted by one or more R 11 replace; When R 1 C 1-6 When alkyl, R 1 By one or more R 11 Replaced with at least 1 R 11 for OH; R 2 are independently H or C 1-6 alkyl; R 3 H, halogen, CN, OH, NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl or 5-10 membered heteroaryl, the C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 The cycloalkyl and 5-10 membered heteroaryl groups are each optionally substituted by one or more R 31 replace; R 4 Halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl and -OC 3-6 The cycloalkyl group is optionally substituted by one or more R 41 replace; Each R 11 Independently H, C 1-6 Alkyl, halogen, OH or CN; Each R 31 are independently H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 The cycloalkyl group is optionally substituted by one or more R c replace; Each R 41 are independently halogen, =O, OH, NH2 or CN; Each R 22 are independently H or C 1-6 alkyl; Each R a are independently H, halogen, =O, OH, NH2, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted by 1, 2 or 3 R groups; Each R b are independently H, =O, halogen, OH, NH2 or C 1-6 alkyl; Each R c are independently H, =O, halogen, OH or NH2; Each R is independently H, =O, halogen, OH, CN or NH2; g is 1, 2, or 3; r is 1, 2, 3 or 4; The "4-12 membered heterocycloalkyl", "4-7 membered heterocycloalkyl", "C 1-6 "heteroalkyl", "5-10 membered heteroaryl" and "C 1-12 The "hetero" in "heteroalkyl" refers to a heteroatom group; the number of the heteroatom groups is 1 or more, each independently being N, -O-, -C(O)-, -N(R 22 )-, -P(O)-, -P(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

2. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It meets one or more of the following conditions: (1) The number of heteroatom groups is 1, 2, 3 or 4; (2) Each R a are independently halogen, =O, OH, NH2, C 1-6 Alkyl or C 1-6 Alkoxy.

3. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It meets one or more of the following conditions: (1)R 1 for or cyclopropyl, and cyclopropyl are each independently substituted with OH; (2) Each R 3 are independently H, halogen, CN, OH, NH2, CH3 or cyclopropyl, wherein CH3 and cyclopropyl are each optionally substituted by one or more R 31 replace; (3) Substituent R 31 The number of is 1, 2, 3 or 4; (4) Each R 31 are independently H, halogen, OH or CN; (5) Each R 4 are independently F, Cl or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted by 1, 2 or 3 R 41 replace; (6)L 1 , L 2 , L 3 and L 4 are independently a single bond, -O-, -C(O)-, -N(R 22 )-, -P(O)-, -P(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-、C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl or C 1-12 Heteroalkyl, wherein the C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl and C 1-12 The heteroalkyl group is optionally substituted by one or more R b Replace; and, L 1 , L 2 , L 3 and L 4 The following conditions must be met: L 1 , L 2 , L 3 and L 4 At least one of them is -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )- or C 1-12 heteroalkyl, in this case, the C 1-12 At least one of the heteroatoms of the heteroalkyl group is -S-, -S(O)-, -S(O)2- or -S(O)2-N(R 22 )-; (7) Each R 22 are independently H or C 1-6 alkyl; (8) Each R b are independently halogen, =O, OH, NH2 or CH3; (9) Ring A, Ring B and Ring D are each independently absent, C 3-6 Cycloalkyl or 4-8 membered heterocycloalkyl, the C 3-6 The cycloalkyl group and the 4-8 membered heterocycloalkyl group are each optionally substituted by one or more R a replace; (10) Substituent R a The number of is 1, 2, 3 or 4; (11) Each R a are independently H, =O, F, Cl, Br, OH, NH2, -CH3, -O-CH3 or -CH2OH.

4. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It meets one or more of the following conditions: (1)R 1 is a cyclopropyl group substituted by OH; (2) Each R 3 are independently H, halogen, CN, OH, NH2 or cyclopropyl, the cyclopropyl being optionally substituted with one or more R 31 replace; (3) Each R 31 are independently H, F, Cl, Br, OH or CN; (4)L 1 , L 2 , L 3 and L 4 are independently a single bond, -O-, -C(O)-, -N(R 22 )-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-、-C 1-6 Alkyl-, -C 2-6 Alkynyl-, -C 1-6 Alkyl-O-, -C 1-6 Alkyl-C(O)-, -C 1-6 Alkyl-N(R 22 )-、-C 1-6 Alkyl-S(O)-, -C 1-6 Alkyl-S(O)2-, -C 1-6 Alkyl-S(O)2-N(R 22 )-、-S(O)2-N(R 22 )-C 1-6 Alkyl-, -C 1-6 Alkyl-OC 1-6 Alkyl-, -C 1-6 Alkyl-N(R 22 )-C 1-6 Alkyl-, -C 1-6 Alkyl-S(O)-C 1-6 Alkyl-, -C 1-6 Alkyl-S(O)2-C 1-6 Alkyl-, -C 1-6 Alkyl-S(O)2-N(R 22 )-C 1-6 Alkyl-, -OC 1-6 Alkyl-O-, -N(R 22 )-C 1-6 Alkyl-N(R 22 )-、-S(O)-C 1-6 Alkyl-S(O)-, -S(O)2-C 1-6 Alkyl-S(O)2-, -S(O)2-N(R 22 )-C 1-6 Alkyl-S(O)2-N(R 22 )-、-OC 1-6 Alkyl-N(R 22 )-, wherein each of said C 1-6 Alkyl and -C 2-6 Alkynyl- is optionally substituted by 1, 2, 3 or 4 R b replace; (5) Each R 22 are independently H or CH3; (6) Ring A, Ring B and Ring D are each independently absent, azetidinyl, cyclohexyl, piperidinyl, piperazinyl or 2-azaspiro[3.3]heptyl, and the cyclohexyl, piperidinyl, piperazinyl and 2-azaspiro[3.3]heptyl are each optionally substituted by one or more R a replace.

5. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It meets one or more of the following conditions: (1) At least one R 3 is optionally represented by one or more R 31 Substituted cyclopropyl, the remaining R 3 are independently H, halogen, CN, OH, NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl or 5-10 membered heteroaryl, the C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 The cycloalkyl and 5-10 membered heteroaryl groups are each optionally substituted by one or more R 31 replace; For example, at least one R 3 for The remaining R 3 are independently H, F or Cl; (2)L 1 is a single bond, -CH2-, -CH(CH3)-, -C(O)-, (3)L 2 is a single bond, -CH2-, -CH(CH3)-, -C(O)-, -S(O)2-, -CO-CH2-, -S(O)2-CH2-, (4)L 3 is a single bond, -CH2-, -CH(CH3)-, -C(O)-, -S(O)2-, -S(O)2-CH2-, (5)L 4 is a single bond, -CH2- or -CH(CH3)-; (6) Ring A is absent, cyclohexyl, piperidinyl or piperazinyl, wherein the cyclohexyl, piperidinyl and piperazinyl are optionally substituted by 1, 2, 3 or 4 R a replace; (7) Ring B is absent, azetidinyl, cyclohexyl, piperidinyl, piperazinyl or 2-azaspiro[3.3]heptyl, wherein the cyclohexyl, piperidinyl, piperazinyl and 2-azaspiro[3.3]heptyl are optionally substituted by 1, 2, 3 or 4 R a replace; (8) Ring D is absent, azetidinyl or piperidinyl, wherein the azetidinyl and piperidinyl are optionally substituted by 1, 2, 3 or 4 R a replace.

6. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It meets one or more of the following conditions: (1)R 1 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more R 11 Replace, for example, R 1 For one or more R 11 Substituted C 1-6 alkyl; (2)R 11 for OH; (3) Each R 3 are independently halogen or C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted with one or more R 31 replace; (4) Substituent R 31 The number of is 2; (5) Each R 31 are independently halogen, such as F; (6) r is 2, one R 3 for Another R 3 are independently H, F or Cl; (7)R 4 is a halogen, such as F; (8) Each R b Independently for C 1-6 alkyl; (9) each R is independently OH; (10) Ring C is a 5-10 membered heteroaryl group, such as pyridyl; (11)L x -C(=O)-NR 2 -; (12) g is 1; (13) The "hetero" in the "4-12 membered heterocycloalkyl", "4-7 membered heterocycloalkyl" and "5-10 membered heteroaryl" is a heteroatom group; the number of the heteroatom groups is one or more, and the heteroatom groups are independently one or more of N, -O- and -S-; when the number of the heteroatom groups is more than one, the heteroatom groups are the same or different; (14) C 1-12 Heteroalkyl and C 1-6 The "hetero" of heteroalkyl is a heteroatom group; the number of the heteroatom groups is 1 or more, and the heteroatom groups are independently one or more of -S(O)2-, -C(O)-, N, -O- and -S-; when the number of the heteroatom groups is more than one, the heteroatom groups are the same or different; (15)L 1 , L 2 , L 3 and L 4 are independently a single bond, -C(O)-, -S(O)2-, -S(O)2-CH2-, -CO-CH2- or C 1-8 Alkyl, wherein the C 1-8 The alkyl group is optionally substituted by one or more R b replace; (16) Ring A, Ring B and Ring D are each independently absent, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl, the 4-12 membered heterocycloalkyl being optionally substituted by 1 or more R a Preferably, ring A, ring B and ring D are each independently absent, azetidinyl, cyclohexyl, piperidinyl or piperazinyl, and the azetidinyl, cyclohexyl, piperidinyl or piperazinyl are each optionally substituted by one or more R a replace; (17) Each R a are independently halogen, OH, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted by 1, 2 or 3 R groups, respectively.

7. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It meets one or more of the following conditions: (1)R 1 for Preferably, R 1 for (2)R 2 is H; (3) Each R 3 are independently F, Cl, (4) Each R 4 are independently F or Cl; (5)L 1 is a single bond; (6)L 2 is a single bond, -CH2-, -CH(CH3)-, -C(O)-, -S(O)2-, -CO-CH2- or -S(O)2-CH2-; (7)L 3 is a single bond; (8) Ring A is absent, Preferably, ring A is (9) Ring B is absent, Preferably, ring B is (10) Ring D is absent, Preferably, ring D is absent or 8. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It meets one or more of the following conditions: (1) for r' is 1, 2 or 3, h is 1, 2 or 3, and the C atom marked with * is S-configuration C, R-configuration C or a mixture thereof; (2) L2 is a single bond, -CH2-, -CH(CH3)-, -C(O)-, -S(O)2- or -CO-CH2-; (3)L 4 is a single bond; (4) Ring A is piperidinyl, preferably, Ring A is Right end With L 2 connect; (5) Ring B is azetidinyl, piperidinyl or piperazinyl, and the azetidinyl, piperidinyl and piperazinyl are optionally substituted by 1, 2, 3 or 4 R a Preferably, ring B is Right end With L 3 connect; (6) Ring D is absent or azetidinyl, wherein the azetidinyl is optionally substituted by 1, 2, 3 or 4 R a Preferably, ring D is absent or Right end With L 4 connect.

9. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It meets one or more of the following conditions: (1) for Among them, ring A, ring B, ring D, L 1 , L 2 and L 3 As defined in claim 1; For example, for (2) for For example (3) for 10. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compound is any of the following: Scheme 1: The compound is a compound represented by formula (IA): in, h is 1, 2, or 3; r' is 1, 2 or 3; R 3 H, halogen, CN, OH, NH2, C 1-6 Alkyl or -OC 1-6 Alkyl, the C 1-6 Alkyl and -OC 1-6 The alkyl group is optionally substituted by one or more R 31 replace; E 1 , L x , R 1 , R 4 , R 31 , g and As defined in claim 1; Scheme 2: The compound is a compound represented by formula (IC): in, h is 1, 2, or 3; r' is 1, 2 or 3; L 2 -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-or optionally 1 or more R b Substituted C 1-12 Heteroalkyl, said "C 1-12 The "hetero" in "heteroalkyl" is a heteroatom group, the number of which is 1 or more, each independently N, -O-, -C(O)-, -N(R 22 )-, -P(O)-, -P(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-; when the number of the heteroatom groups is multiple, the heteroatom groups are the same or different, and at least one of the heteroatom groups is -S-, -S(O)-, -S(O)2- or -S(O)2-N(R 22 )-; Ring A, Ring B, g, E 1 , L x , R 1 , R 4 , R 3 and R 31 As defined in claim 1; Scheme 3: The compound is a compound represented by formula (IB): in, h is 1, 2, or 3; r' is 1, 2 or 3; m is 1, 2, 3 or 4; n is 1, 2, 3 or 4; p is 0 or 1; q is 0 or 1; Z 1 , Z 2 , Z 3 and Z 4 are independently N or CH; R 3 H, halogen, CN, OH, NH2, C 1-6 Alkyl or -OC 1-6 Alkyl, the C 1-6 Alkyl and -OC 1-6 The alkyl group is optionally substituted by one or more R 31 replace; g、E 1 , L x , L 2 , R 1 , R 4 , R 31 and R a As defined in claim 1; Scheme 4: The compound is a compound represented by formula (I-B1): in, h is 1, 2, or 3; r' is 1, 2 or 3; m is 1, 2, 3 or 4; Z 1 and Z 2 are independently N or CH; R 3 H, halogen, CN, OH, NH2, C 1-6 Alkyl or -OC 1-6 Alkyl, the C 1-6 Alkyl and -OC 1-6 The alkyl group is optionally substituted by one or more R 31 replace; g、E 1 , L x , L 2 , R 1 , R 4 , R 31 and R a As defined in claim 1; Option 5: The compound is a compound represented by formula (I-C1): in, g、E 1 , L x , R 1 , R 4 , R 31 and R a As defined in claim 1; h is 1, 2, or 3; r' is 1, 2 or 3; m is 1, 2, 3 or 4; n is 1, 2, 3 or 4; p is 0 or 1; q is 0 or 1; Z 1 , Z 2 , Z 3 and Z 4 are independently N or CH; R 3 H, halogen, CN, OH, NH2, C 1-6 Alkyl or -OC 1-6 Alkyl, the C 1-6 Alkyl and -OC 1-6 The alkyl group is optionally substituted by one or more R 31 replace; L 2 -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-or optionally 1 or more R b Substituted C 1-12 Heteroalkyl, said "C 1-12 The "hetero" in "heteroalkyl" is a heteroatom group, the number of which is 1 or more, each independently N, -O-, -C(O)-, -N(R 22 )-, -P(O)-, -P(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-; when the number of the heteroatom groups is multiple, the heteroatom groups are the same or different, and at least one of the heteroatom groups is -S-, -S(O)-, -S(O)2- or -S(O)2-N(R 22 )-; Preferably, L 2 -S(O)-, -S(O)2-, -S(O)2-N(R 22 )-、-C 1-6 Alkyl-S(O)-, -C 1-6 Alkyl-S(O)2-, -C 1-6 Alkyl-S(O)2-N(R 22 )-、-S(O)2-N(R 22 )-C 1-6 Alkyl-, -C 1-6 Alkyl-S(O)-C 1-6 Alkyl-, -C 1-6 Alkyl-S(O)2-C 1-6 Alkyl-, -C 1-6 Alkyl-S(O)2-N(R 22 )-C 1-6 Alkyl-, -S(O)-C 1-6 Alkyl-S(O)-, -S(O)2-C 1-6 Alkyl-S(O)2- or -S(O)2-N(R 22 )-C 1-6 Alkyl-S(O)2-N(R 22 )-, wherein each of said C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 R b Replacement, R b As defined in claim 1; Preferably, L 2 It is -S(O)2- or -S(O)2-CH2-.

11. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compound is any of the following: Solution 1: E 1 is -CH2- or -C(=O)-; for Ring A, Ring B and Ring D are each independently absent, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl, the C 3-12 The cycloalkyl group and the 4-12 membered heterocycloalkyl group are each optionally substituted by one or more R a replace; L 1 , L 2 , L 3 and L 4 are independently a single bond, -C(O)-, -S(O)2-, -C(O)-CH2-, -S(O)2-CH2- or C 1-8 Alkyl, wherein the C 1-8 The alkyl group is optionally substituted by one or more R b replace; Ring C is a 5-10 membered heteroaryl group; L x -C(=O)-NR 2 -; R 1 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more R 11 replace; When R 1 C 1-6 When alkyl, R 1 By one or more R 11 Replaced with at least 1 R 11 for OH; R 2 independently H; R 3 Halogen or C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted by one or more R 31 replace; R 4 is a halogen; Each R 11 independently OH; Each R 31 are independently halogen; Each R a are independently halogen, OH, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted by 1, 2 or 3 R groups; Each R b Independently for C 1-6 alkyl; Each R is independently OH; g is 1; r is 1 or 2; The "hetero" of the "4-12 membered heterocycloalkyl" and "5-10 membered heteroaryl" is a heteroatom group; the number of the heteroatom groups is 1 or more, and the heteroatom groups are independently 1 or more of N, O, and S; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different; Option 2: E 1 is -CH2- or -C(=O)-; for Ring A is absent, cyclohexyl, piperidinyl or piperazinyl, wherein the cyclohexyl, piperidinyl and piperazinyl are optionally substituted by 1, 2, 3 or 4 R a replace; Ring B is absent, azetidinyl, piperidinyl or piperazinyl, wherein the azetidinyl, piperidinyl and piperazinyl are optionally substituted by 1, 2, 3 or 4 R a replace; Ring D is absent, azetidinyl or piperidinyl, wherein the azetidinyl and piperidinyl are optionally substituted by 1, 2, 3 or 4 R a replace; Ring C is pyridyl; L 1 is a single bond; L 2 is a single bond, -CH2-, -CH(CH3)-, -C(O)-, -S(O)2-, -C(O)-CH2- or -S(O)2-CH2-; L 3 is a single bond; L 4 is a single bond, -CH2- or -CH(CH3)-; L x -C(=O)-NR 2 -; R 1 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more R 11 replace; When R 1 C 1-6 When alkyl, R 1 By one or more R 11 Replaced with at least 1 R 11 for OH; R 2 independently H; R 3 Halogen or C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted by one or more R 31 replace; R 4 is a halogen; Each R 11 independently OH; Each R 31 are independently halogen; Each R a are independently halogen, OH, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted by 1, 2 or 3 R groups; Each R b Independently for C 1-6 alkyl; Each R is independently OH; g is 1; r is 1 or 2.

12. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compound is: And or, the pharmaceutically acceptable salt of the compound is the trifluoroacetate salt of the compound.

13. The compound according to claim 12, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compound is: And or, the pharmaceutically acceptable salt of the compound is the trifluoroacetate salt of the compound.

14. A pharmaceutical composition, characterized in that The invention relates to a pharmaceutical composition comprising a therapeutically effective dose of a compound according to any one of claims 1 to 13, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof and a pharmaceutically acceptable excipient.

15. Use of the compound according to any one of claims 1 to 13, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition according to claim 14 in the preparation of a medicament for treating or preventing a disease associated with IRAK4.

16. The use according to claim 15, characterized in that The medicament is used to treat or prevent cancer, neurodegenerative disorders, viral diseases, autoimmune diseases, inflammatory diseases, genetic disorders, hormone-related diseases, metabolic disorders, diseases related to organ transplantation, immunodeficiency disorders, destructive bone diseases, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T-cell activation, cardiovascular disorders or CNS disorders; Preferably, the medicament can be used to treat or prevent cancer, diseases affecting the nose, systemic lupus erythematosus, rheumatoid arthritis, hyaline membrane disease, kidney disease, glomerular disease, multiple sclerosis, interstitial pulmonary fibrosis, allergic reaction, systemic allergic reaction, sinusitis, eye allergy, silica-induced disease, COPD, lung disease, cystic fibrosis, acid-induced lung damage, pulmonary hypertension, colitis, suppurative hidradenitis, immunoglobulin A nephropathy, interstitial lung disease, psoriasis, otitis, mumps, alopecia areata, urticaria, acute or chronic gout, chronic gouty arthritis, psoriasis, psoriasis arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, cryptopyrin-associated peripheral syndrome or osteoarthritis disorder; the diseases affecting the nose include, for example, allergic rhinitis, and the colitis includes, for example, Crohn's disease and ulcerative colitis.

17. A compound as shown in formula I-13; in, R 1 , L x , ring C, r, R 3 , Ring A, Ring B, Ring D, L 1 , L 2 , L 3 As claimed in any one of claims 1 to 13; And the compound represented by formula I-13 satisfies any of the following conditions: (1) Ring A, Ring B and Ring D all exist; (2) Ring D is absent, L 2 -S(O)2-, -S(O)2-CH2-, one or more R b Substituted C 1-8 Alkyl, each R b are independently =O, halogen, OH, NH2 or C 1-6 alkyl; (3) Ring D is absent, and Ring B is occupied by one or more R a Substituted 4-12 membered heterocycloalkyl, each R a are independently halogen, =O, OH, NH2, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted by 1, 2 or 3 R groups; Preferably, the compound represented by formula I-13 is any of the following compounds:

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